AU2002367554A1

AU2002367554A1 - Protein complexes and methods for their use

Info

Publication number: AU2002367554A1
Application number: AU2002367554A
Authority: AU
Inventors: Angela Bauch; Andreas Bauer; Anne-Claude Gavin; Paola Grandi; Roland Krause; Ulrich Kruse; Bernhard Kuster; Christina Leutwein; Martina Marzioch; Alejandro Merino; Anne-Marie Michon; Jens Rick; Jorg Schultz; Gulio Superti-Furga
Original assignee: Cellzome GmbH
Current assignee: Cellzome GmbH
Priority date: 2001-12-20
Filing date: 2002-12-20
Publication date: 2003-09-09
Also published as: WO2003072602A3; WO2003072602A2; CA2471307A1

Description

WO 03/072602 PCT/EPO2/50003 PROTEIN COMPLEXES AND METHODS FOR THEIR USE 1. FIELD OF THE INVENTION The present invention relates to protein complexes, component proteins of the complexes, fragments and derivatives of the component proteins, and antibodies specific to the complexes. The present invention also relates to methods for use of the complexes in, inter alia, screening, diagnosis, and therapy, as well as to methods of preparing the complexes. 2. BACKGROUND OF THE INVENTION A formidable challenge of postgenomic biology is to understand how genetic information results in the concerted action of gene products in time and space to generate function. In medicine, this is perhaps best reflected in the numerous disorders based on polygenic traits and the notion that the number of human diseases exceeds the number of genes in the genome. Roses, 2000, Pharmacogenetics and the practice of medicine, Nature 405:857-65. Moreover, the total number of human genes does not differ substantially from that of the worm C. elegans, suggesting that complexity may partly rely on the contextual combination of the gene products. Lander et al., 2001, Initial sequencing and analysis of the human genome, Nature 409:860-921. Dissecting the genetic and biochemical circuitry of a cell is a fundamental problem in biology. At the biochemical level, proteins rarely act alone; rather they interact with other proteins to perform particular cellular tasks. Alberts, 1998, The cell as a collection of protein machines: preparing the next generation of molecular biologists, Cell 92:291-294. These assemblies represent more than the sum of their parts by having a new function. Jacob, 1993, The Logic of Life. Princeton University Press. Such "integrons", may then come together to build, in turn, "integrons" of higher order and function, such as a cell, a tissue, an organism. Our knowledge regarding the identity of the building elements of specific complexes is very limited and is based on selected biochemical approaches and genetic analyses. The only comprehensive protein interaction studies to date are based on ex vivo systems and need to be integrated with more physiological approaches. Whenever it has been possible to retrieve and analyze particular cellular protein complexes under WO 03/072602 PCT/EPO2/50003 2 physiological conditions, the insight gained from the analysis has been fundamental for the biological understanding of their function and has often taken the analysis well beyond the limits of genetic analysis. Blackstock & Weir, 1999, Proteomics: quantitative and physical mapping of cellular proteins, Trends Biotechnol. 17:121-127; Pandey & Mann, 2000, Proteomics to study genes and genomes, Nature 405:837-846. Prominent examples are the spliceosome, the cyclosome (Anaphase-Promoting-Complex), the proteasome and the synaptosome. Neubauer et al.,1998, Mass spectrometry and EST database searching allows characterization of the multi-protein spliceosome complex, Nat. Genet. 20:46-50; Zachariae et al., 1996, Identification of subunits of the anaphase promoting complex of Saccharomyces cerevisiae, Science 274:1201-1204; Varga-Weisz et al., 1997, Chromatin-remodelling factor CHRAC contains the ATPases ISWI and topoisomerase II, Nature 388:598-602; Verma et al., 2000, Proteasomal proteomics: identification of nucleotide-sensitive proteasome-interacting proteins by mass spectrometric analysis of affinity-purified proteasomes, Mol. Biol. Cell 11:3425-3439; Neubauer et al., 1997, Identification of the proteins of the yeast U1 small nuclear ribonucleoprotein complex by mass spectrometry, Proc. Natl. Acad. Sci. USA 94:385 390; Husi et al., 2000, Proteomic analysis of NMDA receptor-adhesion protein signaling complexes. Nat. Neurosci. 3:661-669. No systematic analysis of protein complexes from the same cell type using the same technique has yet been reported. Citation of a reference in this or any section of the specification shall not be construed as an admission that such reference is prior art to the present invention. 3. SUMMARY OF THE INVENTION The invention relates to: 1. A protein complex selected from complex (I) and comprising (a) at least one first protein, which first protein is selected from the group of proteins in table 1, sixth column of a given complex, or a functionally active derivative thereof, or a functionally active fragment thereof, or a homologue thereof, or a variant of said protein, the variant being, the variant being encoded by a nucleic acid that hybridizes to the nucleic acid encoding said protein under low stringency conditions; and (b) at least one second protein, which second protein is selected from the group of proteins in table 1, seventh column of said given complex, or a functionally active WO 03/072602 PCT/EPO2/50003 3 derivative thereof, or a functionally active fragment thereof, or a homologue thereof, or a variant of said second protein, said variant being encoded by a nucleic acid that hybridizes to the nucleic acid encoding said protein under low stringency conditions; and a complex (11) comprising at least two of said second proteins, wherein said low stringency conditions comprise hybridization in a buffer comprising 35% formamide, 5X SSC, 50 mM Tris-HCI (pH 7.5), 5 mM EDTA, 0.02% PVP, 0.02% BSA, 100 ug/ml denatured salmon sperm DNA, and 10% (wt/vol) dextran sulfate for 18-20 hours at 400C, washing in a buffer consisting of 2X SSC, 25 mM Tris-HCI (pH 7.4), 5 mM EDTA, and 0.1% SDS for 1-5 hours at 55°C, and washing in a buffer consisting of 2X SSC, 25 mM Tris-HCI (pH 7.4) 5 mM EDTA, and 0.1% SDS for 1.5 hours at 60 0 C. 2. A protein complex comprising a first protein selected from the proteins listed in table 1, second column of a given complex or a homologue or variant thereof, or a functionally active fragment or functionally active derivative of said first protein, the variant being encoded by a nucleic acid that hybridizes to the nucleic acid of said first protein under low stringency conditions, and at least one second protein selected from the group of proteins in table 1, seventh column of a given complex, or a variant or homologue thereof, or a functionally active fragment or a functionally active derivative of said second protein, the variant of said second protein being encoded by a nucleic acid that hybridizes to the nucleic acid of said second protein under low stringency conditions, and wherein said low stringency conditions comprise hybridization in a buffer comprising 35% formamide, 5X SSC, 50 mM Tris-HCI (pH 7.5), 5 mM EDTA, 0.02% PVP, 0.02% BSA, 100 ug/ml denatured salmon sperm DNA, and 10% (wt/vol) dextran sulfate for 18-20 hours at 400C, washing in a buffer consisting of 2X SSC, 25 mM Tris-HCI (pH 7.4), 5 mM EDTA, and 0.1% SDS for 1-5 hours at 550C, and washing in a buffer consisting of 2X SSC, 25 mM Tris-HCl (pH 7.4) 5 mM EDTA, and 0.1% SDS for 1.5 hours at 600C. 3. A protein complex comprising all proteins selected from the proteins in table 1, third column of a given complex or at least one protein being a homologue thereof, or a variant thereof or functionally active fragment or functionally active derivative of said protein, said variant being encoded by a nucleic acid that hybridizes to the nucleic acid of said protein under low stringency conditions; WO 03/072602 PCT/EPO2/50003 4 wherein said low stringency conditions comprise hybridization in a buffer comprising 35% formamide, 5X SSC, 50 mM Tris-HCI (pH 7.5), 5 mM EDTA, 0.02% PVP, 0.02% Ficoll, 0.2% BSA, 100 ug/ml denatured salmon sperm DNA, and 10% (wt/vol) dextran sulfate for 18-20 hours at 400C, washing in a buffer consisting of 2X SSC, 25 mM Tris-HCI (pH 7.4), 5 mM EDTA, and 0.1% SDS for 1-5 hours at 550C, and washing in a buffer consisting of 2X SSC, 25 mM Tris-HCI (pH 7.4), 5 mM EDTA, and 0.1% SDS for 1.5 hours at 60'C. 4. A protein complex that comprises all proteins as listed in table 1, third column for a given complex or at least one protein being a homologue or a variant thereof, or a functionally active fragment or a functionally active derivative thereof, the variant being encoded by a nucleic acid that hybridizes to the nucleic acid of any of said proteins under low stringency conditions, except at least one protein of the proteins listed in table 1, third column, wherein said low stringency conditions comprise hybridization in a buffer comprising 35% formamide, 5X SSC, 50 mM Tris-HCI (pH 7.5), 5 mM EDTA, 0.02% PVP, 0.02% Ficoll, 0.2% BSA, 100 ug/ml denatured salmon sperm DNA, and 10% (wt/vol) dextran sulfate for 18-20 hours at 40'C, washing in a buffer consisting of 2X SSC, 25 mM Tris-HCI (pH 7.4), 5 mM EDTA, and 0.1% SDS for 1-5 hours at 55°C, and washing in a buffer consisting of 2X SSC, 25 mM Tris-HCI (pH 7.4), 5 mM EDTA, and 0.1% SDS for 1.5 hours at 600C, with the provisio that the complex comprises at least one protein selected from table 1, seventh column of a given complex. 5. The complex of any of No. 1 - 4 comprising at least one functionally active derivative of said first protein and/or a functionally active derivative of said second protein, wherein the functionally active derivative is a fusion protein comprising said first protein or said second protein fused to an amino acid sequence different from the first protein or second protein. 6. The complex of No. 5 wherein the functionally active derivative is a fusion protein comprising said first protein or said second protein fused to an affinity tag or label.

WO 03/072602 PCT/EPO2/50003 5 7. The complex of any of No. 1 - 4 comprising a fragment of said first protein and/or a fragment of said second protein, which fragment binds to another protein component of said complex. 8. The complex of any of No. 1 - 7 that is involved in at least one biochemical activity as stated in table 2, column 8 for a given complex. 9. A process for preparing a complex of any of No. 1 - 8 and optionally the components thereof comprising the following steps: expressing a protein of the complex, preferably a tagged protein, in a target cell, or a tissue or an organ, isolating the protein complex which is attached to the protein, preferably the tagged protein, and optionally disassociating the protein complex and isolating the individual complex members. 10. The process according to No. 9 wherein the tagged protein comprises two different tags which allow two separate affinity purification steps. 11. The process according to any of No. 9 - 10 wherein the two tags are separated by a cleavage site for a protease. 12. Component of a protein complex obtainable by a process according to any of No. 9 11. 13. Protein selected from the group of proteins in table 1, ninth column of a given complex or a homologue or a variant of thereof, or a functionally active fragment or a functionally active derivative of said protein, the variant being encoded by a nucleic acid that hybridizes to the nucleic acid encoding said protein under low stringency conditions, wherein said low stringency conditions comprise hybridization in a buffer comprising 35% formamide, 5X SSC, 50 mM Tris-HCI (pH 7.5), 5 mM EDTA, 0.02% PVP, 0.02% Ficoll, 0.2% BSA, 100 ug/ml denatured salmonsperm DNA, and 10% (wt/vol) dextran sulfate for 18-20 hours at 40°C, washing in a buffer consisting of 2X SSC, 25 mM Tris-HCI (pH 7.4), 5 mM EDTA, and 0.1% SDS for 1.5 hours at 550C, and washing in a buffer consisting of 2X SSC, 25 mM Tris-HCI (pH 7.4), 5 mM EDTA, and 0.1% SDS for 1.5 hours at 60'C.

WO 03/072602 PCT/EPO2/50003 6 14. Nucleic acid encoding a protein according to No. 13. 15. Construct, preferably a vector construct, comprising (a) a nucleic acid according to No. 14 and at least one further nucleic acid which is normally not associated with said nucleic acid, or (b) at least two separate nucleic acid sequences each encoding a different protein, or a functionally active fragment or a functionally active derivative thereof, or a homologue or a variant thereof, at least one of said proteins being selected from the first group of proteins according to No. 1 (a) and at least one of said proteins, being selected from the second group of proteins according to No. 1 (b) or (c) at least two separate nucleic acid sequences each encoding a different protein, or a functionally active fragment or a functionally active derivative thereof, or a homologue or a variant thereof, said proteins being selected from the proteins of complex (ll) according to No. 1. 16. Host cell, containing a vector comprising at least one nucleic acid of No. 14 and /or a construct of No. 15 or containing several vectors each comprising at least one nucleic acid encoding at least one protein selected from the first group of proteins according to No. 1 (a) and at least one nucleic acid encoding at least one protein selected from the second group of proteins according to No. 1 (b). 17. An antibody or a fragment of said antibody containing the binding domain thereof, selected from an antibody or fragment thereof, which binds the complex of any of No. 1 - 8 and which does not bind any of the proteins of said complex when uncomplexed and an antibody or a fragment of said antibody containing the binding domain thereof which binds to any of the proteins of the group of proteins according to No. 13. 18. A kit comprising in one or more containers: (a) the complex of any of No. 1 - 8 and/or the proteins of No. 13 andlor (b) an antibody according to No. 17 and/or (c) a nucleic acid encoding a protein of the complex of any of No. 1 - 8 and/or a protein of No. 13 andlor WO 03/072602 PCT/EPO2/50003 7 (d) cells expressing the complex of any of No. 1 - 8 and/or a protein of No. 13 and, optionally, (e) further components such as reagents, buffers and working instructions. 19. The kit according to No. 18 for processing a substrate of a complex of any one of No. 1 - 8. 20. The kit according to No. 18 for the diagnosis or prognosis of a disease or a disease risk, preferentially for a disease or disorder as stated in table 4, third column for a given complex.. 21. Array, preferably a microarray, in which at least a complex according to any of No. 1 8 and/or at least one protein according to No. 13 and/or at least one antibody according to No. 17 is attached to a solid carrier. 22. A process for modifying a substrate of a complex of any one of No. 1 - 8 comprising the step of bringing into contact a complex of any of No. 1 - 8 with said substrate, such that said substrate is modified. 23. A pharmaceutical composition comprising the protein complex of any of No. 1 - 8 and/or a protein according to No. 13. 24. A pharmaceutical composition according to No. 23 for the treatment of diseases and disorders, preferentially for diseases or disorders as stated in table 4, third column of said complex. 25. A method for screening for a molecule that binds to a complex of any one of No. 1 - 8 and/or a protein of No. 13, comprising the following steps: (a) exposing said complex or protein, or a cell or organism containing said complex or said protein, to one or more candidate molecules; and (b) determining whether said candidate molecule is bound to the complex or protein.

WO 03/072602 PCT/EPO2/50003 8 26. A method for screening for a molecule that modulates directly or indirectly the function, activity, composition or formation of a complex of any one of No. 1 - 8 comprising the steps of: (a) exposing said complex, or a cell or organism containing said complex to one or more candidate molecules; and (b) determining the amount of, activity of, protein components of, and/or intracellular localization of, said complex and/or the transcription level of a gene regulated by the complex and/or the abundance and/or activity of a protein or protein complex dependent upon the function of the complex and/or product of a gene dependent on the complex in the presence of the one or more candidate molecules, wherein a change in said amount, activity, protein components or intracellular localization relative to said amount, activity, protein components and/or intracellular localization and/or a change in the transcription level of a gene regulated by the complex and/or the abundance and/or activity of a protein or protein complex dependent on the function of the complex and/or product of a gene dependent on the complex in the absence of said candidate molecules indicates that the molecule modulates function, activity, or composition of said complex. 27. The method of No. 26, wherein the amount of said complex is determined. 28. The method of No. 26, wherein the activity of said complex is determined. 29. The method of No. 28, wherein said determining step comprises isolating from the cell or organism said complex to produce said isolated complex and contacting said isolated complex in the presence or absence of a candidate molecule with a substrate of said complex and determining whether said substrate is processed in the absence of the candidate molecule and whether the processing of said substrate is modified in the presence of said candidate molecule. 30. The method of No. 26, wherein the amount of the individual protein components of said complex is determined.

WO 03/072602 PCT/EPO2/50003 9 31. The method of No. 30, wherein said determining step comprises determining whether any of the proteins listed in table 1, third column of said complex, or a functionally active fragment or a functionally active derivative thereof, or a variant or a homologue thereof, the variant being encoded by a nucleic acid that hybridizes to the nucleic acid of said protein under low-stringency conditions, is present in the complex. 32. The method of any of No. 26 - 31, wherein said method is a method of screening for a drug for treatment or prevention of a disease or disorder, preferentially of a disease or disorder selected from the diseases or disorders as listed in table 4, third column. 33. Use of a molecule that modulates the amount of, activity of, or the protein components of the complex of any one of No. I - 8 for the manufacture of a medicament for the treatment or prevention of a disease or disorder, preferentially of a disease or disorder as listed in table 4, third column. 34. A method for the production of a pharmaceutical composition comprising carrying out the method of No. 26 - 31 to identify a molecule that modulates the function, activity, composition or formation of said complex, and further comprising mixing the identified molecule with a pharmaceutically acceptable carrier. 35. A method for diagnosing or screening for the presence of a disease or disorder or a predisposition for developing a disease or disorder in a subject, which disease or disorder is characterized by an aberrant amount of, component disposition of, or intracellular localization of the complex of any one of the No. 1 - 8, comprising determining the amount of, activity of, protein components of, and/or intracellular localization of, said complex and/or the transcription level of a gene regulated by the complex and/or the abundance and/or activity of a protein or protein complex dependent on the function of the complex and/or product of a gene dependent on the complex in a comparative sample derived from a subject, wherein a difference in said amount, activity, or protein components of, said complex in a corresponding sample from a subject not having the disease or disorder or predisposition indicated the presence in the subject of the disease or disorder or predisposition in the subject. 36. The method of No. 35, wherein the amount of said complex is determined.

WO 03/072602 PCT/EPO2/50003 10 37. The method of No. 35, wherein the activity of said complex is determined. 38. The method of No. 37, wherein said determining step comprises isolating from the cell or organism said complex to produce said isolated complex and contacting said isolated complex in the presence or absence of a candidate molecule with a substrate of said complex and determining whether said substrate is processed in the absence of the candidate molecule and whether the processing of said substrate is modified in the presence of said candidate molecule. 39. The method of No. 35, wherein the amount of the individual protein components of said complex is determined. 40. The method of No. 39, wherein said determining step comprises determining whether any of the proteins according to No. 13 is present in the complex. 41. The complex of any one of No. 1 - 8, or a protein of No. 13 or an antibody or fragment thereof of No. 17, for use in a method of diagnosing a disease or disorder, preferentially of a disease or disorder as listed in table 4, third column of said complex. 42. A method for treating or preventing a disease or disorder characterized by an aberrant amount of, activity of, component composition of or intracellular localization of, the complex of any one of No. 1 - 8, comprising administering to a subject in need of such treatment or prevention a therapeutically effective amount of one or more molecules that modulate the amount of, activity of, or protein composition of, said complex. 43. The method according to No. 42, wherein said disease or disorder involves decreased levels of the amount or activity of said complex. 44. The method according to No. 42, wherein said disease or disorder involves increased levels of the amount or activity of said complex.

WO 03/072602 PCT/EPO2/50003 11 45. Complex of No. 1 - 8 and/or a protein as listed in table 1, seventh column of said complex as a target for an active agent of a pharmaceutical, preferably a drug target, in the treatment or prevention of a disease or disorder, preferentially of a disease or disorder as listed in table 4, third column of said complex. In a preferred embodiment of the present invention, the protein components of the complex are vertebrate homologs of the yeast proteins, or a mixture of yeast and vertebrate homolog proteins. In a more preferred embodiment, the protein components of the complex are mammalian homologs of the yeast proteins, or a mixture of yeast and mammalian homolog proteins. In particular aspects,n the native component proteins, or derivatives or fragments of the complex are obtained from a mammal such as mouse, rat, pig, cow, dog, monkey, human, sheep or horse. In another preferred embodiment, the protein components of the complex are human homologs of the yeast proteins, or a mixture of yeast and human homolog proteins. In yet another preferred embodiment, the protein components of the complex are a mixture of yeast, vertebrate, mammalian and/or human proteins. The present invention is also directed to methods for production of a protein complex of the present invention, and derivatives of the complex and/or fragments and/or derivatives of individual component proteins or the complex, e.g., by isolation from a cell expressing the complex or by recombinantly expressing the component proteins of the complex and combining the component proteins in vitro. Pharmaceutical compositions are also provided. The present invention is further directed to complexes comprising a fusion protein which comprises a component of the complex or a fragment thereof linked via a covalent bond to an amino acid sequence different from said component protein, as well as nucleic acids encoding the protein, fusions and fragments thereof. For example, the non-component protein portion of the fusion protein, which can be added to the N terminal, the C-terminal or inserted into the amino acid sequence of the complex component can comprise a few amino acids, which provide an epitope that is used as a target for affinity purification of the fusion protein and/or complex. The invention is further directed to methods for modulating (i.e., inhibiting or enhancing) the amount of, activity of, or the identity of the protein components of, a complex of the present invention. The protein components of a complex of the present invention have been implicated in many physiological processes. The present invention WO 03/072602 PCT/EPO2/50003 12 is also directed to methods for screening a complex, as well as a derivative of the complex, for the ability to alter a cell function, particularly a cell function in which the complex and/or a component protein of the complex has been implicated. Moreover, the present invention provides a process for the identification and/or preparation of an effector of a composition according to the invention which process comprises the steps of bringing into contact the composition of the invention or of a component thereof with a compound, a mixture of compounds or a library of compounds and determining whether the compounds or certain compounds of the mixture or library bind to the composition of the invention and/or a component thereof and/or affects the biological activity of such a composition or component and then optionally further purifying the compound positively tested as effector by such a process. A major application of the composition according to the invention results in the identification of an active agent capable of binding thereto. Hence, the compositions of the invention are useful tools in screening for new pharmaceutical drugs. The present invention is also directed to a method for isolating the a complex of the invention and the component proteins comprising tagging a protein of the complex with a sequence that allows affinity purification of the tagged protein, expressing such protein in a target cell, isolating the protein complex which is attached to the tagged protein, and optionally disassociating the protein complex and isolating the individual complex members. The present invention further relates to a composition, preferably a protein complex, which is obtainable by the method comprising the following steps: tagging a protein as defined above, i.e. a protein which forms part of a protein complex, with a moiety, preferably an amino acid sequence, that allows affinity purification of the tagged protein and expressing such protein in a target cell and isolating the protein complex which is attached to the tagged protein. The details of such purification are described in WO 00/09716 and in Rigaut, G. et al. (1999), Nature Biotechnology, Vol. 17 (10): 1030 1032 and further herein below. The tagging can essentially be performed with any moiety which is capable of providing a specific interaction with a further moiety, e.g. in the sense of a ligand receptor interaction, antigen antibody interaction or the like. The tagged protein can also be expressed in an amount in the target cell which comes close to the physiological concentration in order to avoid a complex formation merely due to high concentration of the expressed protein but not reflecting the natural occurring complex.

WO 03/072602 PCT/EPO2/50003 13 In a further preferred embodiment, the composition is obtained by using a tagged protein which comprises two different tags which allow two different affinity purification steps. This measure allows a higher degree of purification of the composition in question. In a further preferred embodiment the tagged protein comprises two tags that are separated by a cleavage site for a protease. This allows a step-by-step purification on affinity columns. The present invention is also directed to therapeutic and prophylactic, as well as diagnostic, prognostic, and screening methods and compositions based upon the a complex of the present invention (and the nucleic acids encoding the individual proteins that participate in the complex). Therapeutic compounds of the invention include, but are not limited to, a complex of the invention, and a complex where one or more members of the complex is a derivative or fragment thereof. The present invention is also directed to complex-specific antibodies to and nucleic acids encoding the foregoing; and antisense nucleic acids to the nucleotide sequences encoding the complex components. Diagnostic, prognostic and screening kits are also provided. The present invention further relates to a kit comprising a composition as described above, optionally together with further reagents and working instructions. The further reagents may be, for example, buffers, substrates for enzymes but also carrier material such as beads, filters, microarrays and other solid carries. The working instructions may indicate how to use the ingredients of the kit in order to perform a desired assay. The present invention further relates to a nucleic acid encoding a component of a composition as defined above. Such a nucleic acid may be used for example to express a desired tagged protein in a given cell for the isolation of a complex or component according to the invention. Such a nucleic acid may also be used for the identification and isolation of genes from other organisms by cross species hybridization. The present invention further relates to a construct, preferably a vector construct, which comprises a nucleic acid as described above. Such constructs may comprise expression controlling elements such as promoters, enhancers and terminators in order to express the nucleic acids in a given host cell, preferably under conditions which resemble the physiological concentrations. The present invention further relates to a host cell containing a construct as defined above. Such a host cell can be, e.g., any eukaryotic cell such as yeast, plant or WO 03/072602 PCT/EPO2/50003 14 mammalian, whereas human cells are preferred. Such host cells may form the starting material for isolation of a complex according to the present invention. Animal models and methods of screening for modulators (i.e., agonists, and antagonists) of the amount of, activity of, or protein component composition of, a complex of the present invention are also provided. 3.1 DEFINITIONS The term "activity" as used. herein, refers to the function of a molecule in its broadest sense. It generally includes, but is not limited to, biological, biochemical, physical or chemical functions of the molecule. It includes for example the enzymatic activity, the ability to interact with other molecules and ability to activate, facilitate, stabilize, inhibit, suppress or destabilize the function of other molecules, stability, ability to localize to certain subcellular locations. Where applicable, said term also relates to the function of a protein complex in its broadest sense. The term "agonist" as used herein, means a molecule which modulates the formation of a protein complex or which, when bound to a complex or protein of the invention or a molecule in the protein complex, increases the amount of, or prolongs the duration of, the activity of the complex. The stimulation may be direct or indirect, including effects on the expression of a gene encoding a member of the protein complex, or by a competitive or non-competitive mechanism. Agonists may include proteins, nucleic acids, carbohydrates or any other organic or anorganic molecule or metals. Agonists also include a functional peptide or peptide fragment derived from a protein member of the complexes of the invention or a protein member itself of the complexes of the invention. Preferred activators are those which, when added to the complex and/or the protein of the invention under physiological conditions and/or in vitro assays, including diagnostic or prognostic assays, result in a change of the level of any of the activities of the protein complex and/or the proteins of the invention as exemplary illustrated above by at least 10%, at least 25%, at least 50%, at least 100%, at least, 200%, at least 500% or at least 1000% at a concentration of the activator lpg mf 1 , 10pg m-1, 100pg m1 1 , 500pg mI 1 , 1mg mrl 1 , 10Omg m-1 or 100mg ml-1. Any combination of the above mentioned degrees of percentages and concentration may be used to define an agonist of the invention, with greater effect at lower concentrations being preferred.

WO 03/072602 PCT/EPO2/50003 15 The term "amount" as used herein and as applicable to the embodiment described relates to the amount of the particular protein or protein complex described, including the value of null, i.e. where no protein or protein complex described in that particular embodiment is present under the or any of the conditions which might be specified in that particular embodiment. The term "animal" as used herein includes, but is not limited to mammals, preferably mammals such as cows, pigs, horses, mice, rats, cats, dogs, sheep, goats and most preferably humans. Other animals used in agriculture, such as chickens, ducks etc. are also included in the definition as used herein. The term "animal" as used herein does not include humans if being used in the context of genetic alterations to the germline. The term "antagonist" as used herein, means a molecule which modulates the formation of a protein complex or which, when bound to a complex or protein of the invention or a molecule in the protein complex, decreases the amount of, or the duration or level of activity of the complex. The effect may be direct or indirect, including effects on the expression of a gene encoding a member of the protein complex, or by a competitive or non-competitive mechanism. Antagonists may include proteins, including antibodies, nucleic acids, carbohydrates or any other organic or anorganic molecule or metals. Antagonists also include a functional peptide or peptide fragment derived from a protein member of the complexes of the invention or a protein member itself of the complexes of the invention. Preferred antagonists are those which, when added to the complex and/or the protein of the invention under physiological conditions and/or in vitro assays, including diagnostic or prognostic assays, result in a change of the level of any of the activities of the protein complex and/or the proteins of the invention as exemplary illustrated above by at least 10%, at least 20%, at least 30%, at least 40% at least 50%, at least 60%, at least 70%, at least 80%, at least 90%, at least 95% or at-least 99% at a concentration of the inhibitor of lpg ml 1 , 10pg ml"', 100pg mlf, 500pg ml", 1mg mlr, 10mg ml" or 100mg m-1. Any combination of the above mentioned degrees of percentages and concentration may be used to define antagonist of the invention, with greater effect at lower concentrations being preferred. The term "antibodies" as used herein, include include, but are not limited to, polyclonal, monoclonal, chimeric, single chain, Fab fragments, and an Fab expression library.

WO 03/072602 PCT/EPO2/50003 16 The term "binding" as used herein means a stable or transient association between two molecules, including electrostatic, hydrophobic, ionic and/or hydrogen-bond interaction under physiological conditions and/or conditions being used in diagnostic or prognostic method or process or procedure. The term "carrier" as used herein refers to a diluent, adjuvant, excipient, or vehicle with which the therapeutic is administered. Such pharmaceutical carriers can be sterile liquids, such as water and oils, including those of petroleum, animal, vegetable or synthetic origin, including but not limited to peanut oil, soybean oil, mineral oil, sesame oil and the like. Water is a preferred carrier when the pharmaceutical composition is administered orally. Saline and aqueous dextrose are preferred carriers when the pharmaceutical composition is administered intravenously. Saline solutions and aqueous dextrose and glycerol solutions are preferably employed as liquid carriers for injectable solutions. Suitable pharmaceutical excipients include starch, glucose, lactose, sucrose, gelatin, malt, rice, flour, chalk, silica gel, sodium stearate, glycerol monostearate, talc, sodium chloride, dried skim milk, glycerol, propylene, glycol, water, ethanol and the like. The composition, if desired, can also contain minor amounts of wetting or emulsifying agents, or pH buffering agents. These compositions can take the form of solutions, suspensions, emulsions, tablets, pills, capsules, powders, sustained-release formulations and the like. The composition can be formulated as a suppository, with traditional binders and carriers such as triglycerides. Oral formulation can include standard carriers such as pharmaceutical grades of mannitol, lactose, starch, magnesium stearate, sodium saccharine, cellulose, magnesium carbonate, etc. Examples of suitable pharmaceutical carriers are described in "Remington's Pharmaceutical Sciences" by E.W. Martin. Such compositions will contain a therapeutically effective amount of the therapeutic, preferably in purified form, together with a suitable amount of carrier so as to provide the form for proper administration to the patient. The formulation should suit the mode of administration. If not stated otherwise, the terms "complex" aid "protein complex" are used interchangeably herein and refer to a complex of proteins that is able to perform one or more functions of the wild type protein complex. The protein complex may or may not include and/or be associated with other molecules such as nucleic acid, such as RNA or DNA, or lipids or further cofactors or moieties selected from a metal ions, hormones, second messengers, phosphate, sugars.

WO 03/072602 PCT/EPO2/50003 17 A "complex" of the invention may also be part of or a unit of a larger physiological protein assembly. If not stated otherwise, the term "compound" as used herein are include but are not limited to peptides, nucleic acids, carbohydrates, natural product extract librariesorganic molecules, preferentially small organic molecules, anorganic molecules, including but not limited to chemicals, metals and organometallic molecules. The terms "derivatives" or "analogs of component proteins" or "variants" as used herein include, but are not limited, to molecules comprising regions that are substantially homologous to the component proteins, in various embodiments, by at least 30%, 40%, 50%, 60%, 70%, 80%, 90%, 95% or 99% identity over an amino acid sequence of identical size or when compared to an aligned sequence in which the alignment is done by a computer homology program known in the art, or whose encoding nucleic acid is capable of hybridizing to a sequence encoding the component protein under stringent, moderately stringent, or nonstringent conditions. It means a protein which is the outcome of a modification of the naturally occurring protein, by amino acid substitutions, deletions and additios, respectively, which derivatives still exhibit the biological function of the naturally occurring protein although not necessarily to the same degree. The biological function of such proteins can e.g. be examined by suitable available in vitro assays as provided in the invention. The term "functionally active" as used herein refers to a polypeptide, namely a fragment or derivative, having structural, regulatory, or biochemical functions of the protein according to the embodiment of which this polypeptide, namely fragment or derivative is related to. The term "fragment" as used herein refers to a polypeptide of at least 10, 20, 30, 40 or 50 amino acids of the component protein according to the embodiment. In specific embodiments, such fragments are not larger than 35, 100 or 200 amino acids. The term "gene" as used herein refers to a nucleic acid comprising an open reading frame encoding a polypeptide of, if not stated otherwise, the present invention, including both exon and optionally intron sequences. The terms " homologue" or "homologous gene products" as used herein mean a protein in another species, preferably mammals, which performs the same biological function as the a protein component of the complex further described herein. Such homologues are also termed "orthologous gene products". The algorithm for the detection of orthologue gene pairs from humans and mammalians or other species uses WO 03/072602 PCT/EPO2/50003 18 the whole genome of these organisms. First, pairwise best hits are retrieved, using a full Smith-Waterman alignment of predicted proteins. To further improve reliability, these pairs are clustered with pairwise best hits involving Drosophila melanogaster and C. elegans proteins. Such analysis is given, e.g., in Nature, 2001, 409:860-921. The homologues of the proteins according to the invention can either be isolated based on the sequence homology of the genes encoding the proteins provided herein to the genes of other species by cloning the respective gene applying conventional technology and expressing the protein from such gene, or by isolating proteins of the other species by isolating the analogous complex according to the methods provided herein or to other suitable methods commonly known in the art. The term "host cells" or, were applicable, "cells" or "hosts" as used herein is intended to be understood in a broadest sense and include, but are not limited to mammalian cell systems infected with virus (e.g., vaccinia virus, adenovirus, etc.); insect cell systems infected with virus (e.g., baculovirus); microorganisms such as yeast containing yeast vectors; or bacteria transformed with bacteriophage, DNA, plasmid DNA, or cosmid DNA. The expression elements of vectors vary in their strengths and specificities. Depending on the host-vector system utilized, any one of a number of suitable transcription and translation elements may be used. It is understood that this term not only refers to the particular subject cell but to the progeny or potential progeny of such a cell. Because certain modifications may occur in succeeding generations due to either mutation of environmental influences, such progeny may not, in fact, be identical to the parent cell, but are still included within the scope of the term as used herein. The term "modification" as used herein refers to all modifications of a protein or protein complex of the invention including cleavage and addition or removal of a group. The term "nuleic acid" as used herein refers to polynucleotides such as deoxyribonucleic acid (DNA), and, where appropriate, ribonucleic acid (RNA). They may also be polynucleotides which include within them synthetic or modified nucleotides. A number of different types of modification to polynucleotides are known in the art. These include methylphosphonate and phosphorothioate backbones, addition of acridine or polylysine chains at the 3' and/or 5' ends of the molecule. For the purposes of the present invention, it is to be understood that the polynucleotides described herein may be modified by any method available in the art. Such modifications may be carried out in order to enhance the in vivo activity or lifespan of polynucleotides of the invention. Polynucleotides according to the invention may be produced recombinantly, WO 03/072602 PCT/EPO2/50003 19 synthetically, or by any means available to those of skill in the art. They may also be cloned by standard techniques. The polynucleotides are typically provided in isolated and/or purified form. As applicable to the embodiment being described, they include both single stranded and double-stranded polynucleotides. The term "percent identity", as used herein, means the number of identical residues as defined by an optimal alignment using the Smith-Waterman algorithm divided by the length of the overlap multiplied by 100. The alignment is performed by the search program (Pearson, 1991, Genomics 11:635-650) with the constraint to align the maximum of both sequences. The terms "polypeptides" and "proteins" are, where applicable, used interchangeably herein. They may be chemically modified, e.g. post-translationally modified. For example, they may be glycosylated or comprise modified amino acid residues. They may also be modified by the addition of a signal sequence to promote their secretion from a cell where the polypeptide does not naturally contain such a sequence. They may be tagged with a tag. They may be tagged with different labels which may assists in identification of the proteins in a protein complex. Polypeptides/proteins for use in the invention may be in a substantially isolated form. It will be understood that the polypeptid/protein may be mixed with carriers or diluents which will not interfere with the intended purpose of the polypeptide and still be regarded as substantially isolated. A polypeptide/protein for use in the invention may also be in a substantially purified form, in which case it will generally comprise the polypeptide in a preparation in which more than 50%, e.g. more than 80%, 90%, 95% or 99%, by weight of the polypeptide in the preparation is a polypeptide of the invention. "Target for therapeutic drug" means that the respective protein (target) can bind the active ingredient of a pharmaceutical composition and thereby changes its biological activity in response to the drug binding. The term "tag" as used herein is meant to be understood in its broadest sense and to include, but is not limited to any suitable enzymatic, fluorescent, or radioactive labels and suitable epitopes, incuding but not limited to HA-tag, Myc-tag, T7, His-tag, FLAG-tag, Calmodulin binding proteins, glutathione-S-transferase, strep-tag, KT3 epitope, EEF-epitpopes, green-fluorescent protein and variants thereof. The term "therapeutics" as used herein, includes, but is not limited to, a protein complex of the present invention, the individual component proteins, and analogs and derivatives (including fragments); antibodies thereto; nucleic acids encoding the WO 03/072602 PCT/EPO2/50003 20 component protein, and analogs or derivatives thereof; component protein antisense nucleic acids, and agents that modulate complex formation and/or activity (i.e., agonists and antagonists). The term "vector" as used herein means a nucleic acid molecule capable of transporting another nucleic acid sequence to which it has been linked. Preferred vectors are those capable of autonomous replication and/or expression of nueclic acids to which they linked. The terms "plasmid" and "vector" are used interchangeably herein when applicable to the embodiment. However, vectors other than plasmids are also included herein. The expression elements of vectors vary in their strengths and specificities. Depending on the host-vector system utilized, any one of a number of suitable transcription and translation elements may be used. 4. BRIEF DESCRIPTION OF THE DRAWINGS Fig. 1 shows a synopsis of the screen. Left is a schematic representation of the sequential steps used for the purification and identification of TAP-complexes. Right: Number of experiments and success rate at each step of the procedure. Fig. 2 shows a schematic representation of the gene targeting procedure. The TAP cassette is inserted at the C-terminus of a given yeast ORF by homologous recombination, generating the TAP-tagged fusion protein. Fig. 3 shows the protein pattern obtained for the human Arp2/3-complex using ARPC2 as a bait usint TAP. The proteins identified as members of the complex (ARP3, ARP2, ARPC1A, ARPC2, ARPC3, ARPC4, ARPC5) as well as the yeast orthologs thereof (Arp3, Arp2, Arc40, Arc35, Arcl9, Arcl8, Arc16), which constitute the orthologueos yeast complex, are indicated. Fig. 4 shows elements of mammalian and yeast mRNA, respectively, which are involved in polyadenylation/cleavage of precursor mRNA. Fig. 5. showns the protein pattern obtained by separation of the members of the polyadenylation-complex of yeast using Ptal as a bait using TAP. Protein bands for Cftl, Cft2, Yshl, Rna14, Pabl, PcfI 1, Ref2, Pap1, ClpI, YKLO59c, Pfs2, YGR156w, Fipl, RnaI5, YKL018w, Glc7, Ythl, Ssu72, YOR179c and Ptal (in bold) are labeled. (Further proteins identified as components of the yeast complex as described in the EXAMPLES section (infra) are not stated in the figure) WO 03/072602 PCT/EPO2/50003 21 Fig. 6 shows the protein pattern obtained by the separation of the members of the polyadenylation-complex in some of the reverse tagging-experiments and re-purification of a selection of the novel interactors. The baits using TAP used for the different experiments are given on top of each gel picture. The band constituing the protein used as the bait in the respective experiments is indicated by an arrow. Previously known members of the complex are listed in bold letters. (Note: only experiments using Cft1, Cft2, Pap1, Ref2, YKLO59c, Pfs2, YOR179c and Ptal as a bait are shown and only the proteins bands of Cftl, Cft2, Yshl, Rnal4, Pabl, Ref2, CLpl, Ygrl56w, Fipl, Glc7, Yhtl, Yorl79c, Ptal, Pcf11, Pabl, Yk1059c, Pfs2, Rnal5, Ykl018w and Ssu72 are labelled). Fig 7 shows the protein pattern obtained for the human Ccr4/Not-complex using NOT2 as a bait using TAP. The proteins identified as members of the complex are labeled (KIAA1007,AAHO2928, KIAA1194, Rqcdl, CALIF, CAF1). Furthermore, the respective orthologues in yeast are indicated to the left (Not1, Ccr4, Caf40, Cafl). (The complete yeast complex is described in detail in the EXAMPLES section (infra)). Fig. 8 shows the protein pattern obtained for the human TRAPP-(Bet3) complex using BET3 as a bait using TAP. Identified human proteins are indicated (FASN, CAD, KIAA1012, EHOC-1, AL136752.1, CGI-87, alpha/ig-tubulin, FLJ13611, Glucorticoid Receptor specific elongation factor, hBet3, PTD009, MUM2, R32611_2 (MGC2650), Sedlin. Proteins identified as members of the human TRAPP-complex are KIAA1012, EHOC-1, hBet3, PTD009, MUM2, R32611_2 (MGC2650) and Sedlin. The corresponding yeast orthologues are given on the left. (The complete yeast complex is described in detail in the EXAMPLES-section (infra)). 5. DETAILED DESCRIPTION OF THE INVENTION Our analysis allowed us to group cellular proteins into approximately 380 complexes. These are connected to each other by sharing components. The network that results is a functional description of the eukaryotic proteome at an unprecedented level of organization. Such higher order maps will bring increasing quality to our appreciation of biological systems. It is anticipated that this may provide drug discovery programs with a molecular context for the choice and evaluation of drug targets.

WO 03/072602 PCT/EPO2/50003 22 The invention thus relates to the following embodiments: 1. A protein complex selected from complex (I) and comprising (a) at least one first protein, which first protein is selected from the group of proteins in table 1, sixth column of a given complex, or a functionally active derivative thereof, or a functionally active fragment thereof, or a homologue thereof, or a variant of said protein, the variant being, the variant being encoded by a nucleic acid that hybridizes to the nucleic acid encoding said protein under low stringency conditions; and (b) at least one second protein, which second protein is selected from the group of proteins in table 1, seventh column of said given complex, or a functionally active derivative thereof, or a functionally active fragment thereof, or a homologue thereof, or a variant of said second protein, said variant being encoded by a nucleic acid that hybridizes to the nucleic acid encoding said protein under low stringency conditions; and a complex (11) comprising at least two of said second proteins, wherein said low stringency conditions comprise hybridization in a buffer comprising 35% formamide, 5X SSC, 50 mM Tris-HCI (pH 7.5), 5 mM EDTA, 0.02% PVP, 0.02% BSA, 100 ug/ml denatured salmon sperm DNA, and 10% (wt/vol) dextran sulfate for 18-20 hours at 40 0 C, washing in a buffer consisting of 2X SSC, 25 mM Tris-HCI (pH 7.4), 5 mM EDTA, and 0.1% SDS for 1-5 hours at 550C, and washing in a buffer consisting of 2X SSC, 25 mM Tris-HCI (pH 7.4) 5 mM EDTA, and 0.1% SDS for 1.5 hours at 60 0 C. 2. A protein complex comprising a first protein selected from the proteins listed in table 1, second column of a given complex or a homologue or variant thereof, or a functionally active fragment or functionally active derivative of said first protein, the variant being encoded by a nucleic acid that hybridizes to the nucleic acid of said first protein under low stringency conditions, and at least one second protein selected from the group of proteins in table 1, seventh column of a given complex, or a variant or homologue thereof, or a functionally active fragment or a functionally active derivative of said second protein, the variant of said second protein being encoded by a nucleic acid that hybridizes to the nucleic acid of said second protein under low stringency conditions, and wherein said low stringency conditions comprise hybridization in a buffer comprising 35% formamide, 5X SSC, 50 mM Tris-HCI (pH WO 03/072602 PCT/EPO2/50003 23 7.5), 5 mM EDTA, 0.02% PVP, 0.02% BSA, 100 ug/ml denatured salmon sperm DNA, and 10% (wt/vol) dextran sulfate for 18-20 hours at 400C, washing in a buffer consisting of 2X SSC, 25 mM Tris-HCI (pH 7.4), 5 mM EDTA, and 0.1% SDS for 1-5 hours at 55 0 C, and washing in a buffer consisting of 2X SSC, 25 mM Tris-HCI (pH 7.4) 5 mM EDTA, and 0.1% SDS for 1.5 hours at 600C. 3. A protein complex comprising all proteins selected from the proteins in table 1, third column of a given complex or at least one protein being a homologue thereof, or a variant thereof or functionally active fragment or functionally active derivative of said protein, said variant being encoded by a nucleic acid that hybridizes to the nucleic acid of said protein under low stringency conditions; wherein said low stringency conditions comprise hybridization in a buffer comprising 35% formamide, 5X SSC, 50 mM Tris-HCI (pH 7.5), 5 mM EDTA, 0.02% PVP, 0.02% Ficoll, 0.2% BSA, 100 ug/ml denatured salmon sperm DNA, and 10% (wt/vol) dextran sulfate for 18-20 hours at 400C, washing in a buffer consisting of 2X SSC, 25 mM Tris-HCI (pH 7.4), 5 mM EDTA, and 0.1% SDS for 1-5 hours at 55*C, and washing in a buffer consisting of 2X SSC, 25 mM Tris-HCI (pH 7.4), 5 mM EDTA, and 0.1% SDS for 1.5 hours at 600C. 4. A protein complex that comprises all proteins as listed in table 1, third column for a given complex or at least one protein being a homologue or a variant thereof, or a functionally active fragment or a functionally active derivative thereof, the variant being encoded by a nucleic acid that hybridizes to the nucleic acid of any of said proteins under low stringency conditions, except at least one protein of the proteins listed in table 1, third column, wherein said low stringency conditions comprise hybridization in a buffer comprising 35% formamide, 5X SSC, 50 mM Tris-HCI (pH 7.5), 5 mM EDTA, 0.02% PVP, 0.02% Ficoll, 0.2% BSA, 100 ug/ml denatured salmon sperm DNA, and 10% (wt/vol) dextran sulfate for 18-20 hours at 40'C, washing in a buffer consisting of 2X SSC, 25 mM Tris-HCI (pH 7.4), 5 mM EDTA, and 0.1% SDS for 1-5 hours at 550C, and washing in a buffer consisting of 2X SSC, 25 mM Tris-HCI (pH 7.4), 5 mM EDTA, and 0.1% SDS for 1.5 hours at 600C, with the provisio that the complex comprises at least one protein selected from table 1, seventh column of a given complex.

WO 03/072602 PCT/EPO2/50003 24 5. The complex of any of No. 1 - 4 comprising at least one functionally active derivative of said first protein and/or a functionally active derivative of said second protein, wherein the functionally active derivative is a fusion protein comprising said first protein or said second protein fused to an amino acid sequence different from the first protein or second protein. 6. The complex of No. 5 wherein the functionally active derivative is a fusion protein comprising said first protein or said second protein fused to an affinity tag or label. 7. The complex of any of No. 1 - 4 comprising a fragment of said first protein and/or a fragment of said second protein, which fragment binds to another protein component of said complex. 8. The complex of any of No. 1 - 7 that is involved in at least one biochemical activity as stated in table 2, column 8 for a given complex. 9. A process for preparing a complex of any of No. 1 - 8 and optionally the components thereof comprising the following steps: expressing a protein of the complex, preferably a tagged protein, in a target cell, or a tissue or an organ, isolating the protein complex which is attached to the protein, preferably the tagged protein, and optionally disassociating the protein complex and isolating the individual complex members. 10. The process according to No. 9 wherein the tagged protein comprises two different tags which allow two separate affinity purification steps. 11. The process according to any of No. 9 - 10 wherein the two tags are separated by a cleavage site for a protease. 12. Component of a protein complex obtainable by a process according to any of No. 9 11. 13. Protein selected from the group of proteins in table 1, ninth column of a given complex or a homologue or a variant of thereof, or a functionally active fragment or a WO 03/072602 PCT/EPO2/50003 25 functionally active derivative of said protein, the variant being encoded by a nucleic acid that hybridizes to the nucleic acid encoding said protein under low stringency conditions, wherein said low stringency conditions comprise hybridization in a buffer comprising 35% formamide, 5X SSC, 50 mM Tris-HCI (pH 7.5), 5 mM EDTA, 0.02% PVP, 0.02% Ficoll, 0.2% BSA, 100 ug/ml denatured salmon sperm DNA, and 10% (wt/vol) dextran sulfate for 18-20 hours at 40 0 C, washing in a buffer consisting of 2X SSC, 25 mM Tris-HCI (pH 7.4), 5 mM EDTA, and 0.1% SDS for 1.5 hours at 55°C, and washing in a buffer consisting of 2X SSC, 25 mM Tris-HCI (pH 7.4), 5 mM EDTA, and 0.1% SDS for 1.5 hours at 60 0 C. 14. Nucleic acid encoding a protein according to No. 13. 15. Construct, preferably a vector construct, comprising (a) a nucleic acid according to No. 14 and at least one further nucleic acid which is normally not associated with said nucleic acid, or (b) at least two separate nucleic acid sequences each encoding a different protein, or a functionally active fragment or a functionally active derivative thereof, or a homologue or a variant thereof, at least one of said proteins being selected from the first group of proteins according to No. 1 (a) and at least one of said proteins, being selected from the second group of proteins according to No. 1 (b) or (c) at least two separate nucleic acid sequences each encoding a different protein, or a functionally active fragment or a functionally active derivative thereof, or a homologue or a variant thereof, said proteins being selected from the proteins of complex (11) according to No. 1. 16. Host cell, containing a vector comprising at least one nucleic acid of No. 14 and /or a construct of No. 15 or containing several vectors each comprising at least one nucleic acid encoding at least one protein selected from the first group of proteins according to No. 1 (a) and at least one nucleic acid encoding at least one protein selected from the second group of proteins according to No. 1 (b). 17. An antibody or a fragment of said antibody containing the binding domain thereof, selected from an antibody or fragment thereof, which binds the complex of any of No. 1 - 8 and which does not bind any of the proteins of said complex when uncomplexed WO 03/072602 PCT/EPO2/50003 26 and an antibody or a fragment of said antibody containing the binding domain thereof which binds to any of the proteins of the group of proteins according to No. 13. 18. A kit comprising in one or more containers: (a) the complex of any of No. 1 - 8 and/or the proteins of No. 13 and/or (b) an antibody according to No. 17 and/or (c) a nucleic acid encoding a protein of the complex of any of No. 1 - 8 and/or a protein of No. 13 and/or (d) cells expressing the complex of any of No. 1 - 8 andlor a protein of No. 13 and, optionally, (e) further components such as reagents, buffers and working instructions. 19. The kit according to No. 18 for processing a substrate of a complex of any one of No. 1 - 8. 20. The kit according to No. 18 for the diagnosis or prognosis of a disease or a disease risk, preferentially for a disease or disorder as stated in table 4, third column for a given complex.. 21. Array, preferably a microarray, in which at least a complex according to any of No. 1 8 and/or at least one protein according to No. 13 and/or at least one antibody according to No. 17 is attached to a solid carrier. 22. A process for modifying a substrate of a complex of any one of No. 1 - 8 comprising the step of bringing into contact a complex of any of No. 1 - 8 with said substrate, such that said substrate is modified. 23. A pharmaceutical composition comprising the protein complex of any of No. 1 - 8 and/or a protein according to No. 13. 24. A pharmaceutical composition according to No. 23 for the treatment of diseases and disorders, preferentially for diseases or disorders as stated in table 4, third column of said complex.

WO 03/072602 PCT/EPO2/50003 27 25. A method for screening for a molecule that binds to a complex of any one of No. 1 - 8 and/or a protein of No. 13, comprising the following steps: (a) exposing said complex or protein, or a cell or organism containing said complex or said protein, to one or more candidate molecules; and (b) determining whether said candidate molecule is bound to the complex or protein. 26. A method for screening for a molecule that modulates directly or indirectly the function, activity, composition or formation of a complex of any one of No. 1 - 8 comprising the steps of: (a) exposing said complex, or a cell or organism containing said complex to one or more candidate molecules; and (b) determining the amount of, activity of, protein components of, and/or intracellular localization of, said complex and/or the transcription level of a gene regulated by the complex and/or the abundance and/or activity of a protein or protein complex dependent upon the function of the complex and/or product of a gene dependent on the complex in the presence of the one or more candidate molecules, wherein a change in said amount, activity, protein components or intracellular localization relative to said amount, activity, protein components and/or intracellular localization and/or a change in the transcription level of a gene regulated by the complex and/or the abundance and/or activity of a protein or protein complex dependent on the function of the complex and/or product of a gene dependent on the complex in the absence of said candidate molecules indicates that the molecule modulates function, activity, or composition of said complex. 27. The method of No. 26, wherein the amount of said complex is determined. 28. The method of No. 26, wherein the activity of said complex is determined. 29. The method of No. 28, wherein said determining step comprises isolating from the cell or organism said complex to produce said isolated complex and contacting said isolated complex in the presence or absence of a candidate molecule with a substrate of said complex and determining whether said substrate is processed in the WO 03/072602 PCT/EPO2/50003 28 absence of the candidate molecule and whether the processing of said substrate is modified in the presence of said candidate molecule. 30. The method of No. 26, wherein the amount of the individual protein components of said complex is determined. 31. The method of No. 30, wherein said determining step comprises determining whether any of the proteins listed in table 1, third column of said complex, or a functionally active fragment or a functionally active derivative thereof, or a variant or a homologue thereof, the variant being encoded by a nucleic acid that hybridizes to the nucleic acid of said protein under low-stringency conditions, is present in the complex. 32. The method of any of No. 26 - 31, wherein said method is a method of screening for a drug for treatment or prevention of a disease or disorder, preferentially of a disease or disorder selected from the diseases or disorders as listed in table 4, third column. 33. Use of a molecule that modulates the amount of, activity of, or the protein components of the complex of any one of No. 1 - 8 for the manufacture of a medicament for the treatment or prevention of a disease or disorder, preferentially of a disease or disorder as listed in table 4, third column. 34. A method for the production of a pharmaceutical composition comprising carrying out the method of No. 26 - 31 to identify a molecule that modulates the function, activity, composition or formation of said complex, and further comprising mixing the identified molecule with a pharmaceutically acceptable carrier. 35. A method for diagnosing or screening for the presence of a disease or disorder or a predisposition for developing a disease or disorder in a subject, which disease or disorder is characterized by an aberrant amount of, component disposition of, or intracellular localization of the complex of any one of the No. 1 - 8, comprising determining the amount of, activity of, protein components of, andlor intracellular localization of, said complex and/or the transcription level of a gene regulated by the complex and/or the abundance and/or activity of a protein or protein complex dependent on the function of the complex and/or product of a gene dependent on the WO 03/072602 PCT/EPO2/50003 29 complex in a comparative sample derived from a subject, wherein a difference in said amount, activity, or protein components of, said complex in a corresponding sample from a subject not having the disease or disorder or predisposition indicated the presence in the subject of the disease or disorder or predisposition in the subject. 36. The method of No. 35, wherein the amount of said complex is determined. 37. The method of No. 35, wherein the activity of said complex is determined. 38. The method of No. 37, wherein said determining step comprises isolating from the cell or organism said complex to produce said isolated complex and contacting said isolated complex in the presence or absence of a candidate molecule with a substrate of said complex and determining whether said substrate is processed in the absence of the candidate molecule and whether the processing of said substrate is modified in the presence of said candidate molecule. 39. The method of No. 35, wherein the amount of the individual protein components of said complex is determined. 40. The method of No. 39, wherein said determining step comprises determining whether any of the proteins according to No. 13 is present in the complex. 41. The complex of any one of No. 1 - 8, or a protein of No. 13 or an antibody or fragment thereof of No. 17, for use in a method of diagnosing a disease or disorder, preferentially of a disease or disorder as listed in table 4, third column of said complex. 42. A method for treating or preventing a disease or disorder characterized by an aberrant amount of, activity of, component composition of or intracellular localization of, the complex of any one of No. 1 - 8, comprising administering to a subject in need of such treatment or prevention a therapeutically effective amount of one or more molecules that modulate the amount of, activity of, or protein composition of, said complex.

WO 03/072602 PCT/EPO2/50003 30 43. The method according to No. 42, wherein said disease or disorder involves decreased levels of the amount or activity of said complex. 44. The method according to No. 42, wherein said disease or disorder involves increased levels of the amount or activity of said complex. 45. Complex of No. 1 - 8 and/or a protein as listed in table 1, seventh column of said complex as a target for an active agent of a pharmaceutical, preferably a drug target, in the treatment or prevention of a disease or disorder, preferentially of a disease or disorder as listed in table 4, third column of said complex. In a preferred embodiment of the present invention, the protein components of the complex are vertebrate homologs of the yeast proteins, or a mixture of yeast and vertebrate homolog proteins. In a more preferred embodiment, the protein components of the complex are mammalian homologs of the yeast proteins, or a mixture of yeast and mammalian homolog proteins. In particular aspects,n the native component proteins, or derivatives or fragments of the complex are obtained from a mammal such as mouse, rat, pig, cow, dog, monkey, human, sheep or horse. In another preferred embodiment, the protein components of the complex are human homologs of the yeast proteins, or a mixture of yeast and human homolog proteins. In yet another preferred embodiment, the protein components of the complex are a mixture of yeast, vertebrate, mammalian and/or human proteins. The present invention is also directed to methods for production of a protein complex of the present invention, and derivatives of the complex and/or fragments and/or derivatives of individual component proteins or the complex, e.g., by isolation from a cell expressing the complex or by recombinantly expressing the component proteins of the complex and combining the component proteins in vitro. Pharmaceutical compositions are also provided. The present invention is further directed to complexes comprising a fusion protein which comprises a component of the complex or a fragment thereof linked via a covalent bond to an amino acid sequence different from said component protein, as well as nucleic acids encoding the protein, fusions and fragments thereof. For example, the non-component protein portion of the fusion protein, which can be added to the N terminal, the C-terminal or inserted into the amino acid sequence of the complex WO 03/072602 PCT/EPO2/50003 31 component can comprise a few amino acids, which provide an epitope that is used as a target for affinity purification of the fusion protein and/or complex. The invention is further directed to methods for modulating (i.e., inhibiting or enhancing) the amount of, activity of, or the identity of the protein components of, a complex of the present invention. The protein components of a complex of the present invention have been implicated in many physiological processes. The present invention is also directed to methods for screening a complex, as well as a derivative of the complex, for the ability to alter a cell function, particularly a cell function in which the complex and/or a component protein of the complex has been implicated. Moreover, the present invention provides a process for the identification and/or preparation of an effector of a composition according to the invention which process comprises the steps of bringing into contact the composition of the invention or of a component thereof with a compound, a mixture of compounds or a library of compounds and determining whether the compounds or certain compounds of the mixture or library bind to the composition of the invention and/or a component thereof and/or affects the biological activity of such a composition or component and then optionally further purifying the compound positively tested as effector by such a process. A major application of the composition according to the invention results in the identification of an active agent capable of binding thereto. Hence, the compositions of the invention are useful tools in screening for new pharmaceutical drugs. The present invention is also directed to a method for isolating the a complex of the invention and the component proteins comprising tagging a protein of the complex with a sequence that allows affinity purification of the tagged protein, expressing such protein in a target cell, isolating the protein complex which is attached to the tagged protein, and optionally disassociating the protein complex and isolating the individual complex members. The present invention further relates to a composition, preferably a protein complex, which is obtainable by the method comprising the following steps: tagging a protein as defined above, i.e. a protein which forms part of a protein complex, with a moiety, preferably an amino acid sequence, that allows affinity purification of the tagged protein and expressing such protein in a target cell and isolating the protein complex which is attached to the tagged protein. The details of such purification are described in WO 00/09716 and in Rigaut, G. et al. (1999), Nature Biotechnology, Vol. 17 (10): 1030 1032 and further herein below. The tagging can essentially be performed with any WO 03/072602 PCT/EPO2/50003 32 moiety which is capable of providing a specific interaction with a further moiety, e.g. in the sense of a ligand receptor interaction, antigen antibody interaction or the like. The tagged protein can also be expressed in an amount in the target cell which comes close to the physiological concentration in order to avoid a complex formation merely due to high concentration of the expressed protein but not reflecting the natural occurring complex. In a further preferred embodiment, the composition is obtained by using a tagged protein which comprises two different tags which allow two different affinity purification steps. This measure allows a higher degree of purification of the composition in question. In a further preferred embodiment the tagged protein comprises two tags that are separated by a cleavage site for a protease. This allows a step-by-step purification on affinity columns. The present invention is also directed to therapeutic and prophylactic, as well as diagnostic, prognostic, and screening methods and compositions based upon the a complex of the present invention (and the nucleic acids encoding the individual proteins that participate in the complex). Therapeutic compounds of the invention include, but are not limited to, a complex of the invention, and a complex where one or more members of the complex is a derivative or fragment thereof. The present invention is also directed to complex-specific antibodies to and nucleic acids encoding the foregoing; and antisense nucleic acids to the nucleotide sequences encoding the complex components. Diagnostic, prognostic and screening kits are also provided. The present invention further relates to a kit comprising a composition as described above, optionally together with further reagents and working instructions. The further reagents may be, for example, buffers, substrates for enzymes but also carrier material such as beads, filters, microarrays and other solid carries. The working instructions may indicate how to use the ingredients of the kit in order to perform a desired assay. The present invention further relates to a nucleic acid encoding a component of a composition as defined above. Such a nucleic acid may be used for example to express a desired tagged protein in a given cell for the isolation of a complex or component according to the invention. Such a nucleic acid may also be used for the identification and isolation of genes from other organisms by cross species hybridization. The present invention further relates to a construct, preferably a vector construct, which comprises a nucleic acid as described above. Such constructs may WO 03/072602 PCT/EPO2/50003 33 comprise expression controlling elements such as promoters, enhancers and terminators in order to express the nucleic acids in a given host cell, preferably under conditions which resemble the physiological concentrations. The present invention further relates to a host cell containing a construct as defined above. Such a host cell can be, e.g., any eukaryotic cell such as yeast, plant or mammalian, whereas human cells are preferred. Such host cells may form the starting material for isolation of a complex according to the present invention. Animal models and methods of screening for modulators (i.e., agonists, and antagonists) of the amount of, activity of, or protein component composition of, a complex of the present invention are also provided. TABLES: Table 1: Composition of Complexes: Table A shows the compositions of the yeast complexes, table B shows the composition of the human complexes. First column ('No. of complex') lists the number of the complexes used herein. Second column ('Entry point') lists the bait proteins (TAP-tag fusion proteins) that have been chosen for the isolation of the given complex. Note: in several cases, different baits have been used for validation in reverse tagging experiments. Third column ("Components") lists the proteins of the complex of the invention Fourth column ( 'Known complex') lists any known complexes which have been shown herein to be parts of the complexes as provided herein and their components. Complexes are separated by semicolon. Fifth column ('Known Interactions') briefly lists any known interactions between different members of the complex (Abbrevations: '2-hybrid': interaction as identified in yeast-2 hybrid screens; 'far-western': interaction as identified in far-western experiments; "coipp': interaction as identified by co-immunoprecipitation experiments; 'high-throughput 2 hybrid': interaction as identified by high-throughput yeast-2-hybrid screens; Icopurification': interaction as identified by copurification experiments; 'immuno-affinity columns': interaction as identified in experiments using immuno-affinity columns; 'in vitro binding': interaction as identified in in-vitro-binding experiments. If a core complex has been known previously containing several of the identified proteins, the name of the complex is stated.

WO 03/072602 PCT/EPO2/50003 34 Sixth column ('Known components of the complex') lists the components of the complex of the invention, which have been known to interact with other members of the complex as identified herein.. Seventh column ( 'Novel interactors of the complex') lists the novel members of the complex as provided in the invention. Seventh column ( 'Activity of the complex'): List the biochemical activities of the newly identified complex. Eighth column ( 'Proteins of unknown function'): Separately lists again the members of the newly identified complex whose function has previously been unknown.. Table 2: Individual Yeast Proteins of the Complexes A) Table lists in alphabetical order all yeast proteins which have been identified as members of the complex presented herein (first column). Furthermore, the SEQ ID of the proteins are listed as used herein (second column). Also the systematic name of the individual proteins are listed (third column). The fourth column lists the number of the complex/complexes of the invention in which the protein has been identified. Further columns lists the Accession-Number of the respective sequences in Genbank, MIPS, SWISS-PROT, SGD. In addition, where applicable, the GenBank accession numbers of the respective orthologues in humans is listed listed. B) Table lists again the proteins and SEQ ID as in part A. In addition, the table contains an overview about what has been previously reported on the protein, the biochemical function thereof and the cellular function thereof as stated in YPD (Constanzo, M.C. et al., 2001, Nucl. Acid Res, 29: 75-9; Hodges, P.E. et al., 1999, Nucl. Acids Res 27: 69 73). Table 3: Medical Application of the complexes: First column ('Number of complex') lists the number of the complex as used herein. Second column ('Name of complex') lists a descriptive name of the complex as used herein. Third column ('Cellular role') lists keyword on the cellular role of the complex Forth column ('Medical applications') lists disorder, diseases, disease areas etc. which are treatable and/or preventable and/or diagnosable etc. by therapeutics and methods interacting with/acting via the complex.

WO 03/072602 PCT/EPO2/50003 35 Table 4: Characterization of previously undescribed individual proteins of the complexes: The table provides data on proteins which have not been annotated previously but which have now been linked to a functional complex as described in table 1. Names are listed on the left. In addition the table contains a list of motifs found by sequence analysis which has been part of the invention provided herein. Futhermore, the predicted known human orthologues are listed on the right (By SWISS-PROT Accession numbers). Used Abbrevations are listed at the end of the table. The function of the individual proteins as deduced from the association with the complex, the sequence analysis and the analysis of the predicted ortholgues is listed in the second column ('Putative function'). Table 5: Overview on Experimental Steps: The tables illustrates the construction of a yeast strain expressing a TAP-tagged bait in a high-throuphput fashion. Table 6: Known and Novel Components of the yeast mRNA 3'-end processing machinery: Top part of the table states the different known subcomponents of the polyadenylation complex, the function thereof, the proteins constituting the different subcomplexes as known so far (including their molecular weight and sequence motifs contained in the protein). Bottom part lists the novel components of the complex as provided herein 5.1. PROTEIN COMPLEXES/PROTEINS OF THE INVENTION The protein complexes of the present invention and their component proteins are described in different aspectsin the Tables 1,2,3,4,5 (whereas Table 5 gives an overview on the construction of the yeast strains). The protein complexes and component proteins can be obtained by methods well known in the art for protein purification and recombinant protein expression. For example, the protein complexes of the present invention can be isolated using the TAP method described in Section 6, infra, and in WO 00/09716 and Rigaut et al., 1999, Nature Biotechnology 17:1030-1032, which are each incorporated by reference in their entirety. Additionally, the protein complexes can be isolated by immunoprecipitation of the component proteins and combining the immunoprecipitated proteins. The protein complexes can also be produced by recombinantly expressing the component proteins and combining the expressed proteins.

WO 03/072602 PCT/EPO2/50003 36 The nucleic and amino acid sequences of the component proteins of the protein complexes of the present invention are provided herein (SEQ ID NOS:1-3282), and can be obtained by any method known in the art, e.g., by PCR amplification using synthetic primers hybridizable to the 3' and 5' ends of each sequence, and/or by cloning from a cDNA or genomic library using an oligonucleotide specific for each nucleotide sequence. Homologs (e.g., nucleic acids encoding component proteins from other species) or other related sequences (e.g., variants, paralogs) which are members of a native cellular protein complex can be obtained by low, moderate or high stringency hybridization with all or a portion of the particular nucleic acid sequence as a probe, using methods well known in the art for nucleic acid hybridization and cloning. Exemplary moderately stringent hybridization conditions are as follows: prehybridization of filters containing DNA is carried out for 8 hours to overnight at 65?C in buffer composed of 6X SSC, 50 mM Tris-HCI (pH 7.5), 1 mM EDTA, 0.02% PVP, 0.02% Ficoll, 0.02% BSA, and 500 pg/ml denatured salmon sperm DNA. Filters are hybridized for 48 hours at 65 °C in prehybridization mixture containing 100 pg/ml denatured salmon sperm DNA and 5-20 X 106 cpm of 32 P-labeled probe. Washing of filters is done at 37 0C for 1 hour in a solution containing 2X SSC, 0.01% PVP, 0.01% Ficoll, and 0.01% BSA. This is followed by a wash in 0.1X SSC at 50 'C for 45 min before autoradiography. Alternatively, exemplary conditions of high stringency are as follows: e.g., hybridization to filter-bound DNA in 0.5 M NaHPO 4 , 7% sodium dodecyl sulfate (SDS), 1 mM EDTA at 65 OC, and washing in 0.1xSSC/0.1% SDS at 68 oC (Ausubel F.M. et al., eds., 1989, Current Protocols in Molecular Biology, Vol. I, Green Publishing Associates, Inc., and John Wiley & sons, Inc., New York, at p. 2.10.3). Other conditions of high stringency which may be used are well known in the art. Exemplary low stringency hybridization conditions comprise hybridization in a buffer comprising 35% formamide, 5X SSC, 50 mM Tris-HCI (pH 7.5), 5 mM EDTA, 0.02% PVP, 0.02% Ficoll, 0.2% BSA, 100 pg/ml denatured salmon sperm DNA, and 10% (wt/vol) dextran sulfate for 18-20 hours at 400C, washing in a buffer consisting of 2X SSC, 25 mM Tris-HCI (pH 7.4), 5 mM EDTA, and 0.1% SDS for 1.5 hours at 550C, and washing in a buffer consisting of 2X SSC, 25 mM Tris-HCI (pH 7.4), 5 mM EDTA, and 0.1% SDS for 1.5 hours at 600C. For recombinant expression of one or more of the proteins, the nucleic acid containing all or a portion of the nucleotide sequence encoding the protein can be WO 03/072602 PCT/EPO2/50003 37 inserted into an appropriate expression vector, i.e., a vector that contains the necessary elements for the transcription and translation of the inserted protein coding sequence. The necessary transcriptional and translational signals can also be supplied by the native promoter of the component protein gene, and/or flanking regions. A variety of host-vector systems may be utilized to express the protein coding sequence. These include but are not limited to mammalian cell systems infected with virus (e.g., vaccinia virus, adenovirus, etc.); insect cell systems infected with virus (e.g., baculovirus); microorganisms such as yeast containing yeast vectors; or bacteria transformed with bacteriophage, DNA, plasmid DNA, or cosmid DNA. The expression elements of vectors vary in their strengths and specificities. Depending on the host vector system utilized, any one of a number of suitable transcription and translation elements may be used. In a preferred embodiment, a complex of the present invention is obtained by expressing the entire coding sequences of the component proteins in the same cell, either under the control of the same promoter or separate promoters. In yet another embodiment, a derivative, fragment or homolog of a component protein is recombinantly expressed. Preferably the derivative, fragment or homolog of the protein forms a complex with the other components of the complex, and more preferably forms a complex that binds to an anti-complex antibody. Any method available in the art can be used for the insertion of DNA fragments into a vector to construct expression vectors containing a chimeric gene consisting of appropriate transcriptional/translational control signals and protein coding sequences. These methods may include in vitro recombinant DNA and synthetic techniques and in vivo recombinant techniques (genetic recombination). Expression of nucleic acid sequences encoding a component protein, or a derivative, fragment or homolog thereof, may be regulated by a second nucleic acid sequence so that the gene or fragment thereof is expressed in a host transformed with the recombinant DNA molecule(s). For example, expression of the proteins may be controlled by any promoter/enhancer known in the art. In a specific embodiment, the promoter is not native to the gene for the component protein. Promoters that may be used can be selected from among the many known in the art, and are chosen so as to be operative in the selected host cell. In a specific embodiment, a vector is used that comprises a promoter operably linked to nucleic acid sequences encoding a component protein, or a fragment, WO 03/072602 PCT/EPO2/50003 38 derivative or homolog thereof, one or more origins of replication, and optionally, one or more selectable markers (e.g., an antibiotic resistance gene). In another specific embodiment, an expression vector containing the coding sequence, or a portion thereof, of a component protein, either together or separately, is made by subcloning the gene sequences into the EcoRI restriction site of each of the three pGEX vectors (glutathione S-transferase expression vectors; Smith and Johnson, 1988, Gene 7:31-40). This allows for the expression of products in the correct reading frame. Expression vectors containing the sequences of interest can be identified by three general approaches: (a) nucleic acid hybridization, (b) presence or absence of "marker" gene function, and (c) expression of the inserted sequences. In the first approach, coding sequences can be detected by nucleic acid hybridization to probes comprising sequences homologous and complementary to the inserted sequences. In the second approach, the recombinant vector/host system can be identified and selected based upon the presence or absence of certain "marker" functions (e.g., resistance to antibiotics, occlusion body formation in baculovirus, etc.) caused by insertion of the sequences of interest in the vector. For example, if a component protein gene, or portion thereof, is inserted within the marker gene sequence of the vector, recombinants containing the encoded protein or portion will be identified by the absence of the marker gene function (e.g., loss of beta-galactosidase activity). In the third approach, recombinant expression vectors can be identified by assaying for the component protein expressed by the recombinant vector. Such assays can be based, for example, on the physical or functional properties of the interacting species in in vitro assay systems, e.g., formation of a complex comprising the protein or binding to an anti-complex antibody. Once recombinant component protein molecules are identified and the complexes or individual proteins isolated, several methods known in the art can be used to propagate them. Using a suitable host system and growth conditions, recombinant expression vectors can be propagated and amplified in quantity. As previously described, the expression vectors or derivatives which can be used include, but are not limited to, human or animal viruses such as vaccinia virus or adenovirus; insect viruses such as baculovirus, yeast vectors; bacteriophage vectors such as lambda phage; and plasmid and cosmid vectors. In addition, a host cell strain may be chosen that modulates the expression of the inserted sequences, or modifies or processes the expressed proteins in the WO 03/072602 PCT/EPO2/50003 39 specific fashion desired. Expression from certain promoters can be elevated in the presence of certain inducers; thus expression of the genetically-engineered component proteins may be controlled. Furthermore, different host cells have characteristic and specific mechanisms for the translational and post-translational processing and modification (e.g., glycosylation, phosphorylation, etc.) of proteins. Appropriate cell lines or host systems can be chosen to ensure that the desired modification and processing of the foreign protein is achieved. For example, expression in a bacterial system can be used to produce an unglycosylated core protein, while expression in mammalian cells ensures "native" glycosylation of a heterologous protein. Furthermore, different vector/host expression systems may effect processing reactions to different extents. In other specific embodiments, a component protein or a fragment, homolog or derivative thereof, may be expressed as fusion or chimeric protein product comprising the protein, fragment, homolog, or derivative joined via a peptide bond to a heterologous protein sequence of a different protein. Such chimeric products can be made by ligating the appropriate nucleic acid sequences encoding the desired amino acids to each other by methods known in the art, in the proper coding frame, and expressing the chimeric products in a suitable host by methods commonly known in the art. Alternatively, such a chimeric product can be made by protein synthetic techniques, e.g., by use of a peptide synthesizer. Chimeric genes comprising a portion of a component protein fused to any heterologous protein-encoding sequences may be constructed. In particular, protein component derivatives can be made by altering their sequences by substitutions, additions or deletions that provide for functionally equivalent molecules. Due to the degeneracy of nucleotide coding sequences, other DNA sequences that encode substantially the same amino acid sequence as a component gene or cDNA can be used in the practice of the present invention. These include but are not limited to nucleotide sequences comprising all or portions of the component protein gene that are altered by the substitution of different codons that encode a functionally equivalent amino acid residue within the sequence, thus producing a silent change. Likewise, the derivatives of the invention include, but are not limited to, those containing, as a primary amino acid sequence, all or part of the amino acid sequence of a component protein, including altered sequences in which functionally equivalent amino acid residues are substituted for residues within the sequence resulting in a silent change. For example, one or more amino acid residues within the sequence can be WO 03/072602 PCT/EPO2/50003 40 substituted by another amino acid of a similar polarity that acts as a functional equivalent, resulting in a silent alteration. Substitutes for an amino acid within the sequence may be selected from other members of the class to which the amino acid belongs. For example, the nonpolar (hydrophobic) amino acids include alanine, leucine, isoleucine, valine, proline, phenylalanine, tryptophan and methionine. The polar neutral amino acids include glycine, serine, threonine, cysteine, tyrosine, asparagine, and glutamine. The positively charged (basic) amino acids include arginine, lysine and histidine. The negatively charged (acidic) amino acids include aspartic acid and glutamic acid. In a specific embodiment, up to 1%, 2%, 5%, 10%, 15% or 20% of the total number of amino acids in the wild type protein are substituted or deleted; or 1, 2, 3, 4, 5, or 6 amino acids are inserted, substituted or deleted relative to the wild type protein. In a specific embodiment of the invention, the nucleic acids encoding a protein component and protein components consisting of or comprising a fragment of or consisting of at least 6 (continuous) amino acids of the protein are provided. In other embodiments, the fragment consists of at least 10, 20, 30, 40, or 50 amino acids of the component protein. In specific embodiments, such fragments are not larger than 35, 100 or 200 amino acids. Derivatives or analogs of component proteins include, but are not limited, to molecules comprising regions that are substantially homologous to the component proteins, in various embodiments, by at least 30%, 40%, 50%, 60%, 70%, 80%, 90% or 95% identity over an amino acid sequence of identical size or when compared to an aligned sequence in which the alignment is done by a computer homology program known in the art, or whose encoding nucleic acid is capable of hybridizing to a sequence encoding the component protein under stringent, moderately stringent, or nonstringent conditions. The protein component derivatives and analogs of the invention can be produced by various methods known in the art. The manipulations which result in their production can occur at the gene or protein level. For example, the cloned gene sequences can be modified by any of numerous strategies known in the art (Sambrook et al., 1989, Molecular Cloning, A Laboratory Manual, 2d Ed., Cold Spring Harbor Laboratory Press, Cold Spring Harbor, New York). The sequences can be cleaved at appropriate sites with restriction endonuclease(s), followed by further enzymatic modification if desired, isolated, and ligated in vitro. In the production of the gene encoding a derivative, homolog or analog of a component protein, care should be taken WO 03/072602 PCT/EPO2/50003 41 to ensure that the modified gene retains the original translational reading frame, uninterrupted by translational stop signals, in the gene region where the desired activity is encoded. Additionally, the encoding nucleic acid sequence can be mutated in vitro or in vivo, to create and/or destroy translation, initiation, and/or termination sequences, or to create variations in coding regions and/or form new restriction endonuclease sites or destroy pre-existing ones, to facilitate further in vitro modification. Any technique for mutagenesis known in the art can be used, including but not limited to, chemical mutagenesis and in vitro site-directed mutagenesis (Hutchinson et al., 1978, J. Biol. Chem 253:6551-6558), amplification with PCR primers containing a mutation, etc. Once a recombinant cell expressing a component protein, or fragment or derivative thereof, is identified, the individual gene product or complex can be isolated and analyzed. This is achieved by assays based on the physical and/or functional properties of the protein or complex, including, but not limited to, radioactive labeling of the product followed by analysis by gel electrophoresis, immunoassay, cross-linking to marker-labeled product, etc. The component proteins and complexes may be isolated and purified by standard methods known in the art (either from natural sources or recombinant host cells expressing the complexes or proteins), including but not restricted to column chromatography (e.g., ion exchange, affinity, gel exclusion, reversed-phase high pressure, fast protein liquid, etc.), differential centrifugation, differential solubility, or by any other standard technique used for the purification of proteins. Functional properties may be evaluated using any suitable assay known in the art. Alternatively, once a component protein or its derivative, is identified, the amino acid sequence of the protein can be deduced from the nucleic acid sequence of the chimeric gene from which it was encoded. As a result, the protein or its derivative can be synthesized by standard chemical methods known in the art (e.g., Hunkapiller et al., 1984, Nature 310: 105-111). Manipulations of component protein sequences may be made at the protein level. Included within the scope of the invention is a complex in which the component proteins or derivatives and analogs that are differentially modified during or after translation, e.g., by glycosylation, acetylation, phosphorylation, amidation, derivatization by known protecting/blocking groups, proteolytic cleavage, linkage to an antibody molecule or other cellular ligand, etc. Any of numerous chemical modifications WO 03/072602 PCT/EPO2/50003 42 may be carried out by known techniques, including but not limited to specific chemical cleavage by cyanogen bromide, trypsin, chymotrypsin, papain, V8 protease, NaBH 4 , acetylation, formylation, oxidation, reduction, metabolic synthesis in the presence of tunicamycin, etc. In specific embodiments, the amino acid sequences are modified to include a fluorescent label. In another specific embodiment, the protein sequences are modified to have a heterofunctional reagent; such heterofunctional reagents can be used to crosslink the members of the complex. In addition, complexes of analogs and derivatives of component proteins can be chemically synthesized. For example, a peptide corresponding to a portion of a component protein, which comprises the desired domain or mediates the desired activity in vitro (e.g., complex formation) can be synthesized by use of a peptide synthesizer. Furthermore, if desired, non-classical amino acids or chemical amino acid analogs can be introduced as a substitution or addition into the protein sequence. In cases where natural products are suspected of being mutant or are isolated from new species, the amino acid sequence of a component protein isolated from the natural source, as well as those expressed in vitro, or from synthesized expression vectors in vivoor in vitro, can be determined from analysis of the DNA sequence, or alternatively, by direct sequencing of the isolated protein. Such analysis can be performed by manual sequencing or through use of an automated amino acid sequenator. The complexes can also be analyzed by hydrophilicity analysis (Hopp and Woods, 1981, Proc. Natl. Acad. Sci. USA 78:3824-3828). A hydrophilicity profile can be used to identify the hydrophobic and hydrophilic regions of the proteins, and help predict their orientation in designing substrates for experimental manipulation, such as in binding experiments, antibody synthesis, etc. Secondary structural analysis can also be done to identify regions of the component proteins, or their derivatives, that assume specific structures (Chou and Fasman, 1974, Biochemistry 13:222-23). Manipulation, translation, secondary structure prediction, hydrophilicity and hydrophobicity profile predictions, open reading frame prediction and plotting, and determination of sequence homologies, etc., can be accomplished using computer software programs available in the art. Other methods of structural analysis including but not limited to X-ray crystallography (Engstrom, 1974 Biochem. Exp. Biol. 11:7-13), mass spectroscopy and gas chromatography (Methods in Protein Science, J. Wiley and Sons, New York, 1997), WO 03/072602 PCT/EPO2/50003 43 and computer modeling (Fletterick and Zoller, eds., 1986, Computer Graphics and Molecular Modeling, In: Current Communications in Molecular Biology, Cold Spring Harbor Laboratory, Cold Spring Harbor Press, New York) can also be employed. 5.2. ANTIBODIES TO PROTEIN COMPLEXES According to the present invention, a protein complex of the present invention comprising a first protein, or a functionally active fragment or functionally active derivative thereof, selected from the group consisting of proteins listed in table 1, third column of a given complex, or a functionally active fragment or functionally active derivative thereof, or a homologue thereof or a variant encoded by a nucleic acid of any of said proteins, can be used as an immunogen to generate antibodies which immunospecifically bind such immunogen. Such antibodies include, but are not limited to, polyclonal, monoclonal, chimeric, single chain, Fab fragments, and an Fab expression library. In a specific embodiment, antibodies to a complex comprising human protein components are produced. In another embodiment, a complex formed from a fragment of said first protein and a fragment of said second protein, which fragments contain the protein domain that interacts with the other member of the complex, are used as an immunogen for antibody production. In a preferred embodiment, the antibody specific for the complex in that the antibody does not bind the individual protein components of the complex. Polyclonal antibodies can be prepared as described above by immunizing a suitable subject with a polypeptide of the invention as an immunogen. Preferred polyclonal antibody compositions are ones that have been selected for antibodies directed against a polypeptide or polypeptides of the invention. Particularly preferred polyclonal antibody preparations are ones that contain only antibodies directed against a polypeptide or polypeptides of the invention. Particularly preferred immunogen compositions are those that contain no other human proteins such as, for example, immunogen compositions made using a non-human host cell for recombinant expression of a polypeptide of the invention. In such a manner, the only human epitope or epitopes recognized by the resulting antibody compositions raised against this immunogen will be present as part of a polypeptide or polypeptides of the invention. The antibody titer in the immunized subject can be monitored over time by standard techniques, such as with an enzyme linked immunosorbent assay (ELISA) WO 03/072602 PCT/EPO2/50003 44 using immobilized polypeptide. If desired, the antibody molecules can be isolated from the mammal (e.g., from the blood) and further purified by well-known techniques, such as protein A chromatography to obtain the IgG fraction. Alternatively, antibodies specific for a protein or polypeptide of the invention can be selected for (e.g., partially purified) or purified by, e.g., affinity chromatography. For example, a recombinantly expressed and purified (or partially purified) protein of the invention is produced as described herein, and covalently or non-covalently coupled to a solid support such as, for example, a chromatography column. The column can then be used to affinity purify antibodies specific for the proteins of the invention from a sample containing antibodies directed against a large number of different epitopes, thereby generating a substantially purified antibody composition, i.e., one that is substantially free of contaminating antibodies. By a substantially purified antibody composition is meant, in this context, that the antibody sample contains at most only 30% (by dry weight) of contaminating antibodies directed against epitopes other than those on the desired protein or polypeptide of the invention, and preferably at most 20%, yet more preferably at most 10%, and most preferably at most 5% (by dry weight) of the sample is contaminating antibodies. A purified antibody composition means that at least 99% of the antibodies in the composition are directed against the desired protein or polypeptide of the invention. At an appropriate time after immunization, e.g., when the specific antibody titers are highest, antibody-producing cells can be obtained from the subject and used to prepare monoclonal antibodies by standard techniques, such as the hybridoma technique originally described by Kohler and Milstein, 1975, Nature 256:495-497, the human B cell hybridoma technique (Kozbor et al., 1983, Immunol. Today 4:72), the EBV-hybridoma technique (Cole et al., 1985, Monoclonal Antibodies and Cancer Therapy, Alan R. Liss, Inc., pp. 77-96) or trioma techniques. The technology for producing hybridomas is well known (see generally Current Protocols in Immunology (1994) Coligan et al. (eds.) John Wiley & Sons, Inc., New York, NY). Hybridoma cells producing a monoclonal antibody of the invention are detected by screening the hybridoma culture supernatants for antibodies that bind the polypeptide of interest, e.g., using a standard ELISA assay. Alternative to preparing monoclonal antibody-secreting hybridomas, a monoclonal antibody directed against a polypeptide of the invention can be identified and isolated by screening a recombinant combinatorial immunoglobulin library (e.g., an antibody phage display library) with the polypeptide of interest. Kits for generating and WO 03/072602 PCT/EPO2/50003 45 screening phage display libraries are commercially available (e.g., the Pharmacia Recombinant Phage Antibody System, Catalog No. 27-9400-01; and the Stratagene SurfZAP Phage Display Kit, Catalog No. 240612). Additionally, examples of methods and reagents particularly amenable for use in generating and screening antibody display library can be found in, for example, U.S. Patent No. 5,223,409; PCT Publication No. WO 92/18619; PCT Publication No. WO 91/17271; PCT Publication No. WO 92/20791; PCT Publication No. WO 92/15679; PCT Publication No. WO 93/01288; PCT Publication No. WO 92/01047; PCT Publication No. WO 92/09690; PCT Publication No. WO 90/02809; Fuchs et al., 1991, Bio/Technology 9:1370-1372; Hay et al., 1992, Hum. Antibod. Hybridomas 3:81-85; Huse et al., 1989, Science 246:1275-1281; Griffiths et al., 1993, EMBO J. 12:725-734. Additionally, recombinant antibodies, such as chimeric and humanized monoclonal antibodies, comprising both human and non-human portions, which can be made using standard recombinant DNA techniques, are within the scope of the invention. A chimeric antibody is a molecule in which different portions are derived from different animal species, such as those having a variable region derived from a murine mAb and a human immunoglobulin constant region. (See, e.g., Cabilly et al., U.S. Patent No. 4,816,567; and Boss et al., U.S. Patent No. 4,816,397, which are incorporated herein by reference in their entirety.) Humanized antibodies are antibody molecules from non human species having one or more complementarily determining regions (CDRs) from the non-human species and a framework region from a human immunoglobulin molecule. (See, e.g., Queen, U.S. Patent No. 5,585,089, which is incorporated herein by reference in its entirety.) Such chimeric and humanized monoclonal antibodies can be produced by recombinant DNA techniques known in the art, for example using methods described in PCT Publication No. WO 87/02671; European Patent Application 184,187; European Patent Application 171,496; European Patent Application 173,494; PCT Publication No. WO 86/01533; U.S. Patent No. 4,816,567; European Patent Application 125,023; Better et al., 1988, Science 240:1041-1043; Liu et al., 1987, Proc. Natl. Acad. Sci. USA 84:3439-3443; Liu et al., 1987, J. Immunol. 139:3521-3526; Sun et al., 1987, Proc. Natl. Acad. Sci. USA 84:214-218; Nishimura et al., 1987, Canc. Res. 47:999-1005; Wood et al., 1985, Nature 314:446-449; and Shaw et al., 1988, J. Natl. Cancer Inst. 80:1553-1559); Morrison, 1985, Science 229:1202-1207; Oi et al., 1986, Bio/Techniques 4:214; U.S. Patent 5,225,539; Jones et al., 1986, Nature 321:552-525; Verhoeyan et al., 1988, Science 239:1534; and Beidler et al., 1988, J. Immunol. 141:4053-4060.

WO 03/072602 PCT/EPO2/50003 46 Completely human antibodies are particularly desirable for therapeutic treatment of human patients. Such antibodies can be produced, for example, using transgenic mice which are incapable of expressing endogenous immunoglobulin heavy and light chains genes, but which can express human heavy and light chain genes. The transgenic mice are immunized in the normal fashion with a selected antigen, e.g., all or a portion of a polypeptide of the invention. Monoclonal antibodies directed against the antigen can be obtained using conventional hybridoma technology. The human immunoglobulin transgenes harbored by the transgenic mice rearrange during B cell differentiation, and subsequently undergo class switching and somatic mutation. Thus, using such a technique, it is possible to produce therapeutically useful IgG, IgA and IgE antibodies. For an overview of this technology for producing human antibodies, see Lonberg and Huszar, 1995, Int. Rev. Immunol. 13:65-93). For a detailed discussion of this technology for producing human antibodies and human monoclonal antibodies and protocols for producing such antibodies, see, e.g., U.S. Patent 5,625,126; U.S. Patent 5,633,425; U.S. Patent 5,569,825; U.S. Patent 5,661,016; and U.S. Patent 5,545,806. In addition, companies such as Abgenix, Inc. (Freemont, CA), can be engaged to provide human antibodies directed against a selected antigen using technology similar to that described above. Completely human antibodies which recognize a selected epitope can be generated using a technique referred to as "guided selection." In this approach a selected non-human monoclonal antibody, e.g., a murine antibody, is used to guide the selection of a completely human antibody recognizing the same epitope. (Jespers et al., 1994, Bio/technology 12:899-903). Antibody fragments that contain the idiotypes of the complex can be generated by techniques known in the art. For example, such fragments include, but are not limited to, the F(ab')2 fragment which can be produced by pepsin digestion of the antibody molecule; the Fab' fragment that can be generated by reducing the disulfide bridges of the F(ab')2 fragment; the Fab fragment that can be generated by treating the antibody molecular with papain and a reducing agent; and Fv fragments. In the production of antibodies, screening for the desired antibody can be accomplished by techniques known in the art, e.g., ELISA (enzyme-linked immunosorbent assay). To select antibodies specific to a particular domain of the complex, or a derivative thereof, one may assay generated hybridomas for a product that binds to the fragment of the complex, or a derivative thereof, that contains such a WO 03/072602 PCT/EPO2/50003 47 domain. For selection of an antibody that specifically binds a complex of the present, or a derivative; or homolog thereof, but which does not specifically bind to the individual proteins of the complex, or a derivative, or homolog thereof, one can select on the basis of positive binding to the complex and a lack of binding to the individual protein components. Antibodies specific to a domain of the complex, or a derivative, or homolog thereof, are also provided. The foregoing antibodies can be used in methods known in the art relating to the localization and/or quantification of the complexes of the invention, e.g., for imaging these proteins, measuring levels thereof in appropriate physiological samples (by immunoassay), in diagnostic methods, etc. This hold true also for a derivative, or homolog thereof of a complex. In another embodiment of the invention (see infra), an antibody to a complex or a fragment of such antibodies containing the antibody binding domain, is a Therapeutic. 5.3. DIAGNOSTIC, PROGNOSTIC, AND SCREENING USES OF PROTEIN COMPLEXES The particular protein complexes of the present invention may be markers of normal physiological processes, and thus have diagnostic utility. Further, definition of particular groups of patients with elevations or deficiencies of a protein complex of the present invention, or wherein the protein complex has a change in protein component composition, can lead to new nosological classifications of diseases, furthering diagnostic ability. (see: diseases or disorders in which the complexes provided herein are involved in and/or associated with are listed in table 3) Detecting levels of protein complexes, or individual component proteins that form the complexes, or detecting levels of the mRNAs encoding the components of the complex, may be used in diagnosis, prognosis, and/or staging to follow the course of a disease state, to follow a therapeutic response, etc. A protein complex of the present invention and the individual components of the complex and a derivative, analog or subsequence thereof, encoding nucleic acids (and sequences complementary thereto), and anti-complex antibodies and antibodies directed against individual components that can form the complex, are useful in WO 03/072602 PCT/EPO2/50003 48 diagnostics. The foregoing molecules can be used in assays, such as immunoassays, to detect, prognose, diagnose, or monitor various conditions, diseases, and disorders characterized by aberrant levels of a complex or aberrant component composition of a complex, or monitor the treatment of such various conditions, diseases, and disorders. In particular, such an immunoassay is carried out by a method comprising contacting a sample derived from a patient with an anti-complex antibody under conditions such that immunospecific binding can occur, and detecting or measuring the amount of any immunospecific binding by the antibody. In a specific aspect, such binding of antibody, in tissue sections, can be used to detect aberrant complex localization, or aberrant (e.g., high, low or absent) levels of a protein complex or complexes. In a specific embodiment, an antibody to the complex can be used to assay a patient tissue or serum sample for the presence of the complex, where an aberrant level of the complex is an indication of a diseased condition. By "aberrant levels" is meant increased or decreased levels relative to that present, or a standard level representing that present, in an analogous sample from a portion or fluid of the body, or from a subject not having the disorder. The immunoassays which can be used include but are not limited to competitive and non-competitive assay systems using techniques such as Western blots, radioimmunoassays, ELISA (enzyme linked immunosorbent assay), "sandwich" immunoassays, immunoprecipitation assays, precipitin reactions, gel diffusion precipitin reactions, immunodiffusion assays, agglutination assays, complement-fixation assays, immunoradiometric assays, fluorescent immunoassays, protein A immunoassays, to name but a few known in the art. Nucleic acids encoding the components of the protein complex and related nucleic acid sequences and subsequences, including complementary sequences, can be used in hybridization assays. The nucleic acid sequences, or subsequences thereof, comprising about at least 8 nucleotides, can be used as hybridization probes. Hybridization assays can be used to detect, prognose, diagnose, or monitor conditions, disorders, or disease states associated with aberrant levels of the mRNAs encoding the components of a complex as described, supra. In particular, such a hybridization assay is carried out by a method comprising contacting a sample containing nucleic acid with a nucleic acid probe capable of hybridizing to component protein coding DNA or RNA, under conditions such that hybridization can occur, and detecting or measuring any resulting hybridization.

WO 03/072602 PCT/EPO2/50003 49 In specific embodiments, diseases and disorders involving or characterized by aberrant levels of a protein complex or aberrant complex composition can be diagnosed, or its suspected presence can be screened for, or a predisposition to develop such disorders can be detected, by determining the component protein composition of the complex, or detecting aberrant levels of a member of the complex or un-complexed component proteins or encoding nucleic acids, or functional activity including, but not restricted to, binding to an interacting partner, or by detecting mutations in component protein RNA, DNA or protein (e.g., mutations such as translocations, truncations, changes in nucleotide or amino acid sequence relative to wild-type that cause increased or decreased expression or activity of a complex, and/or component protein. Such diseases and disorders include, but are not limited to, those described in Section 5.4 and its subsections. By way of example, levels of a protein complex and the individual components of a complex can be detected by immunoassay, levels of component protein RNA or DNA can be detected by hybridization assays (e.g., Northern blots, dot blots, RNase protection assays), and binding of component proteins to each other (e.g., complex formation) can be measured by binding assays commonly known in the art. Translocations and point mutations in component protein genes can be detected by Southern blotting, RFLP analysis, PCR using primers that preferably generate a fragment spanning at least most of the gene by sequencing of genomic DNA or cDNA obtained from the patient, etc. Assays well known in the art (e.g., assays described above such as immunoassays, nucleic acid hybridization assays, activity assays, etc.) can be used to determine whether one or more particular protein complexes are present at either increased or decreased levels, or are absent, in samples from patients suffering from a particular disease or disorder, or having a predisposition to develop such a disease or disorder, as compared to the levels in samples from subjects not having such a disease or disorder, or having a predisposition to develop such a disease or disorder. Additionally, these assays can be used to determine whether the ratio of the complex to the un-complexed components of the complex, is increased or decreased in samples from patients suffering from a particular disease or disorder, or having a predisposition to develop such a disease or disorder, as compared to the ratio in samples from subjects not having such a disease or disorder. In the event that levels of one or more particular protein complexes (i.e., complexes formed from component protein derivatives, WO 03/072602 PCT/EPO2/50003 50 homologs, fragments, or analogs) are determined to be increased in patients suffering from a particular disease or disorder, or having a predisposition to develop such a disease or disorder, then the particular disease or disorder, or predisposition for a disease or disorder, can be diagnosed, have prognosis defined for, be screened for, or be monitored by detecting increased levels of the one or more protein complexes, increased levels of the mRNA that encodes one or more members of the one or more particular protein complexes, or by detecting increased complex functional activity. Accordingly, in a specific embodiment of the present invention, diseases and disorders involving increased levels of one or more protein complexes can be diagnosed, or their suspected presence can be screened for, or a predisposition to develop such disorders can be detected, by detecting increased levels of the one or more protein complexes, the mRNA encoding both members of the complex, or complex functional activity, or by detecting mutations in the component proteins that stabilize or enhance complex formation, e.g., mutations such as translocations in nucleic acids, truncations in the gene or protein, changes in nucleotide or amino acid sequence relative to wild-type, that stabilize or enhance complex formation. In the event that levels of one or more particular protein complexes are determined to be decreased in patients suffering from a particular disease or disorder, or having a predisposition to develop such a disease or disorder, then the particular disease or disorder or predisposition for a disease or disorder can be diagnosed, have its prognosis determined, be screened for, or be monitored by detecting decreased levels of the one or more protein complexes, the mRNA that encodes one or more members of the particular one or more protein complexes, or by detecting decreased protein complex functional activity. Accordingly, in a specific embodiment of the invention, diseases and disorders involving decreased levels of one or more protein complexes can be diagnosed, or their suspected presence can be screened for, or a predisposition to develop such disorders can be detected, by detecting decreased levels of the one or more protein complexes, the mRNA encoding one or more members of the one or more complexes, or complex functional activity, or by detecting mutations in the component proteins that decrease complex formation, e.g., mutations such as translocations in nucleic acids, truncations in the gene or protein, changes in nucleotide or amino acid sequence relative to wild-type, that decrease complex formation.

WO 03/072602 PCT/EPO2/50003 51 Accordingly, in a specific embodiment of the invention, diseases and disorders involving aberrant compositions of the complexes can be diagnosed, or their suspected presence can be screened for, or a predisposition to develop such disorders can be detected, by detecting the component proteins of one or more complexes, or the mRNA encoding the members of the one or more complexes. The use of detection techniques, especially those involving antibodies against a protein complex, provides a method of detecting specific cells that express the complex or component proteins. Using such assays, specific cell types can be defined in which one or more particular protein complexes are expressed, and the presence of the complex or component proteins can be correlated with cell viability, state, health, etc. Also embodied are methods to detect a protein complex of the present invention in cell culture models that express particular protein complexes or derivatives thereof, for the purpose of characterizing or preparing the complexes for harvest. This embodiment includes cell sorting of prokaryotes such as but not restricted to bacteria (Davey and Kell, 1996, Microbiol. Rev. 60:641-696), primary cultures and tissue specimens from eukaryotes, including mammalian species such as human (Steele et al., 1996, Clin. Obstet. Gynecol 39:801-813), and continuous cell cultures (Orfao and Ruiz Arguelles, 1996, Clin. Biochem. 29:5-9). Such isolations can be used as methods of diagnosis, described, supra. 5.4. THERAPEUTIC USES OF PROTEIN COMPLEXES The present invention is directed to a method for treatment or prevention of various diseases and disorders by administration of a therapeutic compound (termed herein "Therapeutic"). Such "Therapeutics" include, but are not limited to, a protein complex of the present invention, the individual component proteins, and analogs and derivatives (including fragments) of the foregoing (e.g., as described hereinabove); antibodies thereto (as described hereinabove); nucleic acids encoding the component protein, and analogs or derivatives, thereof (e.g., as described hereinabove); component protein antisense nucleic acids, and agents that modulate complex formation and/or activity (i.e., agonists and antagonists). The protein complexes, as identified herein, are implicated significantly in normal physiological processes. For example, see the processes listed in table 3. Furthermore, the protein complexes as identified herein are implicated in processes which are implicated in or associated with pathological conditions.

WO 03/072602 PCT/EPO2/50003 52 Diseases and disorders which can be treated and/or prevented and/or diagnosed by Therapeutics interacting with any of the complexes provided herein are listed in table 3. These disorders are treated or prevented by administration of a Therapeutic that modulates (i.e. inhibits or promotes) protein complex activity or formation. Diseases or disorders associated with aberrant levels of complex activity or formation, or aberrant levels or activity of the component proteins, or aberrant complex composition, may be treated by administration of a Therapeutic that modulates complex formation or activity or by the administration of a protein complex. Therapeutic may also be administered to modulate complex formation or activity or level thereof in a microbial organism such as yeast, fungi such as candida albicans causing an infectious disease in animals or humans. Diseases and disorders characterized by increased (relative to a subject not suffering from the disease or disorder) complex levels or activity can be treated with Therapeutics that antagonize (i.e., reduce or inhibit) complex formation or activity. Therapeutics that can be used include, but are not limited to, the component proteins or an analog, derivative or fragment of the component protein; anti-complex antibodies (e.g., antibodies specific for the protein complex, or a fragment or derivative of the antibody containing the binding region thereof; nucleic acids encoding the component proteins; antisense nucleic acids complementary to nucleic acids encoding the component proteins; and nucleic acids encoding the component protein that are dysfunctional due to, e.g., a heterologous insertion within the protein coding sequence, that are used to "knockout" endogenous protein function by homologous recombination, see, e.g., Capecchi, 1989, Science 244:1288-1292. In one embodiment, a Therapeutic is 1, 2 or more antisense nucleic acids which are complementary to 1, 2, or more nucleic acids, respectfully, that encode component proteins of a complex. In a specific embodiment of the present invention, a nucleic acid containing a portion of a component protein gene in which gene sequences flank (are both 5' and 3' to) a different gene sequence, is used as a component protein antagonist, or to promote component protein inactivation by homologous recombination (see also, Koller and Smithies, 1989, Proc. Natl. Acad. Sci. USA 86:8932-8935; Zijlstra et al., 1989, Nature 342: 435-438). Additionally, mutants or derivatives of a component protein that has greater affinity for another component protein or the complex than wild type may be administered to compete with wild type protein for binding, thereby reducing the levels of WO 03/072602 PCT/EPO2/50003 53 complexes containing the wild type protein. Other Therapeutics that inhibit complex function can be identified by use of known convenient in vitro assays, e.g., based on their ability to inhibit complex formation, or as described in Section 5.5, infra. In specific embodiments, Therapeutics that antagonize complex formation or activity are administered therapeutically, including prophylactically, (1) in diseases or disorders involving an increased (relative to normal or desired) level of a complex, for example, in patients where complexes are overactive or overexpressed; or (2) in diseases or disorders where an in vitro (or in vivo) assay (see infra) indicates the utility of antagonist administration. Increased levels of a complex can be readily detected, e.g., by quantifying protein and/or RNA, by obtaining a patient tissue sample (e.g., from biopsy tissue) and assaying it in vitrofor RNA or protein levels, or structure and/or activity of the expressed complex (or the encoding mRNA). Many methods standard in the art can be thus employed including, but not limited to, immunoassays to detect complexes and/or visualize complexes (e.g., Western blot analysis, immunoprecipitation followed by sodium dodecyl sulfate polyacrylamide gel electrophoresis [SDS-PAGE], immunocytochemistry, etc.), and/or hybridization assays to detect concurrent expression of component protein mRNA (e.g., Northern assays, dot blot analysis, in situ hybridization, etc.). A more specific embodiment of the present invention is directed to a method of reducing complex expression (i.e., expression of the protein components of the complex and/or formation of the complex) by targeting mRNAs that express the protein moieties. RNA therapeutics currently fall within three classes, antisense species, ribozymes, or RNA aptamers (Good et al., 1997, Gene Therapy 4:45-54). Antisense oligonucleotides have been the most widely used. By way of example, but not limitation, antisense oligonucleotide methodology to reduce complex formation is presented below, infra. Ribozyme therapy involves the administration, induced expression, etc. of small RNA molecules with enzymatic ability to cleave, bind, or otherwise inactivate specific RNAs, to reduce or eliminate expression of particular proteins (Grassi and Marini, 1996, Annals of Medicine 28:499-510; Gibson, 1996, Cancer and Metastasis Reviews 15:287-299). RNA aptamers are specific RNA ligand proteins, such as for Tat and Rev RNA (Good et al., 1997, Gene Therapy 4:45-54) that can specifically inhibit their translation. Aptamers specific for component proteins can be identified by many methods well known in the art, for example, by affecting the formation of a complex in the protein-protein interaction assay described, infra.

WO 03/072602 PCT/EPO2/50003 54 In another embodiment, the activity or levels of a component protein are reduced by administration of another component protein, or the encoding nucleic acid, or an antibody that immunospecifically binds to the component protein, or a fragment or a derivative of the antibody containing the binding domain thereof. In another aspect of the invention, diseases or disorders associated with increased levels of an component protein of the complex may be treated or prevented by administration of a Therapeutic that increases complex formation if the complex formation acts to reduce or inactivate the component protein through complex formation. Such diseases or disorders can be treated or prevented by administration of one component member of the complex, administration of antibodies or other molecules that stabilize the complex, etc. Diseases and disorders associated with underexpression of a complex, or a component protein, are treated or prevented by administration of a Therapeutic that promotes (i.e., increases or supplies) complex levels and/or function, or individual component protein function. Examples of such a Therapeutic include but are not limited to a complex or a derivative, analog or fragment of the complex that are functionally active (e.g., able to form a complex), un-complexed component proteins and derivatives, analogs, and fragments of un-complexed component proteins, and nucleic acids encoding the members of a complex or functionally active derivatives or fragments of the members of the complex, e.g., for use in gene therapy. In a specific embodiment, a Therapeutic includes derivatives, homologs or fragments of a component protein that increase and/or stabilize complex formation. Examples of other agonists can be identified using in vitro assays or animal models, examples of which are described, infra. In yet other specific embodiments of the present invention, Therapeutics that promote complex function are administered therapeutically, including prophylactically, (1) in diseases or disorders involving an absence or decreased (relative to normal or desired) level of a complex, for example, in patients where a complex, or the individual components necessary to form the complex, is lacking, genetically defective, biologically inactive or underactive, or under-expressed; or (2) in diseases or disorders wherein an in vitro or in vivo assay (see, infra) indicates the utility of complex agonist administration. The absence or decreased level of a complex, component protein or function can be readily detected, e.g., by obtaining a patient tissue sample (e.g., from biopsy tissue) and assaying it in vitrofor RNA or protein levels, structure and/or activity of the expressed complex and/or the concurrent expression of mRNA encoding the two WO 03/072602 PCT/EPO2/50003 55 components of the complex. Many methods standard in the art can be thus employed, including but not limited to immunoassays to detect and/or visualize a complex, or the individual components of a complex (e.g., Western blot analysis, immunoprecipitation followed by sodium dodecyl sulfate polyacrylamide gel electrophoresis [SDS-PAGE], immunocytochemistry, etc.) and/or hybridization assays to detect expression of mRNAs encoding the individual protein components of a complex by detecting and/or visualizing component mRNA concurrently or separately using, e.g., Northern assays, dot blot analysis, in situ hybridization, etc. In specific embodiments, the activity or levels of a component protein are increased by administration of another component protein of the same complex, or a derivative, homolog or analog thereof, a nucleic acid encoding the other component, or an agent that stabilizes or enhances the other component, or a fragment or derivative of such an agent. Generally, administration of products of species origin or species reactivity (in the case of antibodies) that is the same species as that of the patient is preferred. Thus, in a preferred embodiment, a human complex, or derivative, homolog or analog thereof; nucleic acids encoding the members of the human complex or a derivative, homolog or analog thereof; an antibody to a human complex, or a derivative thereof; or other human agents that affect component proteins or the complex, are therapeutically or prophylactically administered to a human patient. Preferably, suitable in vitro or in vivo assays are utilized to determine the effect of a specific Therapeutic and whether its administration is indicated for treatment of the affected tissue or individual. In various specific embodiments, in vitro assays can be carried out with representative cells of cell types involved in a patient's disorder, to determine if a Therapeutic has a desired effect upon such cell types. Compounds for use in therapy can be tested in suitable animal model systems prior to testing in humans, including, but not limited to, rats, mice, chicken, cows, monkeys, rabbits, etc. For in vivo testing, prior to administration to humans, any animal model system known in the art may be used. Additional descriptions and sources of Therapeutics that can be used according to the invention are found in Sections 5.1 to 5.3 and 5.7 herein. 5.4.1. GENE THERAPY WO 03/072602 PCT/EPO2/50003 56 In a specific embodiment of the present invention, nucleic acids comprising a sequence encoding the component proteins, or a functional derivative thereof, are administered to modulate complex activity or formation by way of gene therapy. Gene therapy refers to therapy performed by the administration of a nucleic acid to a subject. In this embodiment of the present invention, the nucleic acid expresses its encoded protein(s) that mediates a therapeutic effect by modulating complex activity or formation. Any of the methods for gene therapy available in the art can be used according to the present invention. Exemplary methods are described below. For general reviews of the methods of gene therapy, see Goldspiel et al., 1993, Clinical Pharmacy 12:488-505; Wu and Wu, 1991, Biotherapy 3:87-95; Tolstoshev, 1993, Ann. Rev. Pharmacol. Toxicol. 32:573-596; Mulligan, 1993, Science 260:926-932; Morgan and Anderson, 1993, Ann. Rev. Biochem. 62:191-217; and May, 1993, TIBTECH 11:155-215. Methods commonly known in the art of recombinant DNA technology which can be used are described in Ausubel et al., eds., 1993, Current Protocols in Molecular Biology, John Wiley & Sons, NY; and Kriegler, 1990, Gene Transfer and Expression, A Laboratory Manual, Stockton Press, NY. In a preferred aspect, the Therapeutic comprises a nucleic acid that is part of an expression vector that expresses one or more of the component proteins, or fragments or chimeric proteins thereof, in a suitable host. In particular, such a nucleic acid has a promoter operably linked to the protein coding region(s) (or, less preferably separate promoters linked to the separate coding regions separately), said promoter being inducible or constitutive, and optionally, tissue-specific. In another particular embodiment, a nucleic acid molecule is used in which the coding sequences, and any other desired sequences, are flanked by regions that promote homologous recombination at a desired site in the genome, thus providing for intra-chromosomal expression of the component protein nucleic acids (Koller and Smithies, 1989, Proc. Natl. Acad. Sci. USA 86:8932-8935; Zijlstra et al., 1989, Nature 342:435-438). Delivery of the nucleic acid into a patient may be either direct, in which case the patient is directly exposed to the nucleic acid or nucleic acid-carrying vector, or indirect, in which case, cells are first transformed with the nucleic acid in vitro, then transplanted into the patient. These two approaches are known, respectively, as in vivo or ex vivo gene therapy. In a specific embodiment, the nucleic acid is directly administered in vivo, where it is expressed to produce the encoded product. This can be accomplished by any WO 03/072602 PCT/EPO2/50003 57 of numerous methods known in the art, e.g., by constructing it as part of an appropriate nucleic acid expression vector and administering it so that it becomes intracellular, e.g., by infection using a defective or attenuated retroviral or other viral vector (U.S. Patent No. 4,980,286), or by direct injection of naked DNA, or by use of microparticle bombardment (e.g., a gene gun; Biolistic, Dupont), or coating with lipids or cell-surface receptors, or through use of transfecting agents, by encapsulation in liposomes, microparticles, or microcapsules, or by administering it in linkage to a peptide that is known to enter the nucleus, or by administering it in linkage to a ligand subject to receptor-mediated endocytosis that can be used to target cell types specifically expressing the receptors (e.g., Wu and Wu, 1987, J. Biol. Chem. 262:4429-4432), etc. In another embodiment, a nucleic acid-ligand complex can be formed in which the ligand comprises a fusogenic viral peptide that disrupts endosomes, allowing the nucleic acid to avoid lysosomal degradation. In yet another embodiment, the nucleic acid can be targeted in vivo for cell specific uptake and expression, by targeting a specific receptor (see, e.g., International Patent Publications WO 92106180; WO 92/22635; WO 92/20316; WO 93/14188; and WO 93/20221. Alternatively, the nucleic acid can be introduced intracellularly and incorporated within host cell DNA for expression, by homologous recombination (Koller and Smithies, 1989, Proc. Natl. Acad. Sci. USA 86:8932-8935; Zijlstra et al., 1989, Nature 342:435-438). In a specific embodiment, a viral vector that contains the component protein encoding nucleic acids is used. For example, a retroviral vector can be used (Miller et al., 1993, Meth. Enzymol. 217:581-599). These retroviral vectors have been modified to delete retroviral sequences that are not necessaryfor packaging of the viral genome and integration into host cell DNA. The encoding nucleic acids to be used in gene therapy is/are cloned into the vector, which facilitates delivery of the gene into a patient. More detail about retroviral vectors can be found in Boesen et al., 1994, Biotherapy 6:291-302, which describes the use of a retroviral vector to deliver the mdrl gene to hematopoetic stem cells in order to make the stem cells more resistant to chemotherapy. Other references illustrating the use of retroviral vectors in gene therapy are Clowes et al., 1994, J. Clin. Invest. 93:644-651; Kiem et al., 1994, Blood 83:1467 1473; Salmons and Gunzberg, 1993, Human Gene Therapy 4:129-141; and Grossman and Wilson, 1993, Curr. Opin. in Genetics and Devel. 3:110-114. Adenoviruses are other viral vectors that can be used in gene therapy. Adenoviruses are especially attractive vehicles for delivering genes to respiratory WO 03/072602 PCT/EPO2/50003 58 epithelia. Adenoviruses naturally infect respiratory epithelia where they cause a mild disease. Other targets for adenovirus-based delivery systems are the liver, the central nervous system, endothelial cells and muscle. Adenoviruses have the advantage of being capable of infecting non-dividing cells. Kozarsky and Wilson, 1993, Current Opinion in Genetics and Development 3:499-503, discuss adenovirus-based gene therapy. The use of adenovirus vectors to transfer genes to the respiratory epithelia of rhesus monkeys has been demonstrated by Bout et al., 1994, Human Gene Therapy 5:3 10. Other instances of the use of adenoviruses in gene therapy can be found in Rosenfeld et al., 1991, Science 252:431-434; Rosenfeld et al., 1992, Cell 68:143-155; and Mastrangeli et al., 1993, J. Clin. Invest. 91:225-234. Adeno-associated virus (AAV) has also been proposed for use in gene therapy (Walsh et al., 1993, Proc. Soc. Exp. Biol. Med. 204:289-300. Another approach to gene therapy involves transferring a gene into cells in tissue culture by methods such as electroporation, lipofection, calcium phosphate mediated transfection, or viral infection. Usually, the method of transfer includes the transfer of a selectable marker to the cells. The cells are then placed under selection to isolate those cells that have taken up and are expressing the transferred gene from these that have not. Those cells are then delivered to a patient. In this embodiment, the nucleic acid is introduced into a cell prior to administration in vivo of the resulting recombinant cell. Such introduction can be carried out by any method known in the art including, but not limited to, transfection by electroporation, microinjection, infection with a viral or bacteriophage vector containing the nucleic acid sequences, cell fusion, chromosome-mediated gene transfer, microcell mediated gene transfer, spheroplast fusion, etc. Numerous techniques are known in the art for the introduction of foreign genes into cells (see, e.g., Loeffler and Behr, 1993, Meth. Enzymol. 217:599-618; Cohen et al., 1993, Meth. Enzymol. 217:618-644; Cline, 1985, Pharmac. Ther. 29:69-92) and may be used in accordance with the present invention, provided that the necessary developmental and physiological functions of the recipient cells are not disrupted. The technique should provide for the stable transfer of the nucleic acid to the cell, so that the nucleic acid is expressible by the cell and preferably, is heritable and expressible by its cell progeny. The resulting recombinant cells can be delivered to a patient by various methods known in the art. In a preferred embodiment, epithelial cells are injected, e.g., subcutaneously. In another embodiment, recombinant skin cells may be applied as a WO 03/072602 PCT/EPO2/50003 59 skin graft onto the patient. Recombinant blood cells (e.g., hematopoetic stem or progenitor cells) are preferably administered intravenously. The amount of cells envisioned for use depends on the desired effect, patient state, etc., and can be determined by one skilled in the art. Cells into which a nucleic acid can be introduced for purposes of gene therapy encompass any desired, available cell type, and include but are not limited to epithelial cells, endothelial cells, keratinocytes, fibroblasts, muscle cells, hepatocytes, blood cells such as T lymphocytes, B lymphocytes, monocytes, macrophages, neutrophils, eosinophils, megakaryocytes, and granulocytes, various stem or progenitor cells, in particular hematopoetic stem or progenitor cells, e.g., as obtained from bone marrow, umbilical cord blood, peripheral blood, fetal liver, etc. In a preferred embodiment, the cell used for gene therapy is autologous to the patient. In an embodiment in which recombinant cells are used in gene therapy, a component protein encoding nucleic acid is/are introduced into the cells such that the gene or genes are expressible by the cells or their progeny, and the recombinant cells are then administered in vivo for therapeutic effect. In a specific embodiment, stem or progenitor cells are used. Any stem and/or progenitor cells which can be isolated and maintained in vitro can potentially be used in accordance with this embodiment of the present invention. Such stem cells include but are not limited to hematopoetic stem cells (HSCs), stem cells of epithelial tissues such as the skin and the lining of the gut, embryonic heart muscle cells, liver stem cells (International Patent Publication WO 94/08598), and neural stem cells (Stemple and Anderson, 1992, Cell 71:973-985). Epithelial stem cells (ESCs), or keratinocytes, can be obtained from tissues such as the skin and the lining of the gut by known procedures (Rheinwald, 1980, Meth. Cell Biol. 2A:229). In stratified epithelial tissue such as the skin, renewal occurs by mitosis of stem cells within the germinal layer, the layer closest to the basal lamina. Similarly, stem cells within the lining of the gut provide for a rapid renewal rate of this tissue. ESCs or keratinocytes obtained from the skin or lining of the gut of a patient or donor can be grown in tissue culture (Rheinwald, 1980, Meth. Cell Bio. 2A:229; Pittelkow and Scott, 1986, Mayo Clinic Proc. 61:771). If the ESCs are provided by a donor, a method for suppression of host versus graft reactivity (e.g., irradiation, or drug or antibody administration to promote moderate immunosuppression) can also be used.

WO 03/072602 PCT/EPO2/50003 60 With respect to hematopoetic stem cells (HSCs), any technique that provides for the isolation, propagation, and maintenance in vitro of HSCs can be used in this embodiment of the invention. Techniques by which this may be accomplished include (a) the isolation and establishment of HSC cultures from bone marrow cells isolated from the future host, or a donor, or (b) the use of previously established long term HSC cultures, which may be allogeneic or xenogeneic. Non-autologous HSCs are used preferably in conjunction with a method of suppressing transplantation immune reactions between the future host and patient. In a particular embodiment of the present invention, human bone marrow cells can be obtained from the posterior iliac crest by needle aspiration (see, e.g., Kodo et al., 1984, J. Clin. Invest. 73: 1377-1384). In a preferred embodiment of the present invention, the HSCs can be made highly enriched or in substantially pure form. This enrichment can be accomplished before, during, or after long-term culturing, and can be done by any technique known in the art. Long-term cultures of bone marrow cells can be established and maintained by using, for example, modified Dexter cell culture techniques (Dexter et al., 1977, J. Cell Physiol. 91:335) or Witlock-Witte culture techniques (Witlock and Witte, 1982, Proc. Natl. Acad. Sci. USA 79:3608-3612). In a specific embodiment, the nucleic acid to be introduced for purposes of gene therapy comprises an inducible promoter operably linked to the coding region, such that expression of the nucleic acid is controllable by controlling the presence or absence of the appropriate inducer of transcription. Additional methods can be adapted for use to deliver a nucleic acid encoding the component proteins, or functional derivatives thereof, e.g., as described in Section 5.1, supra. 5.4.2. USE OF ANTISENSE OLIGONUCLEOTIDES FOR SUPPRESSION OF PROTEIN COMPLEX ACTIVITY OR FORMATION In a specific embodiment of the present invention, protein complex activity and formation is inhibited by use of antisense nucleic acids for the component proteins of the complex, that inhibit transcription and/or translation of their complementary sequence. The present invention provides the therapeutic or prophylactic use of nucleic acids of at least six nucleotides that are antisense to a gene or cDNA encoding a component protein, or a portion thereof. An "antisense" nucleic acid as used herein refers to a nucleic acid capable of hybridizing to a sequence-specific portion of a WO 03/072602 PCT/EPO2/50003 61 component protein RNA (preferably mRNA) by virtue of some sequence complementarity. The antisense nucleic acid may be complementary to a coding and/or noncoding region of a component protein mRNA. Such antisense nucleic acids that inhibit complex formation or activity have utility as Therapeutics, and can be used in the treatment or prevention of disorders as described supra. The antisense nucleic acids of the invention can be oligonucleotides that are double-stranded or single-stranded, RNA or DNA, or a modification or derivative thereof, which can be directly administered to a cell, or which can be produced intracellularly by transcription of exogenous, introduced sequences. In another embodiment, the present invention is directed to a method for inhibiting the expression of component protein nucleic acid sequences, in a prokaryotic or eukaryotic cell, comprising providing the cell with an effective amount of a composition comprising an antisense nucleic acid of the component protein, or a derivative thereof, of the invention. The antisense nucleic acids are of at least six nucleotides and are preferably oligonucleotides, ranging from 6 to about 200 nucleotides. In specific aspects, the oligonucleotide is at least 10 nucleotides, at least 15 nucleotides, at least 100 nucleotides, or at least 200 nucleotides. The oligonucleotides can be DNA or RNA or chimeric mixtures, or derivatives or modified versions thereof, and either single-stranded or double-stranded. The oligonucleotide can be modified at the base moiety, sugar moiety, or phosphate backbone. The oligonucleotide may include other appending groups such as peptides, agents facilitating transport across the cell membrane (see, e.g., Letsinger et al., 1989, Proc. Natl. Acad. Sci. U.S.A. 86:6553-6556; Lemaitre et al., 1987, Proc. Natl. Acad. Sci. 84:648-652; International Patent Publication No. WO 88/09810) or blood-brain barrier (see, e.g., International Patent Publication No. WO 89/10134), hybridization-triggered cleavage agents (see, e.g., Krol et al., 1988, BioTechniques 6:958-976), or intercalating agents (see, e.g., Zon, 1988, Pharm. Res. 5:539-549). In a preferred aspect of the invention, an antisense oligonucleotide is provided, preferably as single-stranded DNA. The oligonucleotide may be modified at any position in its structure with constituents generally known in the art. The antisense oligonucleotides may comprise at least one modified base moiety which is selected from the group including but not limited to 5-fluorouracil, 5-bromouracil, 5-chlorouracil, 5-iodouracil, hypoxanthine, xanthine, 4-acetylcytosine, WO 03/072602 PCT/EPO2/50003 62 5-(carboxyhydroxylmethyl)uracil, 5-carboxymethylaminomethyl-2-thio-uridine, 5-carboxymethylaminomethyluracil, dihydrouracil, beta-D-galactosylqueosine, inosine, N6-isopentenyladenine, 1-methylguanine, 1-methylinosine, 2,2-dimethylguanine, 2-methyladenine, 2-methylguanine, 3-methylcytosine, 5-methylcytosine, N6-adenine, 7-methylguanine, 5-methylaminomethyluracil, 5-methoxyaminomethyl-2-thiouracil, beta-D-mannosylqueosine, 5N-methoxycarboxymethyluracil, 5-methoxyuracil, 2-methyl thio-N6-isopentenyladenine, uracil-5-oxyacetic acid (v), wybutoxosine, pseudouracil, queosine, 2-thiocytosine, 5-methyl-2-thiouracil, 2-thiouracil, 4-thiouracil, 5-methyluracil, uracil-5-oxyacetic acid methylester, uracil-5-oxyacetic acid (v), 5-methyl-2-thiouracil, 3-(3-amino-3-N-2-carboxypropyl) uracil, (acp3)w, and 2,6-diaminopurine. In another embodiment, the oligonucleotide comprises at least one modified sugar moiety selected from the group including, but not limited to, arabinose, 2-fluoroarabinose, xylulose, and hexose. In yet another embodiment, the oligonucleotide comprises at least one modified phosphate backbone selected from the group consisting of a phosphorothioate, a phosphorodithioate, a phosphoramidothioate, a phosphoramidate, a phosphordiamidate, a methylphosphonate, an alkyl phosphotriester, and a formacetal, or an analog of the foregoing. In yet another embodiment, the oligonucleotide is a 2-a-anomeric oligonucleotide. An a-anomeric oligonucleotide forms specific double-stranded hybrids with complementary RNA in which, contrary to the usual l-units, the strands run parallel to each other (Gautier et al., 1987, Nucl. Acids Res. 15:6625-6641). The oligonucleotide may be conjugated to another molecule, e.g., a peptide, hybridization-triggered cross-linking agent, transport agent, hybridization triggered cleavage agent, etc. Oligonucleotides of the invention may be synthesized by standard methods known in the art, e.g., by use of an automated DNA synthesizer (such as are commercially avail-able from Biosearch, Applied Biosystems, etc.). As examples, phosphorothioate oligo-nucleotides may be synthesized by the method of Stein et al. (1988, Nucl. Acids Res. 16:3209), methylphosphonate oligonucleotides can be prepared by use of controlled pore glass polymer supports (Sarin et al., 1988, Proc. Natl. Acad. Sci. U.S.A. 85:7448-7451), etc. In a specific embodiment, the antisense oligonucleotides comprise catalytic RNAs, or ribozymes (see, e.g., International Patent Publication No.

WO 03/072602 PCT/EPO2/50003 63 WO 90/11364; Sarver et al., 1990, Science 247:1222-1225). In another embodiment, the oligonucleotide is a 2'-0-methylribonucleotide (Inoue et al., 1987, Nucl. Acids Res. 15:6131-6148), or a chimeric RNA-DNA analog (lnoue et al., 1987, FEBS Lett. 215:327 330). In an alternative embodiment, the antisense nucleic acids of the invention are produced intracellularly by transcription from an exogenous sequence. For example, a vector can be introduced in vivo such that it is taken up by a cell, within which cell the vector or a portion thereof is transcribed, producing an antisense nucleic acid (RNA) of the invention. Such a vector would contain a sequence encoding the component protein. Such a vector can remain episomal or become chromosomally integrated, as long as it can be transcribed to produce the desired antisense RNA. Such vectors can be constructed by recombinant DNA technology methods standard in the art. Vectors can be plasmid, viral, or others known in the art to be capable of replication and expression in mammalian cells. Expression of the sequences encoding the antisense RNAs can be by any promoter known in the art to act in mammalian, preferably human, cells. Such promoters can be inducible or constitutive. Such promoters include, but are not limited to, the SV40 early promoter region (Bernoist and Chambon, 1981, Nature 290:304-310), the promoter contained in the 3' long terminal repeat of Rous sarcoma virus (Yamamoto et al., 1980, Cell 22:787-797), the herpes thymidine kinase promoter (Wagner et al., 1981, Proc. Natl. Acad. Sci. U.S.A. 78:1441-1445), the regulatory sequences of the metallothionein gene (Brinster et al., 1982, Nature 296:39-42), etc. The antisense nucleic acids of the invention comprise a sequence complementary to at least a portion of an RNA transcript of a component protein gene, preferably a human gene. However, absolute complementarity, although preferred, is not required. A sequence "complementary to at least a portion of an RNA," as referred to herein, means a sequence having sufficient complementarity to be able to hybridize with the RNA, forming a stable duplex; in the case of double-stranded antisense nucleic acids, a single strand of the duplex DNA may thus be tested, or triplex formation may be assayed. The ability to hybridize will depend on both the degree of complementarity and the length of the antisense nucleic acid. Generally, the longer the hybridizing nucleic acid, the more base mismatches with a component protein RNA it may contain and still form a stable duplex (or triplex, as the case may be). One skilled in the art can ascertain a tolerable degree of mismatch by use of standard procedures to determine the melting point of the hybridized complex.

WO 03/072602 PCT/EPO2/50003 64 The component protein antisense nucleic acids can be used to treat (or prevent) disorders of a cell type that expresses, or preferably overexpresses, a protein complex. Cell types that express or overexpress component protein RNA can be identified by various methods known in the art. Such methods include, but are not limited to, hybridization with component protein-specific nucleic acids (e.g., by Northern blot hybridization, dot blot hybridization, or in situ hybridization), or by observing the ability of RNA from the cell type to be translated in vitro into the component protein by immunohistochemistry, Western blot analysis, ELISA, etc. In a preferred aspect, primary tissue from a patient can be assayed for protein expression prior to treatment, e.g., by immunocytochemistry, in situ hybridization, or any number of methods to detect protein or mRNA expression. Pharmaceutical compositions of the invention (see Section 5.7, infra), comprising an effective amount of a protein component antisense nucleic acid in a pharmaceutically acceptable carrier can be administered to a patient having a disease or disorder that is of a type that expresses or overexpresses a protein complex of the present invention. The amount of antisense nucleic acid that will be effective in the treatment of a particular disorder or condition will depend on the nature of the disorder or condition, and can be determined by standard clinical techniques. Where possible, it is desirable to determine the antisense cytotoxicity in vitro, and then in useful animal model systems, prior to testing and use in humans. In a specific embodiment, pharmaceutical compositions comprising antisense nucleic acids are administered via liposomes, microparticles, or microcapsules. In various embodiments of the invention, it may be useful to use such compositions to achieve sustained release of the antisense nucleic acids. In a specific embodiment, it may be desirable to utilize liposomes targeted via antibodies to specific identifiable central nervous system cell types (Leonetti et al., 1990, Proc. Natl. Acad. Sci. U.S.A. 87:2448-2451; Renneisen et al., 1990, J. Biol. Chem. 265:16337-16342). 5.5. ASSAYS OF PROTEIN COMPLEXES AND DERIVATIVES AND ANALOGS THEREOF The functional activity of a protein complex of the present invention, or a derivative, fragment or analog thereof, can be assayed by various methods. Potential WO 03/072602 PCT/EPO2/50003 65 modulators (e.g., agonists and antagonists) of complex activity or formation, e.g., anti complex antibodies and antisense nucleic acids, can be assayed for the ability to modulate complex activity or formation. In one embodiment of the present invention, where one is assaying for the ability to bind or compete with a wild-type complex for binding to an anti-complex antibody, various immunoassays known in the art can be used, including but not limited to competitive and non-competitive assay systems using techniques such as radioimmunoassay, ELISA (enzyme linked immunosorbent assay), "sandwich" immunoassays, immunoradiometric assays, gel diffusion precipitin reactions, immunodiffusion assays, in situ immunoassays (using colloidal gold, enzyme or radioisotope labels), western blot analysis, precipitation reactions, agglutination assays (e.g., gel agglutination assays, hemagglutination assays), complement fixation assays, immunofluorescence assays, protein A assays, immunoelectrophoresis assays, etc. In one embodiment, antibody binding is detected by detecting a label on the primary antibody. In another embodiment, the primary antibody is detected by detecting binding of a secondary antibody or reagent to the primary antibody. In a further embodiment, the secondary antibody is labeled. Many means are known in the art for detecting binding in an immunoassay and are within the scope of the present invention. The expression of the component protein genes (both endogenous and those expressed from cloned DNA containing the genes) can be detected using techniques known in the art, including but not limited to Southern hybridization (Southern, 1975, J. Mol. Biol. 98:503-517), northern hybridization (see, e.g., Freeman et al., 1983, Proc. Natl. Acad. Sci. USA 80:4094-4098), restriction endonuclease mapping (Sambrook et al., 1989, Molecular Cloning, A Laboratory Manual, 2 nd Ed. Cold Spring Harbor Laboratory Press, New York), RNase protection assays (Current Protocols in Molecular Biology, John Wiley and Sons, New York, 1997), DNA sequence analysis, and polymerase chain reaction amplification (PCR; U.S. Patent Nos. 4,683,202, 4,683,195, and 4,889,818; Gyllenstein et al., 1988, Proc. Natl. Acad. Sci. USA 85:7652-7657; Ochman et al., 1988, Genetics 120:621-623; Loh et al., 1989, Science 243:217-220) followed by Southern hybridization with probes specific for the component protein genes, in various cell types. Methods of amplification other than PCR commonly known in the art can be employed. In one embodiment, Southern hybridization can be used to detect genetic linkage of component protein gene mutations to physiological or pathological states. Various cell types, at various stages of development, can be characterized for WO 03/072602 PCT/EPO2/50003 66 their expression of component proteins at the same time and in the same cells. The stringency of the hybridization conditions for northern or Southern blot analysis can be manipulated to ensure detection of nucleic acids with the desired degree of relatedness to the specific probes used. Modifications to these methods and other methods commonly known in the art can be used. Derivatives (e.g., fragments), homologs and analogs of one component protein can be assayed for binding to another component protein in the same complex by any method known in the art, for example the modified yeast matrix mating test described in Section 5.6.1 infra, immunoprecipitation with an antibody that binds to the component protein complexed with other component proteins in the same complex, followed by size fractionation of the immunoprecipitated proteins (e.g., by denaturing or nondenaturing polyacrylamide gel electrophoresis), Western blot analysis, etc. One embodiment of the invention provides a method for screening a derivative, homolog or analog of a component protein for biological activity comprising contacting said derivative, homolog or analog of the component protein with the other component proteins in the same complex; and detecting the formation of a complex between said derivative, homolog or analog of the component protein and the other component proteins; wherein detecting formation of said complex indicates that said derivative, homolog or analog of has biological (e.g., binding) activity. The invention also provides methods of modulating the activity of a component protein that can participate in a protein complex by administration of a binding partner of that protein or derivative, homolog or analog thereof. In a specific embodiment of the present invention, a protein complex of the present invention is administered to treat or prevent a disease or disorder, since the complex and/or component proteins have been implicated in the disease and disorder. Accordingly, a protein complex or a derivative, homolog, analog or fragment thereof, nucleic acids encoding the component proteins, anti-complex antibodies, and other modulators of protein complex activity, can be tested for activity in treating or preventing a disease or disorder in in vitro and in vivoassays. In one embodiment, a Therapeutic of the invention can be assayed for activity in treating or preventing a disease by contacting cultured cells that exhibit an indicator of the disease in vitro, with the Therapeutic, and comparing the level of said indicator in the cells contacted with the Therapeutic, with said level of said indicator in WO 03/072602 PCT/EPO2/50003 67 cells not so contacted, wherein a lower level in said contacted cells indicates that the Therapeutic has activity in treating or preventing the disease. In another embodiment of the invention, a Therapeutic of the invention can be assayed for activity in treating or preventing a disease by administering the Therapeutic to a test animal that is predisposed to develop symptoms of a disease, and measuring the change in said symptoms of the disease after administration of said Therapeutic, wherein a reduction in the severity of the symptoms of the disease or prevention of the symptoms of the disease indicates that the Therapeutic has activity in treating or preventing the disease. Such a test animal can be any one of a number of animal models known in the art for disease. These animal models are well known in the art. These animal models include, but are not limited to those which are listed in the section 5.6 (supra) as exemplary animald models to study any of the complexes provided in the invention. 5.6 SCREENING FOR MODULATORS OF THE PROTEIN COMPLEXES A complex of the present invention, the component proteins of the complex and nucleic acids encoding the component proteins, as well as derivatives and fragments of the amino and nucleic acids, can be used to screen for compounds that bind to, or modulate the amount of, activity of, or protein component composition of, said complex, and thus, have potential use as modulators, i.e., agonists or antagonists, of complex activity, and/or complex formation, i.e., the amount of complex formed, and/or protein component composition of the complex. Thus, the present invention is also directed to methods for screening for molecules that bind to, or modulate the function of, amount of, activity of, formation of or protein component composition of, a complex of the present invention. In one embodiment of the invention, the method for screening for a molecule that modulates directly or indirectly the function, activity or formation of a complex of the present invention comprises exposing said complex, or a cell or organism containing the complex machinery, to one or more candidate molecules under conditions conducive to modulation; and determining the amount of, the biochemical activity of, protein components of, and/or intracellular localization of, said complex and/or the transcription level of a gene dependend on the complex and/or the abundance and/or activity of a WO 03/072602 PCT/EPO2/50003 68 protein or protein complex dependend on the function of the complex and/or product of a gene dependent on the complex in the presence of the one or more candidate molecules, wherein a change in said amount, activity, protein components or intracellular localization relative to said amount, activity, protein components and/or intracellular localization and/or a change in the transcription level of a gene dependend on the complex and/or the abundance and/or activity of a protein or protein complex dependent on the function of the complex and/or product of a gene dependent on the complex in the absence of said candidate molecules indicates that the molecule modulates function, activity or composition of said complex. In a further specific embodiment, a modulation of the formation process of a complex can be determined. Such a modulation can either be a change in the typical time course of its formation or a change in the typical steps leading to the formation of the complete complex. Such changes can for example be detected by analysing and comparing the process of complex formation in untreated wild type cells of a particular type and/or cells showing or having the predisposition to develop a certain disease phenotype andlor cells which have been treated with particular conditions and/or particular agents in a particular situation. Methods to study such changes in time course are well known in the art and include for example Western-blot analysis of the proteins in the complex isolated at different steps of its formation. Furthermore an aberrant intracellular localization of the protein complex and/or an abberant transcription level of a gene dependent on the complex and/or the abundance andlor activity of a protein or protein complex dependent on the function of the complex andlor a gene dependent on the complex can serve as a marker for a disease and thus have diagnostic utility for any disease which is caused by an aberrant activity, function, composition or formation of the complex of the invention. Methods to study the intracellular localization are well known in the art and include, but are not limited to immunofluorescence analysis using antibodies specific for components of the protein. Preferentially, double-stainirigs including staining of other cellular structures are being used to facilitate the detection of the intracellular localization. Methods to analyse the transcription levels of a gene dependent on the complex are also well known in the art and include Northern blot analysis, quantitative PCR etc. The abundance of proteins dependent on the protein can be analyzed as described supra.

WO 03/072602 PCT/EPO2/50003 69 Methods to study changes in the activity of proteins dependent on complex depend on the protein. The choice of such methods will be apparent to any person skilled in the art. In another embodiment, the present invention is directed to a method for screening for a molecule that binds a protein complex of the present invention comprising exposing said complex, or a cell or organism containing the complex machinery, to one or more candidate molecules; and determining whether said complex is bound by any of said candidate molecules. Such screening assays can be carried out using cell-free and cell based methods that are commonly known in the art in vitro, in vivo or ex vivo. For example, an isolated complex can be employed, or a cell can be contacted with the candidate molecule and the complex can be isolated from such contacted cells and the isolated complex can be assayed for activity or component composition. In another example, a cell containing the complex can be contacted with the candidate molecule and the levels of the complex in the contacted cell can be measured. Additionally, such assays can be carried out in cells recombinantly expressing a component protein from table 1, third column of a given complex, or a functionally active fragment or functionally active derivative thereof, or a homologue thereof or a variant encoded by a nucleic acid of any of said proteins. For example, assays can be carried out using recombinant cells expressing the protein components of a complex, to screen for molecules that bind to, or interfere with, or promote complex activity or formation. In preferred embodiments, polypeptide derivatives that have superior stabilities but retain the ability to form a complex (e.g., one or more component proteins modified to be resistant to proteolytic degradation in the binding assay buffers, or to be resistant to oxidative degradation), are used to screen for modulators of complex activity or formation. Such resistant molecules can be generated, e.g., by substitution of amino acids at proteolytic cleavage sites, the use of chemically derivatized amino acids at proteolytic susceptible sites, and the replacement of amino acid residues subject to oxidation, i.e. methionine and cysteine. A particular aspect of the present invention relates to identifying molecules that inhibit or promote formation or degradation of a complex of the present invention, e.g., using the method described for isolating the complex and identifying members of the complex using the TAP assay described in Section 6, infra, and in WO 00/09716 and Rigaut et al., 1999, Nature Biotechnology 17:1030-1032, which are each incorporated by reference in their entirety.

WO 03/072602 PCT/EPO2/50003 70 In another embodiment of the invention, a modulator is identified by administering a candidate molecule to a transgenic non-human animal expressing the complex component proteins from promoters that are not the native promoters of the respective proteins, more preferably where the candidate molecule is also recombinantly expressed in the transgenic non-human animal. Alternatively, the method for identifying such a modulator can be carried out in vitro, preferably with a purified complex, and a purified candidate molecule. Agents/molecules (candidate molecules) to be screened can be provided as mixtures of a limited number of specified compounds, or as compound libraries, peptide libraries and the like. Agents/molecules to be screened may also include all forms of antisera, antisense nucleic acids, etc., that can modulate complex activity or formation. Exemplary candidate molecules and libraries for screening are set forth in Section 5.6.1, infra. Screening the libraries can be accomplished by any of a variety of commonly known methods. See, e.g., the following references, which disclose screening of peptide libraries: Parmley and Smith, 1989, Adv. Exp. Med. Biol. 251:215-218; Scott and Smith, 1990, Science 249:386-390; Fowlkes et al., 1992, BioTechniques 13:422 427; Oldenburg et al., 1992, Proc. Natl. Acad. Sci. USA 89:5393-5397; Yu et al., 1994, Cell 76:933-945; Staudt et al., 1988, Science 241:577-580; Bock et al., 1992, Nature 355:564-566; Tuerk et al., 1992, Proc. Natl. Acad. Sci. USA 89:6988-6992; Ellington et al., 1992, Nature 355:850-852; U.S. Patent No. 5,096,815, U.S. Patent No. 5,223,409, and U.S. Patent No. 5,198,346, all to Ladner et al.; Rebar and Pabo, 1993, Science 263:671-673; and International Patent Publication No. WO 94/18318. In a specific embodiment, screening can be carried out by contacting the library members with a complex immobilized on a solid phase, and harvesting those library members that bind to the protein (or encoding nucleic acid or derivative). Examples of such screening methods, termed "panning" techniques, are described by way of example in Parmley and Smith, 1988, Gene 73:305-318; Fowlkes et al., 1992, BioTechniques 13:422-427; International Patent Publication No. WO 94/18318; and in references cited hereinabove. In a specific embodiment, fragments and/or analogs of protein components of a complex, especially peptidomimetics, are screened for activity as competitive or non competitive inhibitors of complex formation (amount of complex or composition of WO 03/072602 PCT/EPO2/50003 71 complex) or activity in the cell, which thereby inhibit complex activity or formation in the cell. In one embodiment, agents that modulate (i.e., antagonize or agonize) complex activity or formation can be screened for using a binding inhibition assay, wherein agents are screened for their ability to modulate formation of a complex under aqueous, or physiological, binding conditions in which complex formation occurs in the absence of the agent to be tested. Agents that interfere with the formation of complexes of the invention are identified as antagonists of complex formation. Agents that promote the formation of complexes are identified as agonists of complex formation. Agents that completely block the formation of complexes are identified as inhibitors of complex formation. Methods for screening may involve labeling the component proteins of the complex with radioligands (e.g., 1251 or 3 H), magnetic ligands (e.g., paramagnetic beads covalently attached to photobiotin acetate), fluorescent ligands (e.g., fluorescein or rhodamine), or enzyme ligands (e.g., luciferase or beta-galactosidase). The reactants that bind in solution can then be isolated by one of many techniques known in the art, including but not restricted to, co-immunoprecipitation of the labeled complex moiety using antisera against the unlabeled binding partner (or labeled binding partner with a distinguishable marker from that used on the second labeled complex moiety), immunoaffinity chromatography, size exclusion chromatography, and gradient density centrifugation. In a preferred embodiment, the labeled binding partner is a small fragment or peptidomimetic that is not retained by a commercially available filter. Upon binding, the labeled species is then unable to pass through the filter, providing for a simple assay of complex formation. Methods commonly known in the art are used to label at least one of the component members of the complex. Suitable labeling methods include, but are not limited to, radiolabeling by incorporation of radiolabeled amino acids, e.g., 3 H-leucine or 35 S-methionine, radiolabeling by post-translational iodination with 1251 or 1311 using the chloramine T method, Bolton-Hunter reagents, etc., or labeling with 32 P using phosphorylase and inorganic radiolabeled phosphorous, biotin labeling with photobiotin acetate and sunlamp exposure, etc. In cases where one of the members of the complex is immobilized, e.g., as described infra, the free species is labeled. Where neither of the interacting species is immobilized, each can be labeled with a distinguishable marker such that isolation of both moieties can be followed to provide for more accurate WO 03/072602 PCT/EPO2/50003 72 quantification, and to distinguish the formation of homomeric from heteromeric complexes. Methods that utilize accessory proteins that bind to one of the modified interactants to improve the sensitivity of detection, increase the stability of the complex, etc., are provided. Typical binding conditions are, for example, but not by way of limitation, in an aqueous salt solution of 10-250 mM NaCl, 5-50 mM Tris-HCI, pH 5-8, and 0.5% Triton X-100 or other detergent that improves specificity of interaction. Metal chelators and/or divalent cations may be added to improve binding and/or reduce proteolysis. Reaction temperatures may include 4, 10, 15, 22, 25, 35, or42 degrees Celsius, and time of incubation is typically at least 15 seconds, but longer times are preferred to allow binding equilibrium to occur. Particular complexes can be assayed using routine protein binding assays to determine optimal binding conditions for reproducible binding. The physical parameters of complex formation can be analyzed by quantification of complex formation using assay methods specific for the label used, e.g., liquid scintillation counting for radioactivity detection, enzyme activity for enzyme-labeled moieties, etc. The reaction results are then analyzed utilizing Scatchard analysis, Hill analysis, and other methods commonly known in the arts (see, e.g., Proteins, Structures, and Molecular Principles, 2 n d Edition (1993) Creighton, Ed., W.H. Freeman and Company, New York). In a second common approach to binding assays, one of the binding species is immobilized on a filter, in a microtiter plate well, in a test tube, to a chromatography matrix, etc., either covalently or non-covalently. Proteins can be covalently immobilized using any method well known in the art, for example, but not limited to the method of Kadonaga and Tjian, 1986, Proc. Natl. Acad. Sci. USA 83:5889 5893, i.e., linkage to a cyanogen-bromide derivatized substrate such as CNBr Sepharose 4B (Pharmacia). Where needed, the use of spacers can reduce steric hindrance by the substrate. Non-covalent attachment of proteins to a substrate include, but are not limited to, attachment of a protein to a charged surface, binding with specific antibodies, binding to a third unrelated interacting protein, etc. Assays of agents (including cell extracts or a library pool) for competition for binding of one member of a complex (or derivatives thereof) with another member of the complex labeled by any means (e.g., those means described above) are provided to screen for competitors or enhancers of complex formation.

WO 03/072602 PCT/EPO2/50003 73 In specific embodiments, blocking agents to inhibit non-specific binding of reagents to other protein components, or absorptive losses of reagents to plastics, immobilization matrices, etc., are included in the assay mixture. Blocking agents include, but are not restricted to bovine serum albumin, beta-casein, nonfat dried milk, Denhardt's reagent, Ficoll, polyvinylpyrolidine, nonionic detergents (NP40, Triton X-100, Tween 20, Tween 80, etc.), ionic detergents (e.g., SDS, LDS, etc.), polyethylene glycol, etc. Appropriate blocking agent concentrations allow complex formation. After binding is performed, unbound, labeled protein is removed in the supernatant, and the immobilized protein retaining any bound, labeled protein is washed extensively. The amount of bound label is then quantified using standard methods in the art to detect the label as described, supra. In another specific embodiments screening for modulators of the protein complexes/protein as provided herein can be carried out by attaching those and/or the antibodies as provided herein to a solid carrier. In a further specific embodiment, the invention relates to an array of said molecules. The preparation of such an array containing different types of proteins, including antibodies) is well known in the art and is apparent to a person skilled in the art (see e.g. Ekins et al., 1989, J. Pharm. Biomed. Anal. 7:155-168; Mitchell et al. 2002, Nature Biotechnol. 20:225-229; Petricoin et al., 2002, Lancet 359:572-577; Templin et al., 2001, Trends Biotechnol. 20:160-166; Wilson and Nock, 2001, Curr. Opin. Chem. Biol. 6:81-85; Lee et al., 2002 Science 295:1702-1705; MacBeath and Schreiber, 2000, Science 289:1760; Blawas and Reichert, 1998, Biomaterials 19:595; Kane et al., 1999, Biomaterials 20:2363; Chen et al., 1997, Science 276:1425; Vaugham et al., 1996, Nature Biotechnol. 14:309-314; Mahler et al., 1997, Immunotechnology 3:31-43; Roberts et al., 1999, Curr. Opin. Chem. Biol. 3:268-273; Nord et al., 1997, Nature Biotechnol. 15:772-777; Nord et al., 2001, Eur. J. Biochem. 268:4269-4277; Brody and Gold, 2000, Rev. Mol. Biotechnol. 74:5-13; Karlstroem and Nygren, 2001, Anal. Biochem. 295:22-30; Nelson et al., 2000, Electrophoresis 21:1155-1163; Honore et al., 2001, Expert Rev. Mol. Diagn. 3:265-274; Albala, 2001, Expert Rev. Mol. Diagn. 2:145-152, Figeys and Pinto, 2001, Electrophoresis 2:208-216 and references in the publications listed here). Complexes can be attached to an array by different means as will be apparent to a person skilled in the art. Complexes can for example be added to the array via a TAP tag (as described in WO/0009716 and in Rigaut et al., 1999, Nature Biotechnol. 10:1030- WO 03/072602 PCT/EPO2/50003 74 1032) after the purification step or by another suitable purification scheme as will be apparent to a person skilled in the art. Optionally, the proteins of the complex can be cross-linked to enhance the stability of the complex. Different methods to cross-link proteins are well known in the art. Reactive end-groups of cross-linking agents include but are not limited to -COOH, -SH, NH2 or N-oxy-succinamate. The spacer of the cross-linking agent should be chosen with respect to the size of the complex to be cross-linked. For small protein complexes, comprising only a few proteins, relatively short spacers are preferable in order to reduce the likelihood of cross-linking separate complexes in the reaction mixture. For larger protein complexes, additional use of larger spacers is preferable in order to facilitate cross-linking between proteins within the complex. It is preferable to check the success-rate of cross-linking before linking the complex to the carrier. As will be apparent to a person skilled in the art, the optimal rate of cross-linking need to be determined on a case by case basis. This can be achieved by methods well known in the art, some of which are exemplary described below. A sufficient rate of cross-linking can be checked f.e. by analysing the cross-linked complex vs. a non-cross-linked complex on a denaturating protein gel. If cross-linking has been performed successfully, the proteins of the complex are expected to be found in the same lane, whereas the proteins of the non-cross-linked complex are expected to be separated according to their individual characteristics. Optionally the presence of all proteins of the complex can be further checked by peptide sequencing of proteins in the respective bands using methods well known in the art such as mass spectrometry and/or Edman degradation. In addition, a rate of crosslinking which is too high should also be avoided. If cross-linking has been carried out too extensively, there will be an increasing amount of cross-linking of the individual protein complex, which potentially interferes with a screening for potential binding partners and/or modulators etc. using the arrays. The presence of such structures can be determined by methods well known in the art and include e.g. gel-filtration experiments comparing the gel filtration profile solutions containing cross-linked complexes vs. uncross-linked complexes.

WO 03/072602 PCT/EPO2/50003 75 Optionally, functional assays as will be apparent to a person skilled in the art, some of which are exemplarily provided herein, can be performed to check the integrity of the complex. Alternatively, members of the protein complex can be expressed as a single fusion protein and coupled to the matrix as will be apparent to a person skilled in the art. Optionally, the attachment of the complex or proteins or antibody as outlined above can be further monitored by various methods apparent to a person skilled in the art. Those include, but are not limited to surface plasmon resonance (see e.g. McDonnel, 2001, Curr. Opin. Chem. Biol. 5:572-577; Lee, 2001, Trends Biotechnol. 19:217-222; Weinberger et al., 2000, 1:395-416; Pearson et al., 2000, Ann. Clin. Biochem. 37:119 145; Vely et al., 2000, Methods Mol. Biol. 121:313-321; Slepak, 2000, J. IVbl Recognit. 13:20-26. Exemplary assays useful for measuring in vitro transcription activity of complex 1 include but are not limited to those described in Arrebola R et al., 1998, Mol Cell Biol, 18:1-9. Exemplary assays useful for measuring UASG-U6 chimeric transcription activity of cells containing complex 1 include but are not limited to those described in Martin MP et al., 2001, Mol Cell Biol, 21:6429-39. Exemplary assays useful for measuring transcription of U6 RNA in cells containing complex 1 include but are not limited to those described in Arrebola R et al., 1998, Mol Cell Biol, 18:1-9. Exemplary assays useful for measuring leucine aminotransferase activity of complex 2 include but are not limited to those described in Taylor RT and Jenkins WT., 1966, J Biol Chem, 241:4391-5. and/or Taylor RT and Jenkins WT., 1966, J Biol Chem, 241:4396-405. Exemplary assays useful for measuring apoptosis induction in cells overexpressing Bcatl belonging to complex 2 include but are not limited to those described in Eden A and Benvenisty N., 1999, FEBS Lett, 457:255-61. Exemplary assays useful for measuring transformation activity of cells containing complex 2 include but are not limited to those described in Land H et al., Nature, 304:596-602.

WO 03/072602 PCT/EPO2/50003 76 Exemplary assays useful for measuring L-glutamine D-fructose 6-phosphate amidotransferase activity of complex 3a include but are not limited to those described in Huynh QK et al., 2000, Arch Biochem Biophys, 379:307-13. andlor Endo A et al., 1970, J Bacteriol, 103:588-94. Exemplary assays useful for measuring ribosomal transporter activity of complex 3b include but are not limited to those described in Moy TI and Silver PA., 1999, Genes Dev, 13:2118-33. Exemplary assays useful for measuring Cl-tetrahydrofolate synthase activity of complex 4a include but are not limited to those described in Appling DR and Rabinowitz JC., 1985, J Biol Chem, 260:1248-56. and/or Paukert JL and Rabinowitz JC., 1980, Methods Enzymol, 66:616-26. and/or Schirch V., 1997, Methods Enzymol, 281:146-61. Exemplary assays useful for measuring tranlational activity of complex 4b include but are not limited to those described in Val~sek L et al., 2001, EMBO J, 20:891-904. Exemplary assays useful for measuring Cl-tetrahydrofolate synthase activity of complex 4b include but are not limited to those described in Appling DR and Rabinowitz JC., 1985, J Biol Chem, 260:1248-56. and/or Paukert JL and Rabinowitz JC., 1980, Methods Enzymol, 66:616-26. and/or Schirch V., 1997, Methods Enzymol, 281:146-61. Exemplary assays useful for measuring ATPase of complex 4b include but are not limited to those described in Kimura K and Hirano T., 1997, Cell, 90:625-34. Exemplary assays useful for measuring protein kinase activity of complex 5a include but are not limited to those described in Bech-Otschir D et al., 2001, EMBO J, 20:1630-9. and/or Seeger M et al., 1998, FASEB J, 12:469-78. Exemplary assays useful for measuring proliferation activity of cells containing complex 5a include but are not limited to those described in Tomoda K et al., 1999, Nature, 398:160-5. Exemplary assays useful for measuring protein kinase activity of complex 5b include but are not limited to those described in Bech-Otschir D et al., 2001, EMBO J, 20:1630-9. Exemplary assays useful for measuring deneddylating activity of complex 5b include but are not limited to those described in Lyapina S et al., 2001, Science, 292:1382-5. Exemplary assays useful for measuring protein kinase activity of complex 5b include but are not limited to those described in Seeger M et al., 1998, FASEB J, 12:469-78.

WO 03/072602 PCT/EPO2/50003 78 2000, Am J Hum Genet, 67:1389-99. andlor Achouri Yet al., 1997, Biochem J, 323 ( Pt 2):365-70. Exemplary assays useful for measuring DNA binding activity of complex 11 include but are not limited to those described in Matangkasombut O et al., 2000, Genes Dev, 14:951-62. Exemplary assays useful for measuring nuclear translocation of RING3 in cells containing complex 11 include but are not limited to those described in Guo N et al., 2000, J Cell Sci, 113 ( Pt 17):3085-91. Exemplary assays useful for measuring proliferation activity of cells containing complex 11 include but are not limited to those described in Denis GV and Green MR., 1996, Genes Dev, 10:261-71. Exemplary assays useful for measuring transcription factor activity of complex 12a include but are not limited to those described in Reines D et al., 1997, Methods, 12:192-202. Exemplary assays useful for measuring BDNF (brain-derived neurotrophic factor) production and secretion in cultured CNS cells containing complex 12a include but are not limited to those described in Zuccato C et al., 2001, Science, 293:493-8. Exemplary animal models useful for assaying compounds interacting with transgenic Huntington's disease (HD) mice complex 12b include but are not limited to those described in Ishiguro H et al., 2001, J Neurosci Res, 65:289-97. Exemplary animal models useful for assaying compounds interacting with transgenic Huntington's disease (HD) mice complex 12b include but are not limited to those described in Hansson O et al., 2001, J Neurochem, 78:694-703. Exemplary assays useful for measuring transcription factor activity of complex 12b include but are not limited to those described in Reines D et al., 1997, Methods, 12:192-202. Exemplary assays useful for measuring BDNF (brain-derived neurotrophic factor) production and secretion in cultured CNS cells containing complex 12b include but are not limited to those described in Zuccato C et al., 2001, Science, 293:493-8. Exemplary assays useful for measuring poly (A)-binding activity of complex 13a include but are not limited to those described in Wahle E., 1991, Cell, 66:759-68. Exemplary assays useful for measuring poly (A)-binding activity of complex 13a include but are not limited to those described in Wahle E et al., 1993, J Biol Chem, 268:2937-45.

WO 03/072602 PCT/EPO2/50003 79 Exemplary assays useful for measuring proliferation activity of cells containing complex 13a include but are not limited to those described in Winstall E et al., 2000, J Biol Chem, 275:21817-26. Exemplary assays useful for measuring subcellular localization/transport of PABP2 in cells containing complex 13a include but are not limited to those described in Calado A et al., 2000, Hum Mol Genet, 9:2321-8. Exemplary assays useful for measuring neuronal survival/death of cells containing complex 13a include but are not limited to those described in Sheline CT and Choi DW., 1998, Neurobiol Dis, 5:47-54. Exemplary animal models useful for assaying compounds interacting with transgenic mice displaying a dentatorubral-pallidoluysian atrophy (DRPLA)-like phenotype complex 13b include but are not limited to those described in Marks KH et al., 1977, Pediatrics, 60:223-6. Exemplary animal models useful for assaying compounds interacting with transgenic Huntington's disease (HD) mice complex 13b include but are not limited to those described in Mangiarini L et al., 1996, Cell, 87:493-506. Exemplary assays useful for measuring poly (A)-binding activity of complex 13b include but are not limited to those described in Wahle E., 1991, Cell, 66:759-68. Exemplary assays useful for measuring poly (A)-binding activity of complex 13b include but are not limited to those described in Wahle E et al., 1993, J Biol Chem, 268:2937-45. Exemplary assays useful for measuring proliferation activity of cells containing complex 13b include but are not limited to those described in Winstall E et al., 2000, J Biol Chem, 275:21817-26. Exemplary assays useful for measuring subcellular localization/transport of PABP2 in cells containing complex 13b include but are not limited to those described in Calado A et al., 2000, Hum Mol Genet, 9:2321-8. Exemplary assays useful for measuring neuronal survival/death of cells containing complex 13b include but are not limited to those described in Sheline CT and Choi DW., 1998, Neurobiol Dis, 5:47-54. Exemplary assays useful for measuring serine hydroxymethyltransferase activity of complex 14a include but are not limited to those described in Elsea SH et al., 1995, Am J Hum Genet, 57:1342-50.

WO 03/072602 PCT/EPO2/50003 80 Exemplary assays useful for measuring serine hydroxymethyltransferase activity of complex 14b include but are not limited to those described in Elsea SH et al., 1995, Am J Hum Genet, 57:1342-50. Exemplary assays useful for measuring guanine nucleotide exchange factor activity of complex 15 include but are not limited to those described in Hart MJ et al., 1996, J Biol Chem, 271:25452-8. Exemplary assays useful for measuring neuronal outgrowth control by Rho GEF in cells containing complex 15 include but are not limited to those described in Gebbink MF et al., 1997, J Cell Biol, 137:1603-13. Exemplary assays useful for measuring serine/threonine protein phosphatase activity of complex 16a include but are not limited to those described in Mumby MC et al., 1987, J Biol Chem, 262:6257-65. Exemplary assays useful for measuring acetyl-coenzyme A carboxylase activity of complex 16b include but are not limited to those described in Oizumi J and Hayakawa K., 1990, J Chromatogr, 529:55-63. Exemplary assays useful for measuring GTP exchange activity of complex 16b include but are not limited to those described in Sasaki T et al., 1990, J Biol Chem, 265:2333-7. Exemplary assays useful for measuring serine/threonine protein phosphatase activity of complex 16b include but are not limited to those described in Mumby MC et al., 1987, J Biol Chem, 262:6257-65. Exemplary assays useful for measuring spermidine synthase activity of complex 17 include but are not limited to those described in Wiest L and Pegg AE., 1998, Methods Mol Biol, 79:51-7. Exemplary assays useful for measuring cell proliferation of mouse leukemia cells containing complex 17 include but are not limited to those described in Bergeron RJ et al., 2001, J Med Chem, 44:2451-9. Exemplary assays useful for measuring phosphoglycerate kinase disulfide reductase activity of complex 18 include but are not limited to those described in Lay AJ et al., 2000, Nature, 408:869-73. Exemplary assays useful for measuring phosphoglycerate kinase secretion by cultured tumour cells (HT1080) containing complex 18 include but are not limited to those described in Lay AJ et al., 2000, Nature, 408:869-73.

WO 03/072602 PCT/EPO2/50003 81 Exemplary assays useful for measuring N-acetyl transferase activity of complex 19 include but are not limited to those described in Bell DA et al., 1995, Cancer Res, 55:5226-9. Exemplary assays useful for measuring glucan synthase activity of complex 19 include but are not limited to those described in Thompson JR et al., 1999, J Bacteriol, 181:444-53. Exemplary assays useful for measuring casein kinase II activity of complex 20 include but are not limited to those described in Hockman DJ and Schultz MC., 1996, Mol Cell Biol, 16:892-8. Exemplary assays useful for measuring nucleosome assembly activity of complex 20 include but are not limited to those described in Bortvin A and Winston F., 1996, Science, 272:1473-6. Exemplary assays useful for measuring phosphorylation of the p53 tumor suppressor protein by protein kinase CKII in cells containing complex 20 include but are not limited to those described in McKendrick L and Meek DW., 1994, Cell Mol Biol Res, 40:555-61. Exemplary assays useful for measuring translocation into ER activity of complex 23a include but are not limited to those described in Mason N et al., 2000, EMBO J, 19:4164-74. and/or Ng DT et al., 1996, J Cell Biol, 134:269-78. Exemplary assays useful for measuring subcellular localization/transport of a reporter protein into the ER in cells containing complex 23a include but are not limited to those described in Mason N et al., 2000, EMBO J, 19:4164-74. and/or Hann BC et al., 1992, Nature, 356:532-3. Exemplary assays useful for measuring translocation into ER activity of complex 23b include but are not limited to those described in Mason N et al., 2000, EMBO J, 19:4164-74. and/or Ng DT et al., 1996, J Cell Biol, 134:269-78. Exemplary assays useful for measuring subcellular localization/transport of a reporter protein into the ER in cells containing complex 23b include but are not limited to those described in Mason N et al., 2000, EMBO J, 19:4164-74. and/or Hann BC et al., 1992, Nature, 356:532-3. Exemplary assays useful for measuring RNA Pol 1I activity of complex 24 include but are not limited to those described in Majello B and Napolitano G., 2001, Front Biosci, 6:1358-68.

WO 03/072602 PCT/EPO2/50003 82 Exemplary assays useful for measuring protein phosphatase 2A activity of complex 25 include but are not limited to those described in Chung H et al., 1999, Biochemistry, 38:10371-6. Exemplary assays useful for measuring transporter activity of complex 26a include but are not limited to those described in Takabatake R et al., 2001, J Biochem (Tokyo), 129:827-33. Exemplary assays useful for measuring nuclear import/export activity of complex 26a include but are not limited to those described in Lindsay ME et al., 2001, J Cell Biol, 153:1391-402. and/or J~kel S and Girlich D., 1998, EMBO J, 17:4491-502. Exemplary assays useful for measuring gene expression of IFNA/B in cells containing complex 26a include but are not limited to those described in Juang YT et al., 1999, J Biol Chem, 274:18060-6. Exemplary assays useful for measuring subcellular localization/transport complex 26a include but are not limited to those described in Kobayashi T et al., 2001, J Virol, 75:3404-12. Exemplary assays useful for measuring transporter activity of complex 26b include but are not limited to those described in Takabatake R et al., 2001, J Biochem (Tokyo), 129:827-33. Exemplary assays useful for measuring nuclear import/export activity of complex 26b include but are not limited to those described in Lindsay ME et al., 2001, J Cell Biol, 153:1391-402. and/or Jakel S and Gbrlich D., 1998, EMBO J, 17:4491-502. Exemplary assays useful for measuring gene expression of IFNA/B in cells containing complex 26b include but are not limited to those described in Juang YT et al., 1999, J Biol Chem, 274:18060-6. Exemplary assays useful for measuring subcellular localization/transport complex 26b include but are not limited to those described in Kobayashi T et al., 2001, J Virol, 75:3404-12. Exemplary assays useful for measuring Cct2 Chaperonin ATP-binding activity of complex 27 include but are not limited to those described in Charpentier AH et al., 2000, Cancer Res, 60:5977-83. Exemplary assays useful for measuring Cct2 specific antibody uptake and nuclear internalization in cells containing complex 27 include but are not limited to those described in Tian PY et al., 1989, Yao Xue Xue Bao, 24:16-21.] WO 03/072602 PCT/EPO2/50003 77 Exemplary assays useful for measuring proliferation activity of cells containing complex 5b include but are not limited to those described in Tomoda K et al., 1999, Nature, 398:160-5. Exemplary assays useful for measuring guanine nucleotide exchange factor activity of complex 6a include but are not limited to those described in Anthony TG et al., 2000, Biochim Biophys Acta, 1492:56-62. Exemplary assays useful for measuring guanine nucleotide exchange factor activity of complex 6b include but are not limited to those described in Anthony TG et al., 2000, Biochim Biophys Acta, 1492:56-62. Exemplary assays useful for measuring ultrazentirfuagtion of complex 6b include but are not limited to those described in Larson DE and Sells BH., 1987, Mol Cell Biochem, 74:5-15. Exemplary assays useful for measuring phosphatidylinositol 4-kinase activity of complex 7a include but are not limited to those described in Barylko B et al., 2001, J Biol Chem, 276:7705-8. and/or Kato H et al., 1989, J Biol Chem, 264:3116-21. andlor Yoshida Set al., 1994, J Biol Chem, 269:1166-72. Exemplary assays useful for measuring protein secretion and endocytosis activity of cells containing complex 7a include but are not limited to those described in Audhya A et al., 2000, Mol Biol Cell, 11:2673-89. Exemplary assays useful for measuring phosphatidylinositol 4-kinase activity of complex 7b include but are not limited to those described in Barylko B et al., 2001, J Biol Chem, 276:7705-8. and/or Kato H et al., 1989, J Biol Chem, 264:3116-21. and/or Yoshida S et al., 1994, J Biol Chem, 269:1166-72. Exemplary assays useful for measuring protein secretion and endocytosis activity of cells containing complex 7b include but are not limited to those described in Audhya A et al., 2000, Mol Biol Cell, 11:2673-89. Exemplary assays useful for measuring glucose-6-phosphate isomerase activity of complex 9a include but are not limited to those described in Gracy RW., 1982, Methods Enzymol, 89 Pt D:550-8. Exemplary assays useful for measuring glucose-6-phosphate isomerase activity of complex 9b include but are not limited to those described in Gracy RW., 1982, Methods Enzymol, 89 Pt D:550-8. Exemplary assays useful for measuring 3- phospoglycerate dehydrogenase activity of complex 10 include but are not limited to those described in Klomp LW et al., WO 03/072602 PCT/EPO2/50003 83 Exemplary assays useful for measuring transketolase activity of complex 28 include but are not limited to those described in Ali M et al., 1987, Comp Biochem Physiol B, 87:833-5. and/or Chamberlain BR et al., 1996, Ann Clin Biochem, 33 ( Pt 4):352-4. Exemplary assays useful for measuring cAMP kinase binding activity of complex 30 include but are not limited to those described in Zakhary DR et al., 2000, J Biol Chem, 275:41389-95. Exemplary assays useful for measuring cAMP kinase activity of complex 30 include but are not limited to those described in Maz6n MJ et al., 1993, Eur J Biochem, 213:501-6. and/or Keryer G et al., 1998, J Biol Chem, 273:34594-602. Exemplary assays useful for measuring cAM P-dependent aggregation of cells containing complex 30 include but are not limited to those described in Faucheux N et al., 2001, Biomaterials, 22:2993-8. Exemplary assays useful for measuring cell cycle regulated subcellular localization of PKA of cells containing complex 30 include but are not limited to those described in Keryer G et al., 1998, J Biol Chem, 273:34594-602. Exemplary assays useful for measuring glutamine synthetase activity of complex 31a include but are not limited to those described in Santoro JC et al., 2001, Anal Biochem, 289:18-25. Exemplary assays useful for measuring glutamine synthetase levels of complex 31a include but are not limited to those described in Gunnersen D and Haley B., 1992, Proc Natl Acad Sci U S A, 89:11949-53. Exemplary assays useful for measuring beta-amyloid induced glutamine synthetase expression in cultured astrocytes containing complex 31a include but are not limited to those described in Pike CJ et al., 1996, Exp Neurol, 139:167-71. Exemplary assays useful for measuring glutamine synthetase activity of complex 31b include but are not limited to those described in Santoro JC et al., 2001, Anal Biochem, 289:18-25. Exemplary assays useful for measuring glutamine synthetase levels of complex 31b include but are not limited to those described in Gunnersen D and Haley B., 1992, Proc Nati Acad Sci U S A, 89:11949-53. Exemplary assays useful for measuring trehalose synthase of complex 31 b include but are not limited to those described in Bell W et al., 1998, J Biol Chem, 273:33311-9.

WO 03/072602 PCT/EPO2/50003 84 Exemplary assays useful for measuring overexpression of trehalose synthase complex 31b include but are not limited to those described in Lao G et al., 2001, Cryobiology, 43:106-13. Exemplary assays useful for measuring beta-amyloid induced glutamine synthetase expression in cultured astrocytes containing complex 31b include but are not limited to those described in Pike CJ et al., 1996, Exp Neurol, 139:167-71. Exemplary assays useful for measuring phosphatidylinositol 4-kinase activity of complex 32a include but are not limited to those described in Barylko B et al., 2001, J Biol Chem, 276:7705-8. Exemplary assays useful for measuring phosphatidylinositol 4-kinase activity of complex 32b include but are not limited to those described in Barylko B et al., 2001, J Biol Chem, 276:7705-8. Exemplary assays useful for measuring Neutral trehalase activity of complex 32b include but are not limited to those described in App H and Holzer H., 1989, J Biol Chem, 264:17583-8. Exemplary assays useful for measuring methionine adenosyltransferase activity of complex 33a include but are not limited to those described in Chamberlin ME et al., 1996, J Clin Invest, 98:1021-7. Exemplary animal models useful for assaying compounds interacting with methionine adenosyltransferase 1A (MATIA) knockout mice complex 33b include but are not limited to those described in Lu SC et al., 2001, Proc Natl Acad Sci U S A, 98:5560-5. Exemplary assays useful for measuring methionine adenosyltransferase activity of complex 33b include but are not limited to those described in Chamberlin ME et al., 1996, J Clin Invest, 98:1021-7. Exemplary assays useful for measuring alcohol dehydrogenase activity of complex 35a include but are not limited to those described in Chrostek L et al., 2001, Hum Exp Toxicol, 20:255-8. and/or Zubarev SF., 1977 Mar-Apr, Zdravookhr Kirg, :53-5.] Exemplary assays useful for measuring Ubp14 protease activity of complex 35a include but are not limited to those described in Wilkinson KD et al., 1995, Biochemistry, 34:14535-46. Exemplary assays useful for measuring isoleucyl tRNA synthetase activity of complex 35a include but are not limited to those described in Nichols RC et al., 1995, Gene, 155:299-304.

WO 03/072602 PCT/EPO2/50003 85 Exemplary assays useful for measuring elF 3 subunit and 40S ribosomal subunit binding activity of complex 35a include but are not limited to those described in Greenberg JR et al., 1998, J Biol Chem, 273:23485-94. Exemplary assays useful for measuring Ubpl4 differentiation in cells containing complex 35a include but are not limited to those described in Lindsey DF et al., 1998, J Biol Chem, 273:29178-87. Exemplary assays useful for measuring Ubpl4 protease activity of complex 35b include but are not limited to those described in Wilkinson KD et al., 1995, Biochemistry, 34:14535-46. Exemplary assays useful for measuring isoleucyl tRNA synthetase activity of complex 35b include but are not limited to those described in Nichols RC et al., 1995, Gene, 155:299-304. Exemplary assays useful for measuring elF 3 subunit and 40S ribosomal subunit binding activity of complex 35b include but are not limited to those described in Greenberg JR et al., 1998, J Biol Chem, 273:23485-94. Exemplary assays useful for measuring Ubpl4 differentiation in cells containing complex 35b include but are not limited to those described in Lindsey DF et al., 1998, J Biol Chem, 273:29178-87. Exemplary assays useful for measuring protein tyrosine phosphatase activity of complex 36a include but are not limited to those described in Mattison CP et al., 1999, Mol Cell Biol, 19:7651-60. Exemplary assays useful for measuring protein serine/threonine kinase activity of complex 36a include but are not limited to those described in Warrior U et al., 1999, J Biomol Screen, 4:129-135. Exemplary assays useful for measuring protein tyrosine phosphatase activity of complex 36b include but are not limited to those described in Mattison CP et al., 1999, Mol Cell Biol, 19:7651-60. Exemplary assays useful for measuring protein serine/threonine kinase activity of complex 36b include but are not limited to those described in Warrior U et al., 1999, J Biomol Screen, 4:129-135. Exemplary assays useful for measuring telomere length in cells containing complex 38a include but are not limited to those described in Mallory JC and Petes TD., 2000, Proc Natl Acad Sci U S A, 97:13749-54.

WO 03/072602 PCT/EPO2/50003 86 Exemplary animal models useful for assaying compounds interacting with ATM deficient mice complex 38b include but are not limited to those described in Liao MJ and Van Dyke T., 1999, Genes Dev, 13:1246-50. Exemplary assays useful for measuring telomere length in cells containing complex 38b include but are not limited to those described in Mallory JC and Petes TD., 2000, Proc Natl Acad Sci U S A, 97:13749-54. Exemplary assays useful for measuring Pdr5p drug transport activity of complex 39a include but are not limited to those described in Conseil G et al., 2000, Biochemistry, 39:6910-7. Exemplary assays useful for measuring rhodamine transport (drug sensitivity assay) in cells containing complex 39a include but are not limited to those described in Kolaczkowski M et al., 1996, J Biol Chem, 271:31543-8. Exemplary assays useful for measuring Pdr5p drug transport activity of complex 39b include but are not limited to those described in Conseil G et al., 2000, Biochemistry, 39:6910-7. Exemplary assays useful for measuring rhodamine transport (drug sensitivity assay) in cells containing complex 39b include but are not limited to those described in Kolaczkowski M et al., 1996, J Biol Chem, 271:31543-8. Exemplary assays useful for measuring alcohol dehydrogenase activity of complex 40 include but are not limited to those described in Vaca G et al., 1982, Hum Genet, 61:338-41. and/or Freund N et al., 1996, Eur J Biochem, 242:86-9. Exemplary assays useful for measuring nuclear import/export activity of complex 40 include but are not limited to those described in Jlkel S and Girlich D., 1998, EMBO J, 17:4491-502. Exemplary animal models useful for assaying compounds interacting with transgenic mice displaying diabetes type 1-like phenotype d complex 41 include but are not limited to those described in Hayashi T and Faustman D., 1999, Mol Cell Biol, 19:8646-59. Exemplary assays useful for measuring ATP-dependent DNA helicase activity of complex 41 include but are not limited to those described in Kanemaki M et al., 1999, J Biol Chem, 274:22437-44. Exemplary assays useful for measuring ATP-dependent RNA helicase activity of complex 41 include but are not limited to those described in Li Q et al., 1999, Mol Cell Biol, 19:7336-46.

WO 03/072602 PCT/EPO2/50003 87 Exemplary assays useful for measuring oncogenic transformation activity of cells containing complex 41 include but are not limited to those described in Wood MA et al., 2000, Mol Cell, 5:321-30. Exemplary assays useful for measuring protein degradation activity of complex 42 include but are not limited to those described in Wang CW et al., 2001, J Biol Chem, 276:30442-51. Exemplary assays useful for measuring thioredoxin reductase activity of complex 42 include but are not limited to those described in Noh DY et al., 2001 May-Jun, Anticancer Res, 21:2085-90. Exemplary assays useful for measuring proliferation activity of cells containing complex 42 include but are not limited to those described in Ludes-Meyers JH et al., 2001, Oncogene, 20:2771-80. Exemplary animal models us eful for assaying compounds interacting with rabbits experimentally infected with immunodeficiency virus complex 43 include but are not limited to those described in Walder R et al., 2001, Comp Immunol Microbiol Infect Dis, 24:1-20. Exemplary animal models useful for assaying compounds interacting with CD4 transgenic rabbits complex 43 include but are not limited to those described in Dunn CS et al., 1995, J Gen Virol, 76 ( Pt 6):1327-36. Exemplary assays useful for measuring reconstituted 40S ribosome binding activity of complex 43 include but are not limited to those described in Li Q et al., 1999, Mol Cell Biol, 19:7336-46. Exemplary assays useful for measuring stress response of cells containing complex 43 include but are not limited to those described in Pereira MD et al., 2001, BMC Microbiol, 1:-. Exemplary assays useful for measuring ATPase activity of complex 44 include but are not limited to those described in Rieger CE et al., 1997, Anal Biochem, 246:86 95. Exemplary assays useful for measuring decay of proto-oncogene mRNA, cytokine mRNA or viral mRNA in HeLa cells containing complex 44 include but are not limited to those described in Laroia G et al., 1999, Science, 284:499-502. Exemplary assays useful for measuring transcription factor activity of complex 45a include but are not limited to those described in Fernandes L et al., 1997, Mol Cell Biol, 17:6982-93.

WO 03/072602 PCT/EPO2/50003 88 Exemplary assays useful for measuring the rate of survival/death of cells containing complex 45a include but are not limited to those described in Fernandes L et al., 1997, Mol Cell Biol, 17:6982-93. Exemplary assays useful for measuring transcription factor activity of complex 45b include but are not limited to those described in Fernandes L et al., 1997, Mol Cell Biol, 17:6982-93. Exemplary assays useful for measuring the rate of survival/death of cells containing complex 45b include but are not limited to those described in Fernandes L et al., 1997, Mol Cell Biol, 17:6982-93. Exemplary assays useful for measuring guanine nucleotide exchange factor activity of complex 46a include but are not limited to those described in Kiyono M et al., 2000, J Biol Chem, 275:29788-93. and/or Haney SA and Broach JR., 1994, J Biol Chem, 269:16541-8. Exemplary assays useful for measuring proliferation activity of cells containing complex 46a include but are not limited to those described in Vanoni M et al., 1999, J Biol Chem, 274:36656-62. Exemplary assays useful for measuring guanine nucleotide exchange factor activity of complex 46b include but are not limited to those described in Kiyono M et al., 2000, J Biol Chem, 275:29788-93. and/or Haney SA and Broach JR., 1994, J Biol Chem, 269:16541-8. Exemplary assays useful for measuring proliferation activity of cells containing complex 46b include but are not limited to those described in Vanoni M et al., 1999, J Biol Chem, 274:36656-62. Exemplary assays useful for measuring arginase activity of complex 47a include but are not limited to those described in Han S and Viola RE., 2001, Anal Biochem, 295:117-9. Exemplary assays useful for measuring antiproliferative and apoptotic actions on arginase-expressing human breast cancer cells containing complex 47a include but are not limited to those described in Singh R et al., 2000, Cancer Res, 60:3305-12. Exemplary animal models useful for assaying compounds interacting with arginase 11 knock-out mice (as model for hyperargininemia) complex 47b include but are not limited to those described in Shi O et al., 2001, Mol Cell Biol, 21:811-3.

WO 03/072602 PCT/EPO2/50003 89 Exemplary assays useful for measuring arginase activity of complex 47b include but are not limited to those described in Han S and Viola RE., 2001, Anal Biochem, 295:117-9. Exemplary assays useful for measuring antiproliferative and apoptotic actions on arginase-expressing human breast cancer cells containing complex 47b include but are not limited to those described in Singh R et al., 2000, Cancer Res, 60:3305-12. Exemplary assays useful for measuring L-glutamine:D-fructose-6 amidotransferase activity of complex 48a include but are not limited to those described in Wu G et al., 2001, Biochem J, 353:245-52. and/or Watzele G and Tanner W., 1989, J Biol Chem, 264:8753-8. Exemplary assays useful for measuring gene expression of glutamine:fructose-6 phosphate-amidotransferase (GFAT) in cells containing complex 48a include but are not limited to those described in Weigert C et al., 2001 Jan 12,, FEBS Lett, 488:95-9. Exemplary assays useful for measuring morphological changes of cells containing complex 48a include but are not limited to those described in Matsui Y et al., 1996, J Cell Biol, 133:865-78. Exemplary assays useful for measuring translational activity of complex 48b include but are not limited to those described in Valdsek L etal., 2001, EMBO J, 20:891 904. Exemplary assays useful for measuring morphological changes of cells containing complex 48b include but are not limited to those described in Matsui Y et al., 1996, J Cell Biol, 133:865-78. Exemplary assays useful for measuring DNA helicase activity of complex 50 include but are not limited to those described in Kanemaki M et al., 1999, J Biol Chem, 274:22437-44. Exemplary assays useful for measuring transcriptional activity of complex 50 include but are not limited to those described in Lim CR et al., 2000, J Biol Chem, 275:22409-17. Exemplary assays useful for measuring transformation activity of cells containing complex 50 include but are not limited to those described in Afar DE et al., 1994, Science, 264:424-6. Exemplary assays useful for measuring aminoacyl-tRNA synthase activity of complex 51 include but are not limited to those described in Targoff IN., 1990, J WO 03/072602 PCT/EPO2/50003 90 Immunol, 144:1737-43. and/or Harris CL and Kolanko CJ., 1995, Biochem J, 309 ( Pt 1):321-4. Exemplary assays useful for measuring proliferation activity of cells containing complex 51 include but are not limited to those described in Cambridge G et al., Clin Exp Rheumatol, 7:27-33. Exemplary assays useful for measuring protein serine/threonine phosphatase activity of complex 52 include but are not limited to those described in Mumby MC et al., 1987, J Biol Chem, 262:6257-65. Exemplary assays useful for measuring DNA polymerase activity of complex 53a include but are not limited to those described in Stoeber K et al., 1998, EMBO J, 17:7219-29. Exemplary assays useful for measuring cell cycle progression and DNA replication in cells containing complex 53a include but are not limited to those described in Calzada A et al., 2001, Nature, 412:355-8. Exemplary assays useful for measuring cell cycle progression of cells containing complex 53a include but are not limited to those described in Stoeber K et al., 2001, J Cell Sci, 114:2027-41. Exemplary assays useful for measuring DNA polymerase activity of complex 53b include but are not limited to those described in Stoeber K et al., 1998, EMBO J, 17:7219-29. Exemplary assays useful for measuring cell cycle progression and DNA replication in cells containing complex 53b include but are not limited to those described in Calzada A et al., 2001, Nature, 412:355-8. Exemplary assays useful for measuring cell cycle progression of cells containing complex 53b include but are not limited to those described in Stoeber K et al., 2001, J Cell Sci, 114:2027-41. Exemplary assays useful for measuring tRNA pseudouridinylation activity of complex 54 include but are not limited to those described in Samuelsson T and Olsson M., 1990, J Biol Chem, 265:8782-7. Exemplary assays useful for measuring rRNA pseudouridinylation activity of complex 54 include but are not limited to those described in Lafontaine DL et al., 1998, Genes Dev, 12:527-37.

WO 03/072602 PCT/EPO2/50003 91 Exemplary assays useful for measuring Kcc4 kinase binding activity of complex 55 include but are not limited to those described in Okuzaki D and Nojima H., 2001, FEBS Lett, 489:197-201. Exemplary assays useful for measuring cytokinesis in cells containing complex 55 include but are not limited to those described in Oegema K et al., 2000, J Cell Biol, 150:539-52. Exemplary assays useful for measuring bud formation and mitotic arrest of cells containing complex 55 include but are not limited to those described in Krishnan R et al., 2000, Genetics, 156:489-500. Exemplary assays useful for measuring DNAse activity of complex 56a include but are not limited to those described in Dake E et al., 1988, J Biol Chem, 263:7691 702. Exemplary assays useful for measuring apoptosis/DNA fragmentation of cells containing complex 56a include but are not limited to those described in Li LY et al., 2001, Nature, 412:95-9. Exemplary animal models useful for assaying compounds interacting with DFF45/ICAD knock-out mice complex 56b include but are not limited to those described in Zhang J et al., 1998, Proc Natl Acad Sci U S A, 95:12480-5. Exemplary assays useful for measuring DNAse activity of complex 56b include but are not limited to those described in Dake E et al., 1988, J Biol Chem, 263:7691 702. Exemplary assays useful for measuring apoptosis/DNA fragmentation of cells containing complex 56b include but are not limited to those described in Li LY et al., 2001, Nature, 412:95-9. Exemplary assays useful for measuring GTPase activity of complex 58 include but are not limited to those described in Tian G et al., 1999, J Biol Chem, 274:24054-8. Exemplary assays useful for measuring mRNA deadenylation/stability in cells containing complex 58 include but are not limited to those described in Olivas W and Parker R., 2000, EMBO J, 19:6602-11. Exemplary assays useful for measuring translational repression in cells containing complex 58 include but are not limited to those described in Wharton RP et al., 1998, Mol Cell, 1:863-72.

WO 03/072602 PCT/EPO2/50003 92 Exemplary assays useful for measuring esterase activity of complex 59 include but are not limited to those described in Borhan B et al., 1995, Biochim Biophys Acta, 1250:171-82. Exemplary assays useful for measuring inhibition of NTE (neuropathy target esterase) in cells containing complex 59 include but are not limited to those described in Ehrich M et al., 1993, Chem Biol Interact, 87:431-7. Exemplary assays useful for measuring chromatin assembly activity of complex 60a include but are not limited to those described in Altheim BA and Schultz MC., 1999, Proc Natl Acad Sci U S A, 96:1345-50. Exemplary assays useful for measuring assay for nucleotide binding of NDP kinase of complex 60b include but are not limited to those described in Prinz H et al., 1999, J Biol Chem, 274:35337-42. Exemplary assays useful for measuring chromatin assembly activity of complex 60b include but are not limited to those described in Altheim BA and Schultz MC., 1999, Proc Natl Acad Sci U S A, 96:1345-50. Exemplary assays useful for measuring mutational analysis of active site of human inosine 5'-monophosphate DH complex 60b include but are not limited to those described in Futer O et al., 2002, Biochim Biophys Acta, 1594:27-39. Exemplary assays useful for measuring phosphofructokinase activity of complex 61 include but are not limited to those described in Layzer RB et al., 1969, J Biol Chem, 244:3823-31. Exemplary assays useful for measuring leukotriene A4 hydrolase activity of complex 61 include but are not limited to those described in Clamagirand C et al., 1998, FEBS Lett, 433:68-72. Exemplary assays useful for measuring aldolase activity of complex 62a include but are not limited to those described in Penhoet EE and Rutter WJ., 1975, Methods Enzymol, 42:240-9. Exemplary assays useful for measuring phosphoglycerate mutase activity of complex 62a include but are not limited to those described in Grisolia S and Carreras J., 1975, Methods Enzymol, 42:435-50. Exemplary assays useful for measuring triosephophate isomerase activity of complex 62a include but are not limited to those described in Fahey RC and Fischer EF., 1974, Anal Biochem, 57:547-54.

WO 03/072602 PCT/EPO2/50003 93 Exemplary assays useful for measuring aldolase activity of complex 62b include but are not limited to those described in Penhoet EE and Rutter WJ., 1975, Methods Enzymol, 42:240-9. Exemplary assays useful for measuring phosphoglycerate mutase activity of complex 62b include but are not limited to those described in Grisolia S and Carreras J., 1975, Methods Enzymol, 42:435-50. Exemplary assays useful for measuring triosephophate isomerase activity of complex 62b include but are not limited to those described in Fahey RC and Fischer EF., 1974, Anal Biochem, 57:547-54. Exemplary assays useful for measuring glutamine:fructose-6-phosphate amidotransferase activity of complex 63a include but are not limited to those described in Traxinger RR and Marshall S., 1991, J Biol Chem, 266:10148-54. Exemplary assays useful for measuring proteasome activity of complex 63b include but are not limited to those described in Kuckelkorn U et al., 2000 Sep-Oct, Biol Chem, 381:1017-23. Exemplary assays useful for measuring homoisocitrtic acid dehydrogenase of complex 63b include but are not limited to those described in Gaillardin CM et al., 1982, Eur J Biochem, 128:489-94. Exemplary assays useful for measuring proteasome activity of complex 63b include but are not limited to those described in Ugai S et al., 1993, J Biochem (Tokyo), 113:754-68. Exemplary assays useful for measuring ATPase activity of complex 63b include but are not limited to those described in Kimura K and Hirano T., 1997, Cell, 90:625-34. Exemplary assays useful for measuring tRNA nucleotidyltransferase activity of complex 64 include but are not limited to those described in Chen JY et al., 1990, J Biol Chem, 265:16221-4. and/or, 1974, Methods Enzymol, 29:706-16. Exemplary assays useful for measuring saccharopine dehydrogenase activity of complex 65a include but are not limited to those described in Papes F et al., 1999, Biochem J, 344 Pt 2:555-63. Exemplary assays useful for measuring saccharopine dehydrogenase activity of complex 65b include but are not limited to those described in Papes F et al., 1999, Biochem J, 344 Pt 2:555-63.

WO 03/072602 PCT/EPO2/50003 94 Exemplary assays useful for measuring saccharopine dehydrogenase activity of complex 66 include but are not limited to those described in Papes F et al., 1999, Biochem J, 344 Pt 2:555-63. Exemplary assays useful for measuring flavoprotein:ubiquinone oxidoreductase activity of complex 67 include but are not limited to those described in Goodman SI et al., 1994, Eur J Biochem, 219:277-86. Exemplary assays useful for measuring methionine adenosyl transferase activity of complex 68a include but are not limited to those described in Cabrero C et al., 1987, Eur J Biochem, 170:299-304. Exemplary assays useful for measuring alpha-ketoglutarate dehydrogenase activity of complex 68a include but are not limited to those described in Gohil K and Jones DA., 1983, Biosci Rep, 3:1-9. Exemplary assays useful for measuring methionine adenosyl transferase activity of complex 68b include but are not limited to those described in Cabrero C et al., 1987, Eur J Biochem, 170:299-304. Exemplary assays useful for measuring alpha-ketoglutarate dehydrogenase activity of complex 68b include but are not limited to those described in Gohil K and Jones DA., 1983, Biosci Rep, 3:1-9. Exemplary assays useful for measuring ubiquitin ligase activity of complex 69a include but are not limited to those described in King RW et al., 1995, Cell, 81:279-88. Exemplary assays useful for measuring metaphase arrest of cells containing complex 69a include but are not limited to those described in Geley S et al., 2001, J Cell Biol, 153:137-48. and/or Kramer KM et al., 1998, EMBO J, 17:498-506. Exemplary assays useful for measuring ubiquitin ligase activity of complex 69b include but are not limited to those described in King RW et al., 1995, Cell, 81:279-88. Exemplary assays useful for measuring metaphase arrest of cells containing complex 69b include but are not limited to those described in Geley S et al., 2001, J Cell Biol, 153:137-48. and/or Kramer KM et al., 1998, EMBO J, 17:498-506. Exemplary assays useful for measuring serine/threonine protein kinase activity of complex 70a include but are not limited to those described in Keller DM et al., 2001, Mol Cell, 7:283-92. Exemplary assays useful for measuring expression of a reporter gene in cells containing complex 70a include but are not limited to those described in Tabtiang RK and Herskowitz I., 1998, Mol Cell Biol, 18:4707-18.

WO 03/072602 PCT/EPO2/50003 95 Exemplary animal models useful for assaying compounds interacting with Csnk2a2 (the human homolog of Cka2) knock-out mice complex 70b include but are not limited to those described in Xu X et al., 1999, Nat Genet, 23:118-21. Exemplary assays useful for measuring serine/threonine protein kinase activity of complex 70b include but are not limited to those described in Keller DM et al., 2001, Mol Cell, 7:283-92. Exemplary assays useful for measuring protein phosphatase of complex 70b include but are not limited to those described in Long X et al., 2002, Apoptosis, 7:31-9. Exemplary assays useful for measuring expression of a reporter gene in cells containing complex 70b include but are not limited to those described in Tabtiang RK and Herskowitz I., 1998, Mol Cell Biol, 18:4707-18. Exemplary assays useful for measuring nitric oxide metabolic activity of complex 71a include but are not limited to those described in Liu L et al., 1999, Proc Natl Acad Sci U S A, 96:6643-7. and/or Liu L et al., 2000, Proc Natl Acad Sci U S A, 97:4672-6. Exemplary assays useful for measuring thiol peroxidase activity of complex 71a include but are not limited to those described in LES Netto et al., 1996, J Biol Chem, 271:15315-21. Exemplary assays useful for measuring endocytosis of complex 71b include but are not limited to those described in Dulic V et al., 1991, Methods Enzymol, 194:697 710. and/or Volland C et al., 1994, J Biol Chem, 269:9833-41. Exemplary assays useful for measuring nucleosome remodeling activity of complex 72a include but are not limited to those described in Tsukiyama T and Wu C., 1995, Cell, 83:1011-20. Exemplary assays useful for measuring DNA repair in fibroblasts containing complex 72a include but are not limited to those described in Emmert S et al., 2000, Proc Natl Acad Sci U S A, 97:2151-6. Exemplary assays useful for measuring nucleosome remodeling activity of complex 72b include but are not limited to those described in Tsukiyama T and Wu C., 1995, Cell, 83:1011-20. Exemplary assays useful for measuring DNA repair in fibroblasts containing complex 72b include but are not limited to those described in Emmert S et al., 2000, Proc NatI Acad Sci U S A, 97:2151-6. Exemplary animal models useful for assaying compounds interacting with mouse p23 knock-out mice complex 73a include but are not limited to those described in Denzel A WO 03/072602 PCT/EPO2/50003 96 et al., 2000, Curr Biol, 10:55-8.(The p24 family member p23 is required for early embryonic development.) Exemplary assays useful for measuring protein transport /sorting activity of complex 73a include but are not limited to those described in Schimmbller F et al., 1995, EMBO J, 14:1329-39. Exemplary animal models useful for assaying compounds interacting with mouse p23 knock-out mice complex 73b include but are not limited to those described in Denzel A et al., 2000, Curr Biol, 10:55-8.(The p24 family member p23 is required for early embryonic development.) Exemplary assays useful for measuring protein transport /sorting activity of complex 73b include but are not limited to those described in Schimm6ller F et al., 1995, EMBO J, 14:1329-39. Exemplary assays useful for measuring DNA-binding activity of complex 74a include but are not limited to those described in Galarneau L et al., 2000, Mol Cell, 5:927-37. Exemplary assays useful for measuring transformation activity of cells containing complex 74a include but are not limited to those described in Afar DE et al., 1994, Science, 264:424-6. Exemplary assays useful for measuring DNA-binding activity of complex 74b include but are not limited to those described in Galarneau L et al., 2000, Mol Cell, 5:927-37. Exemplary assays useful for measuring histone acetylation of complex 74b include but are not limited to those described in Ito K et al., 2001, J Biol Chem, 276:30208-15. Exemplary assays useful for measuring transformation activity of cells containing complex 74b include but are not limited to those described in Afar DE et al., 1994, Science, 264:424-6. Exemplary assays useful for measuring protein serine/threonine kinase activity of complex 75a include but are not limited to those described in McCartney RR and Schmidt MC., 2001, J Biol Chem, 276:36460-6. and/or Mitchelhill KI et al., 1994, J Biol Chem, 269:2361-4. Exemplary assays useful for measuring invasive growth of cells containing complex 75a include but are not limited to those described in Cullen PJ and Sprague GF., 2000, Proc Natl Acad Sci U S A, 97:13619-24.

WO 03/072602 PCT/EPO2/50003 97 Exemplary assays useful for measuring protein serine/threonine kinase activity of complex 75b include but are not limited to those described in McCartney RR and Schmidt MC., 2001, J Biol Chem, 276:36460-6. and/or Mitchelhill KI et al., 1994, J Biol Chem, 269:2361-4. Exemplary assays useful for measuring invasive growth of cells containing complex 75b include but are not limited to those described in Cullen PJ and Sprague GF., 2000, Proc Natl Acad Sci U S A, 97:13619-24. Exemplary assays useful for measuring 1,3-beta-D-glucan synthase activity of complex 76 include but are not limited to those described in Cabib E and Kang MS., 1987, Methods Enzymol, 138:637-42. and/or Douglas CM et al., 1994, Proc NatI Acad Sci US A, 91:12907-11. Exemplary assays useful for measuring beta-1,3-glucan synthase activity in permeabilized fungal cells containing complex 76 include but are not limited to those described in Sestdk S and Farkas V., 2001, Anal Biochem, 292:34-9. Exemplary assays useful for measuring exoribonuclease activity of complex 77 include but are not limited to those described in Brouwer R et al., 2001, J Biol Chem, 276:6177-84. Exemplary assays useful for measuring expression of non-poly(A) mRNAs in cells containing complex 77 include but are not limited to those described in Benard L et al., 1999, J Virol, 73:2893-900. Exemplary assays useful for measuring adenylate cyclase activity of complex 78a include but are not limited to those described in Hatley ME et al., 2000, J Biol Chem, 275:38626-32. Exemplary assays useful for measuring long term potentiation at CA1 hippocampal synapses containing complex 78a include but are not limited to those described in Otmakhova NA et al., 2000, J Neurosci, 20:4446-51. Exemplary assays useful for measuring cyclic AMP-independent growth of cells containing complex 78a include but are not limited to those described in Hatley ME et al., 2000, J Biol Chem, 275:38626-32. Exemplary assays useful for measuring protein kinase assay of complex 78b include but are not limited to those described in Wu JJ et al., 2000, J Biomol Screen, 5:23-30.

WO 03/072602 PCT/EPO2/50003 98 Exemplary assays useful for measuring adenylate cyclase activity of complex 78b include but are not limited to those described in Hatley ME et al., 2000, J Biol Chem, 275:38626-32. Exemplary assays useful for measuring long term potentiation at CA1 hippocampal synapses containing complex 78b include but are not limited to those described in Otmakhova NA et al., 2000, J Neurosci, 20:4446-51. Exemplary assays useful for measuring cyclic AMP-independent growth of cells containing complex 78b include but are not limited to those described in Hatley ME et al., 2000, J Biol Chem, 275:38626-32. Exemplary assays useful for measuring GTP-binding protein/GTPase activity of complex 79a include but are not limited to those described in Beites CL et al., 2001, Methods Enzymol, 329:499-510. and/or Oegema K et al., 1998, Methods Enzymol, 298:279-95. Exemplary assays useful for measuring GTP-binding protein/GTPase activity of complex 79b include but are not limited to those described in Beites CL et al., 2001, Methods Enzymol, 329:499-510. and/or Oegema K et al., 1998, Methods Enzymol, 298:279-95. Exemplary assays useful for measuring protein deacetylase activity of complex 80a include but are not limited to those described in Wu J et al., 2001, Proc Natl Acad Sci U S A, 98:4391-6. Exemplary assays useful for measuring silencing/inhibition of deacetylase activity in cells containing complex 80a include but are not limited to those described in Nielsen AL et al., 1999, EMBO J, 18:6385-95. Exemplary assays useful for measuring protein deacetylase activity of complex 80b include but are not limited to those described in Wu J et al., 2001, Proc Natl Acad Sci U S A, 98:4391-6. Exemplary assays useful for measuring silencinglinhibition of deacetylase activity in cells containing complex 80b include but are not limited to those described in Nielsen AL et al., 1999, EMBO J, 18:6385-95. Exemplary assays useful for measuring actin polymerization activity of complex 81a include but are not limited to those described in Gieselmann R and Mann K., 1992, FEBS Lett, 298:149-53.

WO 03/072602 PCT/EPO2/50003 99 Exemplary assays useful for measuring motility of cells containing complex 81a include but are not limited to those described in Witke W et al., 2001, J Cell Biol, 154:775-84. Exemplary assays useful for measuring actin polymerization activity of complex 81b include but are not limited to those described in Gieselmann R and Mann K., 1992, FEBS Lett, 298:149-53. Exemplary assays useful for measuring motility of cells containing complex 81b include but are not limited to those described in Witke W et al., 2001, J Cell Biol, 154:775-84. Exemplary animal models useful for assaying compounds interacting with Vav-1 and Vav-2 knock-out mice complex 82a include but are not limited to those described in Tedford K et al., 2001, Nat Immunol, 2:548-55.(Compensation between Vav-1 and Vav-2 in B cell development and antigen receptor signaling.) Exemplary assays useful for measuring guanine nucleotide exchange activity of complex 82a include but are not limited to those described in Zheng Y et al., 1995, J Biol Chem, 270:626-30. and/or Han J et al., 1997, Mol Cell Biol, 17:1346-53. Exemplary assays useful for measuring formation of foci of cells containing complex 82a include but are not limited to those described in Han J et al., 1997, Mol Cell Biol, 17:1346-53. Exemplary assays useful for measuring regulation of polarized cell growth of cells containing complex 82a include but are not limited to those described in Nern A and Arkowitz RA., 1998, Nature, 391:195-8. Exemplary animal models useful for assaying compounds interacting with Vav-1 and Vav-2 knock-out mice complex 82b include but are not limited to those described in Tedford K et al., 2001, Nat Immunol, 2:548-55.(Compensation between Vav-1 and Vav-2 in B cell development and antigen receptor signaling.) Exemplary assays useful for measuring guanine nucleotide exchange activity of complex 82b include but are not limited to those described in Zheng Yet al., 1995, J Biol Chem, 270:626-30. and/or Han J et al., 1997, Mol Cell Biol, 17:1346-53. Exemplary assays useful for measuring formation of foci of cells containing complex 82b include but are not limited to those described in Han J et al., 1997, Mol Cell Biol, 17:1346-53.

WO 03/072602 PCT/EPO2/50003 100 Exemplary assays useful for measuring regulation of polarized cell growth of cells containing complex 82b include but are not limited to those described in Nern A and Arkowitz RA., 1998, Nature, 391:195-8. Exemplary assays useful for measuring protein serine/threonine kinase activity of complex 83a include but are not limited to those described in Wu JJ et al., 2000, J Biomol Screen, 5:23-30. Exemplary assays useful for measuring histone H1 kinase activity of complex 83a include but are not limited to those described in Mahalingam S et al., 1998, Proc NatI Acad Sci U S A, 95:3419-24. Exemplary assays useful for measuring cell cycle progression of cells containing complex 83a include but are not limited to those described in Mahalingam S et al., 1998, Proc Natl Acad Sci U S A, 95:3419-24. Exemplary animal models useful for assaying compounds interacting with Cdknla (cyclin-dependent kinase inhibitor 1A (P21), also known as Wafl, P21, CIP1, SDI1, CAP20 and mda6) knock-out mice complex 83b include but are not limited to those described in Deng C et al., 1995, Cell, 82:675-84. Exemplary animal models useful for assaying compounds interacting with Kip1 (cyclin dependent kinase inhibitor 1B (p27)) knock-out mice complex 83b include but are not limited to those described in Kiyokawa H et al., 1996, Cell, 85:721-32. Exemplary assays useful for measuring protein serine/threonine kinase activity of complex 83b include but are not limited to those described in Wu JJ et al., 2000, J Biomol Screen, 5:23-30. Exemplary assays useful for measuring histone H1 kinase activity of complex 83b include but are not limited to those described in Mahalingam S et al., 1998, Proc Natl Acad Sci U S A, 95:3419-24. Exemplary assays useful for measuring cell cycle progression of cells containing complex 83b include but are not limited to those described in Mahalingam S et al., 1998, Proc Natl Acad Sci U S A, 95:3419-24. Exemplary assays useful for measuring phosphoglycerate mutase activity of complex 84 include but are not limited to those described in Zhang J et al., 2001, Gene, 264:273-9. Exemplary assays useful for measuring farnesyltransferase activity of complex 84 include but are not limited to those described in Goodman LE et al., 1990, Proc Natl Acad Sci U S A, 87:9665-9.

WO 03/072602 PCT/EPO2/50003 101 Exemplary assays useful for measuring transformation activity of cells containing complex 84 include but are not limited to those described in Nagase T et al., 1999, Int J Cancer, 80:126-33. Exemplary assays useful for measuring protein deacetylase activity of complex 85 include but are not limited to those described in Nare B et al., 1999, Anal Biochem, 267:390-6. Exemplary assays useful for measuring protease activity of complex 85 include but are not limited to those described in Susan PP and Dunn WA., 2001, J Cell Physiol, 187:48-58. Exemplary assays useful for measuring nuclear import/export activity of complex 85 include but are not limited to those described in J~kel S and Girlich D., 1998, EMBO J, 17:4491-502. Exemplary assays useful for measuring autophagy in cells containing complex 85 include but are not limited to those described in Elmore SP et al., 2001, FASEB J, 15:2286-7. Exemplary animal models useful for assaying compounds interacting with transgenic mice displaying a human prostate cancer-like phenotype complex 86a include but are not limited to those described in Saffran DC et al., 2001, Proc Natl Acad Sci U S A, 98:2658-63. Exemplary assays useful for measuring ATPase activity of complex 86a include but are not limited to those described in Tsukiyama T et al., 1999, Genes Dev, 13:686 97. Exemplary assays useful for measuring transcriptional activity of complex 86a include but are not limited to those described in Kikyo N et al., 2000, Science, 289:2360 2. Exemplary assays useful for measuring the cell cycle regulation activity of complex 86a include but are not limited to those described in Cao Y et al., 1997, Mol Cell Biol, 17:3323-34. Exemplary assays useful for measuring differentiation of cells containing complex 86a include but are not limited to those described in de la Serna IL et al., 2001, Nat Genet, 27:187-90. Exemplary animal models useful for assaying compounds interacting with transgenic mice displaying a human prostate cancer-like phenotype complex 86b include but are WO 03/072602 PCT/EPO2/50003 102 not limited to those described in Saffran DC et al., 2001, Proc NatI Acad Sci U S A, 98:2658-63. Exemplary assays useful for measuring ATPase activity of complex 86b include but are not limited to those described in Tsukiyama T et al., 1999, Genes Dev, 13:686 97. Exemplary assays useful for measuring transcriptional activity of complex 86b include but are not limited to those described in Kikyo N et al., 2000, Science, 289:2360 2. Exemplary assays useful for measuring Chromatine remodelling of complex 86b include but are not limited to those described in Wang W et al., 1996, EMBO J, 15:5370 82. Exemplary assays useful for measuring the cell cycle regulation activity of complex 86b include but are not limited to those described in Cao Y et al., 1997, Mol Cell Biol, 17:3323-34. Exemplary assays useful for measuring differentiation of cells containing complex 86b include but are not limited to those described in de la Serna IL et al., 2001, Nat Genet, 27:187-90. Exemplary assays useful for measuring N-acetyltransferase activity of complex 87a include but are not limited to those described in Kulkarni MS and Sherman F., 1994, J Biol Chem, 269:13141-7. Exemplary assays useful for measuring transformation activity of cells containing complex 87a include but are not limited to those described in Afar DE et al., 1994, Science, 264:424-6. Exemplary assays useful for measuring N-acetyltransferase activity of complex 87b include but are not limited to those described in Kulkarni MS and Sherman F., 1994, J Biol Chem, 269:13141-7. Exemplary assays useful for measuring transformation activity of cells containing complex 87b include but are not limited to those described in Afar DE et al., 1994, Science, 264:424-6. Exemplary assays useful for measuring histone deacetylase activity of complex 88a include but are not limited to those described in Nare B et al., 1999, Anal Biochem, 267:390-6.

WO 03/072602 PCT/EPO2/50003 103 Exemplary assays useful for measuring histone deacetylase activity of complex 88b include but are not limited to those described in Nare B et al., 1999, Anal Biochem, 267:390-6. Exemplary assays useful for measuring ATPase stimulation activity of complex 89a include but are not limited to those described in Steel GJ et al., 1999, Biochemistry, 38:7764-72. Exemplary assays useful for measuring endocytosis via the uptake of the vital dye FM4-64 in cells containing complex 89a include but are not limited to those described in Gurunathan S et al., 2000, Mol Biol Cell, 11:3629-43. Exemplary assays useful for measuring endocytosis of alpha-factor receptor in cells containing complex 89a include but are not limited to those described in Stefan CJ and Blumer KJ., 1999, J Biol Chem, 274:1835-41. Exemplary assays useful for measuring golgi -endosome fusion of complex 89b include but are not limited to those described in Brickner JH et al., 2001, J Cell Biol, 155:969-78. Exemplary assays useful for measuring endocytosis via the uptake of the vital dye FM4-64 in cells containing complex 89b include but are not limited to those described in Gurunathan S et al., 2000, Mol Biol Cell, 11:3629-43. Exemplary assays useful for measuring endocytosis of alpha-factor receptor in cells containing complex 89b include but are not limited to those described in Stefan CJ and Blumer KJ., 1999, J Biol Chem, 274:1835-41. Exemplary assays useful for measuring acetyl-coenzyme A carboxylase activity of complex 90a include but are not limited to those described in Oizumi J and Hayakawa K., 1990, J Chromatogr, 529:55-63. Exemplary assays useful for measuring acetyl-CoA carboxylase activity in isolated hepatocytes containing complex 90a include but are not limited to those described in Bijleveld C and Geelen MJ., 1987, Biochim Biophys Acta, 918:274-83. Exemplary assays useful for measuring acetyl-coenzyme A carboxylase activity of complex 90b include but are not limited to those described in Oizumi J and Hayakawa K., 1990, J Chromatogr, 529:55-63. Exemplary assays useful for measuring acetyl-CoA carboxylase activity in isolated hepatocytes containing complex 90b include but are not limited to those described in Bijleveld C and Geelen MJ., 1987, Biochim Biophys Acta, 918:274-83.

WO 03/072602 PCT/EPO2/50003 104 Exemplary assays useful for measuring guanylyl transferase activity of complex 91a include but are not limited to those described in Itoh N et al., 1984, J Biol Chem, 259:13930-6. Exemplary assays useful for measuring RNA triphosphatase activity of complex 91a include but are not limited to those described in Ho CK et al., 1998, J Biol Chem, 273:34151-6. Exemplary assays useful for measuring guanylyl transferase activity of complex 91b include but are not limited to those described in Itoh N et al., 1984, J Biol Chem, 259:13930-6. Exemplary assays useful for measuring RNA triphosphatase activity of complex 91b include but are not limited to those described in Ho CK et al., 1998, J Biol Chem, 273:34151-6. Exemplary assays useful for measuring serine palmitoyltransferase activity of complex 92a include but are not limited to those described in Pinto WJ et al., 1992, J Bacteriol, 174:2575-81. and/or Weiss B and Stoffel W., 1997, Eur J Biochem, 249:239 47. Exemplary assays useful for measuring differentiation of cells containing complex 92a include but are not limited to those described in Roberts RL et al., 1997, Cell, 89:1055-65. Exemplary assays useful for measuring serine palmitoyltransferase activity of complex 92b include but are not limited to those described in Pinto WJ et al., 1992, J Bacteriol, 174:2575-81. and/or Weiss B and Stoffel W., 1997, Eur J Biochem, 249:239 47. Exemplary assays useful for measuring differentiation of cells containing complex 92b include but are not limited to those described in Roberts RL et al., 1997, Cell, 89:1055-65. Exemplary assays useful for measuring nuclear import/export activity of complex 93a include but are not limited to those described in Singleton DR et al., 1995, J Cell Sci, 108 ( Pt 1):265-72. Exemplary assays useful for measuring receptor/protein translocation activity of complex 93a include but are not limited to those described in Shaywitz DA et al., 1995, J Cell Biol, 128:769-77. and/or Pryer NK et al., 1993, J Cell Biol, 120:865-75.

WO 03/072602 PCT/EPO2/50003 105 Exemplary assays useful for measuring gene expression of a reporter protein and viral replication in cells containing complex 93a include but are not limited to those described in Paca RE et al., 2000, J Virol, 74:9507-14. Exemplary assays useful for measuring nuclear import/export activity of complex 93b include but are not limited to those described in Singleton DR et al., 1995, J Cell Sci, 108 ( Pt 1):265-72. Exemplary assays useful for measuring receptor/protein translocation activity of complex 93b include but are not limited to those described in Shaywitz DA et al., 1995, J Cell Biol, 128:769-77. and/or Pryer NK et al., 1993, J Cell Biol, 120:865-75. Exemplary assays useful for measuring gene expression of a reporter protein and viral replication in cells containing complex 93b include but are not limited to those described in Paca RE et al., 2000, J Virol, 74:9507-14. Exemplary assays useful for measuring protein translocation activity of complex 94a include but are not limited to those described in Brodsky JL and Schekman R., 1993, J Cell Biol, 123:1355-63. Exemplary assays useful for measuring 1,3-beta-D-glucan synthase activity of complex 94a include but are not limited to those described in Mazur P and Baginsky W., 1996, J Biol Chem, 271:14604-9. Exemplary assays useful for measuring in vivo interaction of yeast sec63 using the split-ubiquitin technique in cells containing complex 94a include but are not limited to those described in Wittke S et al., 1999, Mol Biol Cell, 10:2519-30. Exemplary assays useful for measuring protein translocation activity of complex 94b include but are not limited to those described in Brodsky JL and Schekman R., 1993, J Cell Biol, 123:1355-63. Exemplary assays useful for measuring in vivo interaction of yeast sec63 using the split-ubiquitin technique in cells containing complex 94b include but are not limited to those described in Wittke S et al., 1999, Mol Biol Cell, 10:2519-30. Exemplary assays useful for measuring ATP-dependent heteroduplex formation activity of complex 95 include but are not limited to those described in Baumann P and West SC., 1999, J Mol Biol, 291:363-74. Exemplary assays useful for measuring DNA recombination activity of complex 95 include but are not limited to those described in Song B and Sung P., 2000, J Biol Chem, 275:15895-904. and/or Erdile LF et al., 1991, J Biol Chem, 266:12090-8. and/or He Z et al., 1996, J Biol Chem, 271:28243-9.

WO 03/072602 PCT/EPO2/50003 106 Exemplary assays useful for measuring DNA repair in chicken B cells containing complex 95 include but are not limited to those described in Takata M et al., 2001, Mol Cell Biol, 21:2858-66. Exemplary assays useful for measuring Rab recycling activity of complex 96 include but are not limited to those described in Gilbert PM and Burd CG., 2001, J Biol Chem, 276:8014-20. Exemplary assays useful for measuring Rab protein binding activity of complex 96 include but are not limited to those described in D'Adamo P et al., 1998, Nat Genet, 19:134-9. Exemplary assays useful for measuring differentiation of neuronal cells containing complex 96 include but are not limited to those described in D'Adamo P et al., 1998, Nat Genet, 19:134-9. Exemplary animal models useful for assaying compounds interacting with transgenic mice used for the study of ovary development complex 97a include but are not limited to those described in Freiman RN et al., 2001, Science, 293:2084-7. Exemplary assays useful for measuring ATPase activity of complex 97a include but are not limited to those described in Tsukiyama T et al., 1999, Genes Dev, 13:686 97. Exemplary assays useful for measuring transcriptional activity of complex 97a include but are not limited to those described in Kikyo N et al., 2000, Science, 289:2360 2. Exemplary assays useful for measuring cell cycle regulation activity of complex 97a include but are not limited to those described in Cao Y et al., 1997, Mol Cell Biol, 17:3323-34. Exemplary assays useful for measuring differentiation of cells containing complex 97a include but are not limited to those described in de la Serna IL et al., 2001, Nat Genet, 27:187-90. Exemplary assays useful for measuring ATPase activity of complex 97b include but are not limited to those described in Tsukiyama T et al., 1999, Genes Dev, 13:686 97. Exemplary assays useful for measuring transcriptional activity of complex 97b include but are not limited to those described in Kikyo N et al., 2000, Science, 289:2360 2.

WO 03/072602 PCT/EPO2/50003 107 Exemplary assays useful for measuring cell cycle regulation activity of complex 97b include but are not limited to those described in Cao Yet al., 1997, Mol Cell Biol, 17:3323-34. Exemplary animal models useful for assaying compounds interacting with myosin-VA or Rab27a or leaden (In) mutant mice complex 98a include but are not limited to those described in Wilson SM et al., 2000, Proc Natl Acad Sci U S A, 97:7933-8. Exemplary assays useful for measuring Golgi to ER transport activity of complex 98a include but are not limited to those described in Dogic D et al., 1999, Eur J Cell Biol, 78:305-10. Exemplary assays useful for measuring cell free vesicle budding activity of complex 98a include but are not limited to those described in Ahluwalia JP et al., 2001, J Biol Chem, 276:34148-55. Exemplary assays useful for measuring protein transport /sorting activity of complex 98a include but are not limited to those described in Schimm6ller F et al., 1995, EMBO J, 14:1329-39. Exemplary assays useful for measuring hyperplasticity of Golgi in cells containing complex 98a include but are not limited to those described in Carrasco Let al., 2001, J Comp Pathol, 125:1-7. Exemplary assays useful for measuring movements of vaccinia virus intracellular enveloped virions in cells containing complex 98a include but are not limited to those described in Geada MM et al., 2001, J Gen Virol, 82:2747-60. Exemplary animal models useful for assaying compounds interacting with myosin-VA or Rab27a or leaden (In) mutant mice complex 98b include but are not limited to those described in Wilson SM et al., 2000, Proc Nati Acad Sci U S A, 97:7933-8. Exemplary assays useful for measuring Golgi to ER transport activity of complex 98b include but are not limited to those described in Dogic D et al., 1999, Eur J Cell Biol, 78:305-10. Exemplary assays useful for measuring cell free vesicle budding activity of complex 98b include but are not limited to those described in Ahluwalia JP et al., 2001, J Biol Chem, 276:34148-55. Exemplary assays useful for measuring protein transport /sorting activity of complex 98b include but are not limited to those described in Schimm6ller F et al., 1995, EMBO J, 14:1329-39.

WO 03/072602 PCT/EPO2/50003 108 Exemplary assays useful for measuring hyperplasticity of Golgi in cells containing complex 98b include but are not limited to those described in Carrasco L et al., 2001, J Comp Pathol, 125:1-7. Exemplary assays useful for measuring movements of vaccinia virus intracellular enveloped virions in cells containing complex 98b include but are not limited to those described in Geada MM et al., 2001, J Gen Virol, 82:2747-60. Exemplary assays useful for measuring carbamylphosphate synthetase activity of complex 99 include but are not limited to those described in Kaseman DS and Meister A., 1985, Methods Enzymol, 113:305-26. Exemplary assays useful for measuring methionine adenosyl transferase activity of complex 99 include but are not limited to those described in Cabrero C et al., 1987, Eur J Biochem, 170:299-304. Exemplary assays useful for measuring carbamylphosphate synthetase activity of complex 99 include but are not limited to those described in Pierson DL and Brien JM., 1980, J Biol Chem, 255:7891-5. Exemplary assays useful for measuring pyruvate dehydrogenase activity of complex 100a include but are not limited to those described in Pettit FH and Reed LJ., 1982, Methods Enzymol, 89 Pt D:376-86. and/or Chretien D et al., 1995, Clin Chim Acta, 240:129-36. Exemplary assays useful for measuring pyruvate dehydrogenase activity of complex 100b include but are not limited to those described in Pettit FH and Reed LJ., 1982, Methods Enzymol, 89 Pt D:376-86. and/or Chretien D et al., 1995, Clin Chim Acta, 240:129-36. Exemplary animal models useful for assaying compounds interacting with APP family members null transgenic mice or combinations of such transgenes complex 101a include but are not limited to those described in Heber S et al., 2000, J Neurosci, 20:7951-63. Exemplary animal models useful for assaying compounds interacting with ATM knock out mice complex 101a include but are not limited to those described in Spring K et al., 2001, Cancer Res, 61:4561-8. Exemplary assays useful for measuring translational activity of complex 101a include but are not limited to those described in Valisek L et al., 2001, EMBO J, 20:891 904.

WO 03/072602 PCT/EPO2/50003 109 Exemplary assays useful for measuring protease K resistance of complex 101a include but are not limited to those described in Paushkin SV et al., 1997, Science, 277:381-3. Exemplary assays useful for measuring guanine nucleotide exchange activity of complex 101a include but are not limited to those described in Bickle M et al., 1998, EMBO J, 17:2235-45. Exemplary assays useful for measuring apoptosis and radiosensitivity of cells containing complex 101a include but are not limited to those described in Shigeta T et al., 1999, Cancer Res, 59:2602-7. Exemplary assays useful for measuring suppressor activity and foci formation of cells containing complex 101a include but are not limited to those described in Santoso A et al., 2000, Cell, 100:277-88. Exemplary assays useful for measuring amyloid fibrils formation of cells containing complex 101a include but are not limited to those described in Palm M et al., 1997, APMIS, 105:603-8. Exemplary animal models useful for assaying compounds interacting with APP family members null transgenic mice or combinations of such transgenes complex 101b include but are not limited to those described in Heber S et al., 2000, J Neurosci, 20:7951-63. Exemplary animal models useful for assaying compounds interacting with ATM knock out mice complex 101b include but are not limited to those described in Spring K et al., 2001, Cancer Res, 61:4561-8. Exemplary assays useful for measuring translational activity of complex 101b include but are not limited to those described in Valasek L et al., 2001, EMBO J, 20:891 904. Exemplary assays useful for measuring protein kinase assay of complex 101b include but are not limited to those described in Chen H et al., 2001, Biochemistry, 40:11851-9. Exemplary assays useful for measuring protease K resistance of complex 101b include but are not limited to those described in Paushkin SV et al., 1997, Science, 277:381-3. Exemplary assays useful for measuring guanine nucleotide exchange activity of complex 101b include but are not limited to those described in Bickle M et al., 1998, EMBO J, 17:2235-45.

WO 03/072602 PCT/EPO2/50003 110 Exemplary assays useful for measuring apoptosis and radiosensitivity of cells containing complex 101b include but are not limited to those described in Shigeta T et al., 1999, Cancer Res, 59:2602-7. Exemplary assays useful for measuring suppressor activity and foci formation of cells containing complex 101b include but are not limited to those described in Santoso A et al., 2000, Cell, 100:277-88. Exemplary assays useful for measuring amyloid fibrils formation of cells containing complex 101b include but are not limited to those described in Palm M et al., 1997, APMIS, 105:603-8. Exemplary assays useful for measuring vesicle targeting activity of complex 102a include but are not limited to those described in Sacher M et al., 2001, Mol Cell, 7:433 42. Exemplary assays useful for measuring ER to Golgi transport activity of complex 102a include but are not limited to those described in Sacher M et al., 1998, EMBO J, 17:2494-503. Exemplary assays useful for measuring vesicle targeting activity of complex 102b include but are not limited to those described in Sacher M et al., 2001, Mol Cell, 7:433 42. Exemplary assays useful for measuring ER to Golgi transport activity of complex 102b include but are not limited to those described in Sacher M et al., 1998, EMBO J, 17:2494-503. Exemplary animal models useful for assaying compounds interacting with transgenic mice displaying a fragile X syndrome-like phenotype complex 103 include but are not limited to those described in Kooy RF et al., 1996, Am J Med Genet, 64:241-5. and/or Oostra BA and Hoogeveen AT., 1997, Ann Med, 29:563-7. Exemplary assays useful for measuring RNA binding activity of complex 103 include but are not limited to those described in Thisted T et al., 2001, J Biol Chem, 276:17484-96. Exemplary assays useful for measuring kinase activity of complex 103 include but are not limited to those described in Altman R and Kellogg D., 1997, J Cell Biol, 138:119-30. Exemplary animal models useful for assaying compounds interacting with snf5 knock-out mice (homozygous or heterozygous ) complex 105a include but are not limited to those described in Klochendler-Yeivin A et al., 2000, EMBO Rep, 1:500-6.

WO 03/072602 PCT/EPO2/50003 111 Exemplary assays useful for measuring casein kinase I activity of complex 105a include but are not limited to those described in DeMaggio AJ et al., 1992, Proc Natl Acad Sci U S A, 89:7008-12. Exemplary assays useful for measuring nucleosomal remodelling activity of complex 105a include but are not limited to those described in Ostlund Farrants AK et al., 1997, Mol Cell Biol, 17:895-905. and/or Logie C and Peterson CL., 1997, EMBO J, 16:6772-82. Exemplary assays useful for measuring expression of a reporter gene in cells containing complex 105a include but are not limited to those described in Muchardt C and Yaniv M., 1993, EMBO J, 12:4279-90. Exemplary animal models useful for assaying compounds interacting with snf5 knock-out mice (homozygous or heterozygous ) complex 105b include but are not limited to those described in Klochendler-Yeivin A et al., 2000, EMBO Rep, 1:500-6. Exemplary assays useful for measuring transcription assay of complex 105b include but are not limited to those described in Hipskind RA and Nordheim A., 1991, J Biol Chem, 266:19572-82. Exemplary assays useful for measuring nucleosomal remodelling activity of complex 105b include but are not limited to those described in Ostlund Farrants AK et al., 1997, Mol Cell Biol, 17:895-905. and/or Logie C and Peterson CL., 1997, EMBO J, 16:6772-82. Exemplary assays useful for measuring expression of a reporter gene in cells containing complex 105b include but are not limited to those described in Muchardt C and Yaniv M., 1993, EMBO J, 12:4279-90. Exemplary animal models useful for assaying compounds interacting with mice treated with alcohol to inhibit proteasome activity complex 106a include but are not limited to those described in Bardag-Gorce F et al., 2000, Biochem Biophys Res Commun, 279:23-9.(The effect of ethanol-induced cytochrome p4502E1 on the inhibition of proteasome activity by alcohol.) Exemplary assays useful for measuring the protease activity of complex 106a include but are not limited to those described in Kuckelkorn U et al., 2000 Sep-Oct, Biol Chem, 381:1017-23. and/or Ugai S et al., 1993, J Biochem (Tokyo), 113:754-68. Exemplary assays useful for measuring chymotryptic and tryptic activities of the proteasome in cells containing complex 106a include but are not limited to those described in Lightcap ES et al., 2000, Clin Chem, 46:673-83.

WO 03/072602 PCT/EPO2/50003 112 Exemplary assays useful for measuring stability of fluorescent protein markers in cells containing complex 106a include but are not limited to those described in Andreatta C et al., 2001, Biotechniques, 30:656-60. Exemplary animal models useful for assaying compounds interacting with mice treated with alcohol to inhibit proteasome activity complex 106b include but are not limited to those described in Bardag-Gorce F et al., 2000, Biochem Biophys Res Commun, 279:23-9.(The effect of ethanol-induced cytochrome p4502E1 on the inhibition of proteasome activity by alcohol.) Exemplary assays useful for measuring the protease activity of complex 106b include but are not limited to those described in Kuckelkorn U et al., 2000 Sep-Oct, Biol Chem, 381:1017-23. and/or Ugai Set al., 1993, J Biochem (Tokyo), 113:754-68. Exemplary assays useful for measuring chymotryptic and tryptic activities of the proteasome in cells containing complex 106b include but are not limited to those described in Lightcap ES et al., 2000, Clin Chem, 46:673-83. Exemplary assays useful for measuring stability of fluorescent protein markers in cells containing complex 106b include but are not limited to those described in Andreatta C et al., 2001, Biotechniques, 30:656-60. Exemplary assays useful for measuring actin filament motility regulation activity of complex 107a include but are not limited to those described in Evans LL et al., 1998, J Cell Sci, 111 ( Pt 14):2055-66. Exemplary assays useful for measuring motility of cells containing complex 107a include but are not limited to those described in Williams R and Coluccio LM., 1994, Cell Motil Cytoskeleton, 27:41-8. Exemplary animal models useful for assaying compounds interacting with myosin-VA or Rab27a or leaden (In) mutant mice complex 107b include but are not limited to those described in Wilson SM et al., 2000, Proc Natl Acad Sci U S A, 97:7933-8. Exemplary assays useful for measuring RNA 3'-5' exonuclease activity of complex 107b include but are not limited to those described in Benard L et al., 1999, J Virol, 73:2893-900. Exemplary assays useful for measuring ATPase of complex 107b include but are not limited to those described in Kimura K and Hirano T., 1997, Cell, 90:625-34. Exemplary assays useful for measuring actin filament motility regulation activity of complex 107b include but are not limited to those described in Evans LL et al., 1998, J Cell Sci, 111 ( Pt 14):2055-66.

WO 03/072602 PCT/EPO2/50003 113 Exemplary assays useful for measuring motility of cells containing complex 107b include but are not limited to those described in Williams R and Coluccio LM., 1994, Cell Motil Cytoskeleton, 27:41-8. Exemplary assays useful for measuring specific DNA binding activity of complex 108a include but are not limited to those described in Schramke V et al., 2001, Genes Dev, 15:1845-58. Exemplary assays useful for measuring telomere length regulation activity of complex 108a include but are not limited to those described in Corda Y et al., 1999, Nat Genet, 21:204-8. Exemplary assays useful for measuring telomeric silencing of cl containing complex 108a include but are not limited to those described in Gottschling DE et al., 1990, Cell, 63:751-62. Exemplary assays useful for measuring telomeric silencing of cells containing complex 108a include but are not limited to those described in Nislow C et al., 1997, Mol Biol Cell, 8:2421-36. Exemplary assays useful for measuring cell viability after exposure to DNA damaging agents of cells containing complex 108a include but are not limited to those described in Corda Y et al., 1999, Nat Genet, 21:204-8. Exemplary assays useful for measuring specific DNA binding activity of complex 108b include but are not limited to those described in Schramke V et al., 2001, Genes Dev, 15:1845-58. Exemplary assays useful for measuring histon methyltransferase of complex 108b include but are not limited to those described in Roguev A et al., 2001, EMBO J, 20:7137-48. Exemplary assays useful for measuring histone methylation of complex 108b include but are not limited to those described in Briggs SD et al., 2001, Genes Dev, 15:3286-95. Exemplary assays useful for measuring telomere length regulation activity of complex 108b include but are not limited to those described in Corda Yet al., 1999, Nat Genet, 21:204-8. Exemplary assays useful for measuring telomeric silencing of cl containing complex 108b include but are not limited to those described in Gottschling DE et al., 1990, Cell, 63:751-62.

WO 03/072602 PCT/EPO2/50003 114 Exemplary assays useful for measuring telomeric silencing of cells containing complex 108b include but are not limited to those described in Nislow C et al., 1997, Mol Biol Cell, 8:2421-36. Exemplary assays useful for measuring cell viability after exposure to DNA damaging agents of cells containing complex 108b include but are not limited to those described in Corda Yet al., 1999, Nat Genet, 21:204-8. Exemplary assays useful for measuring vacuole fusion activity of complex 109a include but are not limited to those described in Sato TK et al., 2000, Mol Cell, 6:661-71. Exemplary assays useful for measuring alanine/arginine aminopeptidase activity of complex 109a include but are not limited to those described in Caprioglio DR et al., 1993, J Biol Chem, 268:14310-5. Exemplary assays useful for measuring invertase secretion of cells containing complex 109a include but are not limited to those described in Horazdovsky BF et al., 1996, J Biol Chem, 271:33607-15. Exemplary assays useful for measuring vacuole fusion activity of complex 109b include but are not limited to those described in Sato TK et al., 2000, Mol Cell, 6:661-71. Exemplary assays useful for measuring alanine/arginine aminopeptidase activity of complex 109b include but are not limited to those described in Caprioglio DR et al., 1993, J Biol Chem, 268:14310-5. Exemplary assays useful for measuring invertase secretion of cells containing complex 109b include but are not limited to those described in Horazdovsky BF et al., 1996, J Biol Chem, 271:33607-15. Exemplary assays useful for measuring ribonucleotide reductase activity of complex 110a include but are not limited to those described in Chabes A et al., 1999, J Biol Chem, 274:36679-83. Exemplary assays useful for measuring transcriptional activity of complex 11 0a include but are not limited to those described in Paull TT et al., 1996, Genes Dev, 10:2769-81. Exemplary assays useful for measuring ATPase activity of complex 110a include but are not limited to those described in Cairns BR et al., 1996, Cell, 87:1249-60. Exemplary assays useful for measuring gene expression in cells containing complex 110a include but are not limited to those described in Liu M et al., 1999, J Biol Chem, 274:15433-9.

WO 03/072602 PCT/EPO2/50003 115 Exemplary assays useful for measuring drug resistance of cells expressing complex 110a include but are not limited to those described in Choy BK et al., 1988, Cancer Res, 48:2029-35. Exemplary assays useful for measuring ribonucleotide reductase activity of complex 110b include but are not limited to those described in Chabes A et al., 1999, J Biol Chem, 274:36679-83. Exemplary assays useful for measuring transcriptional activity of complex 11 0b include but are not limited to those described in Paull TT et al., 1996, Genes Dev, 10:2769-81. Exemplary assays useful for measuring ATPase activity of complex 110 Ob include but are not limited to those described in Cairns BR et al., 1996, Cell, 87:1249-60. Exemplary assays useful for measuring gene expression in cells containing complex 110b include but are not limited to those described in Liu M et al., 1999, J Biol Chem, 274:15433-9. Exemplary assays useful for measuring drug resistance of cells expressing complex 110b include but are not limited to those described in Choy BK et al., 1988, Cancer Res, 48:2029-35. Exemplary assays useful for measuring transporter activity of complex 111 include but are not limited to those described in Moy TI and Silver PA., 1999, Genes Dev, 13:2118-33. Exemplary assays useful for measuring rRNA synthesis activity of complex 111 include but are not limited to those described in Venema J and Tollervey D., 1996, EMBO J, 15:5701-14. Exemplary assays useful for measuring ribosomal assembly regulation activity of complex 111 include but are not limited to those described in Kressler D et al., 1997, Mol Cell Biol, 17:7283-94. Exemplary assays useful for measuring cell cycle arrest of cells containing complex 111 include but are not limited to those described in Pestov DG et al., 2001, Mol Cell Biol, 21:4246-55. Exemplary assays useful for measuring uncoating of viral nucleocapsids in cells containing complex 111 include but are not limited to those described in Singh I and Helenius A., 1992, J Virol, 66:7049-58.

WO 03/072602 PCT/EPO2/50003 116 Exemplary assays useful for measuring subcellular localization/transport of ribosomal proteins in cells containing complex 111 include but are not limited to those described in Hurt E et al., 1999, J Cell Biol, 144:389-401. Exemplary assays useful for measuring heatshock protein Hsp90 binding activity of complex 112a include but are not limited to those described in Marsh JA et al., 1998, Mol Cell Biol, 18:7353-9. Exemplary assays useful for measuring heat-shock induced protein aggregation in COS cells containing complex 112a include but are not limited to those described in Sittler A et al., 2001, Hum Mol Genet, 10:1307-15. Exemplary assays useful for measuring heatshock protein Hsp90 binding activity of complex 112b include but are not limited to those described in Marsh JA et al., 1998, Mol Cell Biol, 18:7353-9. Exemplary assays useful for measuring heat-shock induced protein aggregation in COS cells containing complex 112b include but are not limited to those described in Sittler A et al., 2001, Hum Mol Genet, 10:1307-15. Exemplary assays useful for measuring casein kinase activity of complex 113a include but are not limited to those described in Park JW and Bae YS., 1999, Biochem Biophys Res Commun, 263:475-81. Exemplary assays useful for measuring transcriptional activity of complex 113a include but are not limited to those described in Shi X et al., 1997, Mol Cell Biol, 17:1160-9. Exemplary assays useful for measuring sensitivity to drugs (6AU or mycophenolix acid) of cells containing complex 113a include but are not limited to those described in Shaw RJ et al., 2001, J Biol Chem, 276:32905-16. Exemplary assays useful for measuring casein kinase activity of complex 113b include but are not limited to those described in Park JW and Bae YS., 1999, Biochem Biophys Res Commun, 263:475-81. Exemplary assays useful for measuring transcriptional activity of complex 113b include but are not limited to those described in Shi X et al., 1997, Mol Cell Biol, 17:1160-9. Exemplary assays useful for measuring sensitivity to drugs (6AU or mycophenolix acid) of cells containing complex 113b include but are not limited to those described in Shaw RJ et al., 2001, J Biol Chem, 276:32905-16.

WO 03/072602 PCT/EPO2/50003 117 Exemplary assays useful for measuring oligosaccharyltransferase activity of complex 114a include but are not limited to those described in Kumar V et al., 1994, Anal Biochem, 219:305-8. Exemplary assays useful for measuring oligosaccharyltransferase activity of complex 114b include but are not limited to those described in Kumar V et al., 1994, Anal Biochem, 219:305-8. Exemplary animal models useful for assaying compounds interacting with ATR knock-out mice (chromosomal fragmentation and early embryonic lethality phenotypes) complex 115 include but are not limited to those described in Brown EJ and Baltimore D., 2000, Genes Dev, 14:397-402. Exemplary assays useful for measuring protein kinase activity of complex 115 include but are not limited to those described in Abe Y et al., 2001, J Biol Chem, 276:44003-11. Exemplary assays useful for measuring ATPase activity of complex 115 include but are not limited to those described in Zhang Y et al., 1998, Cell, 95:279-89. Exemplary assays useful for measuring DNA repair in fibroblasts containing complex 115 include but are not limited to those described in Emmert S et al., 2000, Proc Natl Acad Sci U S A, 97:2151-6. Exemplary animal models useful for assaying compounds interacting with transgenic mice displaying a human prostate cancer-like phenotype complex 116a include but are not limited to those described in Saffran DC et al., 2001, Proc Natl Acad Sci U S A, 98:2658-63. Exemplary assays useful for measuring ATPase activity of complex 116a include but are not limited to those described in Tsukiyama T et al., 1999, Genes Dev, 13:686 97. Exemplary assays useful for measuring transcriptional activity of complex 116a include but are not limited to those described in Kikyo N et al., 2000, Science, 289:2360 2. Exemplary assays useful for measuring differentiation of cells containing complex 116a include but are not limited to those described in de la Serna IL et al., 2001, Nat Genet, 27:187-90. Exemplary animal models useful for assaying compounds interacting with transgenic mice displaying a human prostate cancer-like phenotype complex 116b include but are WO 03/072602 PCT/EPO2/50003 118 not limited to those described in Saffran DC et al., 2001, Proc Natl Acad Sci U S A, 98:2658-63. Exemplary assays useful for measuring ATPase activity of complex 116b include but are not limited to those described in Tsukiyama T et al., 1999, Genes Dev, 13:686 97. Exemplary assays useful for measuring transcriptional activity of complex 116b include but are not limited to those described in Kikyo N et al., 2000, Science, 289:2360 2. Exemplary assays useful for measuring Chromatin remodeling of complex 116b include but are not limited to those described in Wang W et al., 1996, EMBO J, 15:5370 82. Exemplary assays useful for measuring differentiation of cells containing complex 116b include but are not limited to those described in de la Serna IL et al., 2001, Nat Genet, 27:187-90. Exemplary animal models useful for assaying compounds interacting with transgenic mice displaying a breast cancer-like phenotype complex 117 include but are not limited to those described in Stewart TA et al., 1984, Cell, 38:627-37.(Spontaneous mammary adenocarcinomas in transgenic mice that carry and express MTV/myc fusion genes.) Exemplary assays useful for measuring transcriptional activity of complex 117 include but are not limited to those described in Kotova I et al., 2001, Eur J Biochem, 268:4527-36. and/or Carrozza MJ and DeLuca NA., 1996, Mol Cell Biol, 16:3085-93. Exemplary assays useful for measuring gene expression in cells containing complex 117 include but are not limited to those described in Zhu A and Kuziora MA., 1996, J Biol Chem, 271:20993-6. Exemplary assays useful for measuring gene expression activity of complex 118a include but are not limited to those described in Lewis ML et al., 2001, FASEB J, 15:1783-5. Exemplary assays useful for measuring endocytosis regulation activity of complex 118a include but are not limited to those described in Dulic V et al., 1991, Methods Enzymol, 194:697-710. Exemplary assays useful for measuring changes in motility of cells containing complex 118a include but are not limited to those described in Westerberg L et al., 2001, Blood, 98:1086-94.

WO 03/072602 PCT/EPO2/50003 119 Exemplary assays useful for measuring cytoskeletal changes of cells containing complex 118a include but are not limited to those described in Lommel Set al., 2001, EMBO Rep, 2:850-7. Exemplary animal models useful for assaying compounds interacting with transgenic mice displaying a Wiskott-Aldrich syndrome-like phenotype complex 118b include but are not limited to those described in Snapper SB et al., 1998, Immunity, 9:81-91. Exemplary assays useful for measuring gene expression activity of complex 118b include but are not limited to those described in Lewis ML et al., 2001, FASEB J, 15:1783-5. Exemplary assays useful for measuring endocytosis regulation activity of complex 118b include but are not limited to those described in Dulic V et al., 1991, Methods Enzymol, 194:697-710. Exemplary assays useful for measuring changes in motility of cells containing complex 118b include but are not limited to those described in Westerberg L et al., 2001, Blood, 98:1086-94. Exemplary assays useful for measuring cytoskeletal changes of cells containing complex 118b include but are not limited to those described in Lommel Set al., 2001, EMBO Rep, 2:850-7. Exemplary assays useful for measuring nuclear import/export activity of complex 119a include but are not limited to those described in Singleton DR et al., 1995, J Cell Sci, 108 ( Pt 1):265-72. and/or Shulga N et al., 1996, J Cell Biol, 135:329-39. Exemplary assays useful for measuring viral replication activity in cells containing complex 119a include but are not limited to those described in Kim AL et al., 1997, Virology, 239:340-51. Exemplary animal models useful for assaying compounds interacting with Nup214 (CAN) knock-out mice complex 119b include but are not limited to those described in van Deursen J et al., 1996, EMBO J, 15:5574-83. Exemplary assays useful for measuring nuclear import/export activity of complex 119b include but are not limited to those described in Singleton DR et al., 1995, J Cell Sci, 108 ( Pt 1):265-72. and/or Shulga N et al., 1996, J Cell Biol, 135:329-39. Exemplary assays useful for measuring viral replication activity in cells containing complex 119b include but are not limited to those described in Kim AL et al., 1997, Virology, 239:340-51.

WO 03/072602 PCT/EPO2/50003 120 Exemplary assays useful for measuring vacuolar membrane H+ ATPase activity of complex 120a include but are not limited to those described in Uchida E et al., 1988, Methods Enzymol, 157:544-62. Exemplary assays useful for measuring resorption activity in human cells containing complex 120a include but are not limited to those described in James IE et al., 1999, J Bone Miner Res, 14:1562-9. Exemplary assays useful for measuring modulation of the processing of beta amyloid precursor protein (beta-APP) in293 kidney cells containing complex 120a include but are not limited to those described in Haass C et al., 1995, J Biol Chem, 270:6186-92. Exemplary assays useful for measuring vacuolar membrane H+ ATPase activity of complex 120b include but are not limited to those described in Uchida E et al., 1988, Methods Enzymol, 157:544-62. Exemplary assays useful for measuring resorption activity in human cells containing complex 120b include but are not limited to those described in James IE et al., 1999, J Bone Miner Res, 14:1562-9. Exemplary assays useful for measuring modulation of the processing of beta amyloid precursor protein (beta-APP) in293 kidney cells containing complex 120b include but are not limited to those described in Haass C et al., 1995, J Biol Chem, 270:6186-92. Exemplary assays useful for measuring GASP41 protein binding activity of complex 121a include but are not limited to those described in Munnia A et al., 2001, Oncogene, 20:4853-63. Exemplary assays useful for measuring GASP41 protein binding activity of complex 121b include but are not limited to those described in Munnia A et al., 2001, Oncogene, 20:4853-63. Exemplary assays useful for measuring GTP exchange activity of complex 122a include but are not limited to those described in Sasaki T et al., 1990, J Biol Chem, 265:2333-7. Exemplary assays useful for measuring GTP exchange activity of complex 122b include but are not limited to those described in Sasaki T et al., 1990, J Biol Chem, 265:2333-7.

WO 03/072602 PCT/EPO2/50003 121 Exemplary assays useful for measuring translational activity of complex 123a include but are not limited to those described in Pfisterer J and Buetow DE., 1981, Proc Natl Acad Sci U S A, 78:4917-21. Exemplary assays useful for measuring respiration of cells containing complex 123a include but are not limited to those described in K6tter P and Entian KD., 1995, Curr Genet, 28:26-31. Exemplary assays useful for measuring translational activity of complex 123b include but are not limited to those described in Pfisterer J and Buetow DE., 1981, Proc Natl Acad Sci US A, 78:4917-21. Exemplary assays useful for measuring respiration of cells containing complex 123b include but are not limited to those described in K6tter P and Entian KD., 1995, Curr Genet, 28:26-31. Exemplary assays useful for measuring protein kinase activity of complex 124a include but are not limited to those described in Bidwal AP et al., 1993, Arch Biochem Biophys, 300:265-70. Exemplary assays useful for measuring subcellular localization/transport of lysosomal membrane proteins on the surface of AP-3 deficient fibroblasts containing complex 124a include but are not limited to those described in Dell'Angelica EC et al., 1999, Mol Cell, 3:11-21. Exemplary animal models useful for assaying compounds interacting with transgenic mice displaying a Hermansky Pudlak syndrome-like phenotype complex 124b include but are not limited to those described in Swank RT et al., 1998, Pigment Cell Res, 11:60-80. Exemplary animal models useful for assaying compounds interacting with the "pearl" mouse mutant (alterations in AP-3 betal subunit, model for HPS) complex 124b include but are not limited to those described in Feng L et al., 1999, Hum Mol Genet, 8:323-30. Exemplary assays useful for measuring protein kinase activity of complex 124b include but are not limited to those described in Bidwai AP et al., 1993, Arch Biochem Biophys, 300:265-70. Exemplary assays useful for measuring subcellular localization/transport of lysosomal membrane proteins on the surface of AP-3 deficient fibroblasts containing complex 124b include but are not limited to those described in Dell'Angelica EC et al., 1999, Mol Cell, 3:11-21.

WO 03/072602 PCT/EPO2/50003 122 Exemplary animal models useful for assaying compounds interacting with Aurora-like kinase knock-out mice complex 125a include but are not limited to those described in Kaitna S et al., 2000, Curr Biol, 10:1172-81. Exemplary assays useful for measuring DNA binding activity of complex 125a include but are not limited to those described in Kimura K et al., 1999, Cell, 98:239-48. Exemplary assays useful for measuring ATPase activity of complex 125a include but are not limited to those described in Kimura K and Hirano T., 1997, Cell, 90:625-34. Exemplary assays useful for measuring chromatid condensation and cohesion in cells containing complex 125a include but are not limited to those described in Losada A et al., 1998, Genes Dev, 12:1986-97. Exemplary animal models useful for assaying compounds interacting with Aurora-like kinase knock-out mice complex 125b include but are not limited to those described in Kaitna Set al., 2000, Curr Biol, 10:1172-81. Exemplary assays useful for measuring DNA binding activity of complex 125b include but are not limited to those described in Kimura K et al., 1999, Cell, 98:239-48. Exemplary assays useful for measuring ATPase activity of complex 125b include but are not limited to those described in Kimura K and Hirano T., 1997, Cell, 90:625-34. Exemplary assays useful for measuring chromatid condensation and cohesion in cells containing complex 125b include but are not limited to those described in Losada A et al., 1998, Genes Dev, 12:1986-97. Exemplary assays useful for measuring protein deacetylase activity of complex 126a include but are not limited to those described in Nare B et al., 1999, Anal Biochem, 267:390-6. Exemplary assays useful for measuring histone acetyltransferase activity of complex 126a include but are not limited to those described in Ito K et al., 2001, J Biol Chem, 276:30208-15. Exemplary assays useful for measuring PI 3 kinase activity of complex 126a include but are not limited to those described in Serunian LA et al., 1991, Methods Enzymol, 198:78-87. Exemplary assays useful for measuring cell cycle progression of cells containing complex 126a include but are not limited to those described in Mahalingam S et al., 1998, Proc NatI Acad Sci U S A, 95:3419-24.

WO 03/072602 PCT/EPO2/50003 123 Exemplary assays useful for measuring nuclear import/export of ribosomal proteins of cells containing complex 126a include but are not limited to those described in Jlkel S and G6rlich D., 1998, EMBO J, 17:4491-502. Exemplary animal models useful for assaying compounds interacting with Ataxia telangiectasia transgenic mice complex 126b include but are not limited to those described in Barlow C et al., 1996, Cell, 86:159-71. Exemplary assays useful for measuring histone acetyltransferase activity of complex 126b include but are not limited to those described in Ito K et al., 2001, J Biol Chem, 276:30208-15. Exemplary assays useful for measuring cell cycle progression of cells containing complex 126b include but are not limited to those described in Mahalingam S et al., 1998, Proc Natl Acad Sci U S A, 95:3419-24. Exemplary assays useful for measuring guanine nucleotide exchange activity of complex 127a include but are not limited to those described in Nika J et al., 2000, J Biol Chem, 275:26011-7. Exemplary assays useful for measuring proliferation activity of cells complex 127a include but are not limited to those described in Entian KD et al., 1999, Mol Gen Genet, 262:683-702. Exemplary assays useful for measuring guanine nucleotide exchange activity of complex 127b include but are not limited to those described in Nika J et al., 2000, J Biol Chem, 275:26011-7. Exemplary assays useful for measuring mixed-nucleotide exchange experiments of complex 127b include but are not limited to those described in Rudoni S et al., 2001, Biochim Biophys Acta, 1538:181-9. Exemplary assays useful for measuring translation factor activity of complex 127b include but are not limited to those described in Choi SK et al., 1998, Science, 280:1757-60. Exemplary assays useful for measuring proliferation activity of cells complex 127b include but are not limited to those described in Entian KD et al., 1999, Mol Gen Genet, 262:683-702. Exemplary assays useful for measuring aminoacyl-synthetase activity of complex 128a include but are not limited to those described in Shiba K et al., 1997, J Biol Chem, 272:22809-16.

WO 03/072602 PCT/EPO2/50003 124 Exemplary assays useful for measuring RNA helicase activity of complex 128a include but are not limited to those described in Laggerbauer B et al., 1998, Proc Natl Acad Sci U S A, 95:4188-92. Exemplary assays useful for measuring mRNA decay activity of cells containing complex 128a include but are not limited to those described in Bouveret E et al., 2000, EMBO J, 19:1661-71. Exemplary assays useful for measuring nonsense mediated mRNA decay activity of cells containing complex 128a include but are not limited to those described in Sun X et al., 1998, Proc Natl Acad Sci U S A, 95:10009-14. Exemplary animal models useful for assaying compounds interacting with transgenic mice displaying an autoimmune polymyositis-like phenotype complex 128b include but are not limited to those described in Kohyama K and Matsumoto Y., 1999, J Neuroimmunol, 98:130-5. Exemplary animal models useful for assaying compounds interacting with transgenic mice displaying an systemic sclerosis-like phenotype complex 128b include but are not limited to those described in Nguyen VA et al., 2000, J Autoimmun, 14:143-9. Exemplary assays useful for measuring aminoacyl-synthetase activity of complex 128b include but are not limited to those described in Shiba K et al., 1997, J Biol Chem, 272:22809-16. Exemplary assays useful for measuring RNA helicase activity of complex 128b include but are not limited to those described in Laggerbauer B et al., 1998, Proc NatI Acad Sci U S A, 95:4188-92. Exemplary assays useful for measuring mRNA decay activity of cells containing complex 128b include but are not limited to those described in Bouveret E et al., 2000, EMBO J, 19:1661-71. Exemplary assays useful for measuring nonsense mediated mRNA decay activity of cells containing complex 128b include but are not limited to those described in Sun X et al., 1998, Proc Natl Acad Sci U S A, 95:10009-14. Exemplary animal models useful for assaying compounds interacting with transgenic mice displaying a fragile X syndrome-like phenotype complex 129a include but are not limited to those described in Kooy RF et al., 1996, Am J Med Genet, 64:241-5. and/or Oostra BA and Hoogeveen AT., 1997, Ann Med, 29:563-7.

WO 03/072602 PCT/EPO2/50003 125 Exemplary assays useful for measuring dual specificity kinase activity of complex 129a include but are not limited to those described in Menegay HJ et al., 2000, J Cell Sci, 113 ( Pt 18):3241-53. Exemplary assays useful for measuring RNA helicase activity of complex 129a include but are not limited to those described in Rogers GW et al., 2001, J Biol Chem, 276:30914-22. Exemplary assays useful for measuring serinelthreonine protein kinase activity of complex 129a include but are not limited to those described in Hartmann AM et al., 2001, Mol Cell Neurosci, 18:80-90. Exemplary assays useful for measuring nuclear transport activity of cells containing complex 129a include but are not limited to those described in Stauber RH., 2001, Curr Top Microbiol Immunol, 259:119-28. Exemplary animal models useful for assaying compounds interacting with transgenic mice displaying a fragile X syndrome-like phenotype complex 129b include but are not limited to those described in Kooy RF et al., 1996, Am J Med Genet, 64:241-5. and/or Oostra BA and Hoogeveen AT., 1997, Ann Med, 29:563-7. Exemplary assays useful for measuring dual specificity kinase activity of complex 129b include but are not limited to those described in Menegay HJ et al., 2000, J Cell Sci, 113 ( Pt 18):3241-53. Exemplary assays useful for measuring RNA helicase activity of complex 129b include but are not limited to those described in Rogers GW et al., 2001, J Biol Chem, 276:30914-22. Exemplary assays useful for measuring serine/threonine protein kinase activity of complex 129b include but are not limited to those described in Hartmann AM et al., 2001, Mol Cell Neurosci, 18:80-90. Exemplary assays useful for measuring nuclear transport activity of cells containing complex 129b include but are not limited to those described in Stauber RH., 2001, Curr Top Microbiol Immunol, 259:119-28. Exemplary assays useful for measuring topoisomerase II activity of complex 130a include but are not limited to those described in Okada Yet al., 2001, Gene, 272:141-8. Exemplary assays useful for measuring ATPase activity of complex 130a include but are not limited to those described in Rieger CE et al., 1997, Anal Biochem, 246:86 95.

WO 03/072602 PCT/EPO2/50003 126 Exemplary assays useful for measuring sister chromatid cohesion of cells containing complex 130a include but are not limited to those described in Megee PC and Koshland D., 1999, Science, 285:254-7. Exemplary assays useful for measuring cell survival after DNA damage of cells containing complex 130a include but are not limited to those described in Pennaneach Vet al., 2001, Mol Cell, 7:715-27. Exemplary assays useful for measuring cell cycle progression of cells containing complex 130a include but are not limited to those described in Mahalingam S et al., 1998, Proc Natl Acad Sci U S A, 95:3419-24. Exemplary animal models useful for assaying compounds interacting with transgenic mice displaying a Williams-Beuren syndrome-like phenotype complex 130b include but are not limited to those described in Durkin ME et al., 2001, Genomics, 73:20-7. Exemplary assays useful for measuring topoisomerase II activity of complex 130b include but are not limited to those described in Okada Y et al., 2001, Gene, 272:141-8. Exemplary assays useful for measuring ATPase activity of complex 130b include but are not limited to those described in Rieger CE et al., 1997, Anal Biochem, 246:86 95. Exemplary assays useful for measuring sister chromatid cohesion of cells containing complex 130b include but are not limited to those described in Megee PC and Koshland D., 1999, Science, 285:254-7. Exemplary assays useful for measuring cell survival after DNA damage of cells containing complex 130b include but are not limited to those described in Pennaneach Vet al., 2001, Mol Cell, 7:715-27. Exemplary assays useful for measuring cell cycle progression of cells containing complex 130b include but are not limited to those described in Mahalingam S et al., 1998, Proc Natl Acad Sci U S A, 95:3419-24. Exemplary assays useful for measuring serine/threonine protein kinase activity of complex 131a include but are not limited to those described in Shiekhattar R et al., 1995, Nature, 374:283-7. and/or Fisher RP and Morgan DO., 1994, Cell, 78:713-24. Exemplary assays useful for measuring nucleotide excision repair activity of complex 131a include but are not limited to those described in Sung P et al., 1996, J Biol Chem, 271:10821-6.

WO 03/072602 PCT/EPO2/50003 127 Exemplary assays useful for measuring transcription activity of cells containing complex 131a include but are not limited to those described in Shiekhattar R et al., 1995, Nature, 374:283-7. Exemplary assays useful for measuring transcription assay of complex 131b include but are not limited to those described in Hipskind RA and Nordheim A., 1991, J Biol Chem, 266:19572-82. Exemplary assays useful for measuring nucleotide excision repair activity of complex 131b include but are not limited to those described in Sung P et al., 1996, J Biol Chem, 271:10821-6. Exemplary assays useful for measuring transcription activity of cells containing complex 131b include but are not limited to those described in Shiekhattar R et al., 1995, Nature, 374:283-7. Exemplary animal models useful for assaying compounds interacting with transgenic mice displaying systemic sclerosis-like phenotype complex 132a include but are not limited to those described in Yamamoto T et al., 1999, J Invest Dermatol, 112:456-62. and/or Nguyen VA et al., 2000, J Autoimmun, 14:143-9. Exemplary animal models useful for assaying compounds interacting with transgenic mice displaying systemic lupus erythematosus-like phenotype complex 132a include but are not limited to those described in Kyogoku M et al., 1987, Prog Clin Biol Res, 229:95 130. Exemplary animal models useful for assaying compounds interacting with transgenic mice displaying Sjogren syndrome-like phenotype complex 132a include but are not limited to those described in Haneji N et al., 1994, J Immunol, 153:2769-77. Exemplary assays useful for measuring RNA stabilizing activity of complex 132a include but are not limited to those described in McLaren RS et al., 1997, Mol Cell Biol, 17:3028-36. Exemplary assays useful for measuring rRNA pseudouridylation activity of cells containing complex 132a include but are not limited to those described in Lafontaine DL et al., 1998, Genes Dev, 12:527-37. Exemplary animal models useful for assaying compounds interacting with transgenic mice displaying systemic sclerosis-like phenotype complex 132b include but are not limited to those described in Yamamoto T et al., 1999, J Invest Dermatol, 112:456-62.

WO 03/072602 PCT/EPO2/50003 128 Exemplary animal models useful for assaying compounds interacting with transgenic mice displaying aspinal muscular atrophy-like phenotype complex 132b include but are not limited to those described in Monani UR et al., 2000, Hum Mol Genet, 9:333-9. Exemplary animal models useful for assaying compounds interacting with transgenic mice displaying systemic sclerosis-like phenotype complex 132b include but are not limited to those described in Nguyen VA et al., 2000, J Autoimmun, 14:143-9. Exemplary animal models useful for assaying compounds interacting with transgenic mice displaying systemic lupus erythematosus-like phenotype complex 132b include but are not limited to those described in Kyogoku M et al., 1987, Prog Clin Biol Res, 229:95 130. Exemplary animal models useful for assaying compounds interacting with transgenic mice displaying Sjogren syndrome-like phenotype complex 132b include but are not limited to those described in Haneji N et al., 1994, J Immunol, 153:2769-77. Exemplary assays useful for measuring RNA stabilizing activity of complex 132b include but are not limited to those described in McLaren RS et al., 1997, Mol Cell Biol, 17:3028-36. Exemplary assays useful for measuring rRNA pseudouridylation activity of cells containing complex 132b include but are not limited to those described in Lafontaine DL et al., 1998, Genes Dev, 12:527-37. Exemplary assays useful for measuring the protein folding and translocating activity of complex 134a include but are not limited to those described in Gautschi M et al., 2001, Proc Natl Acad Sci U S A, 98:3762-7. Exemplary assays useful for measuring RNA stabilizing activity of complex 134a include but are not limited to those described in Jacobs JS et al., 1998, EMBO J, 17:1497-506. Exemplary assays useful for measuring growth of cells containing complex 134a include but are not limited to those described in Zhang S et al., 1992, EMBO J, 11:3787 96. Exemplary assays useful for measuring translational activity of complex 134b include but are not limited to those described in Valisek L et al., 2001, EMBO J, 20:891 904. Exemplary assays useful for measuring the protein folding and translocating activity of complex 134b include but are not limited to those described in Gautschi M et al., 2001, Proc Nati Acad Sci U S A, 98:3762-7.

WO 03/072602 PCT/EPO2/50003 129 Exemplary assays useful for measuring RNA stabilizing activity of complex 134b include but are not limited to those described in Jacobs JS et al., 1998, EMBO J, 17:1497-506. Exemplary assays useful for measuring growth of cells containing complex 134b include but are not limited to those described in Zhang S et al., 1992, EMBO J, 11:3787 96. Exemplary assays useful for measuring protein phosphatase-2A activity of complex 135a include but are not limited to those described in Cohen P et al., 1988, Methods Enzymol, 159:390-408. Exemplary assays useful for measuring protein phosphatase 4 activity of complex 135a include but are not limited to those described in Hastie CJ and Cohen PT., 1998, FEBS Lett, 431:357-61. Exemplary assays useful for measuring protein phosphatase-2A activity of complex 135b include but are not limited to those described in Cohen P et al., 1988, Methods Enzymol, 159:390-408. Exemplary assays useful for measuring protein phosphatase 4 activity of complex 135b include but are not limited to those described in Hastie CJ and Cohen PT., 1998, FEBS Lett, 431:357-61. Exemplary animal models useful for assaying compounds interacting with transgenic mice used for the study of ovary development complex 136a include but are not limited to those described in Freiman RN et al., 2001, Science, 293:2084-7. Exemplary assays useful for measuring acetylase activity of complex 136a include but are not limited to those described in Fischle W et al., 1999, J Biol Chem, 274:11713-20. Exemplary assays useful for measuring serine/threonine protein kinase activity of complex 136a include but are not limited to those described in Leverson JD et al., 1998, Mol Cell, 2:417-25. Exemplary assays useful for measuring cell cycle progression of cells containing complex 136a include but are not limited to those described in Kruhlak MJ et al., 2001, J Biol Chem, 276:38307-19. Exemplary assays useful for measuring apoptosis induction of cells containing complex 136a include but are not limited to those described in Chen Lf et al., 2001, Science, 293:1653-7.

WO 03/072602 PCT/EPO2/50003 130 Exemplary animal models useful for assaying compounds interacting with the analysis of genetic complementation during T cell development complex 136b include but are not limited to those described in Jacobs H et al., 1999, J Exp Med, 190:1059-68. Exemplary animal models useful for assaying compounds interacting with transgenic mice used for the study of ovary development complex 136b include but are not limited to those described in Freiman RN et al., 2001, Science, 293:2084-7. Exemplary assays useful for measuring acetylase activity of complex 136b include but are not limited to those described in Fischle Wet al., 1999, J Biol Chem, 274:11713-20. Exemplary assays useful for measuring serine/threonine protein kinase activity of complex 136b include but are not limited to those described in Leverson JD et al., 1998, Mol Cell, 2:417-25. Exemplary assays useful for measuring cell cycle progression of cells containing complex 136b include but are not limited to those described in Kruhlak MJ et al., 2001, J Biol Chem, 276:38307-19. Exemplary assays useful for measuring apoptosis induction of cells containing complex 136b include but are not limited to those described in Chen Lf et al., 2001, Science, 293:1653-7. Exemplary animal models useful for assaying compounds interacting with transgenic mice displaying a human prostate cancer-like phenotype complex 137a include but are not limited to those described in Saffran DC et al., 2001, Proc Natl Acad Sci U S A, 98:2658-63. Exemplary animal models useful for assaying compounds interacting with transgenic mice used for the study of ovary development complex 137a include but are not limited to those described in Freiman RN et al., 2001, Science, 293:2084-7. Exemplary assays useful for measuring DNA topoisomerase activity of complex 137a include but are not limited to those described in Merino A et al., 1993, Nature, 365:227-32. and/or MA D et al., 1996, Proc Natl Acad Sci U S A, 93:6583-8. Exemplary animal models useful for assaying compounds interacting with transgenic mice displaying a human prostate cancer-like phenotype complex 137b include but are not limited to those described in Saffran DC et al., 2001, Proc Natl Acad Sci U S A, 98:2658-63.

WO 03/072602 PCT/EPO2/50003 131 Exemplary animal models useful for assaying compounds interacting with transgenic mice used for the study of ovary development complex 137b include but are not limited to those described in Freiman RN et al., 2001, Science, 293:2084-7. Exemplary assays useful for measuring casein kinase activity of complex 137b include but are not limited to those described in Park JW and Bae YS., 1999, Biochem Biophys Res Commun, 263:475-81. Exemplary assays useful for measuring histone deacetylase activity of complex 137b include but are not limited to those described in Hoffmann K et al., 2001 Jan-Feb, Bioconjug Chem, 12:51-5. Exemplary assays useful for measuring DNA topoisomerase activity of complex 137b include but are not limited to those described in Merino A et al., 1993, Nature, 365:227-32. and/or MA D et al., 1996, Proc Natl Acad Sci U S A, 93:6583-8. Exemplary assays useful for measuring translational initiation activity of complex 138a include but are not limited to those described in Valisek L et al., 2001, EMBO J, 20:891-904. and/or Naranda T et al., 1994, J Biol Chem, 269:32286-92. Exemplary assays useful for measuring viability of cells containing complex 138a include but are not limited to those described in Das S and Maitra U., 2000, Mol Cell Biol, 20:3942-50. Exemplary assays useful for measuring translational initiation activity of complex 138b include but are not limited to those described in Valisek L et al., 2001, EMBO J, 20:891-904. and/or Naranda T et al., 1994, J Biol Chem, 269:32286-92. Exemplary assays useful for measuring viability of cells containing complex 138b include but are not limited to those described in Das S and Maitra U., 2000, Mol Cell Biol, 20:3942-50. Exemplary assays useful for measuring DNA helicase activity of complex 139a include but are not limited to those described in Adamkewicz JI et al., 2000, J Biol Chem, 275:21158-68. Exemplary assays useful for measuring protein kinase activity of complex 139a include but are not limited to those described in Chen H et al., 2001, Biochemistry, 40:11851-9. Exemplary assays useful for measuring in vivo acetyltransferase activity in CSC12-cells containing complex 139a include but are not limited to those described in Hamamori Y et al., 1999, Cell, 96:405-13.

WO 03/072602 PCT/EPO2/50003 132 Exemplary assays useful for measuring DNA helicase activity of complex 139b include but are not limited to those described in Adamkewicz JI et al., 2000, J Biol Chem, 275:21158-68. Exemplary assays useful for measuring protein kinase activity of complex 139b include but are not limited to those described in Chen H et al., 2001, Biochemistry, 40:11851-9. Exemplary assays useful for measuring RNA polymerase II activity of complex 139b include but are not limited to those described in Majello B and Napolitano G., 2001, Front Biosci, 6:1358-68. Exemplary assays useful for measuring in vivo acetyltransferase activity in CSC12-cells containing complex 139b include but are not limited to those described in Hamamori Y et al., 1999, Cell, 96:405-13. Exemplary assays useful for measuring translational activity of complex 140a include but are not limited to those described in Finzi E et al., 1981, J Biol Chem, 256:11917-22. Exemplary assays useful for measuring respiration and sensitivity of mtDNA to damaging agents in cells containing complex 140a include but are not limited to those described in Ling F et al., 2000, Nucleic Acids Res, 28:4956-63. Exemplary assays useful for measuring respiration activity of cells containing complex 140a include but are not limited to those described in Levy SB et al., 1976, N EngI J Med, 295:583-8. Exemplary assays useful for measuring translational activity of complex 140b include but are not limited to those described in Finzi E et al., 1981, J Biol Chem, 256:11917-22. Exemplary assays useful for measuring respiration and sensitivity of mtDNA to damaging agents in cells containing complex 140b include but are not limited to those described in Ling F et al., 2000, Nucleic Acids Res, 28:4956-63. Exemplary assays useful for measuring respiration activity of cells containing complex 140b include but are not limited to those described in Levy SB et al., 1976, N EngI J Med, 295:583-8.

WO 03/072602 PCT/EPO2/50003 133 Exemplary assays useful for measuring ATPase activity of complex 141a include but are not limited to those described in Fr6hlich KU et al., 1995, Biochim Biophys Acta, 1253:25-32. Exemplary assays useful for measuring ubiquitin-mediated proteolytic activity in yeast cells containing complex 141a include but are not limited to those described in Ghislain M et al., 1996, EMBO J, 15:4884-99. Exemplary assays useful for measuring protein degradation activity of complex 141b include but are not limited to those described in Wang CW et al., 2001, J Biol Chem, 276:30442-51. Exemplary assays useful for measuring ATPase activity of complex 141b include but are not limited to those described in Fr~hlich KU et al., 1995, Biochim Biophys Acta, 1253:25-32. Exemplary assays useful for measuring ubiquitin-mediated proteolytic activity in yeast cells containing complex 141b include but are not limited to those described in Ghislain M et al., 1996, EMBO J, 15:4884-99. Exemplary assays useful for measuring RNA 3'-5' exonuclease activity of complex 142a include but are not limited to those described in 0 Exemplary assays useful for measuring RNA helicase activity of complex 142a include but are not limited to those described in Wang Yet al., 1998, Curr Biol, 8:441 51. Exemplary assays useful for measuring Ski7 inhibition of virus propagation in yeast cells containing complex 142a include but are not limited to those described in Benard L et al., 1999, J Virol, 73:2893-900. Exemplary animal models useful for assaying compounds interacting with EEF1A2, (the human homolog of Ski7) transgenic in mice complex 142b include but are not limited to those described in Chambers DM et al., 1998, Proc Natl Acad Sci U S A, 95:4463-8. Exemplary assays useful for measuring RNA 3'-5' exonuclease activity of complex 142b include but are not limited to those described in Benard L et al., 1999, J Virol, 73:2893-900. andlor van Hoof A et al., 2000, Mol Cell Biol, 20:8230-43. Exemplary assays useful for measuring RNA helicase activity of complex 142b include but are not limited to those described in Wang Y et al., 1998, Curr Biol, 8:441 51.

WO 03/072602 PCT/EPO2/50003 134 Exemplary assays useful for measuring Ski7 inhibition of virus propagation in yeast cells containing complex 142b include but are not limited to those described in Benard L et al., 1999, J Virol, 73:2893-900. Exemplary assays useful for measuring the effect on elF4E m7cap-binding activity of complex 143a include but are not limited to those described in Altmann M and Trachsel H., 1989, Nucleic Acids Res, 17:5923-31. Exemplary assays useful for measuring control of cell growth of yeast cells containing complex 143a include but are not limited to those described in 0 Exemplary assays useful for measuring control of protein synthesis in human cells containing complex 143a include but are not limited to those described in Jones RM et al., 1996, Mol Cell Biol, 16:4754-64. Exemplary animal models useful for assaying compounds interacting with the analysis elF4E level after the induction of global ischaemia in rat brain complex 143b include but are not limited to those described in Martin de la Vega C et al., 2001, Biochem J, 357:819-26. Exemplary assays useful for measuring the effect on elF4E m7cap-binding activity of complex 143b include but are not limited to those described in Altmann M and Trachsel H., 1989, Nucleic Acids Res, 17:5923-31. Exemplary assays useful for measuring control of cell growth of yeast cells containing complex 143b include but are not limited to those described in Anthony C et al., 2001, J Biol Chem, 276:39645-52. Exemplary assays useful for measuring control of protein synthesis in human cells containing complex 143b include but are not limited to those described in Jones RM et al., 1996, Mol Cell Biol, 16:4754-64. Exemplary assays useful for measuring control of cell growth of yeast cells containing complex 143b include but are not limited to those described in Sonenberg N and Gingras AC., 1998, Curr Opin Cell Biol, 10:268-75. Exemplary assays useful for measuring methyltransferase activity of complex 145a include but are not limited to those described in Aoki A et al., 2001, Nucleic Acids Res, 29:3506-12. Exemplary assays useful for measuring ubiquitylation activity of complex 145a include but are not limited to those described in Jiang J et al., 2001, J Biol Chem, 276:42938-44.

WO 03/072602 PCT/EPO2/50003 135 Exemplary assays useful for measuring immortalizing properties of myeloid progenitors cells containing complex 145a include but are not limited to those described in Luo RT et al., 2001, Mol Cell Biol, 21:5678-87. Exemplary assays useful for measuring methyltransferase activity of complex 145b include but are not limited to those described in Aoki A et al., 2001, Nucleic Acids Res, 29:3506-12. Exemplary assays useful for measuring ubiquitylation activity of complex 145b include but are not limited to those described in Jiang J et al., 2001, J Biol Chem, 276:42938-44. Exemplary assays useful for measuring RNA polymerase II activity of complex 145b include but are not limited to those described in Majello B and Napolitano G., 2001, Front Biosci, 6:1358-68. Exemplary assays useful for measuring immortalizing properties of myeloid progenitors cells complex 145b include but are not limited to those described in Luo RT et al., 2001, Mol Cell Biol, 21:5678-87. Exemplary assays useful for measuring rRNA processing activity of complex 146a include but are not limited to those described in Colley A et al., 2000, Mol Cell Biol, 20:7238-46. and/or Tollervey D et al., 1993, Cell, 72:443-57. Exemplary assays useful for measuring subcellular localization/transport of precursor rRNA in cells containing complex 146a include but are not limited to those described in Dundr M et al., 2000, J Cell Biol, 150:433-46. Exemplary assays useful for measuring rRNA processing activity of complex 146b include but are not limited to those described in Colley A et al., 2000, Mol Cell Biol, 20:7238-46. and/or Tollervey D et al., 1993, Cell, 72:443-57. Exemplary assays useful for measuring subcellular localization/transport of precursor rRNA in cells containing complex 146b include but are not limited to those described in Dundr M et al., 2000, J Cell Biol, 150:433-46. Exemplary assays useful for measuring Golgi to ER transport activity of complex 147a include but are not limited to those described in Dogic D et al., 1999, Eur J Cell Biol, 78:305-10. Exemplary assays useful for measuring GAP activity of complex 147a include but are not limited to those described in Poon PP et al., 1999, EMBO J, 18:555-64.

WO 03/072602 PCT/EPO2/50003 136 Exemplary assays useful for measuring viability of cells containing complex 147a include but are not limited to those described in Duden R et al., 1994, J Biol Chem, 269:24486-95. Exemplary assays useful for measuring Golgi to ER transport activity of complex 147b include but are not limited to those described in Dogic D et al., 1999, Eur J Cell Biol, 78:305-10. Exemplary assays useful for measuring GAP activity of complex 147b include but are not limited to those described in Poon PP et al., 1999, EMBO J, 18:555-64. Exemplary assays useful for measuring viability of cells containing complex 147b include but are not limited to those described in Duden R et al., 1994, J Biol Chem, 269:24486-95. Exemplary animal models useful for assaying compounds interacting with cats infected with the feline immunodeficiency virus complex 148a include but are not limited to those described in Piedimonte G et al., 1999, Exp Cell Res, 248:381-90. Exemplary animal models useful for assaying compounds interacting with transgenic nice displaying an asthma-like phenotype complex 148a include but are not limited to those described in Elliott PJ et al., 1999, J Allergy Clin Immunol, 104:294-300. Exemplary animal models useful for assaying compounds interacting with transgenic nice displaying a diabetes type 1-like phenotype complex 148a include but are not limited to those described in Hayashi T and Faustman D., 1999, Mol Cell Biol, 19:8646 59. Exemplary assays useful for measuring protein degradation activity of complex 148a include but are not limited to those described in Kuckelkorn U et al., 2000 Sep-Oct, Biol Chem, 381:1017-23. and/or Ugai S et al., 1993, J Biochem (Tokyo), 113:754-68. Exemplary assays useful for measuring protein degradation (fluorescence-based assay) in cells containing complex 148a include but are not limited to those described in Andreatta C et al., 2001, Biotechniques, 30:656-60. Exemplary animal models useful for assaying compounds interacting with cats infected with the feline immunodeficiency virus complex 148b include but are not limited to those described in Piedimonte G et al., 1999, Exp Cell Res, 248:381-90. Exemplary animal models useful for assaying compounds interacting with transgenic nice displaying an asthma-like phenotype complex 148b include but are not limited to those described in Elliott PJ et al., 1999, J Allergy Clin Immunol, 104:294-300.

WO 03/072602 PCT/EPO2/50003 137 Exemplary animal models useful for assaying compounds interacting with transgenic nice displaying a diabetes type 1-like phenotype complex 148b include but are not limited to those described in Hayashi T and Faustman D., 1999, Mol Cell Biol, 19:8646 59. Exemplary assays useful for measuring protein degradation activity of complex 148b include but are not limited to those described in Kuckelkorn U et al., 2000 Sep-Oct, Biol Chem, 381:1017-23. and/or Ugai S et al., 1993, J Biochem (Tokyo), 113:754-68. Exemplary assays useful for measuring protein degradation (fluorescence-based assay) in cells containing complex 148b include but are not limited to those described in Andreatta C et al., 2001, Biotechniques, 30:656-60. Exemplary assays useful for measuring DNA helicase activity of complex 149a include but are not limited to those described in Kanemaki M et al., 1999, J Biol Chem, 274:22437-44. Exemplary assays useful for measuring RNAse activity of complex 149a include but are not limited to those described in Daugeron MC et al., 2001, Nucleic Acids Res, 29:2448-55. Exemplary assays useful for measuring DNA endonuclease activity of complex 149a include but are not limited to those described in Zhu FX et al., 1997, Biochemistry, 36:5947-54. Exemplary assays useful for measuring mRNA degradation in vivo in cells containing complex 149a include but are not limited to those described in Daugeron MC et al., 2001, Nucleic Acids Res, 29:2448-55. Exemplary assays useful for measuring DNA helicase activity of complex 149b include but are not limited to those described in Kanemaki M et al., 1999, J Biol Chem, 274:22437-44. Exemplary assays useful for measuring RNAse activity of complex 149b include but are not limited to those described in Daugeron MC et al., 2001, Nucleic Acids Res, 29:2448-55. Exemplary assays useful for measuring DNA endonuclease activity of complex 149b include but are not limited to those described in Zhu FX et al., 1997, Biochemistry, 36:5947-54. Exemplary assays useful for measuring mRNA degradation in vivo in cells containing complex 149b include but are not limited to those described in Daugeron MC et al., 2001, Nucleic Acids Res, 29:2448-55.

WO 03/072602 PCT/EPO2/50003 138 Exemplary assays useful for measuring DNA replication activity of complex 150a include but are not limited to those described in Vashee S et al., 2001, J Biol Chem, 276:26666-73. Exemplary assays useful for measuring Epstein Barr Virus plasmid replication and maintenance in HCT116 colon carcinoma cells containing complex 150a include but are not limited to those described in Dhar SK et al., 2001, Cell, 106:287-96. Exemplary assays useful for measuring DNA replication activity of complex 150b include but are not limited to those described in Vashee S et al., 2001, J Biol Chem, 276:26666-73. Exemplary assays useful for measuring Epstein Barr Virus plasmid replication and maintenance in HCT116 colon carcinoma cells containing complex 150b include but are not limited to those described in Dhar SK et al., 2001, Cell, 106:287-96. Exemplary assays useful for measuring protein-protein binding activity of complex 151a include but are not limited to those described in Sontag E et al., 1999, J Biol Chem, 274:25490-8. Exemplary assays useful for measuring protein phosphatase-2A activity of complex 151a include but are not limited to those described in Cohen P et al., 1988, Methods Enzymol, 159:390-408. Exemplary animal models useful for assaying compounds interacting with ATR knock-out mice (chromosomal fragmentation and early embryonic lethality phenotypes) complex 151b include but are not limited to those described in Brown EJ and Baltimore D., 2000, Genes Dev, 14:397-402. Exemplary assays useful for measuring protein-protein binding activity of complex 151b include but are not limited to those described in Sontag E et al., 1999, J Biol Chem, 274:25490-8. Exemplary assays useful for measuring guanine nucleotide exchange factor activity of complex 151b include but are not limited to those described in Sasaki T et al., 1990, J Biol Chem, 265:2333-7. Exemplary assays useful for measuring protein phosphatase-2A activity of complex 151b include but are not limited to those described in Cohen P et al., 1988, Methods Enzymol, 159:390-408. Exemplary assays useful for measuring guanine nucleotide exchange factor activity of complex 151b include but are not limited to those described in Horiuchi H et al., 1995, J Biol Chem, 270:11257-62.

WO 03/072602 PCT/EPO2/50003 139 Exemplary assays useful for measuring ATPase of complex 151b include but are not limited to those described in Kimura K and Hirano T., 1997, Cell, 90:625-34. Exemplary assays useful for measuring exonuclease activity of complex 152a include but are not limited to those described in Li B and Comai L., 2000, J Biol Chem, 275:28349-52. Exemplary assays useful for measuring DNA topoisomerase of complex 152a include but are not limited to those described in Merino A et al., 1993, Nature, 365:227 32. Exemplary assays useful for measuring genetic complementation of Rad52 mutations in yeast cells containing complex 152a include but are not limited to those described in Huang P et al., 2001, Curr Biol, 11:125-9. Exemplary assays useful for measuring genetic complementation of SGS1 mutations in yeast cells containing complex 152a include but are not limited to those described in Kawabe Yi et al., 2001, J Biol Chem, 276:20364-9. Exemplary assays useful for measuring genetic complementation of Top3 mutations in yeast cells containing complex 152a include but are not limited to those described in Chakraverty RK et al., 2001, Mol Cell Biol, 21:7150-62. Exemplary animal models useful for assaying compounds interacting with Topo Ill defficient mice complex 152b include but are not limited to those described in Kwan KY and Wang JC., 2001, Proc Natl Acad Sci U S A, 98:5717-21. Exemplary animal models useful for assaying compounds interacting with BLM defficient mice complex 152b include but are not limited to those described in Chester N et al., 1998, Genes Dev, 12:3382-93. Exemplary assays useful for measuring exonuclease activity of complex 152b include but are not limited to those described in Li B and Comai L., 2000, J Biol Chem, 275:28349-52. Exemplary assays useful for measuring DNA topoisomerase of complex 152b include but are not limited to those described in Merino A et al., 1993, Nature, 365:227 32. Exemplary assays useful for measuring genetic complementation of Rad52 mutations in yeast cells containing complex 152b include but are not limited to those described in Huang Pet al., 2001, Curr Biol, 11:125-9.

WO 03/072602 PCT/EPO2/50003 140 Exemplary assays useful for measuring genetic complementation of SGS1 mutations in yeast cells containing complex 152b include but are not limited to those described in Kawabe Yi et al., 2001, J Biol Chem, 276:20364-9. Exemplary assays useful for measuring genetic complementation of Top3 mutations in yeast cells containing complex 152b include but are not limited to those described in Chakraverty RK et al., 2001, Mol Cell Biol, 21:7150-62. Exemplary assays useful for measuring actin polymerization activity of complex 153 include but are not limited to those described in Suzuki T et al., 2000, J Exp Med, 191:1905-20. Exemplary assays useful for measuring adhesion properties of cells containing complex 153 include but are not limited to those described in Liu AX et al., 2001, Mol Cell Biol, 21:6906-12. Exemplary assays useful for measuring protein serine/threonine phosphatase activity of complex 154a include but are not limited to those described in Li L et al., 2000, J Biol Chem, 275:2410-4. Exemplary assays useful for measuring chromatin remodelling activity of complex 154a include but are not limited to those described in Kadam S et al., 2000, Genes Dev, 14:2441-51. Exemplary assays useful for measuring DNA helicase activity of complex 154a include but are not limited to those described in Rogers GW et al., 2001, J Biol Chem, 276:30914-22. Exemplary assays useful for measuring transcription factor activity of complex 154a include but are not limited to those described in L'Etoile ND et al., 1994, Proc Natl Acad Sci U S A, 91:1652-6. Exemplary assays useful for measuring chromatin remodelling activity of complex 154a include but are not limited to those described in Wang W et al., 1996, EMBO J, 15:5370-82. Exemplary assays useful for measuring rRNA transcription activity of complex 154a include but are not limited to those described in Keener J et al., 1998, J Biol Chem, 273:33795-802. Exemplary assays useful for measuring proliferation activity of cells containing complex 154a include but are not limited to those described in Sakamoto K et al., 1991, J Biol Chem, 266:3031-8.

WO 03/072602 PCT/EPO2/50003 141 Exemplary animal models useful for assaying compounds interacting with transgenic nice displaying a systemic sclerosis-like phenotype complex 154b include but are not limited to those described in van de Water J and Gershwin ME., 1985, Am J Pathol, 120:478-82. and/or Siracusa LD et al., 1993, Genomics, 17:748-51. Exemplary assays useful for measuring protein serine/threonine phosphatase activity of complex 154b include but are not limited to those described in Li L et al., 2000, J Biol Chem, 275:2410-4. Exemplary assays useful for measuring chromatin remodelling activity of complex 154b include but are not limited to those described in Kadam S et al., 2000, Genes Dev, 14:2441-51. Exemplary assays useful for measuring DNA helicase activity of complex 154b include but are not limited to those described in Rogers GW et al., 2001, J Biol Chem, 276:30914-22. Exemplary assays useful for measuring transcription factor activity of complex 154b include but are not limited to those described in L'Etoile ND et al., 1994, Proc Natl Acad Sci U S A, 91:1652-6. Exemplary assays useful for measuring chromatin remodelling activity of complex 154b include but are not limited to those described in Wang W et al., 1996, EMBO J, 15:5370-82. Exemplary assays useful for measuring rRNA transcription activity of complex 154b include but are not limited to those described in Keener J et al., 1998, J Biol Chem, 273:33795-802. Exemplary assays useful for measuring proliferation activity of cells containing complex 154b include but are not limited to those described in Sakamoto K et al., 1991, J Biol Chem, 266:3031-8. Exemplary assays useful for measuring mRNA splicing activity of complex 155a include but are not limited to those described in 0 Exemplary assays useful for measuring pre-mRNA splicing activity of complex 155a include but are not limited to those described in Schwer B and Gross CH., 1998, EMBO J, 17:2086-94. Exemplary assays useful for measuring gene expression of a reporter protein in cells containing complex 155a include but are not limited to those described in Baudino TA et al., 1998, J Biol Chem, 273:16434-41.

WO 03/072602 PCT/EPO2/50003 142 Exemplary animal models useful for assaying compounds interacting with transgenic nice displaying a lupus nephritis-like phenotype complex 155b include but are not limited to those described in Granholm NA and Cavallo T., 1991, Clin Exp Immunol, 85:270-7. Exemplary animal models useful for assaying compounds interacting with transgenic nice displaying a systemic lupus erythematosus-like phenotype complex 155b include but are not limited to those described in Kyogoku M et al., 1987, Prog Clin Biol Res, 229:95-130. Exemplary animal models useful for assaying compounds interacting with transgenic nice displaying a lupus nephritis-like phenotype complex 155b include but are not limited to those described in Entani C et al., 1993, Nephron, 64:471-5. Exemplary animal models useful for assaying compounds interacting with transgenic nice displaying a xeroderma pigmentosum-like phenotype complex 155b include but are not limited to those described in Takeuchi S et al., 1998, Cancer Res, 58:641-6. Exemplary assays useful for measuring mRNA splicing activity of complex 155b include but are not limited to those described in Chen CH et al., 2001, J Biol Chem, 276:488-94. and/or Lin RJ et al., 1985, J Biol Chem, 260:14780-92. Exemplary assays useful for measuring pre-mRNA splicing activity of complex 155b include but are not limited to those described in Schwer B and Gross CH., 1998, EMBO J, 17:2086-94. Exemplary assays useful for measuring gene expression of a reporter protein in cells containing complex 155b include but are not limited to those described in Baudino TA et al., 1998, J Biol Chem, 273:16434-41. Exemplary animal models useful for assaying compounds interacting with mice with a conditional deletion of a ribosomal protein complex 156a include but are not limited to those described in Volarevic S et al., 2000, Science, 288:2045-7. Exemplary assays useful for measuring casein kinase activity of complex 156a include but are not limited to those described in Park JW and Bae YS., 1999, Biochem Biophys Res Commun, 263:475-81. Exemplary assays useful for measuring rRNA processing activity of complex 156a include but are not limited to those described in Colley A et al., 2000, Mol Cell Biol, 20:7238-46. and/or Kressler D et al., 1997, Mol Cell Biol, 17:7283-94. Exemplary assays useful for measuring cell cycle arrest of cells containing complex 156a include but are not limited to those described in Pestov DG et al., 2001, Mol Cell Biol, 21:4246-55.

WO 03/072602 PCT/EPO2/50003 143 Exemplary assays useful for measuring nuclear export of ribosomal proteins in cells containing complex 156a include but are not limited to those described in Hurt E et al., 1999, J Cell Biol, 144:389-401. Exemplary animal models useful for assaying compounds interacting with mice with a conditional deletion of a ribosomal protein complex 156b include but are not limited to those described in Volarevic S et al., 2000, Science, 288:2045-7. Exemplary assays useful for measuring casein kinase activity of complex 156b include but are not limited to those described in Park JW and Bae YS., 1999, Biochem Biophys Res Commun, 263:475-81. Exemplary assays useful for measuring rRNA processing activity of complex 156b include but are not limited to those described in Colley A et al., 2000, Mol Cell Biol, 20:7238-46. and/or Kressler D et al., 1997, Mol Cell Biol, 17:7283-94. Exemplary assays useful for measuring cell cycle arrest of cells containing complex 156b include but are not limited to those described in Pestov DG et al., 2001, Mol Cell Biol, 21:4246-55. Exemplary assays useful for measuring nuclear export of ribosomal proteins in cells containing complex 156b include but are not limited to those described in Hurt E et al., 1999, J Cell Biol, 144:389-401. Exemplary animal models useful for assaying compounds interacting with cats infected with the feline immunodeficiency virus complex 157a include but are not limited to those described in Piedimonte G et al., 1999, Exp Cell Res, 248:381-90. Exemplary animal models useful for assaying compounds interacting with transgenic nice displaying an asthma-like phenotype complex 157a include but are not limited to those described in Elliott PJ et al., 1999, J Allergy Clin Immunol, 104:294-300. Exemplary animal models useful for assaying compounds interacting with transgenic nice displaying a diabetes type 1-like phenotype complex 157a include but are not limited to those described in Hayashi T and Faustman D., 1999, Mol Cell Biol, 19:8646 59. Exemplary assays useful for measuring proteasome activity of complex 157a include but are not limited to those described in Kuckelkorn U et al., 2000 Sep-Oct, Biol Chem, 381:1017-23. and/or Ugai S et al., 1993, J Biochem (Tokyo), 113:754-68. Exemplary assays useful for measuring protein degradation via the proteasome complex 157a include but are not limited to those described in Lightcap ES et al., 2000, Clin Chem, 46:673-83.

WO 03/072602 PCT/EPO2/50003 144 Exemplary assays useful for measuring protein degradation (fluorescence-based assay) in cells containing complex 157a include but are not limited to those described in Andreatta C et al., 2001, Biotechniques, 30:656-60. Exemplary animal models useful for assaying compounds interacting with cats infected with the feline immunodeficiency virus complex 157b include but are not limited to those described in Piedimonte G et al., 1999, Exp Cell Res, 248:381-90. Exemplary animal models useful for assaying compounds interacting with transgenic nice displaying an asthma-like phenotype complex 157b include but are not limited to those described in Elliott PJ et al., 1999, J Allergy Clin Immunol, 104:294-300. Exemplary animal models useful for assaying compounds interacting with transgenic nice displaying a diabetes type 1-like phenotype complex 157b include but are not limited to those described in Hayashi T and Faustman D., 1999, Mol Cell Biol, 19:8646 59. Exemplary assays useful for measuring proteasome activity of complex 157b include but are not limited to those described in Kuckelkorn U et al., 2000 Sep-Oct, Biol Chem, 381:1017-23. and/or Ugai S et al., 1993, J Biochem (Tokyo), 113:754-68. Exemplary assays useful for measuring protein degradation via the proteasome complex 157b include but are not limited to those described in Lightcap ES et al., 2000, Clin Chem, 46:673-83. Exemplary assays useful for measuring protein degradation (fluorescence-based assay) in cells containing complex 157b include but are not limited to those described in Andreatta C et al., 2001, Biotechniques, 30:656-60. Exemplary assays useful for measuring RNA splicing activity of complex 158a include but are not limited to those described in Romfo CM et al., 2001, RNA, 7:785-92. and/or S6gault V et al., 1995, EMBO J, 14:4010-21. Exemplary animal models useful for assaying compounds interacting with transgenic nice displaying a spinal muscular atrophy-like phenotype complex 158b include but are not limited to those described in Monani UR et al., 2000, Hum Mol Genet, 9:333-9. Exemplary animal models useful for assaying compounds interacting with transgenic nice displaying a spinal lupus nephritis-like phenotype complex 158b include but are not limited to those described in Granholm NA and Cavallo T., 1991, Clin Exp Immunol, 85:270-7. Exemplary animal models useful for assaying compounds interacting with transgenic nice displaying a systemic lupus erythematosus-like phenotype complex 158b include WO 03/072602 PCT/EPO2/50003 145 but are not limited to those described in Kyogoku M et al., 1987, Prog Clin Biol Res, 229:95-130. Exemplary animal models useful for assaying compounds interacting with transgenic nice displaying a spinal lupus nephritis-like phenotype complex 158b include but are not limited to those described in Entani C et al., 1993, Nephron, 64:471-5. Exemplary animal models useful for assaying compounds interacting with transgenic nice displaying a xeroderma pigmentosum-like phenotype complex 158b include but are not limited to those described in Takeuchi S et al., 1998, Cancer Res, 58:641-6. Exemplary assays useful for measuring RNA splicing activity of complex 158b include but are not limited to those described in Romfo CM et al., 2001, RNA, 7:785-92. and/or S6gault V et al., 1995, EMBO J, 14:4010-21. Exemplary assays useful for measuring acetylase activity of complex 159a include but are not limited to those described in Fischle W et al., 1999, J Biol Chem, 274:11713-20. Exemplary assays useful for measuring transcription activity of complex 159a include but are not limited to those described in Kikyo N et al., 2000, Science, 289:2360 2. Exemplary assays useful for measuring protein serine/threonine phosphatase activity of complex 159a include but are not limited to those described in Kusuda K et al., 1998, Biochem J, 332 ( Pt 1):243-50. Exemplary assays useful for measuring protein serine/threonine kinase activity of complex 159a include but are not limited to those described in Leverson JD et al., 1998, Mol Cell, 2:417-25. Exemplary assays useful for measuring cell cycle progression of cells containing complex 159a include but are not limited to those described in Kruhlak MJ et al., 2001, J Biol Chem, 276:38307-19. Exemplary assays useful for measuring Apoptosis induction of cells containing complex 159a include but are not limited to those described in Chen Lf et al., 2001, Science, 293:1653-7. Exemplary animal models useful for assaying compounds interacting with transgenic mice for the study of genetic complementation in T cell during development complex 159b include but are not limited to those described in Jacobs H et al., 1999, J Exp Med, 190:1059-68.

WO 03/072602 PCT/EPO2/50003 146 Exemplary animal models useful for assaying compounds interacting with transgenic mice for the study of ovary development complex 159b include but are not limited to those described in Freiman RN et al., 2001, Science, 293:2084-7. Exemplary animal models useful for assaying compounds interacting with transgenic mice for the study of genetic complementation in lymphomas complex 159b include but are not limited to those described in Verbeek S et al., 1991, Mol Cell Biol, 11:1176-9. Exemplary assays useful for measuring acetylase activity of complex 159b include but are not limited to those described in Fischle Wet al., 1999, J Biol Chem, 274:11713-20. Exemplary assays useful for measuring transcription activity of complex 159b include but are not limited to those described in Kikyo N et al., 2000, Science, 289:2360 2. Exemplary assays useful for measuring protein serine/threonine phosphatase activity of complex 159b include but are not limited to those described in Kusuda K et al., 1998, Biochem J, 332 ( Pt 1):243-50. Exemplary assays useful for measuring protein serine/threonine kinase activity of complex 159b include but are not limited to those described in Leverson JD et al., 1998, Mol Cell, 2:417-25. Exemplary assays useful for measuring cell cycle progression of cells containing complex 159b include but are not limited to those described in Kruhlak MJ et al., 2001, J Biol Chem, 276:38307-19. Exemplary assays useful for measuring Apoptosis induction of cells containing complex 159b include but are not limited to those described in Chen Lf et al., 2001, Science, 293:1653-7. Exemplary assays useful for measuring mRNA splicing activity of complex 160a include but are not limited to those described in Padgett RA et al., 1983, Cell, 35:101-7. Exemplary animal models useful for assaying compounds interacting with transgenic nice displaying a spinal muscular atrophy-like phenotype complex 160b include but are not limited to those described in Monani UR et al., 2000, Hum Mol Genet, 9:333-9. Exemplary animal models useful for assaying compounds interacting with transgenic nice displaying a systemic lupus erythematosus-like phenotype complex 160b include but are not limited to those described in Kyogoku M et al., 1987, Prog Clin Biol Res, 229:95-130.

WO 03/072602 PCT/EPO2/50003 147 Exemplary animal models useful for assaying compounds interacting with transgenic nice displaying a xeroderma pigmentosum-like phenotype complex 160b include but are not limited to those described in Takeuchi S et al., 1998, Cancer Res, 58:641-6. Exemplary assays useful for measuring mRNA splicing activity of complex 160b include but are not limited to those described in Padgett RA et al., 1983, Cell, 35:101-7. Exemplary animal models useful for assaying compounds interacting with transgenic nice displaying a spinal muscular atrophy-like phenotype complex 161a include but are not limited to those described in Monani UR et al., 2000, Hum Mol Genet, 9:333-9. Exemplary animal models useful for assaying compounds interacting with transgenic nice displaying a systemic lupus erythematosus-like phenotype complex 161a include but are not limited to those described in Kyogoku M et al., 1987, Prog Clin Biol Res, 229:95-130. Exemplary animal models useful for assaying compounds interacting with transgenic nice displaying a xeroderma pigmentosum-like phenotype complex 161a include but are not limited to those described in Takeuchi S et al., 1998, Cancer Res, 58:641-6. Exemplary assays useful for measuring Gcn2 kinase activity of complex 161a include but are not limited to those described in Sood R et al., 2000, Genetics, 154:787 801. Exemplary assays useful for measuring mRNA splicing activity of complex 161a include but are not limited to those described in Behlke MA et al., 2000, Biotechniques, 29:892-7. Exemplary assays useful for measuring RNA binding activity of complex 161a include but are not limited to those described in lyer RK and Levinger LF., 1988 Nov Dec, Gene Anal Tech, 5:125-9. Exemplary assays useful for measuring RNA processing activity of complex 161a include but are not limited to those described in S6raphin B., 1995, EMBO J, 14:2089 98. Exemplary animal models useful for assaying compounds interacting with transgenic nice displaying a spinal muscular atrophy-like phenotype complex 161b include but are not limited to those described in Monani UR et al., 2000, Hum Mol Genet, 9:333-9. Exemplary animal models useful for assaying compounds interacting with transgenic nice displaying a systemic lupus erythematosus-like phenotype complex 161b include but are not limited to those described in Kyogoku M et al., 1987, Prog Clin Biol Res, 229:95-130.

WO 03/072602 PCT/EPO2/50003 148 Exemplary animal models useful for assaying compounds interacting with transgenic nice displaying a xeroderma pigmentosum-like phenotype complex 161b include but are not limited to those described in Takeuchi S et al., 1998, Cancer Res, 58:641-6. Exemplary assays useful for measuring Gcn2 kinase activity of complex 161b include but are not limited to those described in Sood R et al., 2000, Genetics, 154:787 801. Exemplary assays useful for measuring mRNA splicing activity of complex 161b include but are not limited to those described in Behlke MA et al., 2000, Biotechniques, 29:892-7. Exemplary assays useful for measuring RNA binding activity of complex 161b include but are not limited to those described in lyer RK and Levinger LF., 1988 Nov Dec, Gene Anal Tech, 5:125-9. Exemplary assays useful for measuring RNA processing activity of complex 161b include but are not limited to those described in S6raphin B., 1995, EMBO J, 14:2089 98. Exemplary assays useful for measuring 3' end mRNA processing activity of complex 162a include but are not limited to those described in Raegsegger U et al., 1996, J Biol Chem, 271:6107-13. and/or Kessler MM et al., 1996, J Biol Chem, 271:27167-75. Exemplary assays useful for measuring 3' end mRNA processing activity of complex 162b include but are not limited to those described in Roegsegger U et al., 1996, J Biol Chem, 271:6107-13. and/or Kessler MM et al., 1996, J Biol Chem, 271:27167-75. Exemplary assays useful for measuring rRNA processing activity of complex 163a include but are not limited to those described in Hong B et al., 1997, Mol Cell Biol, 17:378-88. Exemplary assays useful for measuring rRNA localization of cells containing complex 163a include but are not limited to those described in Jordan P et al., 1996, J Cell Biol, 133:225-34. Exemplary assays useful for measuring nuclear export of ribosomal proteins in cells containing complex 163a include but are not limited to those described in Hurt E et al., 1999, J Cell Biol, 144:389-401.

WO 03/072602 PCT/EPO2/50003 149 Exemplary assays useful for measuring rRNA processing activity of complex 163b include but are not limited to those described in Hong B et al., 1997, Mol Cell Biol, 17:378-88. Exemplary assays useful for measuring rRNA localization of cells containing complex 163b include but are not limited to those described in Jordan P et al., 1996, J Cell Biol, 133:225-34. Exemplary assays useful for measuring nuclear export of ribosomal proteins in cells containing complex 163b include but are not limited to those described in Hurt E et al., 1999, J Cell Biol, 144:389-401. Exemplary assays useful for measuring CTD kinase activity of complex 164a include but are not limited to those described in Morris DP et al., 1997, Methods, 12:264-75. Exemplary assays useful for measuring single strand telomeric DNA binding assay of complex 164b include but are not limited to those described in Lin JJ and Zakian VA., 1994, Nucleic Acids Res, 22:4906-13. Exemplary assays useful for measuring CTD kinase activity of complex 164b include but are not limited to those described in Morris DP et al., 1997, Methods, 12:264-75. Exemplary assays useful for measuring cystathionine beta-synthase activity of complex 165 include but are not limited to those described in Kraus JP., 1987, Methods Enzymol, 143:388-94. Exemplary assays useful for measuring cystathionine synthase activity of complex 165 include but are not limited to those described in Kashiwamata S and Greenberg DM., 1970, Biochim Biophys Acta, 212:488-500. Exemplary assays useful for measuring cystathionine synthase activity in cultured fibroblasts containing complex 165 include but are not limited to those described in Boers GH et al., 1985, Hum Genet, 69:164-9. Exemplary assays useful for measuring adenylosuccinate lyase activity of complex 166 include but are not limited to those described in Park KW et al., 1980, J Biochem Biophys Methods, 2:291-7. Exemplary animal models useful for assaying compounds interacting with transgenic nice displaying a mitochondrial disease-like phenotype complex 167a include but are not limited to those described in Wallace DC., 2001 Spring, Am J Med Genet, 106:71-93.

WO 03/072602 PCT/EPO2/50003 150 Exemplary animal models useful for assaying compounds interacting with transgenic nice displaying a Parkinson's disease-like phenotype complex 167a include but are not limited to those described in Petroske E et al., 2001, Neuroscience, 106:589-601. Exemplary animal models useful for assaying compounds interacting with transgenic nice displaying a diabetes-like phenotype complex 167a include but are not limited to those described in Makino S et al., 1980, Jikken Dobutsu, 29:1-13. Exemplary assays useful for measuring RNA turnover activity of complex 167a include but are not limited to those described in Min J and Zassenhaus HP., 1993, J Bacteriol, 175:6245-53. Exemplary animal models useful for assaying compounds interacting with transgenic nice displaying a mitochondrial disease-like phenotype complex 167b include but are not limited to those described in Wallace DC., 2001 Spring, Am J Med Genet, 106:71-93. Exemplary animal models useful for assaying compounds interacting with transgenic nice displaying a Parkinson's disease-like phenotype complex 167b include but are not limited to those described in Petroske E et al., 2001, Neuroscience, 106:589-601. Exemplary animal models useful for assaying compounds interacting with transgenic nice displaying a diabetes-like phenotype complex 167b include but are not limited to those described in Makino S et al., 1980, Jikken Dobutsu, 29:1-13. Exemplary assays useful for measuring RNA turnover activity of complex 167b include but are not limited to those described in Min J and Zassenhaus HP., 1993, J Bacteriol, 175:6245-53. Exemplary assays useful for measuring alpha-aminoadipate-semialdehyde dehydrogenase activity of complex 168a include but are not limited to those described in Ehmann DE et al., 1999, Biochemistry, 38:6171-7. Exemplary assays useful for measuring alcohol dehydrogenase activity of complex 168a include but are not limited to those described in Chrostek L et al., 2001, Hum Exp Toxicol, 20:255-8. and/or Ganzhorn AJ and Plapp BV., 1988, J Biol Chem, 263:5446-54. Exemplary assays useful for measuring growth of yeast cells containing complex 168a include but are not limited to those described in Winston MK and Bhattacharjee JK., 1982, J Bacteriol, 152:874-9. Exemplary assays useful for measuring alpha-aminoadipate-semialdehyde dehydrogenase activity of complex 168b include but are not limited to those described in Ehmann DE et al., 1999, Biochemistry, 38:6171-7.

WO 03/072602 PCT/EPO2/50003 151 Exemplary assays useful for measuring nuclear import/export activity of complex 168b include but are not limited to those described in Lindsay ME et al., 2001, J Cell Biol, 153:1391-402. and/or Jlkel S and Girlich D., 1998, EMBO J, 17:4491-502. Exemplary assays useful for measuring growth of yeast cells containing complex 168b include but are not limited to those described in Winston MK and Bhattacharjee JK., 1982, J Bacteriol, 152:874-9. Exemplary assays useful for measuring actin-binding activity of complex 169a include but are not limited to those described in Engqvist-Goldstein AE et al., 1999, J Cell Biol, 147:1503-18. Exemplary assays useful for measuring endocytosis activity of complex 169a include but are not limited to those described in Dulic V et al., 1991, Methods Enzymol, 194:697-710. and/or Volland C et al., 1994, J Biol Chem, 269:9833-41. Exemplary assays useful for measuring actin-binding activity of complex 169b include but are not limited to those described in Engqvist-Goldstein AE et al., 1999, J Cell Biol, 147:1503-18. Exemplary assays useful for measuring kinase activity of complex 169b include but are not limited to those described in Volont6 C et al., 1992, Biotechniques, 12:854-8. Exemplary assays useful for measuring endocytosis activity of complex 169b include but are not limited to those described in Dulic V et al., 1991, Methods Enzymol, 194:697-710. and/or Volland C et al., 1994, J Biol Chem, 269:9833-41. Exemplary assays useful for measuring transcription activity of complex 170a include but are not limited to those described in Schlegel BP et al., 2000, Proc Natl Acad Sci U S A, 97:3148-53. Exemplary assays useful for measuring in vivo chromatin remodeling in yeast cells containing complex 170a include but are not limited to those described in Kent NA et al., 2001, Genes Dev, 15:619-26. Exemplary assays useful for measuring transcription activity of complex 170b include but are not limited to those described in Schlegel BP et al., 2000, Proc Natl Acad Sci U S A, 97:3148-53. Exemplary assays useful for measuring protein kinase assay of complex 170b include but are not limited to those described in Ho Y et al., 1997, Proc Natl Acad Sci U S A, 94:581-6.

WO 03/072602 PCT/EPO2/50003 152 Exemplary assays useful for measuring in vivo chromatin remodeling in yeast cells containing complex 170b include but are not limited to those described in Kent NA et al., 2001, Genes Dev, 15:619-26. Exemplary assays useful for measuring enolase activity of complex 171 include but are not limited to those described in Baranowski T and Wolna E., 1975, Methods Enzymol, 42:335-8. and/or Lilley RM et al., 1985, Anal Biochem, 148:282-7. Exemplary assays useful for measuring cystathionase activity of complex 172 include but are not limited to those described in Bergad PL and Rathbun WB., 1986, Ophthalmic Res, 18:343-8. Exemplary assays useful for measuring 3-hydroxy-3-methylglutaryl-CoA synthase activity of complex 173a include but are not limited to those described in Clinkenbeard KD et al., 1975, Methods Enzymol, 35:160-7. Exemplary assays useful for measuring homoisocitric dehydrogenase activity of complex 173a include but are not limited to those described in Gaillardin CM et al., 1982, Eur J Biochem, 128:489-94. Exemplary assays useful for measuring 3-hydroxy-3-methylglutaryl coenzyme A synthase activity of complex 173a include but are not limited to those described in Rokosz LL et al., 1994, Arch Biochem Biophys, 312:1-13. Exemplary assays useful for measuring 3-hydroxy-3-methylglutaryl-CoA synthase activity of complex 173b include but are not limited to those described in Clinkenbeard KD et al., 1975, Methods Enzymol, 35:160-7. Exemplary assays useful for measuring homoisocitric dehydrogenase activity of complex 173b include but are not limited to those described in Gaillardin CM et al., 1982, Eur J Biochem, 128:489-94. Exemplary assays useful for measuring 3-hydroxy-3-methylglutaryl coenzyme A synthase activity of complex 173b include but are not limited to those described in Rokosz LL et al., 1994, Arch Biochem Biophys, 312:1-13. Exemplary assays useful for measuring disulfid bond formation activity of complex 174a include but are not limited to those described in Frand AR and Kaiser CA., 1998, Mol Cell, 1:161-70. Exemplary assays useful for measuring subcellular localisation of a Sec13 marker protein in cells containing complex 174a include but are not limited to those described in Hammond AT and Glick BS., 2000, Mol Biol Cell, 11:3013-30.

WO 03/072602 PCT/EPO2/50003 153 Exemplary assays useful for measuring effects on viability of cells containing complex 174a include but are not limited to those described in Frand AR and Kaiser CA., 1998, Mol Cell, 1:161-70. Exemplary assays useful for measuring disulfid bond formation activity of complex 174b include but are not limited to those described in Frand AR and Kaiser CA., 1998, Mol Cell, 1:161-70. Exemplary assays useful for measuring subcellular localisation of a Secl 3 marker protein in cells containing complex 174b include but are not limited to those described in Hammond AT and Glick BS., 2000, Mol Biol Cell, 11:3013-30. Exemplary assays useful for measuring effects on viability of cells containing complex 174b include but are not limited to those described in Frand AR and Kaiser CA., 1998, Mol Cell, 1:161-70. Exemplary assays useful for measuring GTPase activity of complex 175a include but are not limited to those described in Esters H et al., 2001, J Mol Biol, 310:141-56. Exemplary assays useful for measuring subcellular localization/transport of Sec6 and Sec8 in cells containing complex 175a include but are not limited to those described in Charron AJ et al., 2000, J Cell Biol, 149:111-24. Exemplary assays useful for measuring GTPase activity of complex 175b include but are not limited to those described in Esters H et al., 2001, J Mol Biol, 310:141-56. Exemplary assays useful for measuring subcellular localization/transport of Sec6 and Sec8 in cells containing complex 175b include but are not limited to those described in Charron AJ et al., 2000, J Cell Biol, 149:111-24. Exemplary assays useful for measuring rRNA processing activity of complex 176a include but are not limited to those described in Kressler D et al., 1997, Mol Cell Biol, 17:7283-94. Exemplary assays useful for measuring export of 60S ribosomes in cells containing complex 176a include but are not limited to those described in Stage Zimmermann T et al., 2000, Mol Biol Cell, 11:3777-89. Exemplary assays useful for measuring rRNA processing activity of complex 176b include but are not limited to those described in Kressler D et al., 1997, Mol Cell Biol, 17:7283-94. Exemplary assays useful for measuring export of 60S ribosomes in cells containing complex 176b include but are not limited to those described in Stage Zimmermann T et al., 2000, Mol Biol Cell, 11:3777-89.

WO 03/072602 PCT/EPO2/50003 154 Exemplary assays useful for measuring iron transport activity of complex 178a include but are not limited to those described in Shingles R et al., 2001, Anal Biochem, 296:106-13. Exemplary assays useful for measuring iron uptake by rabbit erythrocytes containing complex 178a include but are not limited to those described in Chan RY et al., 1986, Biochem Int, 13:409-15. Exemplary animal models useful for assaying compounds interacting with a rat model of renal iron transport complex 178b include but are not limited to those described in Wareing M et al., 2000, J Physiol, 524 Pt 2:581-6. Exemplary assays useful for measuring iron transport activity of complex 178b include but are not limited to those described in Shingles R et al., 2001, Anal Biochem, 296:106-13. Exemplary assays useful for measuring iron uptake by rabbit erythrocytes containing complex 178b include but are not limited to those described in Chan RY et al., 1986, Biochem Int, 13:409-15. Exemplary assays useful for measuring protein secretion activity of complex 180a include but are not limited to those described in Zhdankina 0 et al., 2001, Yeast, 18:1-18. Exemplary assays useful for measuring protein binding activity of complex 180a include but are not limited to those described in Zhu Yet al., 2001, Science, 292:1716-8. Exemplary assays useful for measuring subcellular localization of GGA2 in cells containing complex 180a include but are not limited to those described in Hirst J et al., 2000, J Cell Biol, 149:67-80. Exemplary assays useful for measuring protein secretion activity of complex 180b include but are not limited to those described in Zhdankina O et al., 2001, Yeast, 18:1-18. Exemplary assays useful for measuring protein binding activity of complex 180b include but are not limited to those described in Zhu Y et al., 2001, Science, 292:1716-8. Exemplary assays useful for measuring subcellular localization of GGA2 in cells containing complex 180b include but are not limited to those described in Hirst J et al., 2000, J Cell Biol, 149:67-80. Exemplary assays useful for measuring protein glycosylation activity of complex 181 include but are not limited to those described in SOtterlin C et al., 1998, Biochem J, 332 ( Pt 1):153-9.

WO 03/072602 PCT/EPO2/50003 155 Exemplary assays useful for measuring glycolipid labelling in cells containing complex 181 include but are not limited to those described in SItterlin C et al., 1998, Biochem J, 332 ( Pt 1):153-9. Exemplary assays useful for measuring sumoylation activity of complex 182a include but are not limited to those described in Okuma T et al., 1999, Biochem Biophys Res Commun, 254:693-8. Exemplary animal models useful for assaying compounds interacting with transgenic fly overexpressing UBA2 in the developing eye (retinal degeneration phenotype) complex 182b include but are not limited to those described in Long X and Griffith LC., 2000, J Biol Chem, 275:40765-76. Exemplary assays useful for measuring sumoylation activity of complex 182b include but are not limited to those described in Okuma T et al., 1999, Biochem Biophys Res Commun, 254:693-8. Exemplary animal models useful for assaying compounds interacting with mice injected with BL6 melanoma cells (metastasis model) complex 183a include but are not limited to those described in Nakaji T et al., 1999, Cancer Lett, 147:139-47.(A new member of the GTPase superfamily that is upregulated in highly metastatic cells.) Exemplary assays useful for measuring GTP-binding protein/GTPase activity of complex 183a include but are not limited to those described in Ridley AJ et al., 1993, EMBO J, 12:5151-60. Exemplary animal models useful for assaying compounds interacting with mice injected with BL6 melanoma cells (metastasis model) complex 183b include but are not limited to those described in Nakaji T et al., 1999, Cancer Lett, 147:139-47.(A new member of the GTPase superfamily that is upregulated in highly metastatic cells.) Exemplary assays useful for measuring GTP-binding protein/GTPase activity of complex 183b include but are not limited to those described in Ridley AJ et al., 1993, EMBO J, 12:5151-60. Exemplary assays useful for measuring histone deacetylase activity of complex 185a include but are not limited to those described in Grozinger CM et al., 1999, Proc Natl Acad Sci U S A, 96:4868-73. and/or Hoffmann K et al., 2001 Jan-Feb, Bioconjug Chem, 12:51-5. Exemplary assays useful for measuring nuclear localization/transport of retinoic acid and thyroid hormone receptors (SMRT) in cells containing complex 185a include but are not limited to those described in Wu X et al., 2001, J Biol Chem, 276:24177-85.

WO 03/072602 PCT/EPO2/50003 156 Exemplary assays useful for measuring histone deacetylase activity of complex 185b include but are not limited to those described in Grozinger CM et al., 1999, Proc Natl Acad Sci U S A, 96:4868-73. and/or Hoffmann K et al., 2001 Jan-Feb, Bioconjug Chem, 12:51-5. Exemplary assays useful for measuring nuclear localization/transport of retinoic acid and thyroid hormone receptors (SMRT) in cells containing complex 185b include but are not limited to those described in Wu X et al., 2001, J Biol Chem, 276:24177-85. Exemplary assays useful for measuring homogeneous time-resolved fluorescence energy transfer activity of complex 186 include but are not limited to those described in Zhou G et al., 2001, Methods, 25:54-61. Exemplary assays useful for measuring protein stabilizing activity of complex 186 include but are not limited to those described in Bigelis R et al., 1981, J Biol Chem, 256:5144-52. Exemplary assays useful for measuring arsenite toxicity of cells containing complex 186 include but are not limited to those described in Sok J et al., 2001, Cell Stress Chaperones, 6:6-15. Exemplary assays useful for measuring proliferation activity of cells containing complex 186 include but are not limited to those described in Bencsath M et al., 1998, Pathol Oncol Res, 4:121-4. Exemplary animal models useful for assaying compounds interacting with the study of male mating behaviour in Caenorhabditis elegans complex 187a include but are not limited to those described in Yoda A et al., 2000, Genes Cells, 5:885-895. Exemplary assays useful for measuring mRNA decay activity of complex 187a include but are not limited to those described in Gonzlez Cl et al., 2000, Mol Cell, 5:489-99. Exemplary animal models useful for assaying compounds interacting with the study of male mating behaviour in Caenorhabditis elegans complex 187b include but are not limited to those described in Yoda A et al., 2000, Genes Cells, 5:885-895. Exemplary assays useful for measuring mRNA decay activity of complex 187b include but are not limited to those described in Gonzblez Cl et al., 2000, Mol Cell, 5:489-99. Exemplary assays useful for measuring NAD-dependent protein deacetylase activity of complex 188 include but are not limited to those described in Imai S et al., 2000, Nature, 403:795-800.

WO 03/072602 PCT/EPO2/50003 157 Exemplary assays useful for measuring histone deacetylation in senescent human fibroblasts containing complex 188 include but are not limited to those described in Wagner M et al., 2001, FEBS Lett, 499:101-6. Exemplary assays useful for measuring DNA polymerase activity of complex 189 include but are not limited to those described in Han S et al., 2000, Biochem Pharmacol, 60:403-11. Exemplary assays useful for measuring chromatin remodelling activity of complex 189 include but are not limited to those described in Brehm A et al., 2000, EMBO J, 19:4332-41. Exemplary assays useful for measuring DNA topoisomerase activity of complex 189 include but are not limited to those described in Merino A et al., 1993, Nature, 365:227-32. and/or MA D et al., 1996, Proc Natl Acad Sci U S A, 93:6583-8. Exemplary assays useful for measuring RNA polymerase activity of complex 189 include but are not limited to those described in Sturges MR et al., 1999, Nucleic Acids Res, 27:690-4. Exemplary assays useful for measuring differentiation of cells containing complex 189 include but are not limited to those described in de la Serna IL et al., 2001, Nat Genet, 27:187-90. Exemplary assays useful for measuring centromer DNA binding activity of complex 190a include but are not limited to those described in Ortiz J et al., 1999, Genes Dev, 13:1140-55. Exemplary assays useful for measuring changes in subcellular localization of cell cycle marker proteins in cells containing complex 190a include but are not limited to those described in Dalton S and Whitbread L., 1995, Proc Natl Acad Sci U S A, 92:2514-8. Exemplary assays useful for measuring chromosome transmission in cells containing complex 190a include but are not limited to those described in Poddar A et al., 1999, Mol Microbiol, 31:349-60. Exemplary assays useful for measuring centromer DNA binding activity of complex 190b include but are not limited to those described in Ortiz J et al., 1999, Genes Dev, 13:1140-55. Exemplary assays useful for measuring changes in subcellular localization of cell cycle marker proteins in cells containing complex 190b include but are not limited to WO 03/072602 PCT/EPO2/50003 158 those described in Dalton S and Whitbread L., 1995, Proc Natl Acad Sci U S A, 92:2514-8. Exemplary assays useful for measuring chromosome transmission in cells containing complex 190b include but are not limited to those described in Poddar A et al., 1999, Mol Microbiol, 31:349-60. Exemplary assays useful for measuring pyrophosphatase activity of complex 191a include but are not limited to those described in Eriksson Jet al., 2001, Anal Biochem, 293:67-70. Exemplary assays useful for measuring ATP sulfurylase activity of complex 191 a include but are not limited to those described in Daley LA et al., 1986, Anal Biochem, 157:385-95. Exemplary animal models useful for assaying compounds interacting with mice deficient in plasma cell membrane glycoprotein-1 complex 191b include but are not limited to those described in Rutsch F et al., 2001, Am J Pathol, 158:543-54. Exemplary assays useful for measuring pyrophosphatase activity of complex 191b include but are not limited to those described in Eriksson J et al., 2001, Anal Biochem, 293:67-70. Exemplary assays useful for measuring GTP exchange activity of complex 191b include but are not limited to those described in Sasaki T et al., 1990, J Biol Chem, 265:2333-7. Exemplary assays useful for measuring ATP sulfurylase activity of complex 191b include but are not limited to those described in Daley LA et al., 1986, Anal Biochem, 157:385-95. Exemplary assays useful for measuring VMA1 splicing activity of complex 192 include but are not limited to those described in Kawasaki M et al., 1997, J Biol Chem, 272:15668-74. Exemplary assays useful for measuring autophagy on cells containing complex 192 include but are not limited to those described in Kametaka S et al., 1998, J Biol Chem, 273:22284-91. Exemplary assays useful for measuring ATPase activity of complex 193a include but are not limited to those described in Tsukiyama T et al., 1999, Genes Dev, 13:686 97.

WO 03/072602 PCT/EPO2/50003 159 Exemplary assays useful for measuring Isw2 ATP-dependent chromatin remodeling activity of complex 193a include but are not limited to those described in Gelbart ME et al., 2001, Mol Cell Biol, 21:2098-106. Exemplary assays useful for measuring ATPase activity of complex 193b include but are not limited to those described in Tsukiyama T et al., 1999, Genes Dev, 13:686 97. Exemplary assays useful for measuring Isw2 ATP-dependent chromatin remodeling activity of complex 193b include but are not limited to those described in Gelbart ME et al., 2001, Mol Cell Biol, 21:2098-106. Exemplary assays useful for measuring translation factor activity of complex 195 include but are not limited to those described in Choi SK et al., 1998, Science, 280:1757-60. Exemplary assays useful for measuring CD4 internalization of cells containing complex 195 include but are not limited to those described in Lu X et al., 1998, Immunity, 8:647-56. Exemplary assays useful for measuring aminoacyl synthetase activity of complex 196 include but are not limited to those described in Shiba K et al., 1997, J Biol Chem, 272:22809-16. and/or Stark LA and Hay RT., 1998, J Virol, 72:3037-44. Exemplary assays useful for measuring isopropylmalate dehydratase activity of complex 197 include but are not limited to those described in Kohlhaw GB., 1988, Methods Enzymol, 166:423-9. Exemplary assays useful for measuring alcohol dehydrogenase activity of complex 197 include but are not limited to those described in Bennetzen JL and Hall BD., 1982, J Biol Chem, 257:3018-25. Exemplary assays useful for measuring guanine nucleotide exchange factor activity of complex 198a include but are not limited to those described in Sasaki T et al., 1990, J Biol Chem, 265:2333-7. and/or Horiuchi H et al., 1995, J Biol Chem, 270:11257 62. Exemplary assays useful for measuring guanine nucleotide exchange factor activity of complex 198b include but are not limited to those described in Sasaki T et al., 1990, J Biol Chem, 265:2333-7. and/or Horiuchi H et al., 1995, J Biol Chem, 270:11257 62.

WO 03/072602 PCT/EPO2/50003 160 Exemplary assays useful for measuring mitochondrial protein translocation activity of complex 201a include but are not limited to those described in Gordon DM et al., 1999, Hum Mol Genet, 8:2255-62. Exemplary assays useful for measuring protease activity and mitochondrial protein import activity of complex 201a include but are not limited to those described in Geli V et al., 1990, J Biol Chem, 265:19216-22. and/or F6Isch H et al., 1998, EMBO J, 17:6508-15. Exemplary assays useful for measuring proliferation activity of cells containing complex 201a include but are not limited to those described in Kissov6 I et al., 2000, FEBS Lett, 471:113-8. Exemplary assays useful for measuring mitochondrial protein translocation activity of complex 201b include but are not limited to those described in Gordon DM et al., 1999, Hum Mol Genet, 8:2255-62. Exemplary assays useful for measuring protease activity and mitochondrial protein import activity of complex 201b include but are not limited to those described in Geli V et al., 1990, J Biol Chem, 265:19216-22. and/or F6lsch H et al., 1998, EMBO J, 17:6508-15. Exemplary assays useful for measuring proliferation activity of cells containing complex 201b include but are not limited to those described in Kissov4 I et al., 2000, FEBS Lett, 471:113-8. Exemplary assays useful for measuring C 1-tetrahydrofolate synthase activity of complex 203a include but are not limited to those described in Paukert JL and Rabinowitz JC., 1980, Methods Enzymol, 66:616-26. Exemplary assays useful for measuring subcellular localization/transport of mannose-6-phosphate receptor in cells containing complex 203a include but are not limited to those described in Meyer C et al., 2000, EMBO J, 19:2193-203. Exemplary assays useful for measuring trafficking of AP-1 using YFP-tagged mulA subunit of AP-1 in cells containing complex 203a include but are not limited to those described in Huang F et al., 2001, Traffic, 2:345-57. Exemplary animal models useful for assaying compounds interacting with mice deficient in gamma-adaptin (model for AP-1 function) complex 203b include but are not limited to those described in Zizioli D et al., 1999, J Biol Chem, 274:5385-90. Exemplary animal models useful for assaying compounds interacting with mice deficient in mulA-adaptin (model for impaired endosome to TGN trafficking) complex 203b WO 03/072602 PCT/EPO2/50003 161 include but are not limited to those described in Meyer C et al., 2000, EMBO J, 19:2193 203. Exemplary assays useful for measuring C1-tetrahydrofolate synthase activity of complex 203b include but are not limited to those described in Paukert JL and Rabinowitz JC., 1980, Methods Enzymol, 66:616-26. Exemplary assays useful for measuring subcellular localization/transport of mannose-6-phosphate receptor in cells containing complex 203b include but are not limited to those described in Meyer C et al., 2000, EMBO J, 19:2193-203. Exemplary assays useful for measuring trafficking of AP-1 using YFP-tagged mulA subunit of AP-1 in cells containing complex 203b include but are not limited to those described in Huang F et al., 2001, Traffic, 2:345-57. Exemplary assays useful for measuring receptor protein translocation activity of complex 204a include but are not limited to those described in Hill K et al., 1998, Nature, 395:516-21.] Exemplary assays useful for measuring motility and morphology of mitochondria in cells containing complex 204a include but are not limited to those described in Boldogh I et al., 1998, J Cell Biol, 141:1371-81. Exemplary assays useful for measuring receptor protein translocation activity of complex 204b include but are not limited to those described in Hill K et al., 1998, Nature, 395:516-21.] Exemplary assays useful for measuring motility and morphology of mitochondria in cells containing complex 204b include but are not limited to those described in Boldogh I et al., 1998, J Cell Biol, 141:1371-81. Exemplary assays useful for measuring mRNA binding activity of complex 205 include but are not limited to those described in Katahira J et al., 1999, EMBO J, 18:2593-609. Exemplary assays useful for measuring mRNA binding and mRNA export activity of complex 205 include but are not limited to those described in Semmes OJ et al., 1998, J Virol, 72:9526-34. Exemplary assays useful for measuring RNA export in yeast cells containing complex 205 include but are not limited to those described in Kadowaki T et al., 1994, J Cell Biol, 126:649-59.

WO 03/072602 PCT/EPO2/50003 162 Exemplary assays useful for measuring RNA export using HIV rev in HeLa cells containing complex 205 include but are not limited to those described in Kimura T et al., 1996, Biochimie, 78:1075-80. Exemplary animal models useful for assaying compounds interacting with nude mice injected with phospholipase D transformed cells complex 206a include but are not limited to those described in Min DS et al., 2001, Carcinogenesis, 22:1641-7. Exemplary assays useful for measuring phospholipase D activity of complex 206a include but are not limited to those described in Brown HA et al., 1993, Cell, 75:1137-44. and/or Hammond SM et al., 1995, J Biol Chem, 270:29640-3. Exemplary assays useful for measuring phospholipase D activity of complex 206a include but are not limited to those described in Rudge SA et al., 1998, J Cell Biol, 140:81-90. Exemplary assays useful for measuring phopholipase D induced anchorage independent growth in fibroblasts containing complex 206a include but are not limited to those described in Min DS et al., 2001, Carcinogenesis, 22:1641-7. Exemplary animal models useful for assaying compounds interacting with nude mice injected with phospholipase D transformed cells complex 206b include but are not limited to those described in Min DS et al., 2001, Carcinogenesis, 22:1641-7. Exemplary assays useful for measuring phospholipase D activity of complex 206b include but are not limited to those described in Brown HA et al., 1993, Cell, 75:1137-44. and/or Hammond SM et al., 1995, J Biol Chem, 270:29640-3. Exemplary assays useful for measuring phospholipase D activity of complex 206b include but are not limited to those described in Rudge SA et al., 1998, J Cell Biol, 140:81-90. Exemplary assays useful for measuring phopholipase D induced anchorage independent growth in fibroblasts containing complex 206b include but are not limited to those described in Min DS et al., 2001, Carcinogenesis, 22:1641-7. Exemplary animal models useful for assaying compounds interacting with EMK knock out mice complex 207a include but are not limited to those described in Bessone S et al., 1999, Dev Biol, 214:87-101.(EMK protein kinase-null mice: dwarfism and hypofertility associated with alterations in the somatotrope and prolactin pathways.) Exemplary assays useful for measuring protein serinelthreonine kinase activity of complex 207a include but are not limited to those described in Illenberger S et al., 1996, J Biol Chem, 271:10834-43.

WO 03/072602 PCT/EPO2/50003 163 Exemplary assays useful for measuring chromatin assembly activity of complex 207a include but are not limited to those described in McQuibban GA et al., 1998, J Biol Chem, 273:6582-90. Exemplary animal models useful for assaying compounds interacting with EMK knock out mice complex 207b include but are not limited to those described in Bessone S et al., 1999, Dev Biol, 214:87-101.(EMK protein kinase-null mice: dwarfism and hypofertility associated with alterations in the somatotrope and prolactin pathways.) Exemplary assays useful for measuring protein serine/threonine kinase activity of complex 207b include but are not limited to those described in Illenberger S et al., 1996, J Biol Chem, 271:10834-43. Exemplary assays useful for measuring chromatin assembly activity of complex 207b include but are not limited to those described in McQuibban GA et al., 1998, J Biol Chem, 273:6582-90. Exemplary assays useful for measuring GTP-binding and GTPase activity of complex 208 include but are not limited to those described in Zahraoui A et al., 1989, J Biol Chem, 264:12394-401. Exemplary assays useful for measuring ATPase activity of complex 208 include but are not limited to those described in Navarro Izquierdo A et al., 1977, Rev Clin Esp, 147:47-53.] Exemplary assays useful for measuring translation factor activity of complex 209a include but are not limited to those described in Remacha M et al., 1992, J Biol Chem, 267:12061-7. Exemplary assays useful for measuring RNA binding and translation activity of complex 209a include but are not limited to those described in Gustafson WC et al., 1998, Biochem J, 331 ( Pt 2):387-93. Exemplary assays useful for measuring effects on nucleolar localization of marker proteins in cells containing complex 209a include but are not limited to those described in Freeman JW et al., 1991, Cancer Res, 51:1973-8. Exemplary assays useful for measuring translation factor activity of complex 209b include but are not limited to those described in Remacha M et al., 1992, J Biol Chem, 267:12061-7. Exemplary assays useful for measuring RNA binding and translation activity of complex 209b include but are not limited to those described in Gustafson WC et al., 1998, Biochem J, 331 ( Pt 2):387-93.

WO 03/072602 PCT/EPO2/50003 164 Exemplary assays useful for measuring effects on nucleolar localization of marker proteins in cells containing complex 209b include but are not limited to those described in Freeman JW et al., 1991, Cancer Res, 51:1973-8. Exemplary assays useful for measuring protein degradation activity of complex 210a include but are not limited to those described in Wang CW et al., 2001, J Biol Chem, 276:30442-51. Exemplary assays useful for measuring alpha-mannosidase activity of complex 210a include but are not limited to those described in Opheim DJ., 1978, Biochim Biophys Acta, 524:121-30. Exemplary assays useful for measuring autophagy (peroxisome levels) in cells containing complex 210a include but are not limited to those described in Wang CW et al., 2001, J Biol Chem, 276:30442-51. Exemplary assays useful for measuring protein degradation activity of complex 210b include but are not limited to those described in Wang CW et al., 2001, J Biol Chem, 276:30442-51. Exemplary assays useful for measuring alpha-mannosidase activity of complex 210b include but are not limited to those described in Opheim DJ., 1978, Biochim Biophys Acta, 524:121-30. Exemplary assays useful for measuring autophagy (peroxisome levels) in cells containing complex 210b include but are not limited to those described in Wang CW et al., 2001, J Biol Chem, 276:30442-51. Exemplary assays useful for measuring sterol lipid biosynthesis activity of complex 211a include but are not limited to those described in Beh CT et al., 2001, Genetics, 157:1117-40. Exemplary assays useful for measuring subcellular localization of GFP-fusion proteins in cells containing complex 211 a include but are not limited to those described in Levine TP and Munro S., 2001, Mol Biol Cell, 12:1633-44. Exemplary assays useful for measuring sterol lipid biosynthesis activity of complex 211b include but are not limited to those described in Beh CT et al., 2001, Genetics, 157:1117-40. Exemplary assays useful for measuring subcellular localization of GFP-fusion proteins in cells containing complex 211b include but are not limited to those described in Levine TP and Munro S., 2001, Mol Biol Cell, 12:1633-44.

WO 03/072602 PCT/EPO2/50003 165 Exemplary assays useful for measuring protein serine/threonine kinase activity of complex 212 include but are not limited to those described in Blasina A et al., 1999, Curr Biol, 9:1-10. Exemplary assays useful for measuring activation of DNA damage checkpoints of cells containing complex 212 include but are not limited to those described in Tominaga K et al., 1999, J Biol Chem, 274:31463-7. Exemplary assays useful for measuring N-acetylglucosamine-phosphate mutase activity of complex 214 include but are not limited to those described in Hofmann M et al., 1994, Eur J Biochem, 221:741-7. Exemplary animal models useful for assaying compounds interacting with p44 MAPK knock-out mice complex 215a include but are not limited to those described in Pagbs G et al., 1999, Science, 286:1374-7.(Defective thymocyte maturation in p44 MAP kinase (Erk 1) knockout mice.) Exemplary assays useful for measuring protein serine/threonine kinase activity of complex 215a include but are not limited to those described in Boulton TG et al., 1991, Biochemistry, 30:278-86. and/or Tedford K et al., 1997, Curr Biol, 7:228-38. Exemplary animal models useful for assaying compounds interacting with p44 MAPK knock-out mice complex 215b include but are not limited to those described in Pag6s G et al., 1999, Science, 286:1374-7.(Defective thymocyte maturation in p44 MAP kinase (Erk 1) knockout mice.) Exemplary assays useful for measuring protein serine/threonine kinase activity of complex 215b include but are not limited to those described in Boulton TG et al., 1991, Biochemistry, 30:278-86. and/or Tedford K et al., 1997, Curr Biol, 7:228-38. Exemplary assays useful for measuring NAD+-specific isocitrate dehydrogenase activity of complex 217 include but are not limited to those described in Keys DA and McAlister-Henn L., 1990, J Bacteriol, 172:4280-7. Exemplary assays useful for measuring protein kinase C activity of complex 218 include but are not limited to those described in Antonsson B et al., 1994, J Biol Chem, 269:16821-8. Exemplary assays useful for measuring transformation activity of cells containing complex 218 include but are not limited to those described in Wang XY et al., 1999, Exp Cell Res, 250:253-63.

WO 03/072602 PCT/EPO2/50003 166 Exemplary assays useful for measuring sensitivity to hypo-osmolarity of cells containing complex 218 include but are not limited to those described in Shimizu J et al., 1994, Mol Gen Genet, 242:641-8. Exemplary assays useful for measuring DNA replication activity of complex 219a include but are not limited to those described in Pasero Pet al., 1999, Methods, 18:368 76. and/or Biswas EE et al., 1993, Biochemistry, 32:3013-9. Exemplary assays useful for measuring DNA replication of cells containing complex 219a include but are not limited to those described in Cooley M and Mishra NC., 2000, Curr Genet, 38:256-63. Exemplary assays useful for measuring DNA replication activity of complex 219b include but are not limited to those described in Pasero P et al., 1999, Methods, 18:368 76. and/or Biswas EE et al., 1993, Biochemistry, 32:3013-9. Exemplary assays useful for measuring transcriptional assay of complex 219b include but are not limited to those described in Machado AK et al., 1997, J Biol Chem, 272:17045-54. Exemplary assays useful for measuring DNA replication of cells containing complex 219b include but are not limited to those described in Cooley M and Mishra NC., 2000, Curr Genet, 38:256-63. Exemplary assays useful for measuring protein serine/threonine phosphatase activity of complex 221 include but are not limited to those described in Volont6 C et al., 1992, Biotechniques, 12:854-8. Exemplary assays useful for measuring heat-shock induced huntingtin protein aggregation in COS cells containing complex 221 include but are not limited to those described in Sittler A et al., 2001, Hum Mol Genet, 10:1307-15. Exemplary assays useful for measuring gamma-Glutamate kinase activity of complex 222 include but are not limited to those described in Seddon AP et al., 1989, J Biol Chem, 264:11326-35. Exemplary assays useful for measuring nuclear export of mRNA of cells containing complex 222 include but are not limited to those described in Pritchard CE et al., 1999, J Cell Biol, 145:237-54. Exemplary assays useful for measuring pyrroline-5-carboxylate synthase activity of complex 223 include but are not limited to those described in Wakabayashi Y et al., 1991, Arch Biochem Biophys, 291:1-8.

WO 03/072602 PCT/EPO2/50003 167 Exemplary assays useful for measuring gammma-glutamyl phosphate reductase activity of complex 223 include but are not limited to those described in Brandriss MC., 1979, J Bacteriol, 138:816-22. Exemplary assays useful for measuring protein ser/thr phosphatase activity of complex 223 include but are not limited to those described in Robinson MK and Phizicky EM., 1998, Methods Mol Biol, 93:235-42. Exemplary assays useful for measuring effects of heterologous expression of human pyrroline-5-carboxylate synthase (P5CS) in cells containing complex 223 include but are not limited to those described in Hu CA et al., 1999, J Biol Chem, 274:6754-62. Exemplary assays useful for measuring protein phosphatase 2C activity of complex 224a include but are not limited to those described in Cheng A et al., 2000, J Biol Chem, 275:34744-9. Exemplary assays useful for measuring Ptcl/Tpdl protein phosphatase 2C activity of complex 224a include but are not limited to those described in Robinson MK and Phizicky EM., 1998, Methods Mol Biol, 93:235-42. Exemplary assays useful for measuring protein phosphatase 2C activity of complex 224b include but are not limited to those described in Cheng A et al., 2000, J Biol Chem, 275:34744-9. Exemplary assays useful for measuring Ptcl/Tpdl protein phosphatase 2C activity of complex 224b include but are not limited to those described in Robinson MK and Phizicky EM., 1998, Methods Mol Biol, 93:235-42. Exemplary assays useful for measuring protein phosphatase 2C activity of complex 225a include but are not limited to those described in Robinson MK and Phizicky EM., 1998, Methods Mol Biol, 93:235-42. Exemplary assays useful for measuring protein phosphatase 2C activity of complex 225b include but are not limited to those described in Robinson MK and Phizicky EM., 1998, Methods Mol Biol, 93:235-42. Exemplary assays useful for measuring RNA stabilizing activity of complex 226a include but are not limited to those described in Ruiz-Echevarria MJ and Peltz SW., 2000, Cell, 101:741-51. Exemplary assays useful for measuring DNA fragmentation activity of complex 226a include but are not limited to those described in Tian Q et al., 1991, Cell, 67:629 39.

WO 03/072602 PCT/EPO2/50003 168 Exemplary assays useful for measuring transcription termination activity of complex 226a include but are not limited to those described in Gottlieb E and Steitz JA., 1989, EMBO J, 8:851-61. Exemplary assays useful for measuring translation factor activity of complex 226a include but are not limited to those described in Ohlmann T et al., 1995, Nucleic Acids Res, 23:334-40. Exemplary assays useful for measuring induction of apoptosis in cells containing complex 226a include but are not limited to those described in Barry M et al., 2000, Methods Enzymol, 322:40-6. Exemplary animal models useful for assaying compounds interacting with ataxia telangiectasia transgenic mice complex 226b include but are not limited to those described in Inoue T et al., 1986, Basic Life Sci, 39:323-35. Exemplary animal models useful for assaying compounds interacting with transgenic nice displaying a Sjogren's syndrome-like phenotype complex 226b include but are not limited to those described in Haneji N et al., 1994, J Immunol, 153:2769-77. Exemplary assays useful for measuring RNA stabilizing activity of complex 226b include but are not limited to those described in Ruiz-Echevarria MJ and Peltz SW., 2000, Cell, 101:741-51. Exemplary assays useful for measuring DNA fragmentation activity of complex 226b include but are not limited to those described in Tian Q et al., 1991, Cell, 67:629 39. Exemplary assays useful for measuring transcription termination activity of complex 226b include but are not limited to those described in Gottlieb E and Steitz JA., 1989, EMBO J, 8:851-61. Exemplary assays useful for measuring translation factor activity of complex 226b include but are not limited to those described in Ohlmann T et al., 1995, Nucleic Acids Res, 23:334-40. Exemplary assays useful for measuring induction of apoptosis in cells containing complex 226b include but are not limited to those described in Barry M et al., 2000, Methods Enzymol, 322:40-6. Exemplary assays useful for measuring pseudouridinylation activity of complex 227a include but are not limited to those described in Arluison V et al., 1999, J Mol Biol, 289:491-502.

WO 03/072602 PCT/EPO2/50003 169 Exemplary assays useful for measuring pseudouridylation of rRNA in cells containing complex 227a include but are not limited to those described in Zebarjadian Y et al., 1999, Mol Cell Biol, 19:7461-72. Exemplary assays useful for measuring pseudouridinylation activity of complex 227b include but are not limited to those described in Arluison V et al., 1999, J Mol Biol, 289:491-502. Exemplary assays useful for measuring pseudouridylation of rRNA in cells containing complex 227b include but are not limited to those described in Zebarjadian Y et al., 1999, Mol Cell Biol, 19:7461-72. Exemplary assays useful for measuring sister chromatid cohesion activity of complex 228a include but are not limited to those described in Losada A and Hirano T., 2001, Curr Biol, 11:268-72. Exemplary assays useful for measuring mitotic aster assembly activity of complex 228a include but are not limited to those described in Gregson HC et al., 2001, J Biol Chem, 276:47575-82. Exemplary assays useful for measuring ATPase/motor protein activity of complex 228a include but are not limited to those described in Kimura K and Hirano T., 1997, Cell, 90:625-34. Exemplary assays useful for measuring sister chromatid cohesion in cells containing complex 228a include but are not limited to those described in Megee PC and Koshland D., 1999, Science, 285:254-7. Exemplary assays useful for measuring metaphase arrest of cells containing complex 228a include but are not limited to those described in Geley S et al., 2001, J Cell Biol, 153:137-48. Exemplary assays useful for measuring sister chromatid cohesion activity of complex 228b include but are not limited to those described in Losada A and Hirano T., 2001, Curr Biol, 11:268-72. Exemplary assays useful for measuring mitotic aster assembly activity of complex 228b include but are not limited to those described in Gregson HC et al., 2001, J Biol Chem, 276:47575-82. Exemplary assays useful for measuring ATPase/motor protein activity of complex 228b include but are not limited to those described in Kimura K and Hirano T., 1997, Cell, 90:625-34.

WO 03/072602 PCT/EPO2/50003 170 Exemplary assays useful for measuring sister chromatid cohesion in cells containing complex 228b include but are not limited to those described in Megee PC and Koshland D., 1999, Science, 285:254-7. Exemplary assays useful for measuring metaphase arrest of cells containing complex 228b include but are not limited to those described in Geley S et al., 2001, J Cell Biol, 153:137-48. Exemplary animal models useful for assaying compounds interacting with transgenic nice displaying a skin cancer-like phenotype complex 229a include but are not limited to those described in Hanausek M et al., 2001, Proc Natl Acad Sci U S A, 98:11551-6. Exemplary assays useful for measuring DNA helicase activity of complex 229a include but are not limited to those described in Nanduri B et al., 2001, Nucleic Acids Res, 29:2829-35. Exemplary assays useful for measuring lyase activity of complex 229a include but are not limited to those described in Garcfa-Dfaz M et al., 2001, J Biol Chem, 276:34659-63. Exemplary assays useful for measuring DNA damage in cells containing complex 229a include but are not limited to those described in Samper E et al., 2001, J Cell Biol, 154:49-60. Exemplary animal models useful for assaying compounds interacting with transgenic nice displaying a skin cancer-like phenotype complex 229b include but are not limited to those described in Hanausek M et al., 2001, Proc Natl Acad Sci US A, 98:11551-6. Exemplary assays useful for measuring DNA helicase activity of complex 229b include but are not limited to those described in Nanduri B et al., 2001, Nucleic Acids Res, 29:2829-35. Exemplary assays useful for measuring lyase activity of complex 229b include but are not limited to those described in Garcia-D[az M et al., 2001, J Biol Chem, 276:34659-63. Exemplary assays useful for measuring DNA damage in cells containing complex 229b include but are not limited to those described in Samper E et al., 2001, J Cell Biol, 154:49-60. Exemplary animal models useful for assaying compounds interacting with transgenic nice displaying a trichothiodystrophy (basal transcription/DNA repair syndrome)-like phenotype complex 230a include but are not limited to those described in de Boer J et al., 1998, Mol Cell, 1:981-90.

WO 03/072602 PCT/EPO2/50003 171 Exemplary assays useful for measuring DNA helicase activity of complex 230a include but are not limited to those described in Vindigni A et al., 2001, Nucleic Acids Res, 29:1061-7. Exemplary assays useful for measuring ATPase activity of complex 230a include but are not limited to those described in Ozsoy AZ et al., 2001, Nucleic Acids Res, 29:2986-93. Exemplary assays useful for measuring recombination in mouse pJS3-10 and pJS4.7.1 cells containing complex 230a include but are not limited to those described in Saintigny Y et al., 2001, EMBO J, 20:3861-70. Exemplary animal models useful for assaying compounds interacting with transgenic nice displaying a trichothiodystrophy (basal transcription/DNA repair syndrome)-like phenotype complex 230b include but are not limited to those described in de Boer J et al., 1998, Mol Cell, 1:981-90. Exemplary assays useful for measuring DNA helicase activity of complex 230b include but are not limited to those described in Vindigni A et al., 2001, Nucleic Acids Res, 29:1061-7. Exemplary assays useful for measuring ATPase activity of complex 230b include but are not limited to those described in Ozsoy AZ et al., 2001, Nucleic Acids Res, 29:2986-93. Exemplary assays useful for measuring recombination in mouse pJS3-10 and pJS4.7.1 cells containing complex 230b include but are not limited to those described in Saintigny Yet al., 2001, EMBO J, 20:3861-70. Exemplary animal models useful for assaying compounds interacting with systemic lupus erythematosus transgenic mice complex 231a include but are not limited to those described in Talal N., 1975, J Rheumatol, 2:130-4. Exemplary assays useful for measuring protein serine/threonine phosphatase activity of complex 231a include but are not limited to those described in Gee KR et al., 1999, Anal Biochem, 273:41-8. Exemplary assays useful for measuring 5'-->3' RNA exonuclease activity of complex 231a include but are not limited to those described in Kenna M et al., 1993, Mol Cell Biol, 13:341-50. Exemplary animal models useful for assaying compounds interacting with systemic lupus erythematosus transgenic mice complex 231b include but are not limited to those described in Talal N., 1975, J Rheumatol, 2:130-4.

WO 03/072602 PCT/EPO2/50003 172 Exemplary assays useful for measuring protein serine/threonine phosphatase activity of complex 231b include but are not limited to those described in Gee KR et al., 1999, Anal Biochem, 273:41-8. Exemplary assays useful for measuring guanine nucleotide exchange factor activity of complex 231b include but are not limited to those described in Kiyono M et al., 2000, J Biol Chem, 275:29788-93. Exemplary assays useful for measuring GTP binding/GTPase activity of complex 231b include but are not limited to those described in Zahraoui A et al., 1989, J Biol Chem, 264:12394-401. Exemplary assays useful for measuring guanine nucleotide exchange factor activity of complex 231b include but are not limited to those described in Haney SA and Broach JR., 1994, J Biol Chem, 269:16541-8. Exemplary assays useful for measuring 5'-->3' RNA exonuclease activity of complex 231b include but are not limited to those described in Kenna M et al., 1993, Mol Cell Biol, 13:341-50. Exemplary animal models useful for assaying compounds interacting with GSK3 beta knock-out mice complex 232 include but are not limited to those described in Hoeflich KP et al., 2000, Nature, 406:86-90.(Requirement for glycogen synthase kinase-3beta in cell survival and NF-kappaB activation.) Exemplary assays useful for measuring Rim1 1 kinase activity of complex 232 include but are not limited to those described in Zhan XL et al., 2000, Mol Biol Cell, 11:663-76. Exemplary assays useful for measuring GSK3 beta kinase activity of complex 232 include but are not limited to those described in Orefia SJ et al., 2000, J Biol Chem, 275:15765-72. Exemplary assays useful for measuring glycogen synthase kinase-3 activity of complex 232 include but are not limited to those described in Cross D., 2001, Methods Mol Biol, 124:147-59. Exemplary assays useful for measuring cell survival /apoptosis induction in cells containing complex 232 include but are not limited to those described in Cross DA et al., 2001, J Neurochem, 77:94-102. Exemplary assays useful for measuring MICROTUBULE NUCLEATION of complex 233 include but are not limited to those described in Lingle WL and Salisbury JL., 2001, Methods Cell Biol, 67:325-36.

WO 03/072602 PCT/EPO2/50003 173 Exemplary assays useful for measuring PHOSPHOFRUCTOKINASE of complex 233 include but are not limited to those described in Klinder A et al., 1998, Yeast, 14:323-34. Exemplary animal models useful for assaying compounds interacting with zebrafish mutant in spt5 gene complex 238 include but are not limited to those described in Guo S et al., 2000, Nature, 408:366-9. Exemplary assays useful for measuring transcriptional assay of complex 238 include but are not limited to those described in Kikyo N et al., 2000, Science, 289:2360 2. Exemplary assays useful for measuring methyl group transfer to guanosine base activity of complex 238 include but are not limited to those described in Mao X et al., 1995, Mol Cell Biol, 15:4167-74. Exemplary assays useful for measuring mutation of orf complex 238 include but are not limited to those described in Hartzog GA et al., 1998, Genes Dev, 12:357-69. Exemplary assays useful for measuring protein-protein-binding activity of complex 250 include but are not limited to those described in Keen JH and Beck KA., 1989, Biochem Biophys Res Commun, 158:17-23. Exemplary assays useful for measuring ATPase activity of complex 257 include but are not limited to those described in Norcum MT., 1996, Protein Sci, 5:1366-75. Exemplary assays useful for measuring NO deoxygenation of complex 262 include but are not limited to those described in Gardner PR et al., 2000, J Biol Chem, 275:31581-7. Exemplary assays useful for measuring aminopeptidase of complex 262 include but are not limited to those described in Basten DE et al., 2001, Microbiology, 147:2045 50. Exemplary assays useful for measuring atpase of complex 262 include but are not limited to those described in Nadeau K et al., 1993, J Biol Chem, 268:1479-87. Exemplary assays useful for measuring transcription inhibition/repression of complex 265 include but are not limited to those described in Oberholzer U and Collart MA., 1998, Gene, 207:61-9. Exemplary assays useful for measuring Functional complementation complex 265 include but are not limited to those described in Albert TK et al., 2000, Nucleic Acids Res, 28:809-17.

WO 03/072602 PCT/EPO2/50003 174 Exemplary assays useful for measuring transcription assay of complex 274 include but are not limited to those described in Schlegel BP et al., 2000, Proc Natl Acad Sci U S A, 97:3148-53. Exemplary assays useful for measuring protein kinase assay of complex 274 include but are not limited to those described in Chen H et al., 2001, Biochemistry, 40:11851-9. Exemplary animal models useful for assaying compounds interacting with mouse conditional ko of small ribosomal protein S6 complex 281 include but are not limited to those described in Volarevic S et al., 2000, Science, 288:2045-7. Exemplary assays useful for measuring rRNA processing of complex 281 include but are not limited to those described in Colley A et al., 2000, Mol Cell Biol, 20:7238-46. and/or Kressler D et al., 1997, Mol Cell Biol, 17:7283-94. Exemplary assays useful for measuring nuclear export of ribosomal protein complex 281 include but are not limited to those described in Hurt E et al., 1999, J Cell Biol, 144:389-401. Exemplary assays useful for measuring DNA binding of complex 309 include but are not limited to those described in Koering CE et al., 2000, Nucleic Acids Res, 28:2519-26. Exemplary assays useful for measuring ATPase of complex 309 include but are not limited to those described in Norcum MT., 1996, Protein Sci, 5:1366-75. Exemplary assays useful for measuring RNA binding of complex 351 include but are not limited to those described in Kessler MM et al., 1997, Genes Dev, 11:2545-56. Exemplary assays useful for measuring nuclear import activity of complex 351 include but are not limited to those described in Truant R et al., 1998, Mol Cell Biol, 18:1449-58. Exemplary assays useful for measuring Endosom to Golgi Transport of complex 363 include but are not limited to those described in Edgar AJ and Polak JM., 2000, Biochem Biophys Res Commun, 277:622-30. Exemplary assays useful for measuring transcription activity of complex 364 include but are not limited to those described in Lim CR et al., 2000, J Biol Chem, 275:22409-17. Exemplary assays useful for measuring acylation of lysophosphatidic acid activity of complex 364 include but are not limited to those described in Athenstaedt K and Daum G., 1997, J Bacteriol, 179:7611-6.

WO 03/072602 PCT/EPO2/50003 175 Exemplary assays useful for measuring inosine-5'-monophosphate dehydrogenase assay of complex 366 include but are not limited to those described in Metz S et al., 2001, Endocrinology, 142:193-204. Exemplary assays useful for measuring RNA binding assay of complex 366 include but are not limited to those described in lyer RK and Levinger LF., 1988 Nov Dec, Gene Anal Tech, 5:125-9. Exemplary assays useful for measuring single-stranded-DNA endonuclease of complex 367 include but are not limited to those described in Tomkinson AE et al., 1994, Biochemistry, 33:5305-11. andlor Tomkinson AE et al., 1993, Nature, 362:860-2. Exemplary assays useful for measuring exonuclease assay of complex 369 include but are not limited to those described in Brouwer R et al., 2001, J Biol Chem, 276:6177-84. Exemplary assays useful for measuring endonuclease assay of complex 369 include but are not limited to those described in Goldstein JN and Weller SK., 1998, Virology, 244:442-57. Exemplary assays useful for measuring carbamylphosphate synthetase activity of complex 373 include but are not limited to those described in Kaseman DS and Meister A., 1985, Methods Enzymol, 113:305-26. Exemplary assays useful for measuring methionine adenosyl transferase activity of complex 373 include but are not limited to those described in Cabrero C et al., 1987, Eur J Biochem, 170:299-304. Exemplary assays useful for measuring carbamylphosphate synthetase activity of complex 373 include but are not limited to those described in Pierson DL and Brien JM., 1980, J Biol Chem, 255:7891-5. Exemplary assays useful for measuring CTP synthetase of complex 373 include but are not limited to those described in Hashimoto H et al., 1997, J Biol Chem, 272:16308-14. Exemplary animal models useful for assaying compounds interacting with Increased insulin sensitivity and hypoglycaemia in mice lacking the p85-alpha subunit of phosphoinositide 3-kinase complex 376 include but are not limited to those described in Terauchi Y et al., 1999, Nat Genet, 21:230-5. Exemplary assays useful for measuring protein kinase of complex 376 include but are not limited to those described in Mallory JC and Petes TD., 2000, Proc Natl Acad Sci U S A, 97:13749-54.

WO 03/072602 PCT/EPO2/50003 176 Exemplary assays useful for measuring inosine-5'-monophosphate dehydrogenase assay of complex 376 include but are not limited to those described in Metz Set al., 2001, Endocrinology, 142:193-204. Exemplary assays useful for measuring cleavage of L-allo-threonine and L threonine to glycine of complex 376 include but are not limited to those described in Liu JQ et al., 1997, Eur J Biochem, 245:289-93. Exemplary assays useful for measuring ATPase activity of complex 386 include but are not limited to those described in Cairns BR et al., 1996, Cell, 87:1249-60. Exemplary assays useful for measuring protein phosphatase assay of complex 406 include but are not limited to those described in Taylor GS et al., 1997, J Biol Chem, 272:24054-63. Exemplary assays useful for measuring DNA binding assay of complex 407 include but are not limited to those described in Aparicio OM et al., 1997, Cell, 91:59-69. 5.6.1. CANDIDATE MOLECULES Any molecule known in the art can be tested for its ability to modulate (increase or decrease) the amount of, activity of, or protein component composition of a complex of the present invention as detected by a change in the amount of, activity of, or protein component composition of, said complex. By way of example, a change in the amount of the complex can be detected by detecting a change in the amount of the complex that can be isolated from a cell expressing the complex machinery. For identifying a molecule that modulates complex activity, candidate molecules can be directly provided to a cell expressing the complex machinery, or, in the case of candidate proteins, can be provided by providing their encoding nucleic acids under conditions in which the nucleic acids are recombinantly expressed to produce the candidate proteins within the cell expressing the complex machinery, the complex is then isolated from the cell and the isolated complex is assayed for activity using methods well known in the art, not limited to those described, supra. This embodiment of the invention is well suited to screen chemical libraries for molecules which modulate, e.g., inhibit, antagonize, or agonize, the amount of, activity of, or protein component composition of the complex. The chemical libraries can be peptide libraries, peptidomimetic libraries, chemically synthesized libraries, WO 03/072602 PCT/EPO2/50003 177 recombinant, e.g., phage display libraries, and in vitro translation-based libraries, other non-peptide synthetic organic libraries, etc. Exemplary libraries are commercially available from several sources (ArQule, Tripos/PanLabs, ChemDesign, Pharmacopoeia). In some cases, these chemical libraries are generated using combinatorial strategies that encode the identity of each member of the library on a substrate to which the member compound is attached, thus allowing direct and immediate identification of a molecule that is an effective modulator. Thus, in many combinatorial approaches, the position on a plate of a compound specifies that compound's composition. Also, in one example, a single plate position may have from 1-20 chemicals that can be screened by administration to a well containing the interactions of interest. Thus, if modulation is detected, smaller and smaller pools of interacting pairs can be assayed for the modulation activity. By such methods, many candidate molecules can be screened. Many diversity libraries suitable for use are known in the art and can be used to provide compounds to be tested according to the present invention. Alternatively, libraries can be constructed using standard methods. Chemical (synthetic) libraries, recombinant expression libraries, or polysome-based libraries are exemplary types of libraries that can be used. The libraries can be constrained or semirigid (having some degree of structural rigidity), or linear or nonconstrained. The library can be a cDNA or genomic expression library, random peptide expression library or a chemically synthesized random peptide library, or non-peptide library. Expression libraries are introduced into the cells in which the assay occurs, where the nucleic acids of the library are expressed to produce their encoded proteins. In one embodiment, peptide libraries that can be used in the present invention may be libraries that are chemically synthesized in vitro. Examples of such libraries are given in Houghten et al., 1991, Nature 354:84-86, which describes mixtures of free hexapeptides in which the first and second residues in each peptide were individually and specifically defined; Lam et al., 1991, Nature 354:82-84, which describes a "one bead, one peptide" approach in which a solid phase split synthesis scheme produced a library of peptides in which each bead in the collection had immobilized thereon a single, random sequence of amino acid residues; Medynski, 1994, Bio/Technology 12:709-710, which describes split synthesis and T-bag synthesis methods; and Gallop et al., 1994, J. Medicinal Chemistry 37(9):1233-1251. Simply by WO 03/072602 PCT/EPO2/50003 178 way of other examples, a combinatorial library may be prepared for use, according to the methods of Ohlmeyer et al., 1993, Proc. Natl. Acad. Sci. USA 90:10922-10926; Erb et al., 1994, Proc. Natl. Acad. Sci. USA 91:11422-11426; Houghten et al., 1992, Biotechniques 13:412; Jayawickreme et al., 1994, Proc. Natl. Acad. Sci. USA 91:1614-1618; or Salmon et al., 1993, Proc. Natl. Acad. Sci. USA 90:11708-11712. PCT Publication No. WO 93/20242 and Brenner and Lerner, 1992, Proc. Natl. Acad. Sci. USA 89:5381-5383 describe "encoded combinatorial chemical libraries," that contain oligonucleotide identifiers for each chemical polymer library member. In a preferred embodiment, the library screened is a biological expression library that is a random peptide phage display library, where the random peptides are constrained (e.g., by virtue of having disulfide bonding). Further, more general, structurally constrained, organic diversity (e.g., nonpeptide) libraries, can also be used. By way of example, a benzodiazepine library (see e.g., Bunin et al., 1994, Proc. Natl. Acad. Sci. USA 91:4708-4712) may be used. Conformationally constrained libraries that can be used include but are not limited to those containing invariant cysteine residues which, in an oxidizing environment, cross-link by disulfide bonds to form cystines, modified peptides (e.g., incorporating fluorine, metals, isotopic labels, are phosphorylated, etc.), peptides containing one or more non-naturally occurring amino acids, non-peptide structures, and peptides containing a significant fraction of 'barboxyglutamic acid. Libraries of non-peptides, e.g., peptide derivatives (for example, that contain one or more non-naturally occurring amino acids) can also be used. One example of these are peptoid libraries (Simon et al., 1992, Proc. Natl. Acad. Sci. USA 89:9367-9371). Peptoids are polymers of non-natural amino acids that have naturally occurring side chains attached not to the alpha carbon but to the backbone amino nitrogen. Since peptoids are not easily degraded by human digestive enzymes, they are advantageously more easily adaptable to drug use. Another example of a library that can be used, in which the amide functionalities in peptides have been permethylated to generate a chemically transformed combinatorial library, is described by Ostresh et al., 1994, Proc. Natl. Acad. Sci. USA 91:11138-11142). The members of the peptide libraries that can be screened according to the invention are not limited to containing the 20 naturally occurring amino acids. In particular, chemically synthesized libraries and polysome based libraries allow the use of amino acids in addition to the 20 naturally occurring amino acids (by their inclusion in the WO 03/072602 PCT/EPO2/50003 179 precursor pool of amino acids used in library production). In specific embodiments, the library members contain one or more non-natural or non-classical amino acids or cyclic peptides. Non-classical amino acids include but are not limited to the D-isomers of the common amino acids, ?amino isobutyric acid, 4-aminobutyric acid, Abu, 2-amino butyric acid; ?Abu, ?Ahx, 6-amino hexanoic acid; Aib, 2-amino isobutyric acid; 3-amino propionic acid; ornithine; norleucine; norvaline, hydroxyproline, sarcosine, citrulline, cysteic acid, t butylglycine, t-butylalanine, phenylglycine, cyclohexylalanine, 13-alanine, designer amino acids such as f-methyl amino acids, C-nethyl amino acids, NRnethyl amino acids, fluoro-amino acids and amino acid analogs in general. Furthermore, the amino acid can be D (dextrorotary) or L (levorotary). In a specific embodiment, fragments and/or analogs of complexes of the invention, or protein components thereof, especially peptidomimetics, are screened for activity as competitive or non-competitive inhibitors of complex activity or formation. In another embodiment of the present invention, combinatorial chemistry can be used to identify modulators of a the complexes. Combinatorial chemistry is capable of creating libraries containing hundreds of thousands of compounds, many of which may be structurally similar. While high throughput screening programs are capable of screening these vast libraries for affinity for known targets, new approaches have been developed that achieve libraries of smaller dimension but which provide maximum chemical diversity. (See e.g., Matter, 1997, Journal of Medicinal Chemistry 40:1219-1229). One method of combinatorial chemistry, affinity fingerprinting, has previously been used to test a discrete library of small molecules for binding affinities for a defined panel of proteins. The fingerprints obtained by the screen are used to predict the affinity of the individual library members for other proteins or receptors of interest (in the instant invention, the protein complexes of the present invention and protein components thereof.) The fingerprints are compared with fingerprints obtained from other compounds known to react with the protein of interest to predict whether the library compound might similarly react. For example, rather than testing every ligand in a large library for interaction with a complex or protein component, only those ligands having a fingerprint similar to other compounds known to have that activity could be tested. (See, e.g., Kauvar et al., 1995, Chemistry and Biology 2:107-118; Kauvar, 1995, Affinity fingerprinting, Pharmaceutical Manufacturing International. 8:25-28; and Kauvar, Toxic Chemical Detection by Pattern Recognition in New Frontiers in Agrochemical WO 03/072602 PCT/EPO2/50003 180 Immunoassay, D. Kurtz. L. Stanker and J.H. Skerritt. Editors, 1995, AOAC: Washington, D.C., 305-312). Kay et al., 1993, Gene 128:59-65 (Kay) discloses a method of constructing peptide libraries that encode peptides of totally random sequence that are longer than those of any prior conventional libraries. The libraries disclosed in Kay encode totally synthetic random peptides of greater than about 20 amino acids in length. Such libraries can be advantageously screened to identify complex modulators. (See also U.S. Patent No. 5,498,538 dated March 12, 1996; and PCT Publication No. WO 94/18318 dated August 18, 1994). A comprehensive review of various types of peptide libraries can be found in Gallop et al., 1994, J. Med. Chem. 37:1233-1251. 5.7. PHARMACEUTICAL COMPOSITIONS AND THERAPEUTIC/PROPHYLACTIC ADMINISTRATION The invention provides methods of treatment (and prophylaxis) by administration to a subject of an effective amount of a Therapeutic of the invention. In a preferred aspect, the Therapeutic is substantially purified. The subject is preferably an animal including, but not limited to animals such as cows, pigs, horses, chickens, cats, dogs, etc., and is preferably a mammal, and most preferably human. In a specific embodiment, a non-human mammal is the subject. Various delivery systems are known and can be used to administer a Therapeutic of the invention, e.g., encapsulation in liposomes, microparticles, and microcapsules: use of recombinant cells capable of expressing the Therapeutic, use of receptor-mediated endocytosis (e.g., Wu and Wu, 1987, J. Biol. Chem. 262:4429-4432); construction of a Therapeutic nucleic acid as part of a retroviral or other vector, etc. Methods of introduction include but are not limited to intradermal, intramuscular, intraperitoneal, intravenous, subcutaneous, intranasal, epidural, and oral routes. The compounds may be administered by any convenient route, for example by infusion, by bolus injection, by absorption through epithelial or mucocutaneous linings (e.g., oral, rectal and intestinal mucosa, etc.), and may be administered together with other biologically active agents. Administration can be systemic or local. In addition, it may be desirable to introduce the pharmaceutical compositions of the invention into the central nervous system by any suitable route, including intraventricular and intrathecal injection; intraventricular injection may be facilitated by an intraventricular catheter, for example, WO 03/072602 PCT/EPO2/50003 181 attached to a reservoir, such as an Ommaya reservoir. Pulmonary administration can also be employed, e.g., by use of an inhaler or nebulizer, and formulation with an aerosolizing agent. In a specific embodiment, it may be desirable to administer the pharmaceutical compositions of the invention locally to the area in need of treatment. This may be achieved by, for example, and not by way of limitation, local infusion during surgery, topical application, e.g., in conjunction with a wound dressing after surgery, by injection, by means of a catheter, by means of a suppository, or by means of an implant, said implant being of a porous, non-porous, or gelatinous material, including membranes, such as sialastic membranes, or fibers. In one embodiment, administration can be by direct injection at the site (or former site) of a malignant tumor or neoplastic or pre neoplastic tissue. In another embodiment, the Therapeutic can be delivered in a vesicle, in particular a liposome (Langer, 1990, Science 249:1527-1533; Treat et al., 1989, In: Liposomes in the Therapy of Infectious Disease and Cancer, Lopez-Berestein and Fidler, eds., Liss, New York, pp. 353-365; Lopez-Berestein, ibid., pp. 317-327; see generally ibid.) In yet another embodiment, the Therapeutic can be delivered via a controlled release system. In one embodiment, a pump may be used (Langer, supra; Sefton, 1987, CRC Crit. Ref. Biomed. Eng. 14:201-240; Buchwald et al., 1980, Surgery 88:507-516; Saudek et al., 1989, N. Engl. J. Med. 321:574-579). In another embodiment, polymeric materials can be used (Medical Applications of Controlled Release, Langer and Wise, eds., CRC Press, Boca Raton, Florida, 1974; Controlled Drug Bioavailability, Drug Product Design and Performance, Smolen and Ball, eds., Wiley, New York, 1984; Ranger and Peppas, 1983, Macromol. Sci. Rev. Macromol. Chem. 23:61; Levy et al., 1985, Science 228:190-192; During et al., 1989, Ann. Neurol. 25:351-356; Howard et al., 1989, J. Neurosurg. 71:858-863). In yet another embodiment, a controlled release system can be placed in proximity of the therapeutic target, i.e., the brain, thus requiring only a fraction of the systemic dose (e.g., Goodson, 1984, In: Medical Applications of Controlled Release, supra, Vol. 2, pp. 115-138). Other controlled release systems are discussed in the review by Langer (1990, Science 249:1527-1533). In a specific embodiment where the Therapeutic is a nucleic acid encoding a protein Therapeutic, the nucleic acid can be administered in vivo to promote WO 03/072602 PCT/EPO2/50003 182 expression of its encoded protein, by constructing it as part of an appropriate nucleic acid expression vector and administering it so that it becomes intracellular, e.g., by use of a retroviral vector (U.S. Patent No. 4,980,286), or by direct injection, or by use of microparticle bombardment (e.g., a gene gun; Biolistic, Dupont), or by coating it with lipids, cell-surface receptors or transfecting agents, or by administering it in linkage to a homeobox-like peptide which is known to enter the nucleus (e.g., Joliot et al., 1991, Proc. Natl. Acad. Sci. USA 88:1864-1868), etc. Alternatively, a nucleic acid Therapeutic can be introduced intracellularly and incorporated by homologous recombination within host cell DNA for expression. The present invention also provides pharmaceutical compositions. Such compositions comprise a therapeutically effective amount of a Therapeutic, and a pharmaceutically acceptable carrier. In a specific embodiment, the term "pharmaceutically acceptable" means approved by a regulatory agency of the Federal or a state government or listed in the U.S. Pharmacopeia or other generally recognized pharmacopeia for use in animals, and more particularly, in humans. The term "carrier" refers to a diluent, adjuvant, excipient, or vehicle with which the therapeutic is administered. Such pharmaceutical carriers can be sterile liquids, such as water and oils, including those of petroleum, animal, vegetable or synthetic origin, including but not limited to peanut oil, soybean oil, mineral oil, sesame oil and the like. Water is a preferred carrier when the pharmaceutical composition is administered orally. Saline and aqueous dextrose are preferred carriers when the pharmaceutical composition is administered intravenously. Saline solutions and aqueous dextrose and glycerol solutions are preferably employed as liquid carriers for injectable solutions. Suitable pharmaceutical excipients include starch, glucose, lactose, sucrose, gelatin, malt, rice, flour, chalk, silica gel, sodium stearate, glycerol monostearate, talc, sodium chloride, dried skim milk, glycerol, propylene, glycol, water, ethanol and the like. The composition, if desired, can also contain minor amounts of wetting or emulsifying agents, or pH buffering agents. These compositions can take the form of solutions, suspensions, emulsions, tablets, pills, capsules, powders, sustained-release formulations and the like. The composition can be formulated as a suppository, with traditional binders and carriers such as triglycerides. Oral formulation can include standard carriers such as pharmaceutical grades of mannitol, lactose, starch, magnesium stearate, sodium saccharine, cellulose, magnesium carbonate, etc. Examples of suitable pharmaceutical carriers are described in "Remington's Pharmaceutical Sciences" by E.W. Martin. Such WO 03/072602 PCT/EPO2/50003 183 compositions will contain a therapeutically effective amount of the Therapeutic, preferably in purified form, together with a suitable amount of carrier so as to provide the form for proper administration to the patient. The formulation should suit the mode of administration. In a preferred embodiment, the composition is formulated, in accordance with routine procedures, as a pharmaceutical composition adapted for intravenous administration to human beings. Typically, compositions for intravenous administration are solutions in sterile isotonic aqueous buffer. Where necessary, the composition may also include a solubilizing agent and a local anesthetic such as lidocaine to ease pain at the site of the injection. Generally, the ingredients are supplied either separately or mixed together in unit dosage form, for example, as a dry lyophilized powder or water free concentrate in a hermetically sealed container such as an ampoule or sachette indicating the quantity of active agent. Where the composition is to be administered by infusion, it can be dispensed with an infusion bottle containing sterile pharmaceutical grade water or saline. Where the composition is administered by injection, an ampoule of sterile water or saline for injection can be provided so that the ingredients may be mixed prior to administration. The Therapeutics of the invention can be formulated as neutral or salt forms. Pharmaceutically acceptable salts include those formed with free carboxyl groups such as those derived from hydrochloric, phosphoric, acetic, oxalic, tartaric acids, etc., those formed with free amine groups such as those derived from isopropylamine, triethylamine, 2-ethylamino ethanol, histidine, procaine, etc., and those derived from sodium, potassium, ammonium, calcium, and ferric hydroxides, etc. The amount of the Therapeutic of the invention which will be effective in the treatment of a particular disorder or condition will depend on the nature of the disorder or condition, and can be determined by standard clinical techniques. In addition, in vitro assays may optionally be employed to help identify optimal dosage ranges. The precise dose to be employed in the formulation will also depend on the route of administration, and the seriousness of the disease or disorder, and should be decided according to the judgment of the practitioner and each patient's circumstances. However, suitable dosage ranges for intravenous administration are generally about 20 500 micrograms of active compound per kilogram body weight. Suitable dosage ranges for intranasal administration are generally about 0.01 pg/kg body weight to 1 mg/kg body WO 03/072602 PCT/EPO2/50003 184 weight. Effective doses may be extrapolated from dose-response curves derived from in vitro or animal model test systems. Suppositories generally contain active ingredient in the range of 0.5% to 10% by weight; oral formulations preferably contain 10% to 95% active ingredient. The invention also provides a pharmaceutical pack or kit comprising one or more containers filled with one or more of the ingredients of the pharmaceutical compositions of the invention. Optionally associated with such container(s) can be a notice in the form prescribed by a governmental agency regulating the manufacture, use or sale of pharmaceuticals or biological products, which notice reflects approval by the agency of manufacture, use or sale for human administration. The invention also provides a pharmaceutical pack or kit comprising one or more containers filled with one or more of the ingredients of the pharmaceutical compositions of the invention. For example, the kit can comprise in one or more containers a first protein, or a functionally active fragment or functionally active derivative thereof, which first protein is selected from the group consisting of proteins listed in table 1, third column of a given complex, or a functionally active fragment or functionally active derivative thereof, or a homologue thereof or a variant encoded by a nucleic acid of any of said proteins. The kits of the present invention can also contain expression vectors encoding the essential components of the complex machinery, which components after being expressed can be reconstituted in order to form a biologically active complex. Such a kit preferably also contains the required buffers and reagents. Optionally associated with such container(s) can be instructions for use of the kit and/or a notice in the form prescribed by a governmental agency regulating the manufacture, use or sale of pharmaceuticals or biological products, which notice reflects approval by the agency of manufacture, use or sale for human administration. 5.8 ANIMAL MODELS The present invention also provides animal models. In one embodiment, animal models for diseases and disorders involving the protein complexes of the present invention are provided. These animal models are well known in the art. These animal models include, but are not limited to those which are listed in the section 5.6 (supra) as exemplary animald models to study any of the complexes provided in the invention. Such animals can be initially produced by promoting homologous recombination or insertional WO 03/072602 PCT/EPO2/50003 185 mutagenesis between genes encoding the protein components of the complexes in the chromosome, and exogenous genes encoding the protein components of the complexes that have been rendered biologically inactive or deleted (preferably by insertion of a heterologous sequence, e.g., an antibiotic resistance gene). In a preferred aspect, homologous recombination is carried out by transforming embryo-derived stem (ES) cells with one or more vectors containing one or more insertionally inactivated genes, such that homologous recombination occurs, followed by injecting the transformed ES cells into a blastocyst, and implanting the blastocyst into a foster mother, followed by the birth of the chimeric animal ("knockout animal") in which a gene encoding a component protein from table 1, third column of a given complex, or a functionally active fragment or functionally active derivative thereof, or a homologue thereof or a variant encoded by a nucleic acid of any of said proteins, has been inactivated or deleted (Capecchi, 1989, Science 244:1288-1292).. The chimeric animal can be bred to produce additional knockout animals. Such animals can be mice, hamsters, sheep, pigs, cattle, etc., and are preferably non human mammals. In a specific embodiment, a knockout mouse is produced. Such knockout animals are expected to develop, or be predisposed to developing, diseases or disorders associated with mutations involving the protein complexes of the present invention, and thus, can have use as animal models of such diseases and disorders, e.g., to screen for or test molecules (e.g., potential Therapeutics) for such diseases and disorders. In a different embodiment of the invention, transgenic animals that have incorporated and express (or over-express or mis-express) a functional gene encoding a protein component of the complex, e.g. by introducing the a gene encoding one or more of the components of the complex under the control of a heterologous promoter (i.e., a promoter that is not the native promoter of the gene) that either over-expresses the protein or proteins, or expresses them in tissues not normally expressing the complexes or proteins, can have use as animal models of diseases and disorders characterized by elevated levels of the protein complexes. Such animals can be used to screen or test molecules for the ability to treat or prevent the diseases and disorders cited supra. In one embodiment, the present invention provides a recombinant non human animal in which an endogenous gene encoding a first protein, or a functionally active fragment or functionally active derivative thereof, which first protein is selected WO 03/072602 PCT/EPO2/50003 186 from the group of proteins of table 1, third column of a given complex, or a functionally active fragment or functionally active derivative thereof, or a homologue thereof or a variant encoded by a nucleic acid of any of said proteins has been deleted or inactivated by homologous recombination or insertional mutagenesis of said animal or an ancestor thereof. In another embodiment, the present invention provides a recombinant non human animal in which an endogenous gene encoding a first protein, or a functionally active fragment or functionally active derivative thereof, which first protein is selected from the group consisting of proteins of table 1, third column of a given complex, or a functionally active fragment or functionally active derivative thereof, or a homologue thereof or a variant encoded by a nucleic acid of any of said proteins. The following series of examples are presented by way of illustration and not by way of limitation on the scope of the invention. EXAMPLES In order to systematically purify multiprotein complexes, the strategy depicted in Fig. 1 was developed. Gene-specific PCR-generated cassettes containing the tandem affinity purification tag (TAP) (Rigaut, G. et al., Nat Biotechnol 17, 1030-2 (1999)) were inserted by homologous recombination at the 3' end of the genes (Fig. 2). The focus was on 1,143 yeast genes representing eukaryotic orthologs (Lander, E.S. et al., Nature 409, 860-921 (2001)). Orthologs, by definition, have evolved by vertical descent from a common ancestor (Fitch, W.M., Syst Zool 19, 99-113 (1970)) and are presumed to carry out similar function. As a comparison to the orthologs, also a non-orthologous set of 596 genes from chromosome 1, 2 and 4 was targeted. In order to perform the analysis in the absence of the wild-type allele, haploid cells were used. A library of 1,167 yeast strains expressing the tagged proteins was generated. After growing cells to mid-log phase, TAP assemblies were purified from total cellular lysates under mild conditions (Rigaut, G. et al., Nat Biotechnol 17, 1030-2 (1999)). The purified protein assemblies were separated by denaturing gel electrophoresis, bands digested with trypsin, analyzed by MALDI-TOF MS and identified by database search algorithms. 240 proteins were localized at membranes (integral and peripherally associated) (Costanzo, M. C. et al. YPD, Nucleic Acids Res 29, 75-9 (2001)). Of the soluble proteins that could not be tagged, one third WO 03/072602 PCT/EPO2/50003 187 was detected in multiprotein complexes using another tagged protein as "entry point". Within the set of 418 essential genes (Costanzo, M. C. et al. YPD, Nucleic Acids Res 29, 75-9 (2001)), only 18% did not result in viable strains, suggesting that in the majority of cases, the C-terminal TAP tag does not interfere with protein function. The proteins found associated to the 589 successfully purified tagged proteins were analyzed. This generated 20,946 samples for mass spectrometry and a subsequent identification of 16,830 proteins. Of these, 1,440 were distinct gene products, representing more than 30% of the proteome as estimated from transcripts expressed under similar conditions (Holstege, F. C. et al., Cel195, 717-28 (1998)). The analysis covers proteins of various subcellular compartments, suggesting that the strategy has general validity Of all the successfully purified tagged proteins, 78% presented associated partners, suggesting an unexpectedly high level of interactivity and complex cohesion. Different complex entry points often lead to the purification of very similar assemblies. A sequential approach to integrate the 589 different purifications into a reduced number of curated TAP-complexes was taken. All subsequent statistical analysis is based on that set. 245 purifications overlapped with 98 known multiprotein complexes as described in the YPD literature database (Costanzo, M. C. et al., Nucleic Acids Res 29, 75-9. (2001)). Among the set of complexes that were assigned to YPD complexes, coverage of components was very high. 102 proteins were not detected in association with any other protein, neither when used directly for purification nor as part of other complexes. The remaining 242 purifications were assembled manually into 134 novel complexes. Of all 232 curated TAP complexes, only 9% had no novel constituents (Tab. 1). The size of the TAP complexes varied from 2 to 83 components, with an average of 12 components per complex. Cellular roles were ascribed to complexes by computing functional assignments of the individual components as found in YPD (Costanzo, M. C. et al., Nucleic Acids Res 29, 75-9. (2001)) and by literature mining (Tab. 1). In general terms, there is a wide functional distribution of complexes over nine categories, except for membrane-associated complexes that are underrepresented due to the reduced number of TAP membrane proteins used for purification. Orthologous gene products are thought to be responsible for essential cellular activities. It was found that orthologous proteins preferentially interact with complexes enriched with other orthologs. This confirms the existence of an "orthologous proteome" that may represent core functions for the eukaryotic cell (Rubin, G. M. et al. Science 287, 2204-15. (2000).) A particular complex is WO 03/072602 PCT/EPO2/50003 188 not necessarily of invariable composition nor are all its building blocks uniquely associated with that specific complex. A given protein may be only transiently associated with a complex depending on physiological conditions or subcellular compartment. Using several distinct tagged proteins as entry points to purify a complex, core components can be identified and validated systematically, while more dynamic, perhaps regulatory components may be present differentially. The dynamics of complex composition is well illustrated by the cellular signaling complexes formed around the protein phosphatase 2A (yTAP-C151). Tagging different PP2A components resulted in the purification of the known trimeric complexes containing Tpd3 (the regulatory A subunit), either of the two catalytic subunits, Pph21 or Pph22, and either of the two regulatory B subunits, Cdc55 or Rtsl. The Cdc55-containing complexes were found to additionally contain the Zdsl and/or Zds2 proteins, cell-cycle regulators, revealing preferences among the different "sub-complexes" and a link to cell-cycle checkpoints. Additional plasticity of the PP2A complexes is apparent by the interaction with three proteins implicated in bud shape and morphogenesis (Ltel, Kell and YBL104c). This analysis shows that also the interactions of a signaling enzyme may be sufficiently strong to allow the detection of distinct cellular complexes and thus be diagnostic for a role of this enzyme in different cellular activities. An example of a large, cohesive complex is given by the polyadenylation machinery (infra). This example shows that complexes are often sufficiently strong to show high composition integrity even when purified using different entry points. Moreover, the example shows that the TAP method reveals novel components even in well-studied cellular machinery. The results presented herein show that orthologous proteins are more likely to associate with each other than to non-orthologous proteins. Comparison to several human complexes showed that indeed, complexes built around yeast orthologs have counterparts in human. To analyze if the TAP strategy can be applied to retrieve orthologous multiprotein complexes from human cells, complexes from distinct subcellular compartments were purified: WO 03/072602 PCT/EPO2/50003 189 Human complexes analyzed are the Arp2/3.complex, the CCR4-NOT-complex (more fully described below), a nuclear assembly and the TRAPP-complex, a Golgi-associated complex (more fully described below). The Arp2/3 complex, a cytoskeleton-associated complex, is a stable multi-protein assembly required for the nucleation of actin filaments in all eukaryotic cells and consists of 7 proteins in human and yeast (Higgs, H. N. & Pollard, T. D., Annu Rev Biochem 70, 649-676. (2001)). Tandem affinity purification of Arp2 in yeast (yTAP-C153) and ARPC2 in human (Higgs, H. N. & Pollard, T. D., Annu Rev Biochem 70, 649-676. (2001), respectively, resulted in the isolation and identification of all known components. This demonstrates that the TAP-based approach combined with LC-MS/MS is an efficient and sensitive way to retrieve and characterize human multiprotein complexes (Fig. 3). Taken together, these examples show that the analysis of the yeast com plex is predictive of novel components in the human counterparts, suggesting that the large-scale yeast analysis has immediate functional relevance for human biology. To assign cellular functions to novel, non-annotated gene products, as well as understanding the context within which proteins operate, several large-scale approaches have been undertaken. These include mRNA expression monitoring (chips and SAGE) (Lockhart, D. J. & Winzeler, E. A., Nature 405, 827-36. (2000)) loss-of-function approaches combined with subcellular localization screens in yeast (Lockhart, D. J. & Winzeler, E. A., Nature 405, 827-36. (2000) and Ross-Macdonald, P. et al., Nature 402, 413-8. (1999)), RNAi in C. elegans (Fraser, A. G. et al., Nature 408, 325-30. (2000) and Gonczy, P. et al., Nature 408, 331-6. (2000)), gene trap in mice (Friedrich, G. & Soriano, P., Genes Dev 5, 1513-23. (1991) and Leighton, P. A. et al., Nature 410, 174-9. (2001)) in silico methods (based on homology or genomic context, such as gene fusion and neighbourhood (Eisenberg, D., Marcotte, E. M., Xenarios, I. & Yeates, T. O., Nature 405, 823-6. (2000) and Huynen, M., Snel, B., Lathe, W., 3rd & Bork, P., Genome Res 10, 1204-10. (2000)) as well as extensive two-hybrid screens (Fromont-Racine, M., Rain, J. C. & Legrain, P., Nat Genet 16, 277-82. (1997), P. et al., Nature 403, 623-7. (2000) and Ito, T. et al., Proc Natl Acad Sci U S A 98, 4569-74. (2001).

WO 03/072602 PCT/EPO2/50003 190 The TAP-based approach (Rigaut, G. et al., Nat Biotechnol 17, 1030-2 (1999)) proved invaluable for the purification of complexes from different cellular compartments, including complexes associated with cellular membranes. The approach also allows for the efficient identification of low abundance proteins that would not be detectable by expression proteomic approaches. Further, the TAP procedure allows the purification of very large complexes. For example, we have been able to purify yTAP-C116 (INO80), a complex reported to be approximately 1-1.5 MDa in size (Shen, X., Mizuguchi, G., Hamiche, A. & Wu, C., Nature 406, 541-4. (2000)), of which we identified all known and several novel interactors. This work presents the first examples of TAP purifications of mammalian complexes. Side-by-side comparison with selected yeast complexes show that, as in yeast, the technique is efficient and shows little or no background. We sought to gauge the reliability of our data by comparison of our experimental results to those in the published literature. If normalized for the proteins analyzed in this study, It was found that the present data covers 56% of the data present in the YPD protein complex database. In comparison, large-scale yeast two-hybrid approaches (Fromont Racine, M., Rain, J. C. & Legrain, P., Nat Genet 16, 277-82. (1997), Uetz, P. et al., Nature 403, 623-7. (2000), Ito, T. et al., Proc NatlAcad Sci USA 98, 4569-74. (2001)) cover approximately 10% of the YPD complex database (Ito, T. et al., Proc Natl Acad Sci USA 98, 4569-74. (2001), demonstrating that the TAP/MS strategy is particularly well suited for the characterization of multiprotein complexes. Previous approaches to tag large numbers of yeast ORFs for biochemical studies have relied on protein overexpression from heterologous promoters (Martzen, M. R. et al., Science 286, 1153 5. (1999) and Heyman, J. A. et al., Genome Res 9, 383-92. (1999)). The success of the present approach relies on the conditions used for the assembly and retrieval of the complexes. These include maintaining protein concentration, localisation and postranslational modifications in a manner that closely approximate normal physiology. Complex stoichiometry was not analyzed. Yet it is obvious by the intensity of the different protein bands stained after electrophoresis, that there is variability in the amount of purified proteins. This may indicate different affinities and abundance of the individual proteins, but also the possibility that several complexes may co-purify. When size WO 03/072602 PCT/EPO2/50003 191 exclusion chromatography was performed to test complex integrity, we detected instances of pronounced complex cohesion as well as cases where different sub complexes could be distinguished. Finally, TAP-purified complexes from this collection may be used to produce protein chips containing physiological protein complexes (Zhu, H. et al. Science 26, 26 (2001)) and for assessment of biochemical activity of proteins within their molecular environment (Martzen, M. R. et al., Science 286, 1153-5. (1999)). Another interesting outcome of the present invention is the ease and the frequency by which protein complexes can be retrieved from cells. These biophysical properties of protein complexes may suggest co-operative binding. Bridging factors, postranslational modifications, allosteric structural changes, binding of ions and metabolites can all co operate to increase the number of short range interactions between individual proteins in an assembly. Moreover, several proteins with critical regulatory functions are non globular or intrinsically unstructured (Wright, P. E. & Dyson, H. J., J Mol Biol 293, 321-31. (1999)). Folding into ordered structures only occurs upon binding to other proteins, offering the opportunity for control over the thermodynamics of the binding process. Many of the complexes identified in this study will be useful for structural studies. The statistical analysis of the large-scale yeast approach shows a clear tendency of proteins that are part of the set of metazoan orthologs to bind to other proteins of the same set. Moreover, a high propensity to associate is also observed among the products of essential genes. There is a significant overlap between complexes containing orthologs and essential proteins. This experimental observation confirms the proposition that the products of essential genes are also more likely to represent central components in the protein network (Jeong, H., Mason, S. P., Barabasi, A. L. & Oltvai, Z. N., Nature 411, 41-2. (2001)). Thus, "orthologous complexes" may well represent the building blocks of a eukaryotic core proteome (Rubin, G. M. et al. Science 287, 2204-15. (2000) and Jeong, H., Mason, S. P., Barabasi, A. L. & Oltvai, Z. N., Nature 411, 41-2. (2001)). A significant number of the yeast complexes described here has human equivalents which may form the basis for understanding multifactorial diseases. Through the "guilt by association" concept we are able to propose testable cellular roles for proteins that had no previous functional annotation and novel roles for known proteins. Assessment of the WO 03/072602 PCT/EPO2/50003 192 physiological molecular context of proteins, as described here, may be one of the most efficient and unambiguous routes towards the assignment of gene identity and function. The present analysis allowed us to group cellular proteins into approximately 200 complexes. These are connected to each other by sharing components. The network that results is a functional description of the eukaryotic proteome at an unprecedented level of organization. Such higher order maps will bring increasing quality to our appreciation of biological systems. This provides drug discovery programs with a molecular context for the choice and evaluation of drug targets. The Cleavage-Polyadenylation Machinery (Complex No. 162) Polyadenylation of precursor mRNA (pre-mRNAs) is an obligatory step in the maturation of most eukaryotic transcripts. The addition of poly(A) (polyadenosine) tails promote transcription termination and export of the mRNA from the nucleus. Furthermore, the poly(A) tails have the function to increase the efficiency of translation initiation and to help to stabilize mRNAs. Polyadenylation occurs posttranscriptionally in the nucleus of eukaryotic cells in two tightly coupled steps: the endonucleolytic cleavage of the precursor and the addition of a poly(A) tail. In the yeast Saccharomyces cerevisiae, the pre-mRNA 3'-end processing signals are not as well conserved as in mammalian cells (see below). In addition to the cleavage and polyadenylation site, two cis-acting elements, called the efficiency element and the positioning element, are found upstream of the cleavage site. Efficiency elements contain the sequence UAUAUA (or close variants thereof) and are often repeated. The sequence AAUAAA and several related sequences can function as a positioning element. Fractionation of yeast extracts led to the separation of protein factors that are required for mRNA 3'-end formation in vitro. The cleavage reaction requires cleavage factors I and II (CF I and CF 11), whereas polyadenylation involves CF I, polyadenylation factor I (PF 1) and poly(A) polymerase (Papl). CF I can be separated into two activities, CF IA and CF lB. CF IA is needed for both processing steps and is a heterotetrameric protein with subunits of 38, 50, 70 and 76 kDa that are encoded by the RNA5, CLP1, PCF11 and RNA14 genes. Rnal4 shares WO 03/072602 PCT/EPO2/50003 193 significant sequence similarity to the 77 kDa subunit of mammalian cleavage stimulation factor (CstF) and Rnal5 contains a RNA-binding domain homologous to that of the 64 kDa subunit of CstF. In addition to the above mentioned four CFI subunits, Pabi (poly(A) binding protein) was identified in purified CFI fractions. Both biochemical and genetic data indicate an involvement of Pabl in poly(A) length control. CF IB consists of a single protein called Nab4/Hrpl and is required for cleavage site selection and polyadenylation. A multiprotein complex which has CFII-PF I (= CPF) activity consists of nine polypeptides: Pap1 (poly(A) polymerase), Ptal, Pfsl, Pfs2, Fipl, Cftl/Yhhl, Cft2/Ydhl, Yshl/Brr5, and Ythl. Pap1, a 64 kDa protein, was the first component of the yeast 3'-end formation complex to be purified to homogeneity. Ptal is a 90 kDa protein which is required for both cleavage and polyadenylation of mRNA precursors. Pfs2 is a 53 kDa protein that contains seven WD40 repeats. Pfs2 has been shown to directly interact with subunits of CFII-PF1 and CFIA and is thought to function in the assembly and stabilization of the 3'-end processing complex. Fipl has been demonstrated to physically interact with Pap1, Ythl and Rnal4 and it is believed that it tethers Pap1 to its substrate during polyadenylation. Cftl/Yhhl, Cft2/Ydhl, Yshl/Brr5, and Ythl are the counterparts of the four subunits of the mammalian cleavage and polyadenylation specificity factor, CPSF160, CPSF100, CPSF73 and CPSF30, respectively. For the mammalian system, various data have been presented which have given evidence both for a conserved mechanism and also showed some differences between the yeast and the mammalian structures. The composition and function of the mammalian complex based on the data to date is as follows: The cleavage and polyadenylation factor (CPSF) is composed of 4 subunits: CPSF160 (involved in mRNA and poly(A) polymerase (PAP) binding), CPSF100, CPSF 73 and CPSF30 (involved in mRNA and PABII binding). CPSF binds the AAUAAA hexanucleotides. CPSF links the mRNA 3'-end processing to the transcription. CPSF exists as a stable complex with the transcription factor TFIID WO 03/072602 PCT/EPO2/50003 194 complex. The 160 kDa subunit of CPSF binds to several hTAFII. TFIID recruits CPSF to the RNA polymerase 11 pre-initiation complex. Upon transcriptional activation CPSF dissociates from TFII and associates with the elongating RNA pol 1I (CTD carboxy terminal domain of the largest subunit of the RNA polymerase 11). CPSF is thought to travel with RNA pol 1I until they reach the polyadenylation site, where CPSF can bind the AAUAAA element. CPSF is required for the termination of transcription. The interaction between CPSF and the AAUAAA element is weak and not so specific. The binding of CPSF to the hexanucleotide is greatly enhanced by a 2nd component of the poly-adenylation machinery, the cleavage stimulation factor (CstF), which binds the G-U rich motif. CstF also binds the RNA pol 1I through its 50 kDa subunit (CstF50). Furthermore, CstF50 binds another component of the transcriptional machinery: BRCA1 associated RING domain protein (BARD1). BARD1 also interacts with RNA pol 1. BARD1-CstF50 interaction inhibits polyadenylation in vitro and may prevent inappropriate mRNA processing during transcription. CstF is composed of 3 subunits: CstF64 (binds mRNA and symplekin (yeast homolog: Ptal), CstF77 (binds CPSF160, CstF64, CstF50) and CstF50 (binds RNA pol 11 and BARD1). The co-operative binding of CPSF and CstF to the polyadenylation site forms a ternary complex, which functions to recruit the other components of the polyadenylation machinery to the cleavage site: the two cleavage factors (CFIm and CFIIm) and the poly(A) polymerase (PAP). CFIm is an heterodimer of 4 subunits 72, 68, 59, 25 components: one essential, CFIImA and one stimulatory, CFIIB. CFIImA contains hPCF1 1p and hCIplp (binds cPSF and CF I). CF limB contains no factors previously shown to be involved in 3'-end processing and may be a new 3'-end processing factor. Although the identity of the proteins that perform the cleavage step is still unknown, it is well established that both CFIm and CFIIm are required. The reaction products of the cleavage suggest that a metal ion is involved. Surprisingly, PAP (but not its catalytic activity) is required for the cleavage. After the cleavage step CstF, CFIm and CFIlm are dispensable. PAP bound to CPSF (through its 160 kD subunit) can start polyadenylating the cleaved 3'-end, but at that step, the process is very inefficient. The poly(A) binding protein II (PAB II) can bind the nascent poly(A) chain as soon as it reaches a minimal length of 10 poly(A). PAB II also interacts with the CPSF30. The binding of PAB II greatly stabilizes PAP at the 3'-end of WO 03/072602 PCT/EPO2/50003 195 the mRNA, supporting the progressive synthesis of a long poly(A) tail. In the nucleus, the length of the poly(A) tail is restricted to about 250 poly(A). This size restriction is probably achieved through stoichiometric binding of multiple PAB II. It is not yet known how the incorporation of a certain amount of PAB 11 in the complex terminates processive elongation. CstF is part of the mammalian 3'-end processing complex and is a heterotrimeric protein with subunits of 77, 64 and 50 kDa. CstF-50 has been shown to interact with the BRCA1 associated protein BARD1 and this interaction suppresses the nuclear mRNA polyadenylation machinery in vivo. In a recent study it was found that treatment of cells with DNA damage-inducing agents causes a transient, but specific, inhibition of mRNA 3'-end processing in cell extracts. This inhibition reflects the BARDI/CstF interaction and involves enhanced formation of a CstF/BARD1/BRCA1 complex. A tumor-associated germline mutation in BARD1 decreases binding to CstF-50 and renders the protein inactive in polyadenylation inhibition. These results support the existence of a link between mRNA 3'-end formation and DNA repair/tumor suppression. The in vivo function of these interactions may be to inhibit the cleavage and polyadenylation of pre-mRNAs on polymerase molecules that are stalled at sites of DNA repair. Cleavage stimulation factor (CstF) is one of the multiple factors required for mRNA polyadenylation in mammalians. CstF-64 may play a role in regulating gene expression and cell growth in B cells. The concentration of one CstF subunit (CstF-64) increases during activation of B cells, and this is sufficient to switch IgM heavy chain mRNA expression from membrane- bound to secreted form. Reduction in CstF-64 causes reversible cell cycle arrest in GO/G1 phase, while depletion results in apoptotic cell death. In contrast to what is observed in yeast, the sequence elements in mammals, which specify the site of cleavage and polyadenylation, flank the site of endonucleolytic attack. One is the hexanucleotide AAUAAA found 10-30 bases upstream of the cleavage/polyadenylation site. The second is a G-U-rich motif located 20-40 bases downstream of the cleavage/polyadenylation site. These two elements and their spacing determine the site of cleavage/polyadenylation and also the strength of the polyadenylation signal.

WO 03/072602 PCT/EPO2/50003 196 Some other elements, like sequences upstream of the AAUAAA (upstream sequence elements, USEs) play regulatory roles. A schematic presentation of the motifs underlying mammalian polyadenylation and yeast polyadenylation are shown in Fig. 4. A review on the formation of mRNA 3'-ends in eukaryotes is given in Zhao, Hyman and Moore in Microbiology and Molecular Biology Reviews, 1999, pp. 405-445. A comparison of mammalian and yeast pre-mRNA 3'-end processing is also given in Keller and Minvielle-Sebastia in Nucleus and gene expression in Current Opinion in Cell Biology, 1997, Vol. 9, pp. 329-336. There are diseases which involve defects in the function of the polyadenylation machinery. Many viruses interact directly with components of the mRNA processing machinery. The herpes simplex virus type 1 (HSV-1) immediate early (alpha) protein ICP27 is an essential regulatory protein that is involved in the shutoff of host protein synthesis,. It affects mRNA processing at the level of both polyadenylation and splicing. During polyadenylation, ICP27 appears to stimulate 3' mRNA processing at selected poly(A) sites. The opposite effect occurs on host cell splicing. That is, during HSV-1 infection, an inhibition in host cell splicing requires ICP27 expression. This contributes to the shutoff of host protein synthesis by decreasing levels of spliced cellular mRNAs available for translation. A redistribution of splicing factors regulated by ICP27 has also been seen. Epstein-Barr virus BMLF1 gene product EB2 seems to affect mRNA nuclear export of intronless mRNAs and pre-mRNA 3' processing. EB2 contains an Arg-X-Pro tripeptide repeated eight times, similar to that described as an mRNA-binding domain in the herpes simplex virus type 1 protein US11. Interestingly, both viruses have been found to precede the onset of lymphomas. Influenza A virus NS1A protein binds the 30 kDa subunit of the cleavage and polyadenylation specificity factor (CPSF), NS1 protein (NS1A protein) via its effector domain targets the poly(A)-binding protein II (PABII) of the cellular 3'-end processing machinery. In vitro the NSIA protein binds the PABII protein, and in vivo causes PABII WO 03/072602 PCT/EPO2/50003 197 protein molecules to relocalize from nuclear speckles to a uniform distribution throughout the nucleoplasm. In vitro the NS1A protein inhibits the ability of PABII to stimulate the processive synthesis of long poly(A) tails catalyzed by poly(A) polymerase (PAP). Such inhibition also occurs in vivo in influenza virus-infected cells. Consequently, although the NS1A protein also binds the 30 kDa subunit of the cleavage and polyadenylation specificity factor (CPSF), 3' cleavage of some cellular pre-mRNAs still occurs in virus infected cells, followed by the PAP-catalyzed addition of short poly(A) tails. Subsequent elongation of these short poly(A) tails is blocked because the NS1A protein inhibits PABII function. The NS1 effector domain functionally interacts with the cellular 30 kDa subunit of CPSF, an essential component of the 3' end processing machinery of cellular pre mRNAs. Metachromatic leukodystrophy (MLD) is a lysosomal storage disorder caused by the deficiency of arylsulfatase A (ASA). A substantial ASA deficiency has also been described in clinically healthy persons, a condition for which the term pseudodeficiency was introduced. The mutations characteristic for the pseudodeficiency (PD) allele have been identified. Sequence analysis revealed two A-G transitions. One of them changes the first polyadenylation signal downstream of the stop codon from AATAAC to AGTAAC. This causes a severe deficiency of a 2.1-kilobase (kb) mRNA species. The deficiency of the 2.1-kb RNA species provides an explanation for the diminished synthesis of ASA seen in pseudodeficiency fibroblasts. MLD patients have been identified who are homozygous for the ASA-PD allele and it is thought that the allele might play a role in the development and progression of disease. There is a tight link between cell cycle control and polyadenylation machinery suggesting an important role of this machinery in the development of cancer. Cyclin-dependent enzymes seem to regulate the activity of the polyadenylation machinery. The amounts of some factors of the mRNA 3' processing machinery (CstF) increase in mitotically active cells in phases of the cell cycle preceding DNA synthesis. The amount of the 64-kDa subunit CstF-64 increases 5-fold during the GO to S phase transition and concomitant proliferation induced by serum in 3T6 fi-broblasts. The increase in CstF-64 is associated with the GO to S phase transition. Cdc2-cyclin B phosphorylates PAP at the Ser-Thr-rich region.

WO 03/072602 PCT/EPO2/50003 198 However, as it seems now, most diseases associated with defects in mRNA processing are caused by mutations in cis-acting elements that disrupt sequences essential for pre mRNA splicing. These can be canonical sequences at the intron-exon border or located within an exon. They directly affect the expression of a single mutated gene. Approximately 15% of the nucleotide substitutions that cause human diseases disrupt pre-mRNA splicing. Thus these diseases do not seem to be directly caused by alterations in the polyadenyation/cleavage-machinery. However, since recently evidence for a number of interrelationships between polyadenylation/cleavage and splicing is accumulating (for review see Zhao, Hyman and Moore in Microbiology and Molecular Biology Reviews, 1999, pp. 405-445), it might very well be that alterations in the 3'-end processing machinery contribute to the etiology of these diseases. Examples of diseases caused by incorrect splicing are mentioned below: Amyotrophic lateral sclerosis (ALS) is a neurodegenerative disease involving degeneration of cortical motor neurons and spinal/bulbar motor neurons. In the sporadic form of the disease, the neuron degeneration is caused by excessive extracellular glutamate. The glutamate transporter functional in the CNS is the astrocyte EAAT2 which is altered in ALS. The pre-mRNA for EAAT2 is aberrantly spliced in the brain regions affected. The reason for this is still unknown, but the defect lies probably in one or a few auxiliary splicing factors that regulate the splicing of a sub-set of pre-mRNA in these cells. The factors have not yet been identified. The human papillomavirus (HPV) E2 protein plays an important role in transcriptional regulation of viral genes as well as in viral DNA replication. HPV-5 (an EV epidermodysplasia verruciformis-HPV) protein can specifically interact with cellular splicing factors including a set of prototypical SR proteins and two snRNP-associated proteins (Lai, Teh et al. 1999, J. Biol. Chem. 274, pages 11832-41). Interestingly all these three viruses have been associated with cancer progression. Papillomavirus infection precedes cervical cancer, whereas EBV and HSV-8 have been described in association with lymphomas.

WO 03/072602 PCT/EPO2/50003 199 In hepatocellular carcinoma, there is a defect in mRNA splicing. In this disease, there are anti-nuclear antibodies to a 64 kD protein, which has splicing factor motifs. A defect in the regulatory subunit 3 of the protein phosphatase 1(PP1) has been found in haematological malignancies and in lung, ovarian, colorectal and gastric cancers. Low PP1 activity has been observed also in acute myelogenous leukaemia. Heterogeneous nuclear ribonucleoproteins (hnRNP) associate with pre-mRNA and have a role in RNA processing and splice site selection. HnRNP A2 shows a marked overexpression in lung cancer and brain tumours and has thus been used as a biomarker for these tumor types. The development of antinuclear antibodies (ANA) in malignancies has been described but its mechanism is still not understood. A great diversity of ANA specificities is found in hepatocellular carcinoma. In hepatoma sera antibodies co-localize with non-snRNP splicing factor SC35, suggesting that the antigenic targets might be involved in mRNA splicing. Hepatocellular carcinoma has a significantly higher frequency of ANA than chronic hepatitis C, chronic hepatitis B, alcoholic liver cirrhosis or healthy donors. In some autoimmune diseases, a possible link has been detected to a preceding virus infection, like Epstein-Barr virus in SLE. Furthermore it seems that even vaccination is potentially dangerous: a candidate for cytomegalovirus CMV vaccine is glycoprotein gB (UL55). Immunization with an adenovirus-gB construct (Ad-gB) not only induces a significant anti-viral response, but a significant IgG auto-antibody response (p > 0.005) to the U1-70 kDa spliceosome protein. Auto-antibodies to U1-70 kDa are part of the anti ribonucleoprotein response seen in systemic lupus erythematosus and mixed connective tissue disease. At least two molecules which are also part of the complex are known to be inhibited by natural toxins or treatment against various diseases. Protein phosphatase 1 is inhibited by several natural product toxins.

WO 03/072602 PCT/EPO2/50003 200 The marine toxins include the cyanobacteria-derived cyclic heptapeptide microcystin-LR and the polyether fatty acid okadaic acid from dinoflagellate sources. They bind to a common site on PP1. The dephosphorylation of PP1 is inhibited ( among other serine/threonine phosphatases PP2A, PP2B, PP2C and PP5/T/K/H ) by Fumonisin B1 (FB1), a mycotoxin produced by the fungus Fusarium moniliforme. This is a common contaminant of corn, and is suspected to be a cause of human esophageal cancer. FB1 is hepatotoxic and hepatocarcinogenic in rats, although the mechanisms involved have not been clarified. Viral proteins are able to interfere with PP1 activity: The transcription factor EBNA2 of the Epstein-Barr virus induces the expression of LMP1 onco-gene in human B- cells. EBNA2Afrom an EBV-immortalized B-cell line co immunopurifies with a PP1-like protein. A PP1-like activity in nuclear extracts from EBV immortalized B-cell line can be inhibited by a GST-EBNA2A fusion product. Poly(A)polymerase (PAP) is affected by anticancer drugs and is inhibited by some antiviral agents. Anticancer drugs: Most anticancer drugs act through the mechanism of apoptosis. Apoptosis may be regulated at all levels of gene expression including the addition of the poly(A) tail to the 3' end of mRNAs. Drug combinations are more effective than single drugs and various chemotherapeutic strategies have therefore been developed. Dimethylsulfoxide (DMSO) in combination with interferon (IFN) results in pronounced PAP dephosphorylation, activity reduction and apoptosis of HeLa cells. Purine and pyrimidine analogues often affect PAP activity. They are potentially useful agents for chemotherapy of cancer diseases. The anticancer drugs 5-Fluorouracil (5 FU), interferon and tamoxifen mediate both partial dephosphorylation and inactivation of poly(A) polymerase (PAP). PAP (from isolated hepatic nuclei) is inhibited by cordycepin 5'-triphosphate.The nucleoside analogue cordycepin is a therapeutic agent for TdT+ (terminal WO 03/072602 PCT/EPO2/50003 201 deoxynucleotidyl transferase positive) leukemia. In the presence of an adenosine deaminase inhibitor, deoxycoformycin (dCF), cordycepin is cytotoxic to leukemic TdT+ cells. A cordycepin analog of (2'-5') oligo(A) which can be synthesized enzymatically from cordycepin 5'-triphosphate and the core cordycepin analog can replace human fibroblast interferon in preventing the transformation of human lymphocytes after infection with Epstein-Barr virus B95-8 (EBV). The core cordycepin analog is not cytotoxic to uninfected lymphocytes and proliferating lymphoblasts. Not only is PAP affected by anticancer drugs, but it has a possible use as a tumor marker involved in cell commitment and/or induction of apoptosis and could be used to evaluate tumor cell sensitivity to anticancer treatment. Antiviral drugs: Ara-ATP (arabinofuranosyladenosine triphosphate) is an antiherpetic drug that inhibits herpes simplex virus replication. It inhibits poly(A) polymerase activity by competing with ATP. It blocks both cleavage and polyadenylation reactions by interacting with the ATP binding site on poly(A) polymerase, the activity of which is essential for the cleavage reaction. Purine and pyrimidine analogues are also used as antiviral agents. As an example, the most extensively used drug against HSV is idoxyuridine, the 5'-amino analog of thymidine. A decrease in herpes simplex virus transcription and perturbation of RNA polyadenylation is induced by 5'-amino-5'-deoxythymidine (AdThd). The cleavage stimulation factor (CSTF): Treatment with hydroxyurea or ultraviolet light strongly, but transiently, inhibits 3' cleavage. This is accompanied by increased amounts of a CstFIBARD1/BRCA1 complex, though the amount of these proteins remains the same.

WO 03/072602 PCT/EPO2/50003 202 Despite the large body of information already available from the prior art concerning the cleavagelpolyadenylation machinery of precursor mRNA up to now not all components of the machinery are known not to speak of the composition of the complex as a whole. This invention relates to a component of the cleavagelpolyadenylation machinery of precursor mRNA as listed in table 1, ninth colum of the respective complex (No. 162 a/b) By applying the process according to the invention to the isolation of the polyadenylation/cleavage machinery from yeast, which is further described below, thirty two new proteins could be identified in said yeast complex Purifications have been done using different proteins as bait according to the protocols stated further below. Below is a more detailed list of the newly identified components of the polyadenylation complex (see also Tab. 1). The Accession-Number stated is the GenBank-Accession number for the protein. Protein patterns for some of the purifications are shown in Figures 3 and 4. Act1: Is a known and essential protein (GenBank Acc. No. BAA21512.1), which has been shown to be involved in Pol II transcription and has been found to be associated with histone acetylation. It serves as a structural protein. Ckal: Is a known and non-essential protein (GenBank Acc. No. CAA86916.1), which has been found to be involved in Polymerase III transcription and has been found to be associated with the Casein kinase II complex. Eft2: The translation elongation factor EF-2 is a known protein involved in protein synthesis (GenBank AAB64827.1) Eno2: Is a known and essential protein (GenBank Acc. No. AAB68019.1). It has been shown to have lyase activity and is known to be involved in carbohydrate metabolism.

WO 03/072602 PCT/EPO2/50003 203 GIc7 (YER133w) is also a known protein (GenBank Acc. No. AAC03231.1). It is also an essential protein and is a Type I protein serine threonine phosphatase which has been implicated in distinct cellular roles, such as carbohydrate metabolism, meiosis, mitosis and cell polarity. Its occurrence in the cleavage/polyadenylation machinery has not been known before. Gpml: This protein is a phosphoglycerate mutase that converts 2-phosphoglyvcerate to 3-phosphoglycerate in glycolysis. It is an essential protein (GenBank: CAA81994.1) Hhf2: Is a known and non-essential protein (GenBank Acc. No. CAA95892.1) which has been shown to be involved in DNA-binding. It has previously been linked to Histone octamer and the RNA polymerase I upstream activation factor. Htal: Is a known and non-essential protein (GenBank Acc. No. CAA88505.1) which has DNA-binding capability and has been shown to be involved in polymerase II transcription. Hsc82: Is a non-essential protein so far being associated with protein folding. (GenBank Acc. No: CAA89919.1) Imd2: Is an Inosine-5'-monophosphate dehydrogenase so far being associated with nucleotide metabolism. It is non-essential. (GenBank Acc.-No.: AAB69728.1) Imd4: Is a non-essential protein with similiarity to Imd2 so far being associated with nucleotide metabolism (GenBank Acc-No.: CAA86719.1) Met6: Is a homocysteine methyltransferase so far being associated with amino-acid metabolism (GenBank Acc.-No.: AAB64646.1) Pdcl: ls a pyruvate decarboxylase isozymel so far being associated with carbohydrate metabolism (GenBank Acc.-No.: CAA97573.1) Pfkl: Is a known protein (GenBank Acc. No. CAA97268.1) which has previously been described as part of the phosphofructokinase complex.

WO 03/072602 PCT/EPO2/50003 204 Ref2 (YDR195w) is a known protein (GenBank Acc. No. CAA88708.1). It is a non essential gene product. It has been shown to be involved in 3'-end formation prior to the final polyadenylation step. However, Ref2 has never been identified before as a component of the 3'-end processing machinery. Ref2 has been shown to interact with GIc7, another new component of the cleavagelpolyadenylation machinery. Secl3: Is a known and essential protein (GenBank Acc. No AAB67426.1). Sec31: Is a known and essential protein (GenBank Acc. No. CAA98772.1) Ssa3: Is a known and non-essential protein (GenBank Acc. No. CAA84896.1) which so far has been implicated with protein folding/protein transport. Ssu72 (YNL222w) is also a known protein (GenBank Acc. No. CAA96125.1) and is an essential phylogenetically conserved protein which has been shown to interact with the general transcription factor TFIIB (Sua7). TFIIB is an essential component of the RNA polymerase II (RNAP II) core transcriptional machinery. It is thought that this interaction plays a role in the mechanism of start site selection by RNAP II. The finding according to the present invention that Ssu72 is associated with Ptal is likely to be relevant since it is believed that mRNA 3'-end formation is linked with other nuclear processes like transcription, capping and splicing. Furthermore, Ssu 72 has also been clearly identified in a "reverse tagging experiment" as explained herein below by using some of the Ptal associated proteins as bait. However, when Ssu72 itself was used as a bait associated proteins were not found most likely due to the fact that the addition of a C-terminal tag renders Ssu72 non-functional. Taf60: Is a known and essential protein (GenBank Acc. No. CAA96819.1) which has been shown to be involved in Polymerase II transcription. Tkll: Is a non-essential transketolase so far being associated with amino-acid metabolism and carbohydrate metabolism (GenBank Acc-No.: CAA89191.1) WO 03/072602 PCT/EPO2/50003 205 Tsal: Translation initiation factor elF5 which so far has been to shown to catalyze hydrolysis of GTP on the 40S ribosomal subunit-initiation complex followed by joining to 60S ribosomal subunit. (GenBank Acc.-No.: CAA92145.1) Tye7: Is a known protein (GenBank Acc. No. CAA99671.1). It has been shown to be a basic helix-loop-helix transcription factor. Vid24: Is a known and non-essential protein (GenBank Acc. No. CAA89320.1) which has previously been associated with protein degradation and vesicular transport. Vps53: Is a known protein (GenBank Acc. No. CAA89320.1) which has been found to play a role in protein sorting. YCLO46w: Is a non-essential protein (GenBank Acc. No. CAA42371.1). YGR156w is the protein product of an essential gene. This protein also contains a RNA binding motif. (GenBank Acc. No. CAA97170.1). YHLO35c: Is a known and non-essential protein (GenBank Acc. No. AAB65047.1). It is a member of the ATP-binding cassette superfamily. YKL018w is also an essential protein containing a WD40 domain which is a typical protein binding domain. (GenBank Acc. No. CAA81853.1) YLR221c: Is a protein of unknown function (GenBank Acc. No.AAB67410.1) YMLO30w: Is a protein of unknown function (GenBank Acc. No. CAA86625.1) YOR179c shows significant sequence similarity to Yshl(GenBank Acc. No. CAA99388.1) Two further proteins for which binary interactions with members of the polyadenylation complex as known so far have been shown before have also been purified with the complex: WO 03/072602 PCT/EPO2/50003 206 YKLO59c: is the product of an essential gene and is a zinc binding protein containing a C2HC Zinc finger. The presence of this domain predicts a RNA binding function of YKLO59c. We believe the corresponding gene product is identical to Pfsl, a protein which has been mentioned in several publications, but which has never been annotated in the databases (for review see Keller, W. and Minvielle-Sebastia (1997). Curr Opin Cell Biol 11: 352-357). (GenBank Acc. No. CAA81896.1) Tif4632: Is a known and non-essential protein (GenBank Acc. No. CAA96751.1) which has been shown to have an RNA-binding/translation factor activity and is involved in protein synthesis. The present invention further relates to the following embodiments relating to the polyadenylation complex: 1. A protein complex selected from complex (I) and comprising (a) at least one first protein selected from the group consisting of: (i) "CFT1" (SEQ ID No:2837) or a functionally active derivative thereof, or a functionally active fragment thereof, or a homologue thereof, or a variant of "CFTI", the variant being encoded by a nucleic acid that hybridizes to the "CFTI" nucleic acid (SEQ ID No:2838) or its complement under low stringency conditions, (ii) "CFT2" (SEQ ID No:1529) or a functionally active derivative thereof, or a functionally active fragment thereof, or a homologue thereof, or a variant of "CFT2", the variant being encoded by a nucleic acid that hybridizes to the "CFT2" nucleic acid (SEQ ID No:1530) or its complement under low stringency conditions, (iii) "CLPI" (SEQ ID No:2839) or a functionally active derivative thereof, or a functionally active fragment thereof, or a homologue thereof, or a variant of "CLPI1", the variant being encoded by a nucleic acid that hybridizes to the "CLPI" nucleic acid (SEQ ID No:2840) or its complement under low stringency conditions, (iv) "FIPI" (SEQ ID No:1531) or a functionally active derivative thereof, or a functionally active fragment thereof, or a homologue thereof, or a variant of "FIPI1", the variant being encoded by a nucleic acid that hybridizes to the "FIPI" nucleic acid (SEQ ID No:1532) or its complement under low stringency conditions, WO 03/072602 PCT/EPO2/50003 207 (v) "GLC7" (SEQ ID No:929) or a functionally active derivative thereof, or a functionally active fragment thereof, or a homologue thereof, or a variant of "GLC7", the variant being encoded by a nucleic acid that hybridizes to the "GLC7" nucleic acid (SEQ ID No:930 ) or its complement under low stringency conditions, (vi) "PAP1" (SEQ ID No:1541) or a functionally active derivative thereof, or a functionally active fragment thereof, or a homologue thereof, or a variant of "PAP1", the variant being encoded by a nucleic acid that hybridizes to the "PAP1" nucleic acid (SEQ ID No:1542) or its complement under low stringency conditions, (vii) "PCF11" (SEQ ID No:2843) or a functionally active derivative thereof, or a functionally active fragment thereof, or a homologue thereof, or a variant of "PCF1 1", the variant being encoded by a nucleic acid that hybridizes to the "PCF11" nucleic acid (SEQ ID No:2844 ) or its complement under low stringency conditions, (viii) "PFS2" (SEQ ID No:1543) or a functionally active derivative thereof, or a functionally active fragment thereof, or a homologue thereof, or a variant of "PFS2", the variant being encoded by a nucleic acid that hybridizes to the "PFS2" nucleic acid (SEQ ID No:1544) or its complement under low stringency conditions, (ix) "PTAI" (SEQ ID No:1545) or a functionally active derivative thereof, or a functionally active fragment thereof, or a homologue thereof, or a variant of "PTAI", the variant being encoded by a nucleic acid that hybridizes to the "PTAI" nucleic acid (SEQ ID No:1546) or its complement under low stringency conditions, (x) "REF2" (SEQ ID No:1547) or a functionally active derivative thereof, or a functionally active fragment thereof, or a homologue thereof, or a variant of "REF2", the variant being encoded by a nucleic acid that hybridizes to the "REF2" nucleic acid (SEQ ID No:1548) or its complement under low stringency conditions, (xi) "RNA14" (SEQ ID No:1549) or a functionally active derivative thereof, or a functionally active fragment thereof, or a homologue thereof, or a variant of "RNA14", the variant being encoded by a nucleic acid that hybridizes to the "RNA14" nucleic acid (SEQ ID No:1550 ) or its complement under low stringency conditions, (xii) "RNA15" (SEQ ID No:2845) or a functionally active derivative thereof, or a functionally active fragment thereof, or a homologue thereof, or a variant of "RNA15", the variant being encoded by a nucleic acid that hybridizes to the "RNA15" nucleic acid (SEQ ID No:2846 ) or its complement under low stringency conditions, (xiii) "SEC13" (SEQ ID No:1171) or a functionally active derivative thereof, or a functionally active fragment thereof, or a homologue thereof, or a variant of "SEC13", the WO 03/072602 PCT/EPO2/50003 208 variant being encoded by a nucleic acid that hybridizes to the "SEC13" nucleic acid (SEQ ID No: 1172 ) or its complement under low stringency conditions, (xiv) "SEC31" (SEQ ID No:1177) or a functionally active derivative thereof, or a functionally active fragment thereof, or a homologue thereof, or a variant of "SEC31", the variant being encoded by a nucleic acid that hybridizes to the "SEC31" nucleic acid (SEQ ID No:1178 ) or its complement under low stringency conditions, (xv) "YKLO59C" (SEQ ID No:2861) or a functionally active derivative thereof, or a functionally active fragment thereof, or a homologue thereof, or a variant of "YKL059C", the variant being encoded by a nucleic acid that hybridizes to the "YKLO59C" nucleic acid (SEQ ID No:2862 ) or its complement under low stringency conditions, (xvi) "YSHI" (SEQ ID No:1561) or a functionally active derivative thereof, or a functionally active fragment thereof, or a homologue thereof, or a variant of "YSH 1", the variant being encoded by a nucleic acid that hybridizes to the "YSHI" nucleic acid (SEQ ID No:1562 ) or its complement under low stringency conditions, (xvii) "YTHI" (SEQ ID No:2847) or a functionally active derivative thereof, or a functionally active fragment thereof, or a homologue thereof, or a variant of "YTHI", the variant being encoded by a nucleic acid that hybridizes to the "YTHI" nucleic acid (SEQ ID No:2848 ) or its complement under low stringency conditions, (xviii) "PABI" (SEQ ID No:2841) or a functionally active derivative thereof, or a functionally active fragment thereof, or a homologue thereof, or a variant of "PABI", the variant being encoded by a nucleic acid that hybridizes to the "PAB1" nucleic acid (SEQ ID No:2842 ) or its complement under low stringency conditions, and (xix) "HHF2" (SEQ ID No:555) or a functionally active derivative thereof, or a functionally active fragment thereof, or a homologue thereof, or a variant of "HHF2", the variant being encoded by a nucleic acid that hybridizes to the "HHF2" nucleic acid (SEQ ID No:556 ) or its complement under low stringency conditions, and (b) at least one second protein, which second protein is selected from the group consisting of: (i) "ACT1" (SEQ ID No:681) or a functionally active derivative thereof, or a functionally active fragment thereof, or a homologue thereof, or a variant of "ACT1", the variant being encoded by a nucleic acid that hybridizes to the "ACTI" nucleic acid (SEQ ID No:682) or its complement under low stringency conditions, WO 03/072602 PCT/EPO2/50003 209 (ii) "CKAI" (SEQ ID No:133) or a functionally active derivative thereof, or a functionally active fragment thereof, or a homologue thereof, or a variant of "CKA1", the variant being encoded by a nucleic acid that hybridizes to the "CKAI" nucleic acid (SEQ ID No:134) or its complement under low stringency conditions, (iii) "EFT2" (SEQ ID No:39) or a functionally active derivative thereof, or a functionally active fragment thereof, or a homologue thereof, or a variant of "EFT2", the variant being encoded by a nucleic acid that hybridizes to the "EFT2" nucleic acid (SEQ ID No:40 ) or its complement under low stringency conditions, (iv) "ENO2" (SEQ ID No:293) or a functionally active derivative thereof, or a functionally active fragment thereof, or a homologue thereof, or a variant of "ENO2", the variant being encoded by a nucleic acid that hybridizes to the "ENO2" nucleic acid (SEQ ID No:294 ) or its complement under low stringency conditions, (v) "GPMI" (SEQ ID No:597) or a functionally active derivative thereof, or a functionally active fragment thereof, or a homologue thereof, or a variant of "GPMI", the variant being encoded by a nucleic acid that hybridizes to the "GPMI" nucleic acid (SEQ ID No:598 ) or its complement under low stringency conditions, (vi) "HTAI" (SEQ ID No:1029) or a functionally active derivative thereof, or a functionally active fragment thereof, or a homologue thereof, or a variant of "HTAI1", the variant being encoded by a nucleic acid that hybridizes to the "HTAI" nucleic acid (SEQ ID No:1030) or its complement under low stringency conditions, (vii) "IMD2" (SEQ ID No:259) or a functionally active derivative thereof, or a functionally active fragment thereof, or a homologue thereof, or a variant of "IMD2", the variant being encoded by a nucleic acid that hybridizes to the "IMD2" nucleic acid (SEQ ID No:260) or its complement under low stringency conditions, (viii) "IMD4" (SEQ ID No:41) or a functionally active derivative thereof, or a functionally active fragment thereof, or a homologue thereof, or a variant of "IMD4", the variant being encoded by a nucleic acid that hybridizes to the "IMD4" nucleic acid (SEQ ID No:42 ) or its complement under low stringency conditions, (ix) "MET6" (SEQ ID No:1921) or a functionally active derivative thereof, or a functionally active fragment thereof, or a homologue thereof, or a variant of "MET6", the variant being encoded by a nucleic acid that hybridizes to the "MET6" nucleic acid (SEQ ID No:1922) or its complement under low stringency conditions, (x) "PFKI" (SEQ ID No:143) or a functionally active derivative thereof, or a functionally active fragment thereof, or a homologue thereof, or a variant of "PFK1 ", the variant being WO 03/072602 PCT/EPO2/50003 210 encoded by a nucleic acid that hybridizes to the "PFKI" nucleic acid (SEQ ID No:144 ) or its complement under low stringency conditions, (xi) "PTII" (SEQ ID No:1597) or a functionally active derivative thereof, or a functionally active fragment thereof, or a homologue thereof, or a variant of "PTII", the variant being encoded by a nucleic acid that hybridizes to the "PTII" nucleic acid (SEQ ID No:1598) or its complement under low stringency conditions, (xii) "RSA3" (SEQ ID No:2849) or a functionally active derivative thereof, or a functionally active fragment thereof, or a homologue thereof, or a variant of "RSA3", the variant being encoded by a nucleic acid that hybridizes to the "RSA3" nucleic acid (SEQ ID No:2850) or its complement under low stringency conditions, (xiii) "SSA3" (SEQ ID No:723) or a functionally active derivative thereof, or a functionally active fragment thereof, or a homologue thereof, or a variant of "SSA3", the variant being encoded by a nucleic acid that hybridizes to the "SSA3" nucleic acid (SEQ ID No:724 ) or its complement under low stringency conditions, (xiv) "SSU72" (SEQ ID No:2851) or a functionally active derivative thereof, or a functionally active fragment thereof, or a homologue thereof, or a variant of "SSU72", the variant being encoded by a nucleic acid that hybridizes to the "SSU72" nucleic acid (SEQ ID No:2852 ) or its complement under low stringency conditions, (xv) "SWD2" (SEQ ID No:1455) or a functionally active derivative thereof, or a functionally active fragment thereof, or a homologue thereof, or a variant of "SWD2", the variant being encoded by a nucleic acid that hybridizes to the "SWD2" nucleic acid (SEQ ID No:1456 ) or its complement under low stringency conditions, (xvi) "TAF60" (SEQ ID No:825) or a functionally active derivative thereof, or a functionally active fragment thereof, or a homologue thereof, or a variant of "TAF60", the variant being encoded by a nucleic acid that hybridizes to the "TAF60" nucleic acid (SEQ ID No:826) or its complement under low stringency conditions, (xvii) "TIF4632" (SEQ ID No:195) or a functionally active derivative thereof, or a functionally active fragment thereof, or a homologue thereof, or a variant of "TIF4632", the variant being encoded by a nucleic acid that hybridizes to the "TIF4632" nucleic acid (SEQ ID No:196 ) or its complement under low stringency conditions, (xviii) "TKLI" (SEQ ID No:379) or a functionally active derivative thereof, or a functionally active fragment thereof, or a homologue thereof, or a variant of "TKLI ", the variant being encoded by a nucleic acid that hybridizes to the "TKLI" nucleic acid (SEQ ID No:380) or its complement under low stringency conditions, WO 03/072602 PCT/EPO2/50003 211 (xix) "TSAI" (SEQ ID No:733) or a functionally active derivative thereof, or a functionally active fragment thereof, or a homologue thereof, or a variant of "TSAI", the variant being encoded by a nucleic acid that hybridizes to the "TSAI" nucleic acid (SEQ ID No:734 ) or its complement under low stringency conditions, (xx) "TYE7" (SEQ ID No:2853) or a functionally active derivative thereof, or a functionally active fragment thereof, or a homologue thereof, or a variant of "TYE7", the variant being encoded by a nucleic acid that hybridizes to the "TYE7" nucleic acid (SEQ ID No:2854) or its complement under low stringency conditions, (xxi) "VID24" (SEQ ID No:2855) or a functionally active derivative thereof, or a functionally active fragment thereof, or a homologue thereof, or a variant of "VID24", the variant being encoded by a nucleic acid that hybridizes to the "VID24" nucleic acid (SEQ ID No:2856 ) or its complement under low stringency conditions, (xxii) "VPS53" (SEQ ID No:1233) or a functionally active derivative thereof, or a functionally active fragment thereof, or a homologue thereof, or a variant of "VPS53", the variant being encoded by a nucleic acid that hybridizes to the "VPS53" nucleic acid (SEQ ID No:1234) or its complement under low stringency conditions, (xxiii) "YCLO46W" (SEQ ID No:2857) or a functionally active derivative thereof, or a functionally active fragment thereof, or a homologue thereof, or a variant of "YCLO46W", the variant being encoded by a nucleic acid that hybridizes to the "YCLO46W" nucleic acid (SEQ ID No:2858 ) or its complement under low stringency conditions, (xxiv) "YHLO35C" (SEQ ID No:2859) or a functionally active derivative thereof, or a functionally active fragment thereof, or a homologue thereof, or a variant of "YHLO35C", the variant being encoded by a nucleic acid that hybridizes to the "YHLO35C" nucleic acid (SEQ ID No:2860 ) or its complement under low stringency conditions, (xxv) "YMLO30W" (SEQ ID No:2863) or a functionally active derivative thereof, or a functionally active fragment thereof, or a homologue thereof, or a variant of "YMLO30W", the variant being encoded by a nucleic acid that hybridizes to the "YMLO30W" nucleic acid (SEQ ID No:2864 ) or its complement under low stringency conditions, and (xxvi) "YOR179C" (SEQ ID No:2865) or a functionally active derivative thereof, or a functionally active fragment thereof, or a homologue thereof, or a variant of "YOR179C", the variant being encoded by a nucleic acid that hybridizes to the "YOR179C" nucleic acid (SEQ ID No:2866 ) or its complement under low stringency conditions, and a complex (11) comprising at least two of said second proteins, wherein said low stringency conditions comprise hybridization in a buffer comprising 35% formamide, 5X WO 03/072602 PCT/EPO2/50003 212 SSC, 50 mM Tris-HCI (pH 7.5), 5 mM EDTA, 0.02% PVP, 0.02% Ficoll, 0.2% BSA, 100 ug/ml denatured salmon sperm DNA, and 10% (wt/vol) dextran sulfate for 18-20 hours at 40Q C, washing in a buffer consisting of 2X SSC, 25 mM Tris-HCl (pH 7.4), 5 mM EDTA, and 0.1 % SDS for 1.5 hours at 550 C, and washing in a buffer consisting of 2X SSC, 25 mM Tris-HCI (pH 7.4), 5 mM EDTA, and 0.1% SDS for 1.5 hours at 600 C. 2. The protein complex selected from complex (I) and comprising the following proteins: (i) "ACT1" (SEQ ID No:681) or a functionally active derivative thereof, or a functionally active fragment thereof, or a homologue thereof, or a variant of "ACT1", the variant being encoded by a nucleic acid that hybridizes to the "ACT1" nucleic acid (SEQ ID No:682 ) or its complement under low stringency conditions, (ii) "CFTI" (SEQ ID No:2837) or a functionally active derivative thereof, or a functionally active fragment thereof, or a homologue thereof, or a variant of "CFT1I", the variant being encoded by a nucleic acid that hybridizes to the "CFTI" nucleic acid (SEQ ID No:2838) or its complement under low stringency conditions, (iii) "CFT2" (SEQ ID No:1529) or a functionally active derivative thereof, or a functionally active fragment thereof, or a homologue thereof, or a variant of "CFT2", the variant being encoded by a nucleic acid that hybridizes to the "CFT2" nucleic acid (SEQ ID No:1530) or its complement under low stringency conditions, (iv) "CKA1" (SEQ ID No:133) or a functionally active derivative thereof, or a functionally active fragment thereof, or a homologue thereof, or a variant of "CKAI", the variant being encoded by a nucleic acid that hybridizes to the "CKAI" nucleic acid (SEQ ID No:134) or its complement under low stringency conditions, (v) "CLPI" (SEQ ID No:2839) or a functionally active derivative thereof, or a functionally active fragment thereof, or a homologue thereof, or a variant of "CLP1", the variant being encoded by a nucleic acid that hybridizes to the "CLP1" nucleic acid (SEQ ID No:2840) or its complement under low stringency conditions, (vi) "EFT2" (SEQ ID No:39) or a functionally active derivative thereof, or a functionally active fragment thereof, or a homologue thereof, or a variant of "EFT2", the variant being encoded by a nucleic acid that hybridizes to the "EFT2" nucleic acid (SEQ ID No:40 ) or its complement under low stringency conditions, (vii) "ENO2" (SEQ ID No:293) or a functionally active derivative thereof, or a functionally active fragment thereof, or a homologue thereof, or a variant of "ENO2", the variant WO 03/072602 PCT/EPO2/50003 213 being encoded by a nucleic acid that hybridizes to the "ENO2" nucleic acid (SEQ ID No:294 ) or its complement under low stringency conditions, (viii) "FIPI" (SEQ ID No:1531) or a functionally active derivative thereof, or a functionally active fragment thereof, or a homologue thereof, or a variant of "FIPI", the variant being encoded by a nucleic acid that hybridizes to the "FIPI" nucleic acid (SEQ ID No:1532) or its complement under low stringency conditions, (ix) "GLC7" (SEQ ID No:929) or a functionally active derivative thereof, or a functionally active fragment thereof, or a homologue thereof, or a variant of "GLC7", the variant being encoded by a nucleic acid that hybridizes to the "GLC7" nucleic acid (SEQ ID No:930 ) or its complement under low stringency conditions, (x) "GPMI" (SEQ ID No:597) or a functionally active derivative thereof, or a functionally active fragment thereof, or a homologue thereof, or a variant of "GPMI", the variant being encoded by a nucleic acid that hybridizes to the "GPM1" nucleic acid (SEQ ID No:598 ) or its complement under low stringency conditions, (xi) "HTAI" (SEQ ID No:1029) or a functionally active derivative thereof, or a functionally active fragment thereof, or a homologue thereof, or a variant of "HTAI", the variant being encoded by a nucleic acid that hybridizes to the "HTAI" nucleic acid (SEQ ID No:1030) or its complement under low stringency conditions, (xii) "IMD2" (SEQ ID No:259) or a functionally active derivative thereof, or a functionally active fragment thereof, or a homologue thereof, or a variant of "IMD2", the variant being encoded by a nucleic acid that hybridizes to the "IMD2" nucleic acid (SEQ ID No:260) or its complement under low stringency conditions, (xiii) "IMD4" (SEQ ID No:41) or a functionally active derivative thereof, or a functionally active fragment thereof, or a homologue thereof, or a variant of "IMD4", the variant being encoded by a nucleic acid that hybridizes to the "IMD4" nucleic acid (SEQ ID No:42 ) or its complement under low stringency conditions, (xiv) "MET6" (SEQ ID No:1921) or a functionally active derivative thereof, or a functionally active fragment thereof, or a homologue thereof, or a variant of "MET6", the variant being encoded by a nucleic acid that hybridizes to the "MET6" nucleic acid (SEQ ID No:1922 ) or its complement under low stringency conditions, (xv) "PAP1" (SEQ ID No:1541) or a functionally active derivative thereof, or a functionally active fragment thereof, or a homologue thereof, or a variant of "PAP1", the variant being encoded by a nucleic acid that hybridizes to the "PAP1" nucleic acid (SEQ ID No:1542) or its complement under low stringency conditions, WO 03/072602 PCT/EPO2/50003 214 (xvi) "PCF1 1" (SEQ ID No:2843) or a functionally active derivative thereof, or a functionally active fragment thereof, or a homologue thereof, or a variant of "PCF11", the variant being encoded by a nucleic acid that hybridizes to the "PCF11" nucleic acid (SEQ ID No:2844) or its complement under low stringency conditions, (xvii) "PFKI" (SEQ ID No:143) or a functionally active derivative thereof, or a functionally active fragment thereof, or a homologue thereof, or a variant of "PFKI", the variant being encoded by a nucleic acid that hybridizes to the "PFKI" nucleic acid (SEQ ID No:144) or its complement under low stringency conditions, (xviii) "PFS2" (SEQ ID No:1543) or a functionally active derivative thereof, or a functionally active fragment thereof, or a homologue thereof, or a variant of "PFS2", the variant being encoded by a nucleic acid that hybridizes to the "PFS2" nucleic acid (SEQ ID No:1544) or its complement under low stringency conditions, (xix) "PTAI" (SEQ ID No:1545) or a functionally active derivative thereof, or a functionally active fragment thereof, or a homologue thereof, or a variant of "PTAI", the variant being encoded by a nucleic acid that hybridizes to the "PTA1" nucleic acid (SEQ ID No:1546 ) or its complement under low stringency conditions, (xx) "PTI1" (SEQ ID No:1597) or a functionally active derivative thereof, or a functionally active fragment thereof, or a homologue thereof, or a variant of "PTII", the variant being encoded by a nucleic acid that hybridizes to the "PTII" nucleic acid (SEQ ID No:1598) or its complement under low stringency conditions, (xxi) "REF2" (SEQ ID No:1547) or a functionally active derivative thereof, or a functionally active fragment thereof, or a homologue thereof, or a variant of "REF2", the variant being encoded by a nucleic acid that hybridizes to the "REF2" nucleic acid (SEQ ID No:1548) or its complement under low stringency conditions, (xxii) "RNA14" (SEQ ID No:1549) or a functionally active derivative thereof, or a functionally active fragment thereof, or a homologue thereof, or a variant of "RNA14", the variant being encoded by a nucleic acid that hybridizes to the "RNA14" nucleic acid (SEQ ID No:1550 ) or its complement under low stringency conditions, (xxiii) "RNA15" (SEQ ID No:2845) or a functionally active derivative thereof, or a functionally active fragment thereof, or ahomologue thereof, or a variant of "RNA15", the variant being encoded by a nucleic acid that hybridizes to the "RNA15" nucleic acid (SEQ ID No:2846 ) or its complement under low stringency conditions, (xxiv) "RSA3" (SEQ ID No:2849) or a functionally active derivative thereof, or a functionally active fragment thereof, or a homologue thereof, or a variant of "RSA3", the WO 03/072602 PCT/EPO2/50003 215 variant being encoded by a nucleic acid that hybridizes to the "RSA3" nucleic acid (SEQ ID No:2850 ) or its complement under low stringency conditions, (xxv) "SEC13" (SEQ ID No:1171) or a functionally active derivative thereof, or a functionally active fragment thereof, or a homologue thereof, or a variant of "SEC13", the variant being encoded by a nucleic acid that hybridizes to the "SEC13" nucleic acid (SEQ ID No:1172) or its complement under low stringency conditions, (xxvi) "SEC31" (SEQ ID No:1177) or a functionally active derivative thereof, or a functionally active fragment thereof, or a homologue thereof, or a variant of "SEC31", the variant being encoded by a nucleic acid that hybridizes to the "SEC31" nucleic acid (SEQ ID No:1178 ) or its complement under low stringency conditions, (xxvii) "SSA3" (SEQ ID No:723) or a functionally active derivative thereof, or a functionally active fragment thereof, or a homologue thereof, or a variant of "SSA3", the variant being encoded by a nucleic acid that hybridizes to the "SSA3" nucleic acid (SEQ ID No:724) or its complement under low stringency conditions, (xxviii) "SSU72" (SEQ ID No:2851) or a functionally active derivative thereof, or a functionally active fragment thereof, or a homologue thereof, or a variant of "SSU72", the variant being encoded by a nucleic acid that hybridizes to the "SSU72" nucleic acid (SEQ ID No:2852 ) or its complement under low stringency conditions, (xxix) "SWD2" (SEQ ID No:1455) or a functionally active derivative thereof, or a functionally active fragment thereof, or a homologue thereof, or a variant of "SWD2", the variant being encoded by a nucleic acid that hybridizes to the "SWD2" nucleic acid (SEQ ID No:1456 ) or its complement under low stringency conditions, (xxx) "TAF60" (SEQ ID No:825) or a functionally active derivative thereof, or a functionally active fragment thereof, or a homologue thereof, or a variant of "TAF60", the variant being encoded by a nucleic acid that hybridizes to the "TAF60" nucleic acid (SEQ ID No:826 ) or its complement under low stringency conditions, (xxxi) "TIF4632" (SEQ ID No:195) or a functionally active derivative thereof, or a functionally active fragment thereof, or a homologue thereof, or a variant of "TIF4632", the variant being encoded by a nucleic acid that hybridizes to the "TIF4632" nucleic acid (SEQ ID No:196 ) or its complement under low stringency conditions, (xxxii) "TKLI" (SEQ ID No:379) or a functionally active derivative thereof, or a functionally active fragment thereof, or a homologue thereof, or a variant of "TKLI", the variant being encoded by a nucleic acid that hybridizes to the "TKL1" nucleic acid (SEQ ID No:380 ) or its complement under low stringency conditions, WO 03/072602 PCT/EPO2/50003 216 (xxxiii) "TSAI" (SEQ ID No:733) or a functionally active derivative thereof, or a functionally active fragment thereof, or a homologue thereof, or a variant of "TSAI", the variant being encoded by a nucleic acid that hybridizes to the "TSAI" nucleic acid (SEQ ID No:734) or its complement under low stringency conditions, (xxxiv) "TYE7" (SEQ ID No:2853) or a functionally active derivative thereof, or a functionally active fragment thereof, or a homologue thereof, or a variant of "TYE7", the variant being encoded by a nucleic acid that hybridizes to the "TYE7" nucleic acid (SEQ ID No:2854 ) or its complement under low stringency conditions, (xxxv) "VID24" (SEQ ID No:2855) or a functionally active derivative thereof, or a functionally active fragment thereof, or a homologue thereof, or a variant of "VID24", the variant being encoded by a nucleic acid that hybridizes to the "VID24" nucleic acid (SEQ ID No:2856 ) or its complement under low stringency conditions, (xxxvi) "VPS53" (SEQ ID No:1233) or a functionally active derivative thereof, or a functionally active fragment thereof, or a homologue thereof, or a variant of "VPS53", the variant being encoded by a nucleic acid that hybridizes to the "VPS53" nucleic acid (SEQ ID No:1234 ) or its complement under low stringency conditions, (xxxvii) "YCLO46W" (SEQ ID No:2857) or a functionally active derivative thereof, or a functionally active fragment thereof, or a homologue thereof, or a variant of "YCLO46W", the variant being encoded by a nucleic acid that hybridizes to the "YCLO46W" nucleic acid (SEQ ID No:2858 ) or its complement under low stringency conditions, (xxxviii) "YHLO35C" (SEQ ID No:2859) or a functionally active derivative thereof, or a functionally active fragment thereof, or a homologue thereof, or a variant of "YHLO35C", the variant being encoded by a nucleic acid that hybridizes to the "YHLO35C" nucleic acid (SEQ ID No:2860 ) or its complement under low stringency conditions, (xxxix) "YKLO59C" (SEQ ID No:2861) or a functionally active derivative thereof, or a functionally active fragment thereof, or a homologue thereof, or a variant of "YKLO59C", the variant being encoded by a nucleic acid that hybridizes to the "YKLO59C" nucleic acid (SEQ ID No:2862 ) or its complement under low stringency conditions, (xl) "YMLO30W" (SEQ ID No:2863) or a functionally active derivative thereof, or a functionally active fragment thereof, or a homologue thereof, or a variant of "YMLO30W", the variant being encoded by a nucleic acid that hybridizes to the "YMLO30W" nucleic acid (SEQ ID No:2864 ) or its complement under low stringency conditions, (xli) "YOR179C" (SEQ ID No:2865) or a functionally active derivative thereof, or a functionally active fragment thereof, or a homologue thereof, or a variant of "YOR179C", WO 03/072602 PCT/EPO2/50003 217 the variant being encoded by a nucleic acid that hybridizes to the "YOR179C" nucleic acid (SEQ ID No:2866 ) or its complement under low stringency conditions, (xlii) "YSHI" (SEQ ID No:1561) or a functionally active derivative thereof, or a functionally active fragment thereof, or a homologue thereof, or a variant of "YSHI", the variant being encoded by a nucleic acid that hybridizes to the "YSHI" nucleic acid (SEQ ID No:1562 ) or its complement under low stringency conditions, (xliii) "YTHI" (SEQ ID No:2847) or a functionally active derivative thereof, or a functionally active fragment thereof, or a homologue thereof, or a variant of "YTHI", the variant being encoded by a nucleic acid that hybridizes to the "YTHI" nucleic acid (SEQ ID No:2848 ) or its complement under low stringency conditions, and (xliv) "PABI" (SEQ ID No:2841) or a functionally active derivative thereof, or a functionally active fragment thereof, or a homologue thereof, or a variant of "PABI1", the variant being encoded by a nucleic acid that hybridizes to the "PAB1" nucleic acid (SEQ ID No:2842) or its complement under low stringency conditions, and a protein complex selected from complex (II) and comprising the following proteins: (i) "ACT1" (SEQ ID No:681) or a functionally active derivative thereof, or a functionally active fragment thereof, or a homologue thereof, or a variant of "ACT1", the variant being encoded by a nucleic acid that hybridizes to the "ACT1" nucleic acid (SEQ ID No:682) or its complement under low stringency conditions, (ii) "CFTI" (SEQ ID No:2837) or a functionally active derivative thereof, or a functionally active fragment thereof, or a homologue thereof, or a variant of "CFTI", the variant being encoded by a nucleic acid that hybridizes to the "CFTI" nucleic acid (SEQ ID No:2838) or its complement under low stringency conditions, (iii) "CFT2" (SEQ ID No:1529) or a functionally active derivative thereof, or a functionally active fragment thereof, or a homologue thereof, or a variant of "CFT2", the variant being encoded by a nucleic acid that hybridizes to the "CFT2" nucleic acid (SEQ ID No:1530) or its complement under low stringency conditions, (iv) "CKAI" (SEQ ID No:133) or a functionally active derivative thereof, or a functionally active fragment thereof, or a homologue thereof, or a variant of "CKAI", the variant being encoded by a nucleic acid that hybridizes to the "CKA1" nucleic acid (SEQ ID No:134) or its complement under low stringency conditions, (v) "CLPI" (SEQ ID No:2839) or a functionally active derivative thereof, or a functionally active fragment thereof, or a homologue thereof, or a variant of "CLPI", the variant being WO 03/072602 PCT/EPO2/50003 218 encoded by a nucleic acid that hybridizes to the "CLPI" nucleic acid (SEQ ID No:2840) or its complement under low stringency conditions, (vi) "EFT2" (SEQ ID No:39) or a functionally active derivative thereof, or a functionally active fragment thereof, or a homologue thereof, or a variant of "EFT2", the variant being encoded by a nucleic acid that hybridizes to the "EFT2" nucleic acid (SEQ ID No:40 ) or its complement under low stringency conditions, (vii) "ENO2" (SEQ ID No:293) or a functionally active derivative thereof, or a functionally active fragment thereof, or a homologue thereof, or a variant of "ENO2", the variant being encoded by a nucleic acid that hybridizes to the "ENO2" nucleic acid (SEQ ID No:294) or its complement under low stringency conditions, (viii) "FIPI" (SEQ ID No:1531) or a functionally active derivative thereof, or a functionally active fragment thereof, or a homologue thereof, or a variant of "FIPI", the variant being encoded by a nucleic acid that hybridizes to the "FIPI" nucleic acid (SEQ ID No:1532) or its complement under low stringency conditions, (ix) "GLC7" (SEQ ID No:929) or a functionally active derivative thereof, or a functionally active fragment thereof, or a homologue thereof, or a variant of "GLC7", the variant being encoded by a nucleic acid that hybridizes to the "GLC7" nucleic acid (SEQ ID No:930 ) or its complement under low stringency conditions, (x) "GPMI" (SEQ ID No:597) or a functionally active derivative thereof, or a functionally active fragment thereof, or a homologue thereof, or a variant of "GPMI", the variant being encoded by a nucleic acid that hybridizes to the "GPMI1" nucleic acid (SEQ ID No:598 ) or its complement under low stringency conditions, (xi) "PAP1" (SEQ ID No:1541) or a functionally active derivative thereof, or a functionally active fragment thereof, or a homologue thereof, or a variant of "PAP1", the variant being encoded by a nucleic acid that hybridizes to the "PAP1" nucleic acid (SEQ ID No:1542) or its complement under low stringency conditions, (xii) "PCF11" (SEQ ID No:2843) or a functionally active derivative thereof, or a functionally active fragment thereof, or a homologue thereof, or a variant of "PCF1 1", the variant being encoded by a nucleic acid that hybridizes to the "PCF1 1" nucleic acid (SEQ ID No:2844) or its complement under low stringency conditions, (xiii) "PFKI" (SEQ ID No:143) or a functionally active derivative thereof, or a functionally active fragment thereof, or a homologue thereof, or a variant of "PFKI", the variant being encoded by a nucleic acid that hybridizes to the "PFKI" nucleic acid (SEQ ID No:144) or its complement under low stringency conditions, WO 03/072602 PCT/EPO2/50003 219 (xiv) "PFS2" (SEQ ID No:1543) or a functionally active derivative thereof, or a functionally active fragment thereof, or a homologue thereof, or a variant of "PFS2", the variant being encoded by a nucleic acid that hybridizes to the "PFS2" nucleic acid (SEQ ID No:1544) or its complement under low stringency conditions, (xv) "PTAI" (SEQ ID No:1545) or a functionally active derivative thereof, or a functionally active fragment thereof, or a homologue thereof, or a variant of "PTAI1", the variant being encoded by a nucleic acid that hybridizes to the "PTAI" nucleic acid (SEQ ID No:1546) or its complement under low stringency conditions, (xvi) "REF2" (SEQ ID No:1547) or a functionally active derivative thereof, or a functionally active fragment thereof, or a homologue thereof, or a variant of "REF2", the variant being encoded by a nucleic acid that hybridizes to the "REF2" nucleic acid (SEQ ID No:1548 ) or its complement under low stringency conditions, (xvii) "RNA14" (SEQ ID No:1549) or a functionally active derivative thereof, or a functionally active fragment thereof, or a homologue thereof, or a variant of "RNA14", the variant being encoded by a nucleic acid that hybridizes to the "RNA14" nucleic acid (SEQ ID No:1550 ) or its complement under low stringency conditions, (xviii) "RNA15" (SEQ ID No:2845) or a functionally active derivative thereof, or a functionally active fragment thereof, or a homologue thereof, or a variant of "RNA15", the variant being encoded by a nucleic acid that hybridizes to the "RNAI 5" nucleic acid (SEQ ID No:2846 ) or its complement under low stringency conditions, (xix) "RSA3" (SEQ ID tNo:2849) or a functionally active derivative thereof, or a functionally active fragment thereof, or a homologue thereof, or a variant of "RSA3", the variant being encoded by a nucleic acid that hybridizes to the "RSA3" nucleic acid (SEQ ID No:2850 ) or its complement under low stringency conditions, (xx) "SEC13" (SEQ ID No:1171) or a functionally active derivative thereof, or a functionally active fragment thereof, or a homologue thereof, or a variant of "SEC1 3", the variant being encoded by a nucleic acid that hybridizes to the "SEC13" nucleic acid (SEQ ID No:1172 ) or its complement under low stringency conditions, (xxi) "SEC31" (SEQ ID No:1177) or a functionally active derivative thereof, or a functionally active fragment thereof, or a homologue thereof, or a variant of "SEC31", the variant being encoded by a nucleic acid that hybridizes to the "SEC31" nucleic acid (SEQ ID No:1178 ) or its complement under low stringency conditions, (xxii) "SSA3" (SEQ ID No:723) or a functionally active derivative thereof, or a functionally active fragment thereof, or a homologue thereof, or a variant of "SSA3", the variant being WO 03/072602 PCT/EPO2/50003 220 encoded by a nucleic acid that hybridizes to the "SSA3" nucleic acid (SEQ ID No:724 ) or its complement under low stringency conditions, (xxiii) "SSU72" (SEQ ID No:2851) or a functionally active derivative thereof, or a functionally active fragment thereof, or a homologue thereof, or a variant of "SSU72", the variant being encoded by a nucleic acid that hybridizes to the "SSU72" nucleic acid (SEQ ID No:2852) or its complement under low stringency conditions, (xxiv) "TAF60" (SEQ ID No:825) or a functionally active derivative thereof, or a functionally active fragment thereof, or a homologue thereof, or a variant of "TAF60", the variant being encoded by a nucleic acid that hybridizes to the "TAF60" nucleic acid (SEQ ID No:826) or its complement under low stringency conditions, (xxv) "TIF4632" (SEQ ID No:195) or a functionally active derivative thereof, or a functionally active fragment thereof, or a homologue thereof, or a variant of "TIF4632", the variant being encoded by a nucleic acid that hybridizes to the "TIF4632" nucleic acid (SEQ ID No:196 ) or its complement under low stringency conditions, (xxvii) "TKL1" (SEQ ID No:379) or a functionally active derivative thereof, or a functionally active fragment thereof, or a homologue thereof, or a variant of "TKLI", the variant being encoded by a nucleic acid that hybridizes to the "TKL1" nucleic acid (SEQ ID No:380 ) or its complement under low stringency conditions, (xxviii) "TSAI" (SEQ ID No:733) or a functionally active derivative thereof, or a functionally active fragment thereof, or a homologue thereof, or a variant of "TSAI", the variant being encoded by a nucleic acid that hybridizes to the "TSAI" nucleic acid (SEQ ID No:734) or its complement under low stringency conditions, (xxix) "TYET'7" (SEQ ID No:2853) or a functionally active derivative thereof, or a functionally active fragment thereof, or a homologue thereof, or a variant of "TYE7", the variant being encoded by a nucleic acid that hybridizes to the "TYE7" nucleic acid (SEQ ID No:2854) or its complement under low stringency conditions, (xxx) "VID24" (SEQ ID No:2855) or a functionally active derivative thereof, or a functionally active fragment thereof, or a homologue thereof, or a variant of "VID24", the variant being encoded by a nucleic acid that hybridizes to the "VID24" nucleic acid (SEQ ID No:2856) or its complement under low stringency conditions, (xxxi) "VPS53" (SEQ ID No:1233) or a functionally active derivative thereof, or a functionally active fragment thereof, or a homologue thereof, or a variant of "VPS53", the variant being encoded by a nucleic acid that hybridizes to the "VPS53" nucleic acid (SEQ ID No:1234) or its complement under low stringency conditions, WO 03/072602 PCT/EPO2/50003 221 (xxxii) "YCLO46W" (SEQ ID No:2857) or a functionally active derivative thereof, or a functionally active fragment thereof, or a homologue thereof, or a variant of "YCLO46W", the variant being encoded by a nucleic acid that hybridizes to the "YCLO46W" nucleic acid (SEQ ID No:2858) or its complement under low stringency conditions, (xxxiii) "YHLO35C" (SEQ ID No:2859) or a functionally active derivative thereof, or a functionally active fragment thereof, or a homologue thereof, or a variant of "YHLO35C", the variant being encoded by a nucleic acid that hybridizes to the "YHLO35C" nucleic acid (SEQ ID No:2860 ) or its complement under low stringency conditions, (xxxiv) "YKLO59C" (SEQ ID No:2861) or a functionally active derivative thereof, or a functionally active fragment thereof, or a homologue thereof, or a variant of "YKLO59C", the variant being encoded by a nucleic acid that hybridizes to the "YKLO59C" nucleic acid (SEQ ID No:2862) or its complement under low stringency conditions, (xxxv) "YMLO30W" (SEQ ID No:2863) or a functionally active derivative thereof, or a functionally active fragment thereof, or a homologue thereof, or a variant of "YMLO30W", the variant being encoded by a nucleic acid that hybridizes to the "YMLO30W" nucleic acid (SEQ ID No:2864) or its complement under low stringency conditions, (xxxvi) "YOR179C" (SEQ ID No:2865) or a functionally active derivative thereof, or a functionally active fragment thereof, or a homologue thereof, or a variant of "YOR179C", the variant being encoded by a nucleic acid that hybridizes to the "YOR179C" nucleic acid (SEQ ID No:2866 ) or its complement under low stringency conditions, (xxxvii) "YSHI" (SEQ ID No:1561) or a functionally active derivative thereof, or a functionally active fragment thereof, or a homologue thereof, or a variant of "YSHI1", the variant being encoded by a nucleic acid that hybridizes to the "YSH 1" nucleic acid (SEQ ID No:1562) or its complement under low stringency conditions, (xxxviii) "YTHI" (SEQ ID No:2847) or a functionally active derivative thereof, or a functionally active fragment thereof, or a homologue thereof, or a variant of "YTHI", the variant being encoded by a nucleic acid that hybridizes to the "YTHI1" nucleic acid (SEQ ID No:2848) or its complement under low stringency conditions, and (xlix) "PABI" (SEQ ID No:2841) or a functionally active derivative thereof, or a functionally active fragment thereof, or a homologue thereof, or a variant of "PAB1", the variant being encoded by a nucleic acid that hybridizes to the "PAB 1" nucleic acid (SEQ ID No:2842) or its complement under low stringency conditions, (xl) "HHF2" (SEQ ID No:555) or a functionally active derivative thereof, or a functionally active fragment thereof, or a homologue thereof, or a variant of "HHF2", the variant being WO 03/072602 PCT/EPO2/50003 222 encoded by a nucleic acid that hybridizes to the "HHF2" nucleic acid (SEQ ID No:556 ) or its complement under low stringency conditions, 3. The protein complex according to No. 1 comprising all but 1 - 27 of the following proteins: (i) "ACT1" (SEQ ID No:681) or a functionally active derivative thereof, or a functionally active fragment thereof, or a homologue thereof, or a variant of "ACT1", the variant being encoded by a nucleic acid that hybridizes to the "ACT1" nucleic acid (SEQ ID No:682) or its complement under low stringency conditions, (ii) "CFTI" (SEQ ID No:2837) or a functionally active derivative thereof, or a functionally active fragment thereof, or a homologue thereof, or a variant of "CFTI", the variant being encoded by a nucleic acid that hybridizes to the "CFTI" nucleic acid (SEQ ID No:2838) or its complement under low stringency conditions, (iii) "CFT2" (SEQ ID No:1529) or a functionally active derivative thereof, or a functionally active fragment thereof, or a homologue thereof, or a variant of "CFT2", the variant being encoded by a nucleic acid that hybridizes to the "CFT2" nucleic acid (SEQ ID No:1530) or its complement under low stringency conditions, (iv) "CKA1" (SEQ ID No:133) or a functionally active derivative thereof, or a functionally active fragment thereof, or a homologue thereof, or a variant of "CKAI1", the variant being encoded by a nucleic acid that hybridizes to the "CKAI" nucleic acid (SEQ ID No:134) or its complement under low stringency conditions, (v) "CLPI" (SEQ ID No:2839) or a functionally active derivative thereof, or a functionally active fragment thereof, or a homologue thereof, or a variant of "CLPI1", the variant being encoded by a nucleic acid that hybridizes to the "CLPI" nucleic acid (SEQ ID No:2840) or its complement under low stringency conditions, (vi) "EFT2" (SEQ ID No:39) or a functionally active derivative thereof, or a functionally active fragment thereof, or a homologue thereof, or a variant of "EFT2", the variant being encoded by a nucleic acid that hybridizes to the "EFT2" nucleic acid (SEQ ID No:40 ) or its complement under low stringency conditions, (vii) "ENO2" (SEQ ID No:293) or a functionally active derivative thereof, or a functionally active fragment thereof, or a homologue thereof, or a variant of "ENO2", the variant being encoded by a nucleic acid that hybridizes to the "ENO2" nucleic acid (SEQ ID No:294) or its complement under low stringency conditions, WO 03/072602 PCT/EPO2/50003 223 (viii) "FIPI" (SEQ ID No:1531) or a functionally active derivative thereof, or a functionally active fragment thereof, or a homologue thereof, or a variant of "FIPI", the variant being encoded by a nucleic acid that hybridizes to the "FIPI" nucleic acid (SEQ ID No:1532) or its complement under low stringency conditions, (ix) "GLC7" (SEQ ID No:929) or a functionally active derivative thereof, or a functionally active fragment thereof, or a homologue thereof, or a variant of "GLC7", the variant being encoded by a nucleic acid that hybridizes to the "GLC7" nucleic acid (SEQ ID No:930 ) or its complement under low stringency conditions, (x) "GPM1" (SEQ ID No:597) or a functionally active derivative thereof, or a functionally active fragment thereof, or a homologue thereof, or a variant of "GPMI1", the variant being encoded by a nucleic acid that hybridizes to the "GPMI" nucleic acid (SEQ ID No:598) or its complement under low stringency conditions, (xi) "HTAI" (SEQ ID No:1029) or a functionally active derivative thereof, or a functionally active fragment thereof, or a homologue thereof, or a variant of "HTAI1", the variant being encoded by a nucleic acid that hybridizes to the "HTAI" nucleic acid (SEQ ID No:1030) or its complement under low stringency conditions, (xii) "IMD2" (SEQ ID No:259) or a functionally active derivative thereof, or a functionally active fragment thereof, or a homologue thereof, or a variant of "IMD2", the variant being encoded by a nucleic acid that hybridizes to the "IMD2" nucleic acid (SEQ ID No:260 ) or its complement under low stringency conditions, (xiii) "IMD4" (SEQ ID No:41) or a functionally active derivative thereof, or a functionally active fragment thereof, or a homologue thereof, or a variant of "IMD4", the variant being encoded by a nucleic acid that hybridizes to the "IMD4" nucleic acid (SEQ ID No:42 ) or its complement under low stringency conditions, (xiv) "MET6" (SEQ ID No:1921) or a functionally active derivative thereof, or a functionally active fragment thereof, or a homologue thereof, or a variant of "MET6", the variant being encoded by a nucleic acid that hybridizes to the "MET6" nucleic acid (SEQ ID No:1922) or its complement under low stringency conditions, (xv) "PAP1" (SEQ ID No:1541) or a functionally active derivative thereof, or a functionally active fragment thereof, or a homologue thereof, or a variant of "PAP1", the variant being encoded by a nucleic acid that hybridizes to the "PAP1" nucleic acid (SEQ ID No:1542) or its complement under low stringency conditions, (xvi) "PCF11" (SEQ ID No:2843) or a functionally active derivative thereof, or a functionally active fragment thereof, or a homologue thereof, or a variant of "PCF1 1", the WO 03/072602 PCT/EPO2/50003 224 variant being encoded by a nucleic acid that hybridizes to the "PCF11" nucleic acid (SEQ ID No:2844) or its complement under low stringency conditions, (xvii) "PFKI" (SEQ ID No:143) or a functionally active derivative thereof, or a functionally active fragment thereof, or a homologue thereof, or a variant of "PFKI", the variant being encoded by a nucleic acid that hybridizes to the "PFKI" nucleic acid (SEQ ID No:144 ) or its complement under low stringency conditions, (xviii) "PFS2" (SEQ ID No:1543) or a functionally active derivative thereof, or a functionally active fragment thereof, or a homologue thereof, or a variant of "PFS2", the variant being encoded by a nucleic acid that hybridizes to the "PFS2" nucleic acid (SEQ ID No:1544) or its complement under low stringency conditions, (xix) "PTAI" (SEQ ID No:1545) or a functionally active derivative thereof, or a functionally active fragment thereof, or a homologue thereof, or a variant of "PTAI", the variant being encoded by a nucleic acid that hybridizes to the "PTAI" nucleic acid (SEQ ID No:1546 ) or its complement under low stringency conditions, (xx) "PTII" (SEQ ID No:1597) or a functionally active derivative thereof, or a functionally active fragment thereof, or a homologue thereof, or a variant of "PTII", the variant being encoded by a nucleic acid that hybridizes to the "PT11" nucleic acid (SEQ ID No:1598) or its complement under low stringency conditions, (xxi) "REF2" (SEQ ID No:1547) or a functionally active derivative thereof, or a functionally active fragment thereof, or a homologue thereof, or a variant of "REF2", the variant being encoded by a nucleic acid that hybridizes to the "REF2" nucleic acid (SEQ ID No:1548 ) or its complement under low stringency conditions, (xxii) "RNA14" (SEQ ID No:1549) or a functionally active derivative thereof, or a functionally active fragment thereof, or a homologue thereof, or a variant of "RNA14", the variant being encoded by a nucleic acid that hybridizes to the "RNA14" nucleic acid (SEQ ID No:1550 ) or its complement under low stringency conditions, (xxiii) "RNA15" (SEQ ID No:2845) or a functionally active derivative thereof, or a functionally active fragment thereof, or a homologue thereof, or a variant of "RNA15", the variant being encoded by a nucleic acid that hybridizes to the "RNA1 5" nucleic acid (SEQ ID No:2846 ) or its complement under low stringency conditions, (xxiv) "RSA3" (SEQ ID No:2849) or a functionally active derivative thereof, or a functionally active fragment thereof, or a homologue thereof, or a variant of "RSA3", the variant being encoded by a nucleic acid that hybridizes to the "RSA3" nucleic acid (SEQ ID No:2850) or its complement under low stringency conditions, WO 03/072602 PCT/EPO2/50003 225 (xxv) "SEC13" (SEQ ID No:1171) or a functionally active derivative thereof, or a functionally active fragment thereof, or a homologue thereof, or a variant of "SEC13", the variant being encoded by a nucleic acid that hybridizes to the "SEC13" nucleic acid (SEQ ID No:1172 ) or its complement under low stringency conditions, (xxvi) "SEC31" (SEQ ID No:1177) or a functionally active derivative thereof, or a functionally active fragment thereof, or a homologue thereof, or a variant of "SEC31", the variant being encoded by a nucleic acid that hybridizes to the "SEC31" nucleic acid (SEQ ID No:1178 ) or its complement under low stringency conditions, (xxvii) "SSA3" (SEQ ID No:723) or a functionally active derivative thereof, or a functionally active fragment thereof, or a homologue thereof, or a variant of "SSA3", the variant being encoded by a nucleic acid that hybridizes to the "SSA3" nucleic acid (SEQ ID No:724 ) or its complement under low stringency conditions, (xxviii) "SSU72" (SEQ ID No:2851) or a functionally active derivative thereof, or a functionally active fragment thereof, or a homologue thereof, or a variant of "SSU72", the variant being encoded by a nucleic acid that hybridizes to the "SSU72" nucleic acid (SEQ ID No:2852) or its complement under low stringency conditions, (xxix) "SWD2" (SEQ ID No:1455) or a functionally active derivative thereof, or a functionally active fragment thereof, or a homologue thereof, or a variant of "SWD2", the variant being encoded by a nucleic acid that hybridizes to the "SWD2" nucleic acid (SEQ ID No:1456 ) or its complement under low stringency conditions, (xxx) "TAF60" (SEQ ID No:825) or a functionally active derivative thereof, or a functionally active fragment thereof, or a homologue thereof, or a variant of "TAF60", the variant being encoded by a nucleic acid that hybridizes to the "TAF60" nucleic acid (SEQ ID No:826) or its complement under low stringency conditions, (xxxi) "TIF4632" (SEQ ID No:195) or a functionally active derivative thereof, or a functionally active fragment thereof, or a homologue thereof, or a variant of "TIF4632", the variant being encoded by a nucleic acid that hybridizes to the "TIF4632" nucleic acid (SEQ ID No:196 ) or its complement under low stringency conditions, (xxxii) "TKLI" (SEQ ID No:379) or a functionally active derivative thereof, or a functionally active fragment thereof, or a homologue thereof, or a variant of "TKLI", the variant being encoded by a nucleic acid that hybridizes to the "TKLI" nucleic acid (SEQ ID No:380) or its complement under low stringency conditions, (xxxiii) "TSA1" (SEQ ID No:733) or a functionally active derivative thereof, or a functionally active fragment thereof, or a homologue thereof, or a variant of "TSAI", the WO 03/072602 PCT/EPO2/50003 226 variant being encoded by a nucleic acid that hybridizes to the "TSAI" nucleic acid (SEQ ID No:734) or its complement under low stringency conditions, (xxxiv) "TYE7" (SEQ ID No:2853) or a functionally active derivative thereof, or a functionally active fragment thereof, or a homologue thereof, or a variant of "TYE7", the variant being encoded by a nucleic acid that hybridizes to the "TYE7" nucleic acid (SEQ ID No:2854) or its complement under low stringency conditions, (xxxv) "VID24" (SEQ ID No:2855) or a functionally active derivative thereof, or a functionally active fragment thereof, or a homologue thereof, or a variant of "VID24", the variant being encoded by a nucleic acid that hybridizes to the "VID24" nucleic acid (SEQ ID No:2856 ) or its complement under low stringency conditions, (xxxvi) "VPS53" (SEQ ID No:1233) or a functionally active derivative thereof, or a functionally active fragment thereof, or a homologue thereof, or a variant of "VPS53", the variant being encoded by a nucleic acid that hybridizes to the "VPS53" nucleic acid (SEQ ID No:1234 ) or its complement under low stringency conditions, (xxxvii) "YCLO46W" (SEQ ID No:2857) or a functionally active derivative thereof, or a functionally active fragment thereof, or a homologue thereof, or a variant of "YCLO46W", the variant being encoded by a nucleic acid that hybridizes to the "YCLO46W" nucleic acid (SEQ ID No:2858 ) or its complement under low stringency conditions, (xxxviii) "YHLO35C" (SEQ ID No:2859) or a functionally active derivative thereof, or a functionally active fragment thereof, or a homologue thereof, or a variant of "YHLO35C", the variant being encoded by a nucleic acid that hybridizes to the "YHLO35C" nucleic acid (SEQ ID No:2860 ) or its complement under low stringency conditions, (xxxix) "YKLO59C" (SEQ ID No:2861) or a functionally active derivative thereof, or a functionally active fragment thereof, or a homologue thereof, or a variant of "YKLO59C", the variant being encoded by a nucleic acid that hybridizes to the "YKLO59C" nucleic acid (SEQ ID No:2862 ) or its complement under low stringency conditions, (xl) "YMLO30W" (SEQ ID No:2863) or a functionally active derivative thereof, or a functionally active fragment thereof, or a homologue thereof, or a variant of "YMLO30W", the variant being encoded by a nucleic acid that hybridizes to the "YMLO30W" nucleic acid (SEQ ID No:2864 ) or its complement under low stringency conditions, (xli) "YOR179C" (SEQ ID No:2865) or a functionally active derivative thereof, or a functionally active fragment thereof, or a homologue thereof, or a variant of "YOR179C", the variant being encoded by a nucleic acid that hybridizes to the "YOR179C" nucleic acid (SEQ ID No:2866 ) or its complement under low stringency conditions, WO 03/072602 PCT/EPO2/50003 227 (xlii) "YSHI" (SEQ ID No:1561) or a functionally active derivative thereof, or a functionally active fragment thereof, or a homologue thereof, or a variant of "YSHI1", the variant being encoded by a nucleic acid that hybridizes to the "YSHI" nucleic acid (SEQ ID No:1562) or its complement under low stringency conditions, (xliii) "YTHI" (SEQ ID No:2847) or a functionally active derivative thereof, or a functionally active fragment thereof, or a homologue thereof, or a variant of "YTHI", the variant being encoded by a nucleic acid that hybridizes to the "YTH 1" nucleic acid (SEQ ID No:2848 ) or its complement under low stringency conditions, (xliv) "PABI" (SEQ ID No:2841) or a functionally active derivative thereof, or a functionally active fragment thereof, or a homologue thereof, or a variant of "PABI", the variant being encoded by a nucleic acid that hybridizes to the "PABI" nucleic acid (SEQ ID No:2842) or its complement under low stringency conditions, and (xiv) "HHF2" (SEQ ID No:555) or a functionally active derivative thereof, or a functionally active fragment thereof, or a homologue thereof, or a variant of "HHF2", the variant being encoded by a nucleic acid that hybridizes to the "HHF2" nucleic acid (SEQ ID No:556 ) or its complement under low stringency conditions. 4. The complex of any of No. 1 - 3 comprising a functionally active derivative of said first protein and/or a functionally active derivative of said second protein, wherein the functionally active derivative is a fusion protein comprising said first protein or said second protein fused to an amino acid sequence different from the first protein or second protein, respectively. 5. The complex of No. 4 wherein the functionally active derivative is a fusion protein comprising said first protein or said second protein fused to an affinity tag or label. 6. The complex of any of No. 1 - 3 comprising a fragment of said first protein and/or a fragment of said second protein, which fragment binds to another protein component of said complex. 7. The complex of any of No. 1 -6 that is involved in the 3' end mRNA processing activity ; 3' end mRNA processing activity.

WO 03/072602 PCT/EPO2/50003 228 8. A process for preparing complex of any of No. 1 - 7 and optionally the components thereof comprising the following steps: Expressing a protein (bait) of the complex, preferably the tagged protein, in a target cell, or a tissue or an organ, isolating the protein complex which is attached to the bait protein, and optionally disassociating the protein complex and isolating the individual complex members. 9. The process according to No. 8 wherein the tagged protein comprises two different tags which allow two separate affinity purification steps. 10. The process according to any of No. 8 - 9 wherein the two tags are separated by a cleavage site for a protease. 11. Component of the polyadenylation complex obtainable by a process according to any of No. 8- 10. 12. Protein of the polyadenylation complex selected from (i) "YCLO46W" (SEQ ID No:2857) or a functionally active derivative thereof, or a functionally active fragment thereof, or a homologue thereof, or a variant of "YCLO46W", the variant being encoded by a nucleic acid that hybridizes to the "YCLO46W" nucleic acid (SEQ ID No:2858 ) or its complement under low stringency conditions, (ii) "YHLO35C" (SEQ ID No:2859) or a functionally active derivative thereof, or a functionally active fragment thereof, or a homologue thereof, or a variant of "YHLO35C", the variant being encoded by a nucleic acid that hybridizes to the "YHLO35C" nucleic acid (SEQ ID No:2860 ) or its complement under low stringency conditions, (iii) "YKLO59C" (SEQ ID No:2861) or a functionally active derivative thereof, or a functionally active fragment thereof, or a homologue thereof, or a variant of "YKLO59C", the variant being encoded by a nucleic acid that hybridizes to the "YKLO59C" nucleic acid (SEQ ID No:2862) or its complement under low stringency conditions, (iv) "YMLO30W" (SEQ ID No:2863) or a functionally active derivative thereof, or a functionally active fragment thereof, or a homologue thereof, or a variant of "YMLO30W", the variant being encoded by a nucleic acid that hybridizes to the "YMLO30W" nucleic acid (SEQ ID No:2864 ) or its complement under low stringency conditions, and WO 03/072602 PCT/EPO2/50003 229 (v) "YOR179C" (SEQ ID No:2865) or a functionally active derivative thereof, or a functionally active fragment thereof, or a homologue thereof, or a variant of "YOR179C", the variant being encoded by a nucleic acid that hybridizes to the "YOR179C" nucleic acid (SEQ ID No:2866 ) or its complement under low stringency conditions, wherein said low stringency conditions comprise hybridization in a buffer comprising 35% formamide, 5X SSC, 50 mM Tris-HCI (pH 7.5), 5 mM EDTA, 0.02% PVP, 0.02% Ficoll, 0.2% BSA, 100 ug/ml denatured salmon sperm DNA, and 10% (wt/vol) dextran sulfate for 18-20 hours at 400 C, washing in a buffer consisting of 2X SSC, 25 mM Tris-HCI (pH 7.4), 5 mM EDTA, and 0.1 % SDS for 1.5 hours at 550 C, and washing in a buffer consisting of 2X SSC, 25 mM Tris-HCI (pH 7.4), 5 mM EDTA, and 0.1% SDS for 1.5 hours at 600 C. 13. Nucleic acid encoding a protein according to No. 12. 14. Construct, preferably a vector construct, comprising (a) a nucleic acid according to No. 13 and at least one further nucleic acid which is normally not associated with said nucleic acid, or (b) at least two separate nucleic acid sequences each encoding a different protein, or a functionally active fragment or a functionally active derivative thereof at least one of said proteins, or functionally active fragments or functionally active derivative thereof being selected from the first group of proteins according to No. 1 (a) and at least one of said proteins, or functionally active fragments or functionally active derivative thereof being selected from the second group of proteins according to No. 1 (b) or (c)at least two separate nucleic acid sequences each encoding a different protein, or a functionally active fragment or a functionally active derivative thereof, or a homologue or a variant thereof, said proteins being selected from the proteins of complex (11) according to No. 1. 15. Host cell containing a vector comprising at least the nucleic acid of No. 13 andlor a construct of No. 14 or containing several vectors each comprising at least one nucleic acid sequence encoding at least one of the proteins, or functionally active fragments or functionally active derivatives thereof selected from the first group of proteins according to No. 1(a) and the proteins, or functionally active fragments or functionally active derivatives thereof selected from the second group of proteins according to No. 1(b).

WO 03/072602 PCT/EPO2/50003 230 16. An antibody or a fragment of said antibody containing the binding domain thereof, selected from an antibody or fragment thereof, which binds the complex of any of No. 1 7 and which does not bind any of the proteins of said complex when uncomplexed and an antibody or a fragment of said antibody which binds to any of the proteins according to No. 12. 17. A kit comprising in one or more container: (a) the complex of any of No. 1 - 7 and/or the proteins of No. 12 and/or (b) an antibody according to No. 16 and/or (c) a nucleic acid encoding a protein of the complex of any of No. 1 - 7 and/or a protein of No. 12 and/or (d) cells expressing the complex of any of No. 1 - 7 and/or the proteins of No. 12 and optionally (e) further components such as reagents and working instructions. 18. A kit according to No. 17 for processing a substrate of said complex. 19. A kit according to No. 17 for the diagnosis or prognosis of a disease or a disease risk, preferentially for a disease or disorder such as viral infections such as herpes simplex infections, Epstein-Barr-infections, influenza; metabolic diseases such as metachromatic leukodystrophy; neurodegenerative disorders such as amyotrophic lateral sclerosis; cancer. 20. Array, preferably a microarray, in which at least a complex according to any of No. 1 7 and/or at least one antibody according to No. 16 is attached to a solid carrier. 21. A process for modifying a physiological substrate of the complex comprising the step of bringing into contact a complex of any of No. 1 - 7 with said substrate, such that said substrate is modified. 22. A pharmaceutical composition comprising the protein complex of any of No. 1 - 7 and/or any of the following the proteins: (i) "YCLO46W" (SEQ ID No:2857) or a functionally active derivative thereof, or a functionally active fragment thereof, or a homologue thereof, or a variant of "YCLO46W", WO 03/072602 PCT/EPO2/50003 231 the variant being encoded by a nucleic acid that hybridizes to the "YCLO46W" nucleic acid (SEQ ID No:2858 ) or its complement under low stringency conditions, (ii) "YHLO35C" (SEQ ID No:2859) or a functionally active derivative thereof, or a functionally active fragment thereof, or a homnologue thereof, or a variant of "YHLO35C", the variant being encoded by a nucleic acid that hybridizes to the "YHLO35C" nucleic acid (SEQ ID No:2860 ) or its complement under low stringency conditions, (iii) "YKLO59C" (SEQ ID No:2861) or a functionally active derivative thereof, or a functionally active fragment thereof, or a homologue thereof, or a variant of "YKLO59C", the variant being encoded by a nucleic acid that hybridizes to the "YKLO59C" nucleic acid (SEQ ID No:2862 ) or its complement under low stringency conditions, (iv) "YMLO30W" (SEQ ID No:2863) or a functionally active derivative thereof, or a functionally active fragment thereof, or a homologue thereof, or a variant of "YMLO30W", the variant being encoded by a nucleic acid that hybridizes to the "YMLO30W" nucleic acid (SEQ ID No:2864 ) or its complement under low stringency conditions, and/or (v) "YOR179C" (SEQ ID No:2865) or a functionally active derivative thereof, or a functionally active fragment thereof, or a homologue thereof, or a variant of "YOR179C", the variant being encoded by a nucleic acid that hybridizes to the "YOR179C" nucleic acid (SEQ ID No:2866 ) or its complement under low stringency conditions, and a pharmaceutical acceptable carrier. 23. A pharmaceutical composition according to No. 22 for the treatment of diseases and disorders such as viral infections such as herpes simplex infections, Epstein-Barr infections, influenza; metabolic diseases such as metachromatic leukodystrophy; neurodegenerative disorders such as amyotrophic lateral sclerosis; cancer. 24. A method for screening for a molecule that binds to a complex of anyone of No. 1 - 7 and/or any of the following proteins: (i) "YCLO46W" (SEQ ID No:2857) or a functionally active derivative thereof, or a functionally active fragment thereof, or a homologue thereof, or a variant of "YCLO46W", the variant being encoded by a nucleic acid that hybridizes to the "YCLO46W" nucleic acid (SEQ ID No:2858 ) or its complement under low stringency conditions, (ii) "YHLO35C" (SEQ ID No:2859) or a functionally active derivative thereof, or a functionally active fragment thereof, or a homologue thereof, or a variant of "YHLO35C", WO 03/072602 PCT/EPO2/50003 232 the variant being encoded by a nucleic acid that hybridizes to the "YHLO35C" nucleic acid (SEQ ID No:2860 ) or its complement under low stringency conditions, (iii) "YKLO59C" (SEQ ID No:2861) or a functionally active derivative thereof, or a functionally active fragment thereof, or a homologue thereof, or a variant of "YKLO59C", the variant being encoded by a nucleic acid that hybridizes to the "YKLO59C" nucleic acid (SEQ ID No:2862 ) or its complement under low stringency conditions, (iv) "YMLO30W" (SEQ ID No:2863) or a functionally active derivative thereof, or a functionally active fragment thereof, or a homologue thereof, or a variant of "YMLO30W", the variant being encoded by a nucleic acid that hybridizes to the "YMLO30W" nucleic acid (SEQ ID No:2864 ) or its complement under low stringency conditions, and/or (v) "YOR179C" (SEQ ID No:2865) or a functionally active derivative thereof, or a functionally active fragment thereof, or a homologue thereof, or a variant of "YOR179C", the variant being encoded by a nucleic acid that hybridizes to the "YOR179C" nucleic acid (SEQ ID No:2866 ) or its complement under low stringency conditions, comprising the steps of (a) exposing said complex, or a cell or organism containing same to one or more candidate molecules; and (b) determining whether said candidate molecule is bound to the complex or protein. 25. A method for screening for a molecule that modulates directly or indirectly the function, activity, composition or formation of the complex of any one of No. 1 - 7 comprising the steps of (a) exposing said complex, or a cell or organism containing polyadenylation complex to one or more candidate molecules; and (b) determining the amount of activity of protein components of, and/or intracellular localization of, said complex and/or the transcription level of a gene regulated by the complex and/or the abundance and/or activity of a protein or protein complex dependend on the function of the complex and/or product of a gene dependent on the complex in the presence of the one or more candidate molecules, wherein a change in said amount, activity, protein components or intracellular localization relative to said amount, activity, protein components and/or intracellular localization and/or a change in the transcription level of a gene dependend on the complex and/or the abundance and/or activity of a protein or protein complex dependent on the function of the complex and/or product of a WO 03/072602 PCT/EPO2/50003 233 gene dependent on the complex in the absence of said candidate molecules indicates that the molecule modulates function, activity or composition of said complex. 26. The method of No. 25, wherein the amount of said complex is determined. 27. The method of No. 25, wherein the activity of said complex is determined. 28. The method of No. 27, wherein said determining step comprises isolating from the cell or organism said complex to produce said isolated complex and contacting said isolated complex in the presence or absence of a candidate molecule with a substrate of said complex and determining the processing of said substrate is modified in the presence of said candidate molecule. 29. The method of No. 25, wherein the amount of the individual protein components of said complex are determined. 30. The method of No. 29, wherein said determining step comprises determining whether (i) "ACT1" (SEQ ID No:681) or a functionally active derivative thereof, or a functionally active fragment thereof, or a homologue thereof, or a variant of "ACT1", the variant being encoded by a nucleic acid that hybridizes to the "ACT1" nucleic acid (SEQ ID No:682) or its complement under low stringency conditions,and/or (ii) "CFTI" (SEQ ID No:2837) or a functionally active derivative thereof, or a functionally active fragment thereof, or a homologue thereof, or a variant of "CFTI", the variant being encoded by a nucleic acid that hybridizes to the "CFTI" nucleic acid (SEQ ID No:2838) or its complement under low stringency conditions,and/or (iii) "CFT2" (SEQ ID No:1529) or a functionally active derivative thereof, or a functionally active fragment thereof, or a homologue thereof, or a variant of "CFT2", the variant being encoded by a nucleic acid that hybridizes to the "CFT2" nucleic acid (SEQ ID No:1530) or its complement under low stringency conditions,and/or (iv) "CKA1" (SEQ ID No:133) or a functionally active derivative thereof, or a functionally active fragment thereof, or a homologue thereof, or a variant of "CKAI", the variant being encoded by a nucleic acid that hybridizes to the "CKA1" nucleic acid (SEQ ID No:134) or its complement under low stringency conditions,and/or WO 03/072602 PCT/EPO2/50003 234 (v) "CLPI" (SEQ ID No:2839) or a functionally active derivative thereof, or a functionally active fragment thereof, or a homologue thereof, or a variant of "CLPI", the variant being encoded by a nucleic acid that hybridizes to the "CLPI" nucleic acid (SEQ ID No:2840) or its complement under low stringency conditions,and/or (vi) "EFT2" (SEQ ID No:39) or a functionally active derivative thereof, or a functionally active fragment thereof, or a homologue thereof, or a variant of "EFT2", the variant being encoded by a nucleic acid that hybridizes to the "EFT2" nucleic acid (SEQ ID No:40 ) or its complement under low stringency conditions,and/or (vii) "ENO2" (SEQ ID No:293) or a functionally active derivative thereof, or a functionally active fragment thereof, or a homologue thereof, or a variant of "ENO2", the variant being encoded by a nucleic acid that hybridizes to the "ENO2" nucleic acid (SEQ ID No:294) or its complement under low stringency conditions,and/or (viii) "FIPI" (SEQ ID No:1531) or a functionally active derivative thereof, or a functionally active fragment thereof, or a homologue thereof, or a variant of "FIPI", the variant being encoded by a nucleic acid that hybridizes to the "FlPI" nucleic acid (SEQ ID No:1532) or its complement under low stringency conditions,and/or (ix) "GLC7" (SEQ ID No:929) or a functionally active derivative thereof, or a functionally active fragment thereof, or a homologue thereof, or a variant of "GLC7", the variant being encoded by a nucleic acid that hybridizes to the "GLC7" nucleic acid (SEQ ID No:930) or its complement under low stringency conditions,and/or (x) "GPM1" (SEQ ID No:597) or a functionally active derivative thereof, or a functionally active fragment thereof, or a homologue thereof, or a variant of "GPM1", the variant being encoded by a nucleic acid that hybridizes to the "GPMI" nucleic acid (SEQ ID No:598 ) or its complement under low stringency conditions,and/or (xi) "HTAI" (SEQ ID No:1029) or a functionally active derivative thereof, or a functionally active fragment thereof, or a homologue thereof, or a variant of "HTAI", the variant being encoded by a nucleic acid that hybridizes to the "HTAI" nucleic acid (SEQ ID No:1030) or its complement under low stringency conditions,and/or (xii) "IMD2" (SEQ ID No:259) or a functionally active derivative thereof, or a functionally active fragment thereof, or a homologue thereof, or a variant of "IMD2", the variant being encoded by a nucleic acid that hybridizes to the "IMD2" nucleic acid (SEQ ID No:260) or its complement under low stringency conditions,and/or (xiii) "IMD4" (SEQ ID No:41) or a functionally active derivative thereof, or a functionally active fragment thereof, or a homologue thereof, or a variant of "IMD4", the variant being WO 03/072602 PCT/EPO2/50003 235 encoded by a nucleic acid that hybridizes to the "IMD4" nucleic acid (SEQ ID No:42) or its complement under low stringency conditions,and/or (xiv) "MET6" (SEQ ID No:1921) or a functionally active derivative thereof, or a functionally active fragment thereof, or a homologue thereof, or a variant of "MET6", the variant being encoded by a nucleic acid that hybridizes to the "MET6" nucleic acid (SEQ ID No:1922) or its complement under low stringency conditions,and/or (xv) "PAP1" (SEQ ID No:1541) or a functionally active derivative thereof, or a functionally active fragment thereof, or a homologue thereof, or a variant of "PAP1", the variant being encoded by a nucleic acid that hybridizes to the "PAP1" nucleic acid (SEQ ID No:1542) or its complement under low stringency conditions,and/or (xvi) "PCF1 1" (SEQ ID No:2843) or a functionally active derivative thereof, or a functionally active fragment thereof, or a homologue thereof, or a variant of "PCF1 1", the variant being encoded by a nucleic acid that hybridizes to the "PCF11" nucleic acid (SEQ ID No:2844 ) or its complement under low stringency conditions,and/or (xvii) "PFKI" (SEQ ID No:143) or a functionally active derivative thereof, or a functionally active fragment thereof, or a homologue thereof, or a variant of "PFKI", the variant being encoded by a nucleic acid that hybridizes to the "PFKI" nucleic acid (SEQ ID No:144 ) or its complement under low stringency conditions,and/or (xviii) "PFS2" (SEQ ID No:1543) or a functionally active derivative thereof, or a functionally active fragment thereof, or a homologue thereof, or a variant of "PFS2", the variant being encoded by a nucleic acid that hybridizes to the "PFS2" nucleic acid (SEQ ID No:1544 ) or its complement under low stringency conditions,and/or (xix) "PTAI" (SEQ ID No:1545) or a functionally active derivative thereof, or a functionally active fragment thereof, or a homologue thereof, or a variant of "PTAI", the variant being encoded by a nucleic acid that hybridizes to the "PTAI" nucleic acid (SEQ ID No:1546 ) or its complement under low stringency conditions,and/or (xx) "PTII" (SEQ ID No:1597) or a functionally active derivative thereof, or a functionally active fragment thereof, or a homologue thereof, or a variant of "PTII", the variant being encoded by a nucleic acid that hybridizes to the "PTII" nucleic acid (SEQ ID No:1598) or its complement under low stringency conditions,and/or (xxi) "REF2" (SEQ ID No:1547) or a functionally active derivative thereof, or a functionally active fragment thereof, or a homologue thereof, or a variant of "REF2", the variant being encoded by a nucleic acid that hybridizes to the "REF2" nucleic acid (SEQ ID No:1548 ) or its complement under low stringency conditions,and/or WO 03/072602 PCT/EPO2/50003 236 (xxii) "RNA14" (SEQ ID No:1549) or a functionally active derivative thereof, or a functionally active fragment thereof, or a homologue thereof, or a variant of "RNA14", the variant being encoded by a nucleic acid that hybridizes to the "RNA14" nucleic acid (SEQ ID No:1550 ) or its complement under low stringency conditions,and/or (xxiii) "RNA15" (SEQ ID No:2845) or a functionally active derivative thereof, or a functionally active fragment thereof, or a homologue thereof, or a variant of "RNA15", the variant being encoded by a nucleic acid that hybridizes to the "RNA15" nucleic acid (SEQ ID No:2846 ) or its complement under low stringency conditions,and/or (xxiv) "RSA3" (SEQ ID No:2849) or a functionally active derivative thereof, or a functionally active fragment thereof, or a homologue thereof, or a variant of "RSA3", the variant being encoded by a nucleic acid that hybridizes to the "RSA3" nucleic acid (SEQ ID No:2850 ) or its complement under low stringency conditions,and/or (xxv) "SEC13" (SEQ ID No:1171) or a functionally active derivative thereof, or a functionally active fragment thereof, or a homologue thereof, or a variant of "SEC1 3", the variant being encoded by a nucleic acid that hybridizes to the "SEC13" nucleic acid (SEQ ID No:1172) or its complement under low stringency conditions,and/or (xxvi) "SEC31" (SEQ ID No:1177) or a functionally active derivative thereof, or a functionally active fragment thereof, or a homologue thereof, or a variant of "SEC31", the variant being encoded by a nucleic acid that hybridizes to the "SEC31" nucleic acid (SEQ ID No:1178 ) or its complement under low stringency conditions,and/or (xxvii) "SSA3" (SEQ ID No:723) or a functionally active derivative thereof, or a functionally active fragment thereof, or a homologue thereof, or a variant of "SSA3", the variant being encoded by a nucleic acid that hybridizes to the "SSA3" nucleic acid (SEQ ID No:724) or its complement under low stringency conditions,and/or (xxviii) "SSU72" (SEQ ID No:2851) or a functionally active derivative thereof, or a functionally active fragment thereof, or a homologue thereof, or a variant of "SSU72", the variant being encoded by a nucleic acid that hybridizes to the "SSU72" nucleic acid (SEQ ID No:2852) or its complement under low stringency conditions,and/or (xxix) "SWD2" (SEQ ID No:1455) or a functionally active derivative thereof, or a functionally active fragment thereof, or a homologue thereof, or a variant of "SWD2", the variant being encoded by a nucleic acid that hybridizes to the "SWD2" nucleic acid (SEQ ID No:1456 ) or its complement under low stringency conditions,and/or (xxx) "TAF60" (SEQ ID No:825) or a functionally active derivative thereof, or a functionally active fragment thereof, or a homologue thereof, or a variant of "TAF60", the WO 03/072602 PCT/EPO2/50003 237 variant being encoded by a nucleic acid that hybridizes to the "TAF60" nucleic acid (SEQ ID No:826 ) or its complement under low stringency conditions,and/or (xxxi) "TIF4632" (SEQ ID No:195) or a functionally active derivative thereof, or a functionally active fragment thereof, or a homologue thereof, or a variant of "TIF4632", the variant being encoded by a nucleic acid that hybridizes to the 'TIF4632" nucleic acid (SEQ ID No:196 ) or its complement under low stringency conditions,and/or (xxxii) "TKLI" (SEQ ID No:379) or a functionally active derivative thereof, or a functionally active fragment thereof, or a homologue thereof, or a variant of "TKLI", the variant being encoded by a nucleic acid that hybridizes to the "TKLI" nucleic acid (SEQ ID No:380 ) or its complement under low stringency conditions,and/or (xxxiii) "TSAI" (SEQ ID No:733) or a functionally active derivative thereof, or a functionally active fragment thereof, or a homologue thereof, or a variant of "TSAI", the variant being encoded by a nucleic acid that hybridizes to the "TSA1" nucleic acid (SEQ ID No:734 ) or its complement under low stringency conditions,and/or (xxxiv) "TYE7" (SEQ ID No:2853) or a functionally active derivative thereof, or a functionally active fragment thereof, or a homologue thereof, or a variant of "TYE7", the variant being encoded by a nucleic acid that hybridizes to the "TYE7" nucleic acid (SEQ ID No:2854 ) or its complement under low stringency conditions,and/or (xxxv) "VlD24" (SEQ ID No:2855) or a functionally active derivative thereof, or a functionally active fragment thereof, or a homologue thereof, or a variant of "VID24", the variant being encoded by a nucleic acid that hybridizes to the "VID24" nucleic acid (SEQ ID No:2856 ) or its complement under low stringency conditions,and/or (xxxvi) "VPS53" (SEQ ID No:1233) or a functionally active derivative thereof, or a functionally active fragment thereof, or a homologue thereof, or a variant of "VPS53", the variant being encoded by a nucleic acid that hybridizes to the "VPS53" nucleic acid (SEQ ID No:1234 ) or its complement under low stringency conditions,and/or (xxxvii) "YCLO46W" (SEQ ID No:2857) or a functionally active derivative thereof, or a functionally active fragment thereof, or a homologue thereof, or a variant of "YCLO46W", the variant being encoded by a nucleic acid that hybridizes to the "YCLO46W" nucleic acid (SEQ ID No:2858 ) or its complement under low stringency conditions,and/or (xxxviii) "YHLO35C" (SEQ ID No:2859) or a functionally active derivative thereof, or a functionally active fragment thereof, or a homologue thereof, or a variant of "YHLO35C", the variant being encoded by a nucleic acid that hybridizes to the "YHLO35C" nucleic acid (SEQ ID No:2860 ) or its complement under low stringency conditions,and/or WO 03/072602 PCT/EPO2/50003 238 (xxxix) "YKLO59C" (SEQ ID No:2861) or a functionally active derivative thereof, or a functionally active fragment thereof, or a horn ologue thereof, or a variant of "YKLO59C", the variant being encoded by a nucleic acid that hybridizes to the "YKLO59C" nucleic acid (SEQ ID No:2862 ) or its complement under low stringency conditions,and/or (xl) "YMLO30W" (SEQ ID No:2863) or a functionally active derivative thereof, or a functionally active fragment thereof, or a homologue thereof, or a variant of "YMLO30W", the variant being encoded by a nucleic acid that hybridizes to the "YMLO30W" nucleic acid (SEQ ID No:2864 ) or its complement under low stringency conditions,and/or (xli) "YOR179C" (SEQ ID No:2865) or a functionally active derivative thereof, or a functionally active fragment thereof, or a homologue thereof, or a variant of "YOR179C", the variant being encoded by a nucleic acid that hybridizes to the "YOR179C" nucleic acid (SEQ ID No:2866 ) or its complement under low stringency conditions,and/or (xlii) "YSHI" (SEQ ID No:1561) or a functionally active derivative thereof, or a functionally active fragment thereof, or a homologue thereof, or a variant of "YSH1", the variant being encoded by a nucleic acid that hybridizes to the "YSHI" nucleic acid (SEQ ID No:1562) or its complement under low stringency conditions, and/or (xliii) "YTHI" (SEQ ID No:2847) or a functionally active derivative thereof, or a functionally active fragment thereof, or a homologue thereof, or a variant of "YTH 1", the variant being encoded by a nucleic acid that hybridizes to the "YTHI" nucleic acid (SEQ ID No:2848 ) or its complement under low stringency conditions, and/or (xliv) "PAB1" (SEQ ID No:2841) or a functionally active derivative thereof, or a functionally active fragment thereof, or a homologue thereof, or a variant of "PABI", the variant being encoded by a nucleic acid that hybridizes to the "PABI" nucleic acid (SEQ ID No:2842) or its complement under low stringency conditions, and/or (xlv) "HHF2" (SEQ ID No:555) or a functionally active derivative thereof, or a functionally active fragment thereof, or a homologue thereof, or a variant of "HHF2", the variant being encoded by a nucleic acid that hybridizes to the "HHF2" nucleic acid (SEQ ID No:556) or its complement under low stringency conditions, is present in the complex. 31. The method of any of No. 25 - 30, wherein said method is a method of screening for a drug for treatment or prevention of a disease or disorder such as viral infections such as herpes simplex infections, Epstein-Barr-infections, influenza; metabolic diseases such WO 03/072602 PCT/EPO2/50003 239 as metachromatic leukodystrophy; neurodegenerative disorders such as amyotrophic lateral sclerosis; cancer. 32. Use of a molecule that modulates the amount of, activity of, or the protein components of the complex of any one of No. 1 - 7 for the manufacture of a medicament for the treatment or prevention of a disease or disorder such as viral infections such as herpes simplex infections, Epstein-Barr-infections, influenza; metabolic diseases such as metachromatic leukodystrophy; neurodegenerative disorders such as amyotrophic lateral sclerosis; cancer. 33. A method for the production of a pharmaceutical composition comprising carrying out the method of any of No. 1 - 7 to identify a molecule that modulates the function, activity, composition or formation of said complex, and further comprising mixing the identified molecule with a pharmaceutically acceptable carrier. 34. A method for diagnosing or screening for the presence of a disease or disorder or a predisposition for developing a disease or disorder in a subject, which disease or disorder is characterized by an aberrant amount of, activity of, or component composition of, or intracellular localization of the complex of any one of the No. 1 - 7, comprising determining the amount of, activity of, protein components of, and/or intracellular localization of, said complex and/or the transcription level of a gene dependend on the complex and/or the abundance and/or activity of a protein or protein complex dependend on the function of the complex and/or product of a gene dependent on the complex in a comparative sample derived from a subject, wherein a difference in said amount, activity, or protein components of, said complex in a corresponding sample from a subject not having the disease or disorder or predisposition indicates the presence in the subject of the disease or disorder or predisposition in the subject. 35. The method of No. 34, wherein the amount of said complex is determined. 36. The method of No. 34, wherein the activity of said complex is determined. 37. The method of No. 36, wherein said determining step comprises isolating from the subject said complex to produce said isolated complex and contacting said isolated WO 03/072602 PCT/EPO2/50003 240 complex in the presence or absence of a candidate molecule with a substrate of said complex and determining whether said substrate is processed in the absence of the candidate molecule and whether the processing of said substrate is modified in the presence of said candidate molecule. 38. The method of No. 34, wherein the amount of the individual protein components of said complex are determined. 39. The method of No. 38, wherein said determining step comprises determining whether (i) "ACT1" (SEQ ID No:681) or a functionally active derivative thereof, or a functionally active fragment thereof, or a homologue thereof, or a variant of "ACT1", the variant being encoded by a nucleic acid that hybridizes to the "ACT1" nucleic acid (SEQ ID No:682 ) or its complement under low stringency conditions, and/or (ii) "CFTI" (SEQ ID No:2837) or a functionally active derivative thereof, or a functionally active fragment thereof, or a homologue thereof, or a variant of "CFTI", the variant being encoded by a nucleic acid that hybridizes to the "CFTI" nucleic acid (SEQ ID No:2838) or its complement under low stringency conditions, and/or (iii) "CFT2" (SEQ ID No:1529) or a functionally active derivative thereof, or a functionally active fragment thereof, or a homologue thereof, or a variant of "CFT2", the variant being encoded by a nucleic acid that hybridizes to the "CFT2" nucleic acid (SEQ ID No:1530) or its complement under low stringency conditions, and/or (iv) "CKAI" (SEQ ID No:133) or a functionally active derivative thereof, or a functionally active fragment thereof, or a homologue thereof, or a variant of "CKAI", the variant being encoded by a nucleic acid that hybridizes to the "CKA1" nucleic acid (SEQ ID No:134) or its complement under low stringency conditions, and/or (v) "CLPI" (SEQ ID No:2839) or a functionally active derivative thereof, or a functionally active fragment thereof, or a homologue thereof, or a variant of "CLP1I", the variant being encoded by a nucleic acid that hybridizes to the "CLPI" nucleic acid (SEQ ID No:2840) or its complement under low stringency conditions, and/or (vi) "EFT2" (SEQ ID No:39) or a functionally active derivative thereof, or a functionally active fragment thereof, or a homologue thereof, or a variant of "EFT2", the variant being encoded by a nucleic acid that hybridizes to the "EFT2" nucleic acid (SEQ ID No:40 ) or its complement under low stringency conditions, and/or WO 03/072602 PCT/EPO2/50003 241 (vii) "ENO2" (SEQ ID No:293) or a functionally active derivative thereof, or a functionally active fragment thereof, or a homologue thereof, or a variant of "ENO2", the variant being encoded by a nucleic acid that hybridizes to the "ENO2" nucleic acid (SEQ ID No:294) or its complement under low stringency conditions, and/or (viii) "FIPI" (SEQ ID No:1531) or a functionally active derivative thereof, or a functionally active fragment thereof, or a homologue thereof, or a variant of "FIPl", the variant being encoded by a nucleic acid that hybridizes to the "FIPI" nucleic acid (SEQ ID No:1532) or its complement under low stringency conditions, and/or (ix) "GLC7" (SEQ ID No:929) or a functionally active derivative thereof, or a functionally active fragment thereof, or a homologue thereof, or a variant of "GLC7", the variant being encoded by a nucleic acid that hybridizes to the "GLC7" nucleic acid (SEQ ID No:930 ) or its complement under low stringency conditions, and/or (x) "GPM 1" (SEQ ID No:597) or a functionally active derivative thereof, or a functionally active fragment thereof, or a homologue thereof, or a variant of "GPM 1", the variant being encoded by a nucleic acid that hybridizes to the "GPMI" nucleic acid (SEQ ID No:598 ) or its complement under low stringency conditions, and/or (xi) "HTAI" (SEQ ID No:1029) or a functionally active derivative thereof, or a functionally active fragment thereof, or a homologue thereof, or a variant of "HTAI", the variant being encoded by a nucleic acid that hybridizes to the "HTAI" nucleic acid (SEQ ID No:1030) or its complement under low stringency conditions, and/or (xii) "IMD2" (SEQ ID No:259) or a functionally active derivative thereof, or a functionally active fragment thereof, or a homologue thereof, or a variant of "IMD2", the variant being encoded by a nucleic acid that hybridizes to the "IMD2" nucleic acid (SEQ ID No:260 ) or its complement under low stringency conditions, and/or (xiii) "IMD4" (SEQ ID No:41) or a functionally active derivative thereof, or a functionally active fragment thereof, or a homologue thereof, or a variant of "IMD4", the variant being encoded by a nucleic acid that hybridizes to the "IMD4" nucleic acid (SEQ ID No:42) or its complement under low stringency conditions, and/or (xiv) "MET6" (SEQ ID No:1921) or a functionally active derivative thereof, or a functionally active fragment thereof, or a homologue thereof, or a variant of "MET6", the variant being encoded by a nucleic acid that hybridizes to the "MET6" nucleic acid (SEQ ID No:1922 ) or its complement under low stringency conditions, and/or (xv) "PAP1" (SEQ ID No:1541) or a functionally active derivative thereof, or a functionally active fragment thereof, or a homologue thereof, or a variant of "PAP1", the variant being WO 03/072602 PCT/EPO2/50003 242 encoded by a nucleic acid that hybridizes to the "PAP1" nucleic acid (SEQ ID No:1542) or its complement under low stringency conditions, and/or (xvi) "PCF11" (SEQ ID No:2843) or a functionally active derivative thereof, or a functionally active fragment thereof, or a homologue thereof, or a variant of "PCF 11", the variant being encoded by a nucleic acid that hybridizes to the "PCF 11" nucleic acid (SEQ ID No:2844 ) or its complement under low stringency conditions, and/or (xvii) "PFKI" (SEQ ID No:143) or a functionally active derivative thereof, or a functionally active fragment thereof, or a homologue thereof, or a variant of "PFKI", the variant being encoded by a nucleic acid that hybridizes to the "PFKI" nucleic acid (SEQ ID No:144 ) or its complement under low stringency conditions, and/or (xviii) "PFS2" (SEQ ID No:1543) or a functionally active derivative thereof, or a functionally active fragment thereof, or a homologue thereof, or a variant of "PFS2", the variant being encoded by a nucleic acid that hybridizes to the "PFS2" nucleic acid (SEQ ID No:1544 ) or its complement under low stringency conditions, and/or (xix) "PTAI" (SEQ ID No:1545) or a functionally active derivative thereof, or a functionally active fragment thereof, or a homologue thereof, or a variant of "PTAI", the variant being encoded by a nucleic acid that hybridizes to the "PTAI" nucleic acid (SEQ ID No:1546 ) or its complement under low stringency conditions, and/or (xx) "PTII" (SEQ ID No:1597) or a functionally active derivative thereof, or a functionally active fragment thereof, or a homologue thereof, or a variant of "PTII", the variant being encoded by a nucleic acid that hybridizes to the "PTII" nucleic acid (SEQ ID No:1598) or its complement under low stringency conditions, and/or (xxi) "REF2" (SEQ ID No:1547) or a functionally active derivative thereof, or a functionally active fragment thereof, or a homologue thereof, or a variant of "REF2", the variant being encoded by a nucleic acid that hybridizes to the "REF2" nucleic acid (SEQ ID No:1548) or its complement under low stringency conditions, and/or (xxii) "RNA14" (SEQ ID No:1549) or a functionally active derivative thereof, or a functionally active fragment thereof, or a homologue thereof, or a variant of "RNA14", the variant being encoded by a nucleic acid that hybridizes to the "RNA14" nucleic acid (SEQ ID No:1550 ) or its complement under low stringency conditions, and/or (xxiii) "RNA15" (SEQ ID No:2845) or a functionally active derivative thereof, or a functionally active fragment thereof, or a homologue thereof, or a variant of "RNA15", the variant being encoded by a nucleic acid that hybridizes to the "RNA1 5" nucleic acid (SEQ ID No:2846 ) or its complement under low stringency conditions, and/or WO 03/072602 PCT/EPO2/50003 243 (xxiv) "RSA3" (SEQ ID No:2849) or a functionally active derivative thereof, or a functionally active fragment thereof, or a homologue thereof, or a variant of "RSA3", the variant being encoded by a nucleic acid that hybridizes to the "RSA3" nucleic acid (SEQ ID No:2850) or its complement under low stringency conditions, and/or (xxv) "SEC13" (SEQ ID No:1171) or a functionally active derivative thereof, or a functionally active fragment thereof, or a homologue thereof, or a variant of "SEC13", the variant being encoded by a nucleic acid that hybridizes to the "SEC13" nucleic acid (SEQ ID No:1172 ) or its complement under low stringency conditions, and/or (xxvi) "SEC31" (SEQ ID No:1177) or a functionally active derivative thereof, or a functionally active fragment thereof, or a homologue thereof, or a variant of "SEC31", the variant being encoded by a nucleic acid that hybridizes to the "SEC31" nucleic acid (SEQ ID No:1178 ) or its complement under low stringency conditions, and/or (xxvii) "SSA3" (SEQ ID No:723) or a functionally active derivative thereof, or a functionally active fragment thereof, or a homologue thereof, or a variant of "SSA3", the variant being encoded by a nucleic acid that hybridizes to the "SSA3" nucleic acid (SEQ ID No:724) or its complement under low stringency conditions, and/or (xxviii) "SSU72" (SEQ ID No:2851) or a functionally active derivative thereof, or a functionally active fragment thereof, or a homologue thereof, or a variant of "SSU72", the variant being encoded by a nucleic acid that hybridizes to the "SSU72" nucleic acid (SEQ ID No:2852) or its complement under low stringency conditions, and/or (xxix) "SWD2" (SEQ ID No:1455) or a functionally active derivative thereof, or a functionally active fragment thereof, or a homologue thereof, or a variant of "SWD2", the variant being encoded by a nucleic acid that hybridizes to the "SWD2" nucleic acid (SEQ ID No:1456 ) or its complement under low stringency conditions, and/or (xxx) "TAF60" (SEQ ID No:825) or a functionally active derivative thereof, or a functionally active fragment thereof, or a homologue thereof, or a variant of "TAF60", the variant being encoded by a nucleic acid that hybridizes to the "TAF60" nucleic acid (SEQ ID No:826) or its complement under low stringency conditions, and/or (xxxi) "TIF4632" (SEQ ID No:195) or a functionally active derivative thereof, or a functionally active fragment thereof, or a homologue thereof, or a variant of "TIF4632", the variant being encoded by a nucleic acid that hybridizes to the "TIF4632" nucleic acid (SEQ ID No:196 ) or its complement under low stringency conditions, and/or (xxxii) "TKLI" (SEQ ID No:379) or a functionally active derivative thereof, or a functionally active fragment thereof, or a homologue thereof, or a variant of "TKLI", the WO 03/072602 PCT/EPO2/50003 244 variant being encoded by a nucleic acid that hybridizes to the "TKLI" nucleic acid (SEQ ID No:380) or its complement under low stringency conditions, and/or (xxxiii) "TSAI" (SEQ ID No:733) or a functionally active derivative thereof, or a functionally active fragment thereof, or a homologue thereof, or a variant of "TSAI", the variant being encoded by a nucleic acid that hybridizes to the "TSAI" nucleic acid (SEQ ID No:734) or its complement under low stringency conditions, and/or (xxxiv) "TYE7" (SEQ ID No:2853) or a functionally active derivative thereof, or a functionally active fragment thereof, or a homologue thereof, or a variant of "TYE7", the variant being encoded by a nucleic acid that hybridizes to the "TYE7" nucleic acid (SEQ ID No:2854) or its complement under low stringency conditions, and/or (xxxv) "VID24" (SEQ ID No:2855) or a functionally active derivative thereof, or a functionally active fragment thereof, or a homologue thereof, or a variant of "VID24", the variant being encoded by a nucleic acid that hybridizes to the "VID24" nucleic acid (SEQ ID No:2856 ) or its complement under low stringency conditions, and/or (xxxvi) "VPS53" (SEQ ID No:1233) or a functionally active derivative thereof, or a functionally active fragment thereof, or a homologue thereof, or a variant of "VPS53", the variant being encoded by a nucleic acid that hybridizes to the "VPS53" nucleic acid (SEQ ID No:1234 ) or its complement under low stringency conditions, and/or (xxxvii) "YCLO46W" (SEQ ID No:2857) or a functionally active derivative thereof, or a functionally active fragment thereof, or a homologue thereof, or a variant of "YCLO46W", the variant being encoded by a nucleic acid that hybridizes to the "YCLO46W" nucleic acid (SEQ ID No:2858 ) or its complement under low stringency conditions, and/or (xxxviii) "YHLO35C" (SEQ ID No:2859) or a functionally active derivative thereof, or a functionally active fragment thereof, or a homologue thereof, or a variant of "YHLO35C", the variant being encoded by a nucleic acid that hybridizes to the "YHLO35C" nucleic acid (SEQ ID No:2860 ) or its complement under low stringency conditions, and/or (xxxix) "YKLO59C" (SEQ ID No:2861) or a functionally active derivative thereof, or a functionally active fragment thereof, or a homologue thereof, or a variant of "YKLO59C", the variant being encoded by a nucleic acid that hybridizes to the "YKLO59C" nucleic acid (SEQ ID No:2862 ) or its complement under low stringency conditions, and/or (xl) "YMLO30W" (SEQ ID No:2863) or a functionally active derivative thereof, or a functionally active fragment thereof, or a homologue thereof, or a variant of "YMLO30W", the variant being encoded by a nucleic acid that hybridizes to the "YMLO30W" nucleic acid (SEQ ID No:2864 ) or its complement under low stringency conditions, and/or WO 03/072602 PCT/EPO2/50003 245 (xli) "YOR179C" (SEQ ID No:2865) or a functionally active derivative thereof, or a functionally active fragment thereof, or a homologue thereof, or a variant of "YOR179C", the variant being encoded by a nucleic acid that hybridizes to the "YOR179C" nucleic acid (SEQ ID No:2866 ) or its complement under low stringency conditions, and/or (xlii) "YSHI" (SEQ ID No:1561) or a functionally active derivative thereof, or a functionally active fragment thereof, or a homologue thereof, or a variant of "YSHI", the variant being encoded by a nucleic acid that hybridizes to the "YSH 1" nucleic acid (SEQ ID No:1562 ) or its complement under low stringency conditions, and/or (xliii) "YTH1" (SEQ ID No:2847) or a functionally active derivative thereof, or a functionally active fragment thereof, or a homologue thereof, or a variant of "YTHI", the variant being encoded by a nucleic acid that hybridizes to the "YTH1" nucleic acid (SEQ ID No:2848 ) or its complement under low stringency conditions, and/or (xliv) "PABI" (SEQ ID No:2841) or a functionally active derivative thereof, or a functionally active fragment thereof, or a homologue thereof, or a variant of "PABI", the variant being encoded by a nucleic acid that hybridizes to the "PAB1" nucleic acid (SEQ ID No:2842) or its complement under low stringency conditions, and/or (xlv) "HHF2" (SEQ ID No:555) or a functionally active derivative thereof, or a functionally active fragment thereof, or a homologue thereof, or a variant of "HHF2", the variant being encoded by a nucleic acid that hybridizes to the "HHF2" nucleic acid (SEQ ID No:556 ) or its complement under low stringency conditions. is present in the complex. 40. The complex of any one of No. 1 - 7, or proteins of No. 12 or the antibody or fragment of No. 16, for use in a method of diagnosing a disease or disorder such as viral infections such as herpes simplex infections, Epstein-Barr-infections, influenza; metabolic diseases such as metachromatic leukodystrophy; neurodegenerative disorders such as amyotrophic lateral sclerosis; cancer. 41. A method for treating or preventing a disease or disorder characterized by an aberrant amount of, activity or component composition of or intracellular localization of, the complex of anyone of No. 1 - 7, comprising administering to a subject in need of such treatment or prevention a therapeutically effective amount of one or more molecules that modulate the amount of, 3' end mRNA processing activity; 3' end mRNA processing activity , or protein composition of, said complex.

WO 03/072602 PCT/EPO2/50003 246 42. The method according to No. 41, wherein said disease or disorder involves decreased levels of the amount or activity of said complex. 43. The method according to No. 41 , wherein said disease or disorder involves increased levels of the amount or activity of said complex. 44. Complex of any of No. 1 - 7 and/or protein selected from the following proteins (i) "ACT1" (SEQ ID No:681) or a functionally active derivative thereof, or a functionally active fragment thereof, or a homologue thereof, or a variant of "ACT1", the variant being encoded by a nucleic acid that hybridizes to the "ACT1" nucleic acid (SEQ ID No:682) or its complement under low stringency conditions,and (ii) "CFTI" (SEQ ID No:2837) or a functionally active derivative thereof, or a functionally active fragment thereof, or a homologue thereof, or a variant of "CFTI", the variant being encoded by a nucleic acid that hybridizes to the "CFTI" nucleic acid (SEQ ID No:2838) or its complement under low stringency conditions,and (iii) "CFT2" (SEQ ID No:1529) or a functionally active derivative thereof, or a functionally active fragment thereof, or a homologue thereof, or a variant of "CFT2", the variant being encoded by a nucleic acid that hybridizes to the "CFT2" nucleic acid (SEQ ID No:1530) or its complement under low stringency conditions,and (iv) "CKAI" (SEQ ID No:133) or a functionally active derivative thereof, or a functionally active fragment thereof, or a homologue thereof, or a variant of "CKAI", the variant being encoded by a nucleic acid that hybridizes to the "CKAI" nucleic acid (SEQ ID No:134 ) or its complement under low stringency conditions,and (v) "CLPI" (SEQ ID No:2839) or a functionally active derivative thereof, or a functionally active fragment thereof, or a homologue thereof, or a variant of "CLP1", the variant being encoded by a nucleic acid that hybridizes to the "CLPI" nucleic acid (SEQ ID No:2840) or its complement under low stringency conditions,and (vi) "EFT2" (SEQ ID No:39) or a functionally active derivative thereof, or a functionally active fragment thereof, or a homologue thereof, or a variant of "EFT2", the variant being encoded by a nucleic acid that hybridizes to the "EFT2" nucleic acid (SEQ ID No:40 ) or its complement under low stringency conditions,and (vii) "ENO2" (SEQ ID No:293) or a functionally active derivative thereof, or a functionally active fragment thereof, or a homologue thereof, or a variant of "ENO2", the variant WO 03/072602 PCT/EPO2/50003 247 being encoded by a nucleic acid that hybridizes to the "ENO2" nucleic acid (SEQ ID No:294) or its complement under low stringency conditions,and (viii) "FIPI" (SEQ ID No:1531) or a functionally active derivative thereof, or a functionally active fragment thereof, or a homologue thereof,,or a variant of "FIPI", the variant being encoded by a nucleic acid that hybridizes to the "FIPI" nucleic acid (SEQ ID No:1532) or its complement under low stringency conditions,and (ix) "GLC7" (SEQ ID No:929) or a functionally active derivative thereof, or a functionally active fragment thereof, or a homologue thereof, or a variant of "GLC7", the variant being encoded by a nucleic acid that hybridizes to the "GLC7" nucleic acid (SEQ ID No:930) or its complement under low stringency conditions,and (x) "GPMI" (SEQ ID No:597) or a functionally active derivative thereof, or a functionally active fragment thereof, or a homologue thereof, or a variant of "GPM 1", the variant being encoded by a nucleic acid that hybridizes to the "GPMI1" nucleic acid (SEQ ID No:598 ) or its complement under low stringency conditions,and (xi) "HTAI" (SEQ ID No:1029) or a functionally active derivative thereof, or a functionally active fragment thereof, or a homologue thereof, or a variant of "HTAI", the variant being encoded by a nucleic acid that hybridizes to the "HTAI" nucleic acid (SEQ ID No:1030) or its complement under low stringency conditions,and (xii) "IMD2" (SEQ ID No:259) or a functionally active derivative thereof, or a functionally active fragment thereof, or a homologue thereof, or a variant of "IMD2", the variant being encoded by a nucleic acid that hybridizes to the "IMD2" nucleic acid (SEQ ID No:260) or its complement under low stringency conditions,and (xiii) "IMD4" (SEQ ID No:41) or a functionally active derivative thereof, or a functionally active fragment thereof, or a homologue thereof, or a variant of "IMD4", the variant being encoded by a nucleic acid that hybridizes to the "IMD4" nucleic acid (SEQ ID No:42 ) or its complement under low stringency conditions,and (xiv) "MET6" (SEQ ID No:1921) or a functionally active derivative thereof, or a functionally active fragment thereof, or a homologue thereof, or a variant of "MET6", the variant being encoded by a nucleic acid that hybridizes to the "MET6" nucleic acid (SEQ ID No:1922 ) or its complement under low stringency conditions,and (xv) "PAP1" (SEQ ID No:1541) or a functionally active derivative thereof, or a functionally active fragment thereof, or a homologue thereof, or a variant of "PAP1", the variant being encoded by a nucleic acid that hybridizes to the "PAP1" nucleic acid (SEQ ID No:1542) or its complement under low stringency conditions,and WO 03/072602 PCT/EPO2/50003 248 (xvi) "PCF 11" (SEQ ID No:2843) or a functionally active derivative thereof, or a functionally active fragment thereof, or a homologue thereof, or a variant of "PCF 11", the variant being encoded by a nucleic acid that hybridizes to the "PCF1 1" nucleic acid (SEQ ID No:2844 ) or its complement under low stringency conditions,and (xvii) "PFKI" (SEQ ID No:143) or a functionally active derivative thereof, or a functionally active fragment thereof, or a homologue thereof, or a variant of "PFK1", the variant being encoded by a nucleic acid that hybridizes to the "PFKI" nucleic acid (SEQ ID No:144) or its complement under low stringency conditions,and (xviii) "PFS2" (SEQ ID No:1543) or a functionally active derivative thereof, or a functionally active fragment thereof, or a homologue thereof, or a variant of "PFS2", the variant being encoded by a nucleic acid that hybridizes to the "PFS2" nucleic acid (SEQ ID No:1544) or its complement under low stringency conditions,and (xix) "PTAI" (SEQ ID No:1545) or a functionally active derivative thereof, or a functionally active fragment thereof, or a homologue thereof, or a variant of "PTAI", the variant being encoded by a nucleic acid that hybridizes to the "PTAI" nucleic acid (SEQ ID No:1546 ) or its complement under low stringency conditions,and (xx) "PTII" (SEQ ID No:1597) or a functionally active derivative thereof, or a functionally active fragment thereof, or a homologue thereof, or a variant of "PTII ", the variant being encoded by a nucleic acid that hybridizes to the "PTII" nucleic acid (SEQ ID No:1598) or its complement under low stringency conditions,and (xxi) "REF2" (SEQ ID No:1547) or a functionally active derivative thereof, or a functionally active fragment thereof, or a homologue thereof, or a variant of "REF2", the variant being encoded by a nucleic acid that hybridizes to the "REF2" nucleic acid (SEQ ID No:1548 ) or its complement under low stringency conditions,and (xxii) "RNA14" (SEQ ID No:1549) or a functionally active derivative thereof, or a functionally active fragment thereof, or a homologue thereof, or a variant of "RNA14", the variant being encoded by a nucleic acid that hybridizes to the "RNA14" nucleic acid (SEQ ID No:1550 ) or its complement under low stringency conditions,and (xxiii) "RNA15" (SEQ ID No:2845) or a functionally active derivative thereof, or a functionally active fragment thereof, or a homologue thereof, or a variant of "RNA15", the variant being encoded by a nucleic acid that hybridizes to the "RNA1 5" nucleic acid (SEQ ID No:2846 ) or its complement under low stringency conditions,and (xxiv) "RSA3" (SEQ ID No:2849) or a functionally active derivative thereof, or a functionally active fragment thereof, or a homologue thereof, or a variant of "RSA3", the WO 03/072602 PCT/EPO2/50003 249 variant being encoded by a nucleic acid that hybridizes to the "RSA3" nucleic acid (SEQ ID No:2850) or its complement under low stringency conditions,and (xxv) "SEC13" (SEQ ID No:1171) or a functionally active derivative thereof, or a functionally active fragment thereof, or a homologue thereof, or a variant of "SEC1 3", the variant being encoded by a nucleic acid that hybridizes to the "SEC13" nucleic acid (SEQ ID No:1172) or its complement under low stringency conditions,and (xxvi) "SEC31" (SEQ ID No:1177) or a functionally active derivative thereof, or a functionally active fragment thereof, or a homologue thereof, or a variant of "SEC31", the variant being encoded by a nucleic acid that hybridizes to the "SEC31" nucleic acid (SEQ ID No:1178) or its complement under low stringency conditions,and (xxvii) "SSA3" (SEQ ID No:723) or a functionally active derivative thereof, or a functionally active fragment thereof, or a homologue thereof, or a variant of "SSA3", the variant being encoded by a nucleic acid that hybridizes to the "SSA3" nucleic acid (SEQ ID No:724 ) or its complement under low stringency conditions,and (xxviii) "SSU72" (SEQ ID No:2851) or a functionally active derivative thereof, or a functionally active fragment thereof, or a homologue thereof, or a variant of "SSU72", the variant being encoded by a nucleic acid that hybridizes to the "SSU72" nucleic acid (SEQ ID No:2852 ) or its complement under low stringency conditions,and (xxix) "SWD2" (SEQ ID No:1455) or a functionally active derivative thereof, or a functionally active fragment thereof, or a homologue thereof, or a variant of "SWD2", the variant being encoded by a nucleic acid that hybridizes to the "SWD2" nucleic acid (SEQ ID No:1456) or its complement under low stringency conditions,and (xxx) "TAF60" (SEQ ID No:825) or a functionally active derivative thereof, or a functionally active fragment thereof, or a homologue thereof, or a variant of "TAF60", the variant being encoded by a nucleic acid that hybridizes to the "TAF60" nucleic acid (SEQ ID No:826) or its complement under low stringency conditions,and (xxxi) "TIF4632" (SEQ ID No:195) or a functionally active derivative thereof, or a functionally active fragment thereof, or a homologue thereof, or a variant of "TIF4632", the variant being encoded by a nucleic acid that hybridizes to the "TIF4632" nucleic acid (SEQ ID No:196 ) or its complement under low stringency conditions,and (xxxii) "TKLI" (SEQ ID No:379) or a functionally active derivative thereof, or a functionally active fragment thereof, or a homologue thereof, or a variant of "TKLI", the variant being encoded by a nucleic acid that hybridizes to the "TKL1" nucleic acid (SEQ ID No:380 ) or its complement under low stringency conditions,and WO 03/072602 PCT/EPO2/50003 250 (xxxiii) "TSAI" (SEQ ID No:733) or a functionally active derivative thereof, or a functionally active fragment thereof, or a homologue thereof, or a variant of "TSAI ", the variant being encoded by a nucleic acid that hybridizes to the "TSAI" nucleic acid (SEQ ID No:734) or its complement under low stringency conditions,and (xxxiv) "TYE7" (SEQ ID No:2853) or a functionally active derivative thereof, or a functionally active fragment thereof, or a homologue thereof, or a variant of "TYE7", the variant being encoded by a nucleic acid that hybridizes to the "TYE7" nucleic acid (SEQ ID No:2854 ) or its complement under low stringency conditions,and (xxxv) "VID24" (SEQ ID No:2855) or a functionally active derivative thereof, or a functionally active fragment thereof, or a homologue thereof, or a variant of "VID24", the variant being encoded by a nucleic acid that hybridizes to the "VID24" nucleic acid (SEQ ID No:2856) or its complement under low stringency conditions,and (xxxvi) "VPS53" (SEQ ID No:1233) or a functionally active derivative thereof, or a functionally active fragment thereof, or a homologue thereof, or a variant of "VPS53", the variant being encoded by a nucleic acid that hybridizes to the "VPS53" nucleic acid (SEQ ID No:1234 ) or its complement under low stringency conditions,and (xxxvii) "YCLO46W" (SEQ ID No:2857) or a functionally active derivative thereof, or a functionally active fragment thereof, or a homologue thereof, or a variant of "YCLO46W", the variant being encoded by a nucleic acid that hybridizes to the "YCLO46W" nucleic acid (SEQ ID No:2858 ) or its complement under low stringency conditions,and (xxxviii) "YHLO35C" (SEQ ID No:2859) or a functionally active derivative thereof, or a functionally active fragment thereof, or a homologue thereof, or a variant of "YHLO35C", the variant being encoded by a nucleic acid that hybridizes to the "YHLO35C" nucleic acid (SEQ ID No:2860 ) or its complement under low stringency conditions,and (xxxix) "YKLO59C" (SEQ ID No:2861) or a functionally active derivative thereof, or a functionally active fragment thereof, or a homologue thereof, or a variant of "YKLO59C", the variant being encoded by a nucleic acid that hybridizes to the "YKLO59C" nucleic acid (SEQ ID No:2862) or its complement under low stringency conditions,and (xl) "YMLO30W" (SEQ ID No:2863) or a functionally active derivative thereof, or a functionally active fragment thereof, or a homologue thereof, or a variant of "YMLO30W", the variant being encoded by a nucleic acid that hybridizes to the "YMLO30W" nucleic acid (SEQ ID No:2864 ) or its complement under low stringency conditions,and (xli) "YOR179C" (SEQ ID No:2865) or a functionally active derivative thereof, or a functionally active fragment thereof, or a homologue thereof, or a variant of "YOR179C", WO 03/072602 PCT/EPO2/50003 251 the variant being encoded by a nucleic acid that hybridizes to the "YOR179C" nucleic acid (SEQ ID No:2866 ) or its complement under low stringency conditions,and (xlii) "YSHI" (SEQ ID No:1561) or a functionally active derivative thereof, or a functionally active fragment thereof, or a homologue thereof, or a variant of "YSHI1", the variant being encoded by a nucleic acid that hybridizes to the "YSHI" nucleic acid (SEQ ID No:1562) or its complement under low stringency conditions, andlor (xiii) "YTH1" (SEQ ID No:2847) or a functionally active derivative thereof, or a functionally active fragment thereof, or a homologue thereof, or a variant of "YTH1", the variant being encoded by a nucleic acid that hybridizes to the "YTHI" nucleic acid (SEQ ID No:2848 ) or its complement under low stringency conditions, and/or (xliv) "PABI" (SEQ ID No:2841) or a functionally active derivative thereof, or a functionally active fragment thereof, or a homologue thereof, or a variant of "PABI", the variant being encoded by a nucleic acid that hybridizes to the "PABI" nucleic acid (SEQ ID No:2842 ) or its complement under low stringency conditions, and/or (xlv) "HHF2" (SEQ ID No:555) or a functionally active derivative thereof, or a functionally active fragment thereof, or a homologue thereof, or a variant of "HHF2", the variant being encoded by a nucleic acid that hybridizes to the "HHF2" nucleic acid (SEQ ID No:556) or its complement under low stringency conditions, as a target for an active agent of a pharmaceutical, preferably a drug target in the treatment or prevention of a disease or disorder such as viral infections such as herpes simplex infections, Epstein-Barr-infections, influenza; metabolic diseases such as metachromatic leukodystrophy; neurodegenerative disorders such as amyotrophic lateral sclerosis; cancer. In a preferred embodiment of the present invention, the protein components of the complex are vertebrate homologs of the yeast proteins, or a mixture of yeast and vertebrate homolog proteins. In a more preferred embodiment the present invention relates to a complex which is useful for cleaving and/or polyadenylating a nucleic acid. In a more preferred embodiment, the protein components of the complex are mammalian homologs of the yeast proteins, or a mixture of yeast and mammalian homolog proteins. In particular aspects,n the native component proteins, or derivatives or fragments of the complex are obtained from a mammal such as mouse, rat, pig, cow, dog, monkey, human, sheep or horse. In another preferred embodiment, the protein components of the complex are human homologs of the yeast proteins, or a mixture of WO 03/072602 PCT/EPO2/50003 252 yeast and human homolog proteins. In yet another preferred embodiment, the protein components of the complex are a mixture of yeast, vertebrate, mammalian and/or human proteins. As used herein, a "functionally active complex" refers to that material displaying one or more known functional attributes of a wild type complex, including but not limited to binding to a complex-specific antibody or physiological function (for physiological functions of the protein complexes of the present invention, A specific embodiment of the present invention is directed to a complex comprising of a fragment of a component protein that can be bound by an anti component protein antibody or bound by an antibody specific for the protein complex or wherein the fragment is able to bind another component protein of the complex. In another specific embodiments, the present invention is directed to a complex comprising a fragment of one or more members of the complex. Fragments, or proteins comprising fragments, lacking a region of a member of the complex, are also provided. Nucleic acids encoding the foregoing are also provided in the present invention. The present invention is also directed to methods for production of a protein complex of the present invention and derivatives of the complex and/or fragments and/or derivatives of individual component proteins or the complex e. g. by the TAP method described further below. Pharmaceutical compositions are also provided. The present invention is further directed to complexes comprising a fusion protein which comprises a component of the complex or a fragment thereof linked via a covalent bond to an amino acid sequence different from said component protein, as well as nucleic acids encoding the protein, fusions and fragments thereof. For example, the non-component protein portion of the fusion protein, which can be added to the N terminal, the C-terminal or inserted into the amino acid sequence of the complex component can comprise a few amino acids, which provide an epitope that is used as a target for affinity purification of the fusion protein and/or complex. The invention is further directed to methods for modulating (i.e., inhibiting or enhancing) the amount of, the cleavage and/or polyadenylating activity of RNA of, or the identity of the protein components of, a complex of the present invention. The protein components of a complex of the present invention have been implicated in many physiological processes. The present invention is also directed to methods for screening a complex, as well as a derivative of the complex, for the ability to alter a cell function, WO 03/072602 PCT/EPO2/50003 253 particularly a cell function in which the complex and/or a component protein of the complex has been implicated. Moreover, the present invention provides a process for the identification and/or preparation of an effector of a composition according to the invention which process comprises the steps of bringing into contact the composition of the invention or of a component thereof with a compound, a mixture of compounds or a library of compounds and determining whether the compounds or certain compounds of the mixture or library bind to the composition of the invention and/or a component thereof and/or affects the cleavage and/or polyadenylation of nucleic acid activity of such a composition or component and then optionally further purifying the compound positively tested as effector by such a process. A major application of the composition according to the invention results in the identification of an active agent capable of binding thereto. Hence, the compositions of the invention are useful tools in screening for new pharmaceutical drugs. The present invention is also directed to a method for isolating the complex and the component proteins comprising tagging a protein of the complex with a sequence that allows affinity purification of the tagged protein, expressing such protein in a target cell, isolating the protein complex which is attached to the tagged protein, and optionally disassociating the protein complex and isolating the individual complex members. The present invention further relates to a composition, preferably a protein complex, which is obtainable by the method comprising the following steps: tagging a protein as defined above, i.e. a protein which forms part of a protein complex, with a moiety, preferably an amino acid sequence, that allows affinity purification of the tagged protein and expressing such protein in a target cell and isolating the protein complex which is attached to the tagged protein. The details of such purification are described in WO 00/09716 and in Rigaut, G. et al. (1999), Nature Biotechnology, Vol. 17 (10): 1030 1032 and further herein below. The tagging can essentially be performed with any moiety which is capable of providing a specific interaction with a further moiety, e.g. in the sense of a ligand receptor interaction, antigen antibody interaction or the like. The tagged protein can also be expressed in an amount in the target cell which comes close to the physiological concentration in order to avoid a complex formation merely due to high concentration of the expressed protein but not reflecting the natural occurring complex.

WO 03/072602 PCT/EPO2/50003 254 In a further preferred embodiment, the composition is obtained by using a tagged protein which comprises two different tags which allow two different affinity purification steps. This measure allows a higher degree of purification of the composition in question. In a further preferred embodiment the tagged protein comprises two tags that are separated by a cleavage site for a protease. This allows a step-by-step purification on affinity columns. The present invention is also directed to therapeutic and prophylactic, as well as diagnostic, prognostic, and screening methods and compositions based upon the complex (and the nucleic acids encoding the individual proteins that participate in the complex). Therapeutic compounds of the invention include, but are not limited to, a complex of the invention, and a complex where one or more members of the complex is a derivative or fragment thereof. The present invention is also directed to complex specific antibodies to and nucleic acids encoding the foregoing; and antisense nucleic acids to the nucleotide sequences encoding the complex components. Diagnostic, prognostic and screening kits are also provided. The present invention further relates to a kit comprising a composition as described above, optionally together with further reagents and working instructions. The further reagents may be, for example, buffers, substrates for enzymes but also carrier material such as beads, filters, microarrays and other solid carries. The working instructions may indicate how to use the ingredients of the kit in order to perform a desired assay. The present invention further relates to a nucleic acid encoding a component of a composition as defined above. Such a nucleic acid may be used for example to express a desired tagged protein in a given cell for the isolation of a complex or component according to the invention. Such a nucleic acid may also be used for the identification and isolation of genes from other organisms by cross species hybridization. The present invention further relates to a construct, preferably a vector construct, which comprises a nucleic acid as described above. Such constructs may comprise expression controlling elements such as promoters, enhancers and terminators in order to express the nucleic acids in a given host cell, preferably under conditions which resemble the physiological concentrations. The present invention further relates to a host cell containing a construct as defined above. Such a host cell can be, e.g., any eukaryotic cell such as yeast, plant WO 03/072602 PCT/EPO2/50003 255 or mammalian, whereas human cells are preferred. Such host cells may form the starting material for isolation of a complex according to the present invention. Animal models and methods of screening for modulators (i.e., agonists, and antagonists) of the amount of, activity of, or protein component composition of, a complex of the present invention are also provided. The present invention further relates to a kit comprising a composition as described above, optionally together with further reagents and working instructions. The further reagents may be, for example, buffers, substrates for enzymes but also carrier material such as beads, filters, microarrays and other solid carries. The working instructions may indicate how to use the ingredients of the kit in order to perform a desired assay. The following examples further illustrate the invention as it relates to the polyadenylation complex. Construction of a yeast strain expressing TAP-tagged Ptal: see Tab. 6 Purification of proteins associated with Ptal: The TAP-technology, which is more fully described in WO 00/09716 and in Rigaut, G. et. al. (1999), Nature Biotechnology. Vol. 17 (10): 1030-1032 respectively was used for protein complex purification. The Ptal protein was C-terminally tagged with a TAP-tag which consists of calmodulin-binding peptide (CBP), a cleavage site for TEV protease followed by two IgG-binding units of protein A (Rigaut, G. et. al. (1999), Nature Biotechnology. Vol. 17 (10): 1030-1032). Ptal is an essential protein which has been reported to be a component of PFI. Ptal-TAP was used as a bait to identify associated partners from cell lysates using the two-step TAP purification procedure. Proteins were separated by 1D gel electrophoresis and visualized by staining with Coomassie. More than a total of 20 bands could be detected on the gel (see Fig. 5). The identity of the proteins was determined by mass spectrometry. 13 of these are known components of the pre-mRNA processing machinery: Cftl, Cft2, Ysh, Ptal, Rnal4, Pabl, Pcf 1, Pap1, Clpl, Pfs2, Fipl, Rnal5 and Ythl. The remaining seven proteins (see Fig 5) have not previously been found associated with Ptal: Ref2, YK059c, YGR156w, YKL018w, Glc7, Ssu72 and YOR179c. Further experiments using the TAP-technology using different WO 03/072602 PCT/EPO2/50003 256 baits have identified additional 18 proteins which have now found to be associated with the complex, thus increasing the size of the complex to 38 proteins in total (as described further above). Validation of interactions found with Ptal: A reciprocal experiment to the one described above was performed. For this purpose a subset of the interactors found in the above described Pta purification (both known and novel interactors) were chosen as a bait for a further round of purification. In the case of some proteins the C-terminally tagged versions could not be recovered. The likely reason for this is that the addition of the TAP tag at the C-terminus interferes with the function of these proteins (a selection of the reciprocal experiments undertaken is shown in Fig. 6) Results for the polyadenylation complex thus show, that, complexes are often sufficiently strong to show high composition integrity even when purified using different entry points. Moreover, the example shows that the TAP method reveals novel components even in well-studied cellular machinery. Sequence analysis of members of the complex: The process of mRNA processing is highly conserved in eukaryotes. Accordingly, for significant proportion of the yeast proteins, human orthologs could be found. This illustrates that many of the functions found in the yeast complex can be transferred to humans. Also the enzymatic activity of this complex has long been known, the enzymatically active member could not yet be unraveled. Using extensive sequence similarity searches it could be shown that Yshl is homologous to a class of bacterial beta-lactamases. The active center of this protein family contains 2 zinc ions which are bound by histidines. As these residues are conserved in Yshl and it was shown that enzymatic activity of the yeast complex is zinc dependent predicted that Yshl is responsible for the catalytic activity of the complex. Two other proteins found in the complex, Cft2 and YOR179c, are homologous to the Yshl N- and C-terminus, respectively. Though Cft2 is homologous to the enzymatic region of Yshl it misses the zinc binding histidines indicating that it lacks enzymatic activity. Thus, Cft 2 and YOR179c could compete with Yshl for the same binding slot of the complex, suggesting WO 03/072602 PCT/EPO2/50003 257 a novel type of regulation of polyadenylation. A similar way of regulation might be used in the case of Pfs2 and YKL018w, which both consist of multiple WD40 domains. Prediction of mammalian proteins: To allow the transfer of function information from yeast to human proteins, we did not only use an identity cutoff, but also the 'orthology' concept. Orthology defines genes which arose via a speciation event, in contrast to genes which arose via gene duplication. Orthologs genes are supposed to perform the same function in different organisms, therefore more detailed function information can be transferred. The algorithm for the detection of orthologous gene pairs from yeast and human uses the whole genome of these organisms. First, pairwise best hits were retrieved, using a full Smith-Waterman alignment of predicted proteins. To further improve reli-ability, these pairs were clustered with pairwise best hits involving Drosophila melanogaster and Caenorhabditis elegans proteins. See "Initial sequencing and analysis of the human genome", Nature 2001 Feb 15; 409(6822):860-921 for a detailed description of the analysis. Bioinformatic analysis of the Complex: Functional domains of all members of the complex were analyzed using SMART (SMART: a web-based tool for the study of genetically mobile domains. Nucleic Acids Res 2000 Jan 1; 28(1):231-4) and Pfam (Pfam: protein families database, Nucleic Acids Res 2000 Jan 1; 28(1):263-6). Comparison of the yeast and mammalian polyadenylation complex: The sequence of many of the polypeptides which have been proposed to be involved in 3'-end formation so far are conserved form yeast to mammals, although the sequence elements on the substrate pre-mRNA differ (see Tab. 7). Purification of the protein complexes from yeast using Ptal as a bait: WO 03/072602 PCT/EPO2/50003 258 Yeast strain Sc0051 expressing TAP-tagged Ptal was cultured in 4 I of YPD medium to an OD600 of 2. After harvesting, the cell pellet was frozen in liquid nitrogen and stored at -80oC. All further manipulations were done at 4 0 C except where noted. For preparation of protein lysates the cells were resuspended in lysis buffer (50 mM Tris-HCI pH 7.5, 100 mM NaCI, 0.15 % NP-40, 1.5 mM MgCI2, 0.5 mM DTT, protease inhibitors) and subjected to mechanical disruption with glass beads. Lysates were clarified by two successive centrifugation steps at 20.000 x g for 10 min and 100.000 x g for 1 hour. After addition of glycerol to 5 % final concentration the lysates were frozen in liquid nitrogen and stored at -80'C. For the first purification step 500 pl of rabbit IgG-Agarose (50:50 slurry, Sigma A2909) pre-equilibrated in lysis buffer were added to the lysate and the sample was rotated for 2 hours. The unbound fraction was discarded and the beads with the bound material were transferred to a 0.8 ml column (MoBiTec M1002, 90 pm filter). The beads were washed with 10 ml of lysis buffer followed by 5 ml of TEV cleavage buffer (10 mM Tris-HCI pH 8.0, 100 mM NaCI, 0.1 % NP-40, 0.5 mM EDTA, 1 mM DTT). 150 pl of TEV cleavage buffer and 4 pl of TEV protease were added to the column and the sample was incubated on a shaker at 16 oC for 2 hours. The eluate was recovered by pressing with a syringe. 150 pl of Calmodulin dilution buffer (10 mM Tris-HCI pH 8.0, 100 mM NaCI, 0.1 % NP-40, 2 mM MgAc, 2 mM imidazole, 4 mM CaCI2, 1 mM DTT) was added to the previous eluate and this mixture was transferred to a MoBiTec column containing 300 pl (bead volume) of Calmodulin affinity resin (Stratagene #214303) which was prewashed in Calmodulin wash buffer (10 mM Tris-HCI pH 8.0, 100 mM NaCI, 0.1 % NP-40, 1 mM MgAc, 1 mM imidazole, 2 mM CaCI2, 1 mM DTT). The samples were rotated for 1 hour at 4 OC. After washing of the beads with 10 ml of Calmodulin wash buffer, protein complexes were eluted with 600 pl of elution buffer (10 mM Tris-HCI pH 8.0, 5 mM EDTA). The samples were concentrated in siliconised tubes in a speed vac to a final volume of 10-20 pl. Proteins were detected by polyacrylamide gel electrophoresis followed by staining with colloidal Coomassie blue.

WO 03/072602 PCT/EPO2/50003 259 The following preferred embodiments can be obtained and characterized with the methodology as explained above for the polyadenylation complex as well as the respective protocols for yeast as described in section 'protocols' (infra) (There, also protocols for mammalian cells and membrane proteins are given). Basically, the same steps are applied to each complex with the exception that different baits are used for the isolation of different complexes. The Ccr4-Not-complex (complex 149) Gene regulation plays a crucial role in every physiological aspect of all organisms. Transcription activation and repression is at the heart of highly regulated processes like development, adaptation, differentiation, aging, etc. The CCR4-NOT complex plays a critical role in the yeast adaptation process to utilize different carbon sources. The mechanism by which alters gene expression is not clear yet multiple genetic interactions with the basal transcription machinery have been described (Collart, M.A., 1996, Mol. Cell. Biol. 16: 6668-6676 and Collart, M.A. and Struhl K, 1994, Genes Dev 8: 525-37) . This complex was first identified by genetic means (Collart, M.A. and Struhl K, 1994, Genes Dev 8: 525-37) and later on biochemically as a 1 MDa complex in yeast cell extracts (Liu, H et al, 1998, EMBO J. 17: 1096-106). The genetic isolation of yNOTs was based on suppression of the defect of a mutant GCN4 transcriptional activator and on the yeast HIS3 promoter. Subsequent analysis showed that all suppressors were loss-of-function alleles leading to an up regulation of the low, constitutive level of HIS3 transcription rather than enhancing function of the defective GCN4 allele. Whereas mutations in NOTs de-repress constitutive HIS3 transcription, mutations in subunits of TFIID have the opposite effect (Collart, M.A., 1996, Mol. Cell. Bioo. 16: 6668-6676 and Moqtaderi, Z et al, 1996, Nature 383: 188-191). Biochemical fractionation and characterization of yNOT proteins (NOT1 to 5) showed that they reside in a multi-subunit complex also harboring yCCR4 and yCAF1, which are also global regulators of transcription. Biochemical and genetic evidences have proposed a model for the architecture of this complex. CAF1 is presumed to bind to residues 667 to 1152 of NOT1, CCR4 binds to CAF1, and NOT2 and NOT5 interact with the C-terminal residues 1490 to 2108 of NOT1 in no particular order. NOT4 is placed on the periphery of NOT2 and NOT5, and it is presumed that NOT3 makes contacts with WO 03/072602 PCT/EPO2/50003 260 NOT2, NOT5 or NNOT4 and the Nterminus of NOT1 (Bai, Y et al, 1999, Mol Cell Biol 19: 6642-6651). At least two additional subunits have also been proposed to be part of the CCR4/NOT complex, Dhhlp and DBF2, however they seem to be part of a larger 1.9 MDa complex. Potential human orthologues for hNOT2, hNOT3, hNOT4 and CALIF (a CAF1-like protein) have been identified and cloned (Albert, T.K. et al, 2000, Nucl Acid Res 28: 809 817). As expected, multiple two-hybrid interactions exists between the human NOTs and that hNOT4 and hNOT4 can cross-complement their yeast orthologues yet no data supporting a higher complex has been described. In order to better understand the function of the CCR4-NOT multi-protein complex, we decided to TAP tag the yeast CCR4 and the human Not2 subunit of this regulatory complex of RNA Polymerase II transcription. Caf40, and Cafl 30, two novel components of the yeast CCR4/NOT complex were identified. Interestingly, Rqcdl, a human homologue of Caf40, was conversely identified as a novel component of the human CCR4/NOT complex. Other human orthologues of Not1 (KIAA1007), CCR4 (KIAA1194), were also identified as components of the human CCR4/Not complex. Here we show for the first time that CALIF and CAF1, which represent the counterpart of CAF1 in yeast, are also part of this complex together with hNot2 and hNot3. Despite the large body of information already available from the prior art concerning the Ccr4-Not complex up to now not all components of the complex are known not to speak of the composition of the complex as a whole. This invention relates to a component of the Ccr4-Not-complex selected from: Yeast proteins YDR214w functionally active fragements or functionally active derivatives thereof, the mammalian homologs thereof, or variants thereof encoded by a nucleic acid that hybridizes to any of the above proteins or their complements under low stringency conditions.

WO 03/072602 PCT/EPO2/50003 261 By applying the process according to the invention to the isolation of the Ccr4/Not complex from yeast thirteen new proteins could be identified in said yeast complex. The proteins are listed below (see also Tab. 2). The Accession-Number is the GenBank Accession number for the protein. Atp11: Is a known and essential protein (GenBank Acc. No.: CAA96245.1)). It has been previously linked to roles in protein complex assembly. Caf130: Is a non-essential protein of unknown function (GenBank Acc. NO.: CAA97147.1) Caf40: Is a non-essential protein of unknown function (GenBank Acc. NO.: CAA96205.1) Cct6: Is an essential protein having ATPaselChaperonin-function which has been shown to be involved in protein folding (GenBank Acc. NO.: CAA86694.1) Fas2: Is an essential protein with oxidoreductase/transferase activity which has been shown to be involved in lipid-, fatty-acid and sterol metabolism (GenBank Acc. NO.: CAA97948. 1) Gcnl: Is a known and non-essential protein which has been shown to be involved in amino-acid metabolism (GenBank Acc. No.: CAA96907.1) Pdcl: Is a known and non-essential protein which has lyase-activity and has been shown to be involved in carbohydrate metabolism (GenBank Acc. No. CAA97573.1) Rvb2: Is a known and essential protein which has been shown to be involved in Pol II transcription and RNA processing/modification. It has Helicase activity (GenBank Acc. No.: CAA97952.1) Sam1: Is a known and non-essential protein (GenBank Acc. No.: AAB67461.1) which has transferase activity and has been shown to be involved in amino-acid metabolism.

WO 03/072602 PCT/EPO2/50003 262 Tfcl: Is a known and essential protein which has been shown to be involved in RNA pol Ill transcription initiation (GenBank Acc. No.: CAA85080.1). Vmal: Is a known and non-essential protein which has been shown to be involved in small molecule transport and has Hydrolase/ATPase activity (GenBank Acc. No.: CAA98761.1). Catalytic subunit (subunit A) of the vacuolar H(+) ATPase V1 complex. Ydr214w: Is a non-essential protein of unknown function (GenBank Acc. No.: CAA92357.1) Yral: Is a known and essential protein with RNA:RNA annealing activity, involved in mRNA packaging for export from the nucleus (GenBank Acc. No.: AAC09951.1) In addition, the invention relates to the human Ccr4-Not-complex The previously uncharacterised human Ccr4-Not-complex was - by applying the protocols for protein complex isolation in mammalian cells as described in section 'Protocols' (infra) and using hNot2 as a bait - found to be composed of the following proteins (see Fig. 7 and Tab. 2b): KIAA1007 (homolog of yNotl): GenBank Acc. No of protein: NP_057368 KIAA1194 (homolog of yCcr4): GenBank Acc. No. of protein: XP_003851 hNot2: GenBank Acc. No. of protein: NP_055330 hCafl (homolog of yCafl): GenBank Acc. No. of protein NP_037486 Calif (homolog of yCafl): GenBank Acc. No. of protein NP_004770 Rqcd (homolog of Caf40); GenBank Acc. No. of protein NP_005435 AAH02928: GenBank Acc. No. of protein AAH02928 So far, for the mammalian proteins, only two-hybrid interactions between Calif and hNot2 as well as Calif and KIAA1194 have been described. Components of the complex are believed to be involved in the 5q-syndrome. The 5q syndrome is a myelodysplastic syndrome associated with an interstitial deletion of the WO 03/072602 PCT/EPO2/50003 263 5q31-33 region. Fiedler et al (Fiedler et al, 1999, Genomics 56: 134-136) found that the human POP2 (CALIF) gene is located within this region. The predicted 292-amino-acid human protein shares 75%, 44% and 38% sequence identity with mouse Cafl, C.elegans Cafl and yeast POP2, respectively. Northern blot analysis revealed that human POP2 was expressed as an approximately 2,5 kb mRNA in all tissues tested. The authors concluded that POP2 is a candidate for the tumor suppressor gene associated with the development of 5q-syndrome. Furthermore, the complex is a potential drug target for the treatment of forms of cancer such as leukaemia and prostate cancer. The complex is a potential entry point for agents affecting the regulation of aging processes. The present invention further relates to complex 149a 1. A protein complex selected from complex (I) and comprising (a) at least one first protein selected from the group consisting of: (i) "CCR4" (SEQ ID No:2587) or a functionally active derivative thereof, or a functionally active fragment thereof, or a homologue thereof, or a variant of "CCR4", the variant being encoded by a nucleic acid that hybridizes to the "CCR4" nucleic acid (SEQ ID No:2588) or its complement under low stringency conditions, (ii) "CDC36" (SEQ ID No:2589) or a functionally active derivative thereof, or a functionally active fragment thereof, or a homologue thereof, or a variant of "CDC36", the variant being encoded by a nucleic acid that hybridizes to the "CDC36" nucleic acid (SEQ ID No:2590 ) or its complement under low stringency conditions, (iii) "CDC39" (SEQ ID No:1695) or a functionally active derivative thereof, or a functionally active fragment thereof, or a homologue thereof, or a variant of "CDC39", the variant being encoded by a nucleic acid that hybridizes to the "CDC39" nucleic acid (SEQ ID No:1696 ) or its complement under low stringency conditions, (iv) "COP1" (SEQ ID No:2379) or a functionally active derivative thereof, or a functionally active fragment thereof, or a homologue thereof, or a variant of "COP1", the variant being encoded by a nucleic acid that hybridizes to the "COP1" nucleic acid (SEQ ID No:2380) or its complement under low stringency conditions, (v) "NOT3" (SEQ ID No:2591) or a functionally active derivative thereof, or a functionally active fragment thereof, or a homologue thereof, or a variant of "NOT3", the variant being WO 03/072602 PCT/EPO2/50003 264 encoded by a nucleic acid that hybridizes to the "NOT3" nucleic acid (SEQ ID No:2592) or its complement under low stringency conditions, (vi) "NOT5" (SEQ ID No:2593) or a functionally active derivative thereof, or a functionally active fragment thereof, or a homologue thereof, or a variant of"NOT5", the variant being encoded by a nucleic acid that hybridizes to the "NOT5" nucleic acid (SEQ ID No:2594) or its complement under low stringency conditions, (vii) "POLl" (SEQ ID No:2595) or a functionally active derivative thereof, or a functionally active fragment thereof, or a homologue thereof, or a variant of "POLl", the variant being encoded by a nucleic acid that hybridizes to the "POLl" nucleic acid (SEQ ID No:2596) or its complement under low stringency conditions, (viii) "POL12" (SEQ ID No:2597) or a functionally active derivative thereof, or a functionally active fragment thereof, or a homologue thereof, or a variant of "POL12", the variant being encoded by a nucleic acid that hybridizes to the "POL12" nucleic acid (SEQ ID No:2598 ) or its complement under low stringency conditions, (ix) "POP2" (SEQ ID No:2599) or a functionally active derivative thereof, or a functionally active fragment thereof, or a homologue thereof, or a variant of "POP2", the variant being encoded by a nucleic acid that hybridizes to the "POP2" nucleic acid (SEQ ID No:2600) or its complement under low stringency conditions, (x) "PRII" (SEQ ID No:2601) or a functionally active derivative thereof, or a functionally active fragment thereof, or a homologue thereof, or a variant of "PRII", the variant being encoded by a nucleic acid that hybridizes to the "PRII" nucleic acid (SEQ ID No:2602) or its complement under low stringency conditions, (xi) "PRI2" (SEQ ID No:2603) or a functionally active derivative thereof, or a functionally active fragment thereof, or a homologue thereof, or a variant of "PRI2", the variant being encoded by a nucleic acid that hybridizes to the "PRI2" nucleic acid (SEQ ID No:2604) or its complement under low stringency conditions, (xii) "SEC27" (SEQ ID No:1245) or a functionally active derivative thereof, or a functionally active fragment thereof, or a homologue thereof, or a variant of "SEC27", the variant being encoded by a nucleic acid that hybridizes to the "SEC27" nucleic acid (SEQ ID No:1246 ) or its complement under low stringency conditions, and (xiii) "SIG1" (SEQ ID No:2605) or a functionally active derivative thereof, or a functionally active fragment thereof, or a homologue thereof, or a variant of "SIG1", the variant being encoded by a nucleic acid that hybridizes to the "SIGI" nucleic acid (SEQ ID No:2606 ) or its complement under low stringency conditions, WO 03/072602 PCT/EPO2/50003 265 and (b) at least one second protein, which second protein is selected from the group consisting of: (i) "ATP1 1" (SEQ ID No:2607) or a functionally active derivative thereof, or a functionally active fragment thereof, or a homologue thereof, or a variant of "ATP 11", the variant being encoded by a nucleic acid that hybridizes to the "ATPII" nucleic acid (SEQ ID No:2608 ) or its complement under low stringency conditions, (ii) "CAF1 30" (SEQ ID No:2609) or a functionally active derivative thereof, or a functionally active fragment thereof, or a homologue thereof, or a variant of "CAF130", the variant being encoded by a nucleic acid that hybridizes to the "CAF130" nucleic acid (SEQ ID No:2610 ) or its complement under low stringency conditions, (iii) "CAF40" (SEQ ID No:2611) or a functionally active derivative thereof, or a functionally active fragment thereof, or a homologue thereof, or a variant of "CAF40", the variant being encoded by a nucleic acid that hybridizes to the "CAF40" nucleic acid (SEQ ID No:2612) or its complement under low stringency conditions, (iv) "CCT6" (SEQ ID No:347) or a functionally active derivative thereof, or a functionally active fragment thereof, or a homologue thereof, or a variant of "CCT6", the variant being encoded by a nucleic acid that hybridizes to the "CCT6" nucleic acid (SEQ ID No:348 ) or its complement under low stringency conditions, (v) "FAS2" (SEQ ID No:573) or a functionally active derivative thereof, or a functionally active fragment thereof, or a homologue thereof, or a variant of "FAS2", the variant being encoded by a nucleic acid that hybridizes to the "FAS2" nucleic acid (SEQ ID No:574 ) or its complement under low stringency conditions, (vi) "GCN1" (SEQ ID No:853) or a functionally active derivative thereof, or a functionally active fragment thereof, or a homologue thereof, or a variant of "GCN1", the variant being encoded by a nucleic acid that hybridizes to the "GCNI" nucleic acid (SEQ ID No:854) or its complement under low stringency conditions, (vii) "PDCI" (SEQ ID No:359) or a functionally active derivative thereof, or a functionally active fragment thereof, or a homologue thereof, or a variant of "PDCI", the variant being encoded by a nucleic acid that hybridizes to the "PDCI" nucleic acid (SEQ ID No:360) or its complement under low stringency conditions, (viii) "RVB2" (SEQ ID No:515) or a functionally active derivative thereof, or a functionally active fragment thereof, or a homologue thereof, or a variant of "RVB2", the variant being WO 03/072602 PCT/EPO2/50003 266 encoded by a nucleic acid that hybridizes to the "RVB2" nucleic acid (SEQ ID No:516 ) or its complement under low stringency conditions, (ix) "SAM1" (SEQ ID No:449) or a functionally active derivative thereof, or a functionally active fragment thereof, or a homologue thereof, or a variant of "SAM1", the variant being encoded by a nucleic acid that hybridizes to the "SAM1" nucleic acid (SEQ ID No:450) or its complement under low stringency conditions, (x) "TFC7" (SEQ ID No:9) or a functionally active derivative thereof, or a functionally active fragment thereof, or a homologue thereof, or a variant of "TFC7", the variant being encoded by a nucleic acid that hybridizes to the "TFC7" nucleic acid (SEQ ID No:10 ) or its complement under low stringency conditions, (xi) "VMAI" (SEQ ID No:275) or a functionally active derivative thereof, or a functionally active fragment thereof, or a homologue thereof, or a variant of "VMAI", the variant being encoded by a nucleic acid that hybridizes to the "VMAI" nucleic acid (SEQ ID No:276 ) or its complement under low stringency conditions, (xii) "YDR214W" (SEQ ID No:337) or a functionally active derivative thereof, or a functionally active fragment thereof, or a homologue thereof, or a variant of "YDR214W", the variant being encoded by a nucleic acid that hybridizes to the "YDR214W" nucleic acid (SEQ ID No:338 ) or its complement under low stringency conditions, and (xiii) "YRAI" (SEQ ID No:1195) or a functionally active derivative thereof, or a functionally active fragment thereof, or a homologue thereof, or a variant of "YRAI", the variant being encoded by a nucleic acid that hybridizes to the "YRAI" nucleic acid (SEQ ID No:1196) or its complement under low stringency conditions, and a complex (II) comprising at least two of said second proteins, wherein said low stringency conditions comprise hybridization in a buffer comprising 35% formamide, 5X SSC, 50 mM Tris-HCI (pH 7.5), 5 mM EDTA, 0.02% PVP, 0.02% Ficoll, 0.2% BSA, 100 ug/ml denatured salmon sperm DNA, and 10% (wt/vol) dextran sulfate for 18-20 hours at 400 C, washing in a buffer consisting of 2X SSC, 25 mM Tris-HCI (pH 7.4), 5 mM EDTA, and 0.1 % SDS for 1.5 hours at 550 C, and washing in a buffer consisting of 2X SSC, 25 mM Tris-HCI (pH 7.4), 5 mM EDTA, and 0.1% SDS for 1.5 hours at 600 C. 2. The protein complex comprising the following proteins: (i) "ATPI 1" (SEQ ID No:2607) or a functionally active derivative thereof, or a functionally active fragment thereof, or a homologue thereof, or a variant of "ATP11", the variant WO 03/072602 PCT/EPO2/50003 267 being encoded by a nucleic acid that hybridizes to the "ATP11" nucleic acid (SEQ ID No:2608 ) or its complement under low stringency conditions, (ii) "CAF130" (SEQ ID No:2609) or a functionally active derivative thereof, or a functionally active fragment thereof, or a homologue thereof, or a variant of "CAF130", the variant being encoded by a nucleic acid that hybridizes to the "CAF130" nucleic acid (SEQ ID No:2610 ) or its complement under low stringency conditions, (iii) "CAF40" (SEQ ID No:2611) or a functionally active derivative thereof, or a functionally active fragment thereof, or a homologue thereof, or a variant of "CAF40", the variant being encoded by a nucleic acid that hybridizes to the "CAF40" nucleic acid (SEQ ID No:2612) or its complement under low stringency conditions, (iv) "CCR4" (SEQ ID No:2587) or a functionally active derivative thereof, or a functionally active fragment thereof, or a homologue thereof, or a variant of "CCR4", the variant being encoded by a nucleic acid that hybridizes to the "CCR4" nucleic acid (SEQ ID No:2588 ) or its complement under low stringency conditions, (v) "CCT6" (SEQ ID No:347) or a functionally active derivative thereof, or a functionally active fragment thereof, or a homologue thereof, or a variant of "CCT6", the variant being encoded by a nucleic acid that hybridizes to the "CCT6" nucleic acid (SEQ ID No:348 ) or its complement under low stringency conditions, (vi) "CDC36" (SEQ ID No:2589) or a functionally active derivative thereof, or a functionally active fragment thereof, or a homologue thereof, or a variant of "CDC36", the variant being encoded by a nucleic acid that hybridizes to the "CDC36" nucleic acid (SEQ ID No:2590 ) or its complement under low stringency conditions, (vii) "CDC39" (SEQ ID No:1695) or a functionally active derivative thereof, or a functionally active fragment thereof, or a homologue thereof, or a variant of "CDC39", the variant being encoded by a nucleic acid that hybridizes to the "CDC39" nucleic acid (SEQ ID No:1696 ) or its complement under low stringency conditions, (viii) "COP1" (SEQ ID No:2379) or a functionally active derivative thereof, or a functionally active fragment thereof, or a homologue thereof, or a variant of "COP1", the variant being encoded by a nucleic acid that hybridizes to the "COP1" nucleic acid (SEQ ID No:2380 ) or its complement under low stringency conditions, (ix) "FAS2" (SEQ ID No:573) or a functionally active derivative thereof, or a functionally active fragment thereof, or a homologue thereof, or a variant of "FAS2", the variant being encoded by a nucleic acid that hybridizes to the "FAS2" nucleic acid (SEQ ID No:574 ) or its complement under low stringency conditions, WO 03/072602 PCT/EPO2/50003 268 (x) "GCNI" (SEQ ID No:853) or a functionally active derivative thereof, or a functionally active fragment thereof, or a homologue thereof, or a variant of "GCNI1", the variant being encoded by a nucleic acid that hybridizes to the "GCN 1" nucleic acid (SEQ ID No:854) or its complement under low stringency conditions, (xi) "NOT3" (SEQ ID No:2591) or a functionally active derivative thereof, or a functionally active fragment thereof, or a homologue thereof, or a variant of "NOT3", the variant being encoded by a nucleic acid that hybridizes to the "NOT3" nucleic acid (SEQ ID No:2592) or its complement under low stringency conditions, (xii) "NOT5" (SEQ ID No:2593) or a functionally active derivative thereof, or a functionally active fragment thereof, or a homologue thereof, or a variant of "NOT5", the variant being encoded by a nucleic acid that hybridizes to the "NOT5" nucleic acid (SEQ ID No:2594) or its complement under low stringency conditions, (xiii) "PDCI" (SEQ ID No:359) or a functionally active derivative thereof, or a functionally active fragment thereof, or a homologue thereof, or a variant of "PDCI", the variant being encoded by a nucleic acid that hybridizes to the "PDC1" nucleic acid (SEQ ID No:360) or its complement under low stringency conditions, (xiv) "POLl" (SEQ ID No:2595) or a functionally active derivative thereof, or a functionally active fragment thereof, or a homologue thereof, or a variant of "POLl", the variant being encoded by a nucleic acid that hybridizes to the "POLl" nucleic acid (SEQ ID No:2596 ) or its complement under low stringency conditions, (xv) "POL12" (SEQ ID No:2597) or a functionally active derivative thereof, or a functionally active fragment thereof, or a homologue thereof, or a variant of "POLl 2", the variant being encoded by a nucleic acid that hybridizes to the "POLl 2" nucleic acid (SEQ ID No:2598 ) or its complement under low stringency conditions, (xvi) "POP2" (SEQ ID No:2599) or a functionally active derivative thereof, or a functionally active fragment thereof, or a homologue thereof, or a variant of "POP2", the variant being encoded by a nucleic acid that hybridizes to the "POP2" nucleic acid (SEQ ID No:2600 ) or its complement under low stringency conditions, (xvii) "PRII" (SEQ ID No:2601) or a functionally active derivative thereof, or a functionally active fragment thereof, or a homologue thereof, or a variant of "PRII", the variant being encoded by a nucleic acid that hybridizes to the "PRII" nucleic acid (SEQ ID No:2602) or its complement under low stringency conditions, (xviii) "PRI2" (SEQ ID No:2603) or a functionally active derivative thereof, or a functionally active fragment thereof, or a homologue thereof, or a variant of "PRI2", the WO 03/072602 PCT/EPO2/50003 269 variant being encoded by a nucleic acid that hybridizes to the "PRI2" nucleic acid (SEQ ID No:2604) or its complement under low stringency conditions, (xix) "RVB2" (SEQ ID No:515) or a functionally active derivative thereof, or a functionally active fragment thereof, or a homologue thereof, or a variant of "RVB2", the variant being encoded by a nucleic acid that hybridizes to the "RVB2" nucleic acid (SEQ ID No:516 ) or its complement under low stringency conditions, (xx) "SAM1" (SEQ ID No:449) or a functionally active derivative thereof, or a functionally active fragment thereof, or a homologue thereof, or a variant of "SAM1", the variant being encoded by a nucleic acid that hybridizes to the "SAM1" nucleic acid (SEQ ID No:450) or its complement under low stringency conditions, (xxi) "SEC27" (SEQ ID No:1245) or a functionally active derivative thereof, or a functionally active fragment thereof, or a homologue thereof, or a variant of "SEC27", the variant being encoded by a nucleic acid that hybridizes to the "SEC27" nucleic acid (SEQ ID No:1246 ) or its complement under low stringency conditions, (xxii) "SIG1" (SEQ ID No:2605) or a functionally active derivative thereof, or a functionally active fragment thereof, or a homologue thereof, or a variant of "SIGI", the variant being encoded by a nucleic acid that hybridizes to the "SIGI" nucleic acid (SEQ ID No:2606 ) or its complement under low stringency conditions, (xxiii) "TFC7" (SEQ ID No:9) or a functionally active derivative thereof, or a functionally active fragment thereof, or a homologue thereof, or a variant of "TFC7", the variant being encoded by a nucleic acid that hybridizes to the "TFC7" nucleic acid (SEQ ID No:10 ) or its complement under low stringency conditions, (xxiv) "VMAI" (SEQ ID No:275) or a functionally active derivative thereof, or a functionally active fragment thereof, or a homologue thereof, or a variant of "VMA1", the variant being encoded by a nucleic acid that hybridizes to the "VMAI" nucleic acid (SEQ ID No:276) or its complement under low stringency conditions, (xxv) "YDR214W" (SEQ ID No:337) or a functionally active derivative thereof, or a functionally active fragment thereof, or a homologue thereof, or a variant of "YDR214W", the variant being encoded by a nucleic acid that hybridizes to the "YDR214W" nucleic acid (SEQ ID No:338 ) or its complement under low stringency conditions, and (xxvi) "YRAI" (SEQ ID No:1195) or a functionally active derivative thereof, or a functionally active fragment thereof, or a homologue thereof, or a variant of "YRAI", the variant being encoded by a nucleic acid that hybridizes to the "YRAI" nucleic acid (SEQ ID No:1196 ) or its complement under low stringency conditions,.

WO 03/072602 PCT/EPO2/50003 270 3. The protein complex according to No. 1 comprising all but 1 - 12 of the following proteins: (i) "ATP 11" (SEQ ID No:2607) or a functionally active derivative thereof, or a functionally active fragment thereof, or a homologue thereof, or a variant of "ATP11", the variant being encoded by a nucleic acid that hybridizes to the "ATP11" nucleic acid (SEQ ID No:2608) or its complement under low stringency conditions, (ii) "CAF130" (SEQ ID No:2609) or a functionally active derivative thereof, or a functionally active fragment thereof, or a homologue thereof, or a variant of "CAF130", the variant being encoded by a nucleic acid that hybridizes to the "CAF130" nucleic acid (SEQ ID No:2610 ) or its complement under low stringency conditions, (iii) "CAF40" (SEQ ID No:2611) or a functionally active derivative thereof, or a functionally active fragment thereof, or a homologue thereof, or a variant of "CAF40", the variant being encoded by a nucleic acid that hybridizes to the "CAF40" nucleic acid (SEQ ID No:2612 ) or its complement under low stringency conditions, (iv) "CCR4" (SEQ ID No:2587) or a functionally active derivative thereof, or a functionally active fragment thereof, or a homologue thereof, or a variant of "CCR4", the variant being encoded by a nucleic acid that hybridizes to the "CCR4" nucleic acid (SEQ ID No:2588) or its complement under low stringency conditions, (v) "CCT6" (SEQ ID No:347) or a functionally active derivative thereof, or a functionally active fragment thereof, or a homologue thereof, or a variant of "CCT6", the variant being encoded by a nucleic acid that hybridizes to the "CCT6" nucleic acid (SEQ ID No:348 ) or its complement under low stringency conditions, (vi) "CDC36" (SEQ ID No:2589) or a functionally active derivative thereof, or a functionally active fragment thereof, or a homologue thereof, or a variant of "CDC36", the variant being encoded by a nucleic acid that hybridizes to the "CDC36" nucleic acid (SEQ ID No:2590 ) or its complement under low stringency conditions, (vii) "CDC39" (SEQ ID No:1695) or a functionally active derivative thereof, or a functionally active fragment thereof, or a homologue thereof, or a variant of "CDC39", the variant being encoded by a nucleic acid that hybridizes to the "CDC39" nucleic acid (SEQ ID No:1696 ) or its complement under low stringency conditions, (viii) "COP1" (SEQ ID No:2379) or a functionally active derivative thereof, or a functionally active fragment thereof, or a homologue thereof, or a variant of "COP1", the WO 03/072602 PCT/EPO2/50003 271 variant being encoded by a nucleic acid that hybridizes to the "COP1" nucleic acid (SEQ ID No:2380 ) or its complement under low stringency conditions, (ix) "FAS2" (SEQ ID No:573) or a functionally active derivative thereof, or a functionally active fragment thereof, or a homologue thereof, or a variant of "FAS2", the variant being encoded by a nucleic acid that hybridizes to the "FAS2" nucleic acid (SEQ I1 No:574 ) or its complement under low stringency conditions, (x) "GCN1" (SEQ ID No:853) or a functionally active derivative thereof, or a functionally active fragment thereof, or a homologue thereof, or a variant of "GCN1", the variant being encoded by a nucleic acid that hybridizes to the "GCNI" nucleic acid (SEQ ID No:854 ) or its complement under low stringency conditions, (xi) "NOT3" (SEQ ID No:2591) or a functionally active derivative thereof, or a functionally active fragment thereof, or a homologue thereof, or a variant of "NOT3", the variant being encoded by a nucleic acid that hybridizes to the "NOT3" nucleic acid (SEQ ID No:2592) or its complement under low stringency conditions, (xii) "NOT5" (SEQ ID No:2593) or a functionally active derivative thereof, or a functionally active fragment thereof, or a homologue thereof, or a variant of "NOT5", the variant being encoded by a nucleic acid that hybridizes to the "NOT5" nucleic acid (SEQ ID No:2594) or its complement under low stringency conditions, (xiii) "PDCI" (SEQ ID No:359) or a functionally active derivative thereof, or a functionally active fragment thereof, or a homologue thereof, or a variant of "PDC1", the variant being encoded by a nucleic acid that hybridizes to the "PDCI" nucleic acid (SEQ ID No:360) or its complement under low stringency conditions, (xiv) "POLl" (SEQ ID No:2595) or a functionally active derivative thereof, or a functionally active fragment thereof, or a homologue thereof, or a variant of "POLl ", the variant being encoded by a nucleic acid that hybridizes to the "POLl" nucleic acid (SEQ ID No:2596) or its complement under low stringency conditions, (xv) "POL12" (SEQ ID No:2597) or a functionally active derivative thereof, or a functionally active fragment thereof, or a homologue thereof, or a variant of "POL12", the variant being encoded by a nucleic acid that hybridizes to the "POLl2" nucleic acid (SEQ ID No:2598) or its complement under low stringency conditions, (xvi) "POP2" (SEQ ID No:2599) or a functionally active derivative thereof, or a functionally active fragment thereof, or a homologue thereof, or a variant of "POP2", the variant being encoded by a nucleic acid that hybridizes to the "POP2" nucleic acid (SEQ ID No:2600 ) or its complement under low stringency conditions, WO 03/072602 PCT/EPO2/50003 272 (xvii) "PRII" (SEQ ID No:2601) or a functionally active derivative thereof, or a functionally active fragment thereof, or a homologue thereof, or a variant of "PRIl", the variant being encoded by a nucleic acid that hybridizes to the "PRII" nucleic acid (SEQ ID No:2602) or its complement under low stringency conditions, (xviii) "PRI2" (SEQ ID No:2603) or a functionally active derivative thereof, or a functionally active fragment thereof, or a homologue thereof, or a variant of "PRI2", the variant being encoded by a nucleic acid that hybridizes to the "PRI2" nucleic acid (SEQ ID No:2604) or its complement under low stringency conditions, (xix) "RVB2" (SEQ ID No:515) or a functionally active derivative thereof, or a functionally active fragment thereof, or a homologue thereof, or a variant of "RVB2", the variant being encoded by a nucleic acid that hybridizes to the "RVB2" nucleic acid (SEQ ID No:516 ) or its complement under low stringency conditions, (xx) "SAM1" (SEQ ID No:449) or a functionally active derivative thereof, or a functionally active fragment thereof, or a homologue thereof, or a variant of "SAM1", the variant being encoded by a nucleic acid that hybridizes to the "SAM1" nucleic acid (SEQ ID No:450 ) or its complement under low stringency conditions, (xxi) "SEC27" (SEQ ID No:1245) or a functionally active derivative thereof, or a functionally active fragment thereof, or a homologue thereof, or a variant of "SEC27", the variant being encoded by a nucleic acid that hybridizes to the "SEC27" nucleic acid (SEQ ID No:1246) or its complement under low stringency conditions, (xxii) "SIGI" (SEQ ID No:2605) or a functionally active derivative thereof, or a functionally active fragment thereof, or a homologue thereof, or a variant of "SIG1", the variant being encoded by a nucleic acid that hybridizes to the "SIG1" nucleic acid (SEQ ID No:2606 ) or its complement under low stringency conditions, (xxiii) "TFC7" (SEQ ID No:9) or a functionally active derivative thereof, or a functionally active fragment thereof, or a homologue thereof, or a variant of "TFC7", the variant being encoded by a nucleic acid that hybridizes to the "TFC7" nucleic acid (SEQ ID No:10 ) or its complement under low stringency conditions, (xxiv) "VMAI" (SEQ ID No:275) or a functionally active derivative thereof, or a functionally active fragment thereof, or a homologue thereof, or a variant of "VMAI", the variant being encoded by a nucleic acid that hybridizes to the "VMAI" nucleic acid (SEQ ID No:276 ) or its complement under low stringency conditions, (xxv) "YDR214W" (SEQ ID No:337) or a functionally active derivative thereof, or a functionally active fragment thereof, or a homologue thereof, or a variant of "YDR214W", WO 03/072602 PCT/EPO2/50003 273 the variant being encoded by a nucleic acid that hybridizes to the "YDR214W" nucleic acid (SEQ ID No:338 ) or its complement under low stringency conditions, and (xxvi) "YRAI" (SEQ ID No:1195) or a functionally active derivative thereof, or a functionally active fragment thereof, or a homologue thereof, or a variant of "YRA1", the variant being encoded by a nucleic acid that hybridizes to the "YRA1" nucleic acid (SEQ ID No:1196 ) or its complement under low stringency conditions. 4. The complex of any of No. 1 - 3 comprising a functionally active derivative of said first protein and/or a functionally active derivative of said second protein, wherein the functionally active derivative is a fusion protein comprising said first protein or said second protein fused to an amino acid sequence different from the first protein or second protein, respectively. 5. The complex of No. 4 wherein the functionally active derivative is a fusion protein comprising said first protein or said second protein fused to an affinity tag or label. 6. The complex of any of No. 1 - 3 comprising a fragment of said first protein and/or a fragment of said second protein, which fragment binds to another protein component of said complex. 7. The complex of any of No. 1 -6 that is involved in the DNA endonuclease activity and/or DNA helicase activity and/or RNAse activity. 8. A process for preparing complex of any of No. 1 - 7 and optionally the components thereof comprising the following steps: Expressing a protein (bait) of the complex, preferably the tagged protein, in a target cell, or a tissue or an organ, isolating the protein complex which is attached to the bait protein, and optionally disassociating the protein complex and isolating the individual complex members. 9. The process according to No. 8 wherein the tagged protein comprises two different tags which allow two separate affinity purification steps.

WO 03/072602 PCT/EPO2/50003 274 10. The process according to any of No. 8 - 9 wherein the two tags are separated by a cleavage site for a protease. 11. Component of the CCR4-NOT-subcomplex obtainable by a process according to any of No. 8- 10. 12. Protein of the CCR4-NOT-subcomplex selected from (i) "YDR214W" (SEQ ID No:337) or a functionally active derivative thereof, or a functionally active fragment thereof, or a homologue thereof, or a variant of "YDR214W", the variant being encoded by a nucleic acid that hybridizes to the "YDR214W" nucleic acid (SEQ ID No:338 ) or its complement under low stringency conditions, wherein said low stringency conditions comprise hybridization in a buffer comprising 35% formamide, 5X SSC, 50 mM Tris-HCI (pH 7.5), 5 mM EDTA, 0.02% PVP, 0.02% Ficoll, 0.2% BSA, 100 ug/ml denatured salmon sperm DNA, and 10% (wt/vol) dextran sulfate for 18-20 hours at 400 C, washing in a buffer consisting of 2X SSC, 25 mM Tris-HCI (pH 7.4), 5 mM EDTA, and 0.1 % SDS for 1.5 hours at 55' C, and washing in a buffer consisting of 2X SSC, 25 mM Tris-HCI (pH 7.4), 5 mM EDTA, and 0.1% SDS for 1.5 hours at 600 C. 13. Nucleic acid encoding a protein according to No. 12. 14. Construct, preferably a vector construct, comprising (a) a nucleic acid according to No. 13 and at least one further nucleic acid which is normally not associated with said nucleic acid, or (b) at least two separate nucleic acid sequences each encoding a different protein, or a functionally active fragment or a functionally active derivative thereof at least one of said proteins, or functionally active fragments or functionally active derivative thereof being selected from the first group of proteins according to No. 1 (a) and at least one of said proteins, or functionally active fragments or functionally active derivative thereof being selected from the second group of proteins according to No. 1 (b) or (c)at least two separate nucleic acid sequences each encoding a different protein, or a functionally active fragment or a functionally active derivative thereof, or a homologue or a variant thereof, said proteins being selected from the proteins of complex (11) according to No. 1.

WO 03/072602 PCT/EPO2/50003 275 15. Host cell containing a vector comprising at least the nucleic acid of No. 13 and/or a construct of No. 14 or containing several vectors each comprising at least one nucleic acid sequence encoding at least one of the proteins, or functionally active fragments or functionally active derivatives thereof selected from the first group of proteins according to No. 1(a) and the proteins, or functionally active fragments or functionally active derivatives thereof selected from the second group of proteins according to No. 1(b). 16. An antibody or a fragment of said antibody containing the binding domain thereof, selected from an antibody or fragment thereof, which binds the complex of any of No. 1 7 and which does not bind any of the proteins of said complex when uncomplexed and an antibody or a fragment of said antibody which binds to any of the proteins according to No. 12. 17. A kit comprising in one or more container: (a) the complex of any of No. 1 - 7 and/or the proteins of No. 12 and/or (b) an antibody according to No. 16 and/or (c) a nucleic acid encoding a protein of the complex of any of No. 1 - 7 and/or a protein of No. 12 and/or (d) cells expressing the complex of any of No. 1 - 7 and/or the proteins of No. 12 and optionally (e) further components such as reagents and working instructions. 18. A kit according to No. 17 for processing a substrate of said complex. 19. A kit according to No. 17 for the diagnosis or prognosis of a disease or a disease risk, preferentially for a disease or disorder such as cancer such as leukemia, prostate cancer; target for affecting the regulation of aging processes. 20. Array, preferably a microarray, in which at least a complex according to any of No. 1 7 and/or at least one antibody according to No. 16 is attached to a solid carrier. 21. A process for modifying a physiological substrate of the complex comprising the step of bringing into contact a complex of any of No. 1 - 7 with said substrate, such that said substrate is modified.

WO 03/072602 PCT/EPO2/50003 276 22. A pharmaceutical composition comprising the protein complex of any of No. 1 - 7 and/or any of the following the proteins: (i) "YDR214W" (SEQ ID No:337) or a functionally active derivative thereof, or a functionally active fragment thereof, or a homologue thereof, or a variant of "YDR214W", the variant being encoded by a nucleic acid that hybridizes to the "YDR214W" nucleic acid (SEQ ID No:338 ) or its complement under low stringency conditions, and a pharmaceutical acceptable carrier. 23. A pharmaceutical composition according to No. 22 for the treatment of diseases and disorders such as cancer such as leukemia, prostate cancer; target for affecting the regulation of aging processes. 24. A method for screening for a molecule that binds to a complex of anyone of No. 1 - 7 and/or any of the following proteins: (i) "YDR214W" (SEQ ID No:337) or a functionally active derivative thereof, or a functionally active fragment thereof, or a homologue thereof, or a variant of "YDR214W", the variant being encoded by a nucleic acid that hybridizes to the "YDR214W" nucleic acid (SEQ ID No:338 ) or its complement under low stringency conditions, comprising the steps of (a) exposing said complex, or a cell or organism containing same to one or more candidate molecules; and (b) determining whether said candidate molecule is bound to the complex or protein. 25. A method for screening for a molecule that modulates directly or indirectly the function, activity, composition or formation of the complex of any one of No. 1 - 7 comprising the steps of (a) exposing said complex, or a cell or organism containing CCR4-NOT-subcomplex to one or more candidate molecules; and (b) determining the amount of activity of protein components of, and/or intracellular localization of, said complex and/or the transcription level of a gene regulated by the complex and/or the abundance and/or activity of a protein or protein complex dependend on the function of the complex and/or product of a gene dependent on the complex in the presence of the one or more candidate molecules, wherein a change in said amount, WO 03/072602 PCT/EPO2/50003 277 activity, protein components or intracellular localization relative to said amount, activity, protein components and/or intracellular localization and/or a change in the transcription level of a gene dependend on the complex and/or the abundance and/or activity of a protein or protein complex dependent on the function of the complex and/or product of a gene dependent on the complex in the absence of said candidate molecules indicates that the molecule modulates function, activity or composition of said complex. 26. The method of No. 25, wherein the amount of said complex is determined. 27. The method of No. 25, wherein the activity of said complex is determined. 28. The method of No. 27, wherein said determining step comprises isolating from the cell or organism said complex to produce said isolated complex and contacting said isolated complex in the presence or absence of a candidate molecule with a substrate of said complex and determining the processing of said substrate is modified in the presence of said candidate molecule. 29. The method of No. 25, wherein the amount of the individual protein components of said complex are determined. 30. The method of No. 29, wherein said determining step comprises determining whether (i) "ATP11" (SEQ ID No:2607) or a functionally active derivative thereof, or a functionally active fragment thereof, or a homologue thereof, or a variant of "ATP11", the variant being encoded by a nucleic acid that hybridizes to the "ATP1 1" nucleic acid (SEQ ID No:2608) or its complement under low stringency conditions,and/or (ii) "CAF130" (SEQ ID No:2609) or a functionally active derivative thereof, or a functionally active fragment thereof, or a homologue thereof, or a variant of "CAF130", the variant being encoded by a nucleic acid that hybridizes to the "CAF1 30" nucleic acid (SEQ ID No:2610 ) or its complement under low stringency conditions,and/or (iii) "CAF40" (SEQ ID No:2611) or a functionally active derivative thereof, or a functionally active fragment thereof, or a homologue thereof, or a variant of "CAF40", the variant being encoded by a nucleic acid that hybridizes to the "CAF40" nucleic acid (SEQ ID No:2612) or its complement under low stringency conditions,andlor WO 03/072602 PCT/EPO2/50003 278 (iv) "CCR4" (SEQ ID No:2587) or a functionally active derivative thereof, or a functionally active fragment thereof, or a homologue thereof, or a variant of "CCR4", the variant being encoded by a nucleic acid that hybridizes to the "CCR4" nucleic acid (SEQ ID No:2588) or its complement under low stringency conditions,and/or (v) "CCT6" (SEQ ID No:347) or a functionally active derivative thereof, or a functionally active fragment thereof, or a homologue thereof, or a variant of "CCT6", the variant being encoded by a nucleic acid that hybridizes to the "CCT6" nucleic acid (SEQ ID No:348 ) or its complement under low stringency conditions,and/or (vi) "CDC36" (SEQ ID No:2589) or a functionally active derivative thereof, or a functionally active fragment thereof, or a homologue thereof, or a variant of "CDC36", the variant being encoded by a nucleic acid that hybridizes to the "CDC36" nucleic acid (SEQ ID No:2590 ) or its complement under low stringency conditions,and/or (vii) "CDC39" (SEQ ID No:1695) or a functionally active derivative thereof, or a functionally active fragment thereof, or a homologue thereof, or a variant of "CDC39", the variant being encoded by a nucleic acid that hybridizes to the "CDC39" nucleic acid (SEQ ID No:1696 ) or its complement under low stringency conditions,and/or (viii) "COP1" (SEQ ID No:2379) or a functionally active derivative thereof, or a functionally active fragment thereof, or a homologue thereof, or a variant of "COP1", the variant being encoded by a nucleic acid that hybridizes to the "COP1" nucleic acid (SEQ ID No:2380 ) or its complement under low stringency conditions,and/or (ix) "FAS2" (SEQ ID No:573) or a functionally active derivative thereof, or a functionally active fragment thereof, or a homologue thereof, or a variant of "FAS2", the variant being encoded by a nucleic acid that hybridizes to the "FAS2" nucleic acid (SEQ ID No:574 ) or its complement under low stringency conditions,and/or (x) "GCN1" (SEQ ID No:853) or a functionally active derivative thereof, or a functionally active fragment thereof, or a homologue thereof, or a variant of "GCNI1", the variant being encoded by a nucleic acid that hybridizes to the "GCNI" nucleic acid (SEQ ID No:854) or its complement under low stringency conditions,and/or (xi) "NOT3" (SEQ ID No:2591) or a functionally active derivative thereof, or a functionally active fragment thereof, or a homologue thereof, or a variant of "NOT3", the variant being encoded by a nucleic acid that hybridizes to the "NOT3" nucleic acid (SEQ ID No:2592) or its complement under low stringency conditions,and/or (xii) "NOT5" (SEQ ID No:2593) or a functionally active derivative thereof, or a functionally active fragment thereof, or a homologue thereof, or a variant of "NOT5", the variant being WO 03/072602 PCT/EPO2/50003 279 encoded by a nucleic acid that hybridizes to the "NOT5" nucleic acid (SEQ ID No:2594) or its complement under low stringency conditions,and/or (xiii) "PDC1" (SEQ ID No:359) or a functionally active derivative thereof, or a functionally active fragment thereof, or a homologue thereof, or a variant of "PDC1", the variant being encoded by a nucleic acid that hybridizes to the "PDC1" nucleic acid (SEQ ID No:360) or its complement under low stringency conditions,and/or (xiv) "POLl" (SEQ ID No:2595) or a functionally active derivative thereof, or a functionally active fragment thereof, or a homologue thereof, or a variant of "POLl", the variant being encoded by a nucleic acid that hybridizes to the "POLl" nucleic acid (SEQ ID No:2596 ) or its complement under low stringency conditions,and/or (xv) "POLI2" (SEQ ID No:2597) or a functionally active derivative thereof, or a functionally active fragment thereof, or a homologue thereof, or a variant of "POLl 2", the variant being encoded by a nucleic acid that hybridizes to the "POLl12" nucleic acid (SEQ ID No:2598) or its complement under low stringency conditions,and/or (xvi) "POP2" (SEQ ID No:2599) or a functionally active derivative thereof, or a functionally active fragment thereof, or a homologue thereof, or a variant of "POP2", the variant being encoded by a nucleic acid that hybridizes to the "POP2" nucleic acid (SEQ ID No:2600 ) or its complement under low stringency conditions,and/or (xvii) "PRII" (SEQ ID No:2601) or a functionally active derivative thereof, or a functionally active fragment thereof, or a homologue thereof, or a variant of "PRII1", the variant being encoded by a nucleic acid that hybridizes to the "PRII" nucleic acid (SEQ ID No:2602) or its complement under low stringency conditions,and/or (xviii) "PRI2" (SEQ ID No:2603) or a functionally active derivative thereof, or a functionally active fragment thereof, or a homdologue thereof, or a variant of "PRI2", the variant being encoded by a nucleic acid that hybridizes to the "PRI2" nucleic acid (SEQ ID No:2604) or its complement under low stringency conditions,and/or (xix) "RVB2" (SEQ ID No:515) or a functionally active derivative thereof, or a functionally active fragment thereof, or a homologue thereof, or a variant of "RVB2", the variant being encoded by a nucleic acid that hybridizes to the "RVB2" nucleic acid (SEQ ID No:516) or its complement under low stringency conditions,and/or (xx) "SAMI1" (SEQ ID No:449) or a functionally active derivative thereof, or a functionally active fragment thereof, or a homologue thereof, or a variant of "SAM 1", the variant being encoded by a nucleic acid that hybridizes to the "SAM1" nucleic acid (SEQ ID No:450 ) or its complement under low stringency conditions,and/or WO 03/072602 PCT/EPO2/50003 280 (xxi) "SEC27" (SEQ ID No:1245) or a functionally active derivative thereof, or a functionally active fragment thereof, or a homologue thereof, or a variant of "SEC27", the variant being encoded by a nucleic acid that hybridizes to the "SEC27" nucleic acid (SEQ ID No:1246) or its complement under low stringency conditions,and/or (xxii) "SIGI" (SEQ ID No:2605) or a functionally active derivative thereof, or a functionally active fragment thereof, or a homologue thereof, or a variant of "SIG1", the variant being encoded by a nucleic acid that hybridizes to the "SIGI" nucleic acid (SEQ ID No:2606 ) or its complement under low stringency conditions,and/or (xxiii) "TFC7" (SEQ ID No:9) or a functionally active derivative thereof, or a functionally active fragment thereof, or a homologue thereof, or a variant of "TFC7", the variant being encoded by a nucleic acid that hybridizes to the "TFC7" nucleic acid (SEQ ID No:10) or its complement under low stringency conditions,and/or (xxiv) "VMAI" (SEQ ID No:275) or a functionally active derivative thereof, or a functionally active fragment thereof, or a homologue thereof, or a variant of "VMAI", the variant being encoded by a nucleic acid that hybridizes to the "VMA1" nucleic acid (SEQ ID No:276 ) or its complement under low stringency conditions,andlor (xxv) "YDR214W" (SEQ ID No:337) or a functionally active derivative thereof, or a functionally active fragment thereof, or a homologue thereof, or a variant of "YDR214W", the variant being encoded by a nucleic acid that hybridizes to the "YDR214W" nucleic acid (SEQ ID No:338 ) or its complement under low stringency conditions, and/or (xxvi) "YRAI" (SEQ ID No:1195) or a functionally active derivative thereof, or a functionally active fragment thereof, or a homologue thereof, or a variant of "YRA1", the variant being encoded by a nucleic acid that hybridizes to the "YRAI" nucleic acid (SEQ ID No:1196) or its complement under low stringency conditions, is present in the complex. 31. The method of any of No. 25 - 30, wherein said method is a method of screening for a drug for treatment or prevention of a disease or disorder such as cancer such as leukemia, prostate cancer; target for affecting the regulation of aging processes. 32. Use of a molecule that modulates the amount of, activity of, or the protein components of the complex of any one of No. 1 - 7 for the manufacture of a medicament for the treatment or prevention of a disease or disorder such as cancer such as leukemia, prostate cancer; target for affecting the regulation of aging processes.

WO 03/072602 PCT/EPO2/50003 281 33. A method for the production of a pharmaceutical composition comprising carrying out the method of any of No. 1 - 7 to identify a molecule that modulates the function, activity, composition or formation of said complex, and further comprising mixing the identified molecule with a pharmaceutically acceptable carrier. 34. A method for diagnosing or screening for the presence of a disease or disorder or a predisposition for developing a disease or disorder in a subject, which disease or disorder is characterized by an aberrant amount of, activity of, or component composition of, or intracellular localization of the complex of any one of the No. 1 - 7, comprising determining the amount of, activity of, protein components of, and/or intracellular localization of, said complex and/or the transcription level of a gene dependend on the complex and/or the abundance and/or activity of a protein or protein complex dependend on the function of the complex and/or product of a gene dependent on the complex in a comparative sample derived from a subject, wherein a difference in said amount, activity, or protein components of, said complex in a corresponding sample from a subject not having the disease or disorder or predisposition indicates the presence in the subject of the disease or disorder or predisposition in the subject. 35. The method of No. 34, wherein the amount of said complex is determined. 36. The method of No. 34, wherein the activity of said complex is determined. 37. The method of No. 36, wherein said determining step comprises isolating from the subject said complex to produce said isolated complex and contacting said isolated complex in the presence or absence of a candidate molecule with a substrate of said complex and determining whether said substrate is processed in the absence of the candidate molecule and whether the processing of said substrate is modified in the presence of said candidate molecule. 38. The method of No. 34, wherein the amount of the individual protein components of said complex are determined.

WO 03/072602 PCT/EPO2/50003 282 39. The method of No. 38, wherein said determining step comprises determining whether (i) "ATP11" (SEQ ID No:2607) or a functionally active derivative thereof, or a functionally active fragment thereof, or a homologue thereof, or a variant of "ATP11", the variant being encoded by a nucleic acid that hybridizes to the "ATP11" nucleic acid (SEQ ID No:2608 ) or its complement under low stringency conditions, and/or (ii) "CAF130" (SEQ ID No:2609) or a functionally active derivative thereof, or a functionally active fragment thereof, or a homologue thereof, or a variant of "CAF130", the variant being encoded by a nucleic acid that hybridizes to the "CAF1 30" nucleic acid (SEQ ID No:2610 ) or its complement under low stringency conditions, and/or (iii) "CAF40" (SEQ ID No:2611) or a functionally active derivative thereof, or a functionally active fragment thereof, or a homologue thereof, or a variant of "CAF40", the variant being encoded by a nucleic acid that hybridizes to the "CAF40" nucleic acid (SEQ ID No:2612 ) or its complement under low stringency conditions, and/or (iv) "CCR4" (SEQ ID No:2587) or a functionally active derivative thereof, or a functionally active fragment thereof, or a homologue thereof, or a variant of "CCR4", the variant being encoded by a nucleic acid that hybridizes to the "CCR4" nucleic acid (SEQ ID No:2588) or its complement under low stringency conditions, and/or (v) "CCT6" (SEQ ID No:347) or a functionally active derivative thereof, or a functionally active fragment thereof, or a homologue thereof, or a variant of "CCT6", the variant being encoded by a nucleic acid that hybridizes to the "CCT6" nucleic acid (SEQ ID No:348 ) or its complement under low stringency conditions, and/or (vi) "CDC36" (SEQ ID No:2589) or a functionally active derivative thereof, or a functionally active fragment thereof, or a homologue thereof, or a variant of "CDC36", the variant being encoded by a nucleic acid that hybridizes to the "CDC36" nucleic acid (SEQ ID No:2590 ) or its complement under low stringency conditions, and/or (vii) "CDC39" (SEQ ID No:1695) or a functionally active derivative thereof, or a functionally active fragment thereof, or a homologue thereof, or a variant of "CDC39", the variant being encoded by a nucleic acid that hybridizes to the "CDC39" nucleic acid (SEQ ID No:1696 ) or its complement under low stringency conditions, and/or (viii) "COP1" (SEQ ID No:2379) or a functionally active derivative thereof, or a functionally active fragment thereof, or a homologue thereof, or a variant of "COP1", the variant being encoded by a nucleic acid that hybridizes to the "COP1" nucleic acid (SEQ ID No:2380 ) or its complement under low stringency conditions, and/or WO 03/072602 PCT/EPO2/50003 283 (ix) "FAS2" (SEQ ID No:573) or a functionally active derivative thereof, or a functionally active fragment thereof, or a homologue thereof, or a variant of "FAS2", the variant being encoded by a nucleic acid that hybridizes to the "FAS2" nucleic acid (SEQ ID No:574) or its complement under low stringency conditions, and/or (x) "GCNI" (SEQ ID No:853) or a functionally active derivative thereof, or a functionally active fragment thereof, or a homologue thereof, or a variant of "GCNI", the variant being encoded by a nucleic acid that hybridizes to the "GCNI" nucleic acid (SEQ ID No:854 ) or its complement under low stringency conditions, and/or (xi) "NOT3" (SEQ ID No:2591) or a functionally active derivative thereof, or a functionally active fragment thereof, or a homologue thereof, or a variant of "NOT3", the variant being encoded by a nucleic acid that hybridizes to the "NOT3" nucleic acid (SEQ ID No:2592) or its complement under low stringency conditions, and/or (xii) "NOT5" (SEQ ID No:2593) or a functionally active derivative thereof, or a functionally active fragment thereof, or a homologue thereof, or a variant of "NOT5", the variant being encoded by a nucleic acid that hybridizes to the "NOT5" nucleic acid (SEQ ID No:2594) or its complement under low stringency conditions, and/or (xiii) "PDCI" (SEQ ID No:359) or a functionally active derivative thereof, or a functionally active fragment thereof, or a homologue thereof, or a variant of "PDC1 ", the variant being encoded by a nucleic acid that hybridizes to the "PDCI" nucleic acid (SEQ ID No:360) or its complement under low stringency conditions, and/or (xiv) "POLl" (SEQ ID No:2595) or a functionally active derivative thereof, or a functionally active fragment thereof, or a homologue thereof, or a variant of "POLl", the variant being encoded by a nucleic acid that hybridizes to the "POLl" nucleic acid (SEQ ID No:2596 ) or its complement under low stringency conditions, and/or (xv) "POL12" (SEQ ID No:2597) or a functionally active derivative thereof, or a functionally active fragment thereof, or a homologue thereof, or a variant of "POLl2", the variant being encoded by a nucleic acid that hybridizes to the "POL12" nucleic acid (SEQ ID No:2598 ) or its complement under low stringency conditions, and/or (xvi) "POP2" (SEQ ID No:2599) or a functionally active derivative thereof, or a functionally active fragment thereof, or a homologue thereof, or a variant of "POP2", the variant being encoded by a nucleic acid that hybridizes to the "POP2" nucleic acid (SEQ ID No:2600 ) or its complement under low stringency conditions, and/or (xvii) "PRII" (SEQ ID No:2601) or a functionally active derivative thereof, or a functionally active fragment thereof, or a homologue thereof, or a variant of "PRIl", the variant being WO 03/072602 PCT/EPO2/50003 284 encoded by a nucleic acid that hybridizes to the "PRII" nucleic acid (SEQ ID No:2602) or its complement under low stringency conditions, and/or (xviii) "PRI2" (SEQ ID No:2603) or a functionally active derivative thereof, or a functionally active fragment thereof, or a homologue thereof, or a variant of "PRI2", the variant being encoded by a nucleic acid that hybridizes to the "PRI2" nucleic acid (SEQ ID No:2604 ) or its complement under low stringency conditions, and/or (xix) "RVB2" (SEQ ID No:515) or a functionally active derivative thereof, or a functionally active fragment thereof, or a homologue thereof, or a variant of "RVB2", the variant being encoded by a nucleic acid that hybridizes to the "RVB2" nucleic acid (SEQ ID No:516 ) or its complement under low stringency conditions, and/or (xx) "SAM1" (SEQ ID No:449) or a functionally active derivative thereof, or a functionally active fragment thereof, or a homologue thereof, or a variant of "SAM1", the variant being encoded by a nucleic acid that hybridizes to the "SAM1" nucleic acid (SEQ ID No:450 ) or its complement under low stringency conditions, and/or (xxi) "SEC27" (SEQ ID No:1245) or a functionally active derivative thereof, or a functionally active fragment thereof, or a homologue thereof, or a variant of "SEC27", the variant being encoded by a nucleic acid that hybridizes to the "SEC27" nucleic acid (SEQ ID No:1246 ) or its complement under low stringency conditions, and/or (xxii) "SIG1" (SEQ ID No:2605) or a functionally active derivative thereof, or a functionally active fragment thereof, or a homologue thereof, or a variant of "SIG1", the variant being encoded by a nucleic acid that hybridizes to the "SIGI" nucleic acid (SEQ ID No:2606 ) or its complement under low stringency conditions, and/or (xxiii) "TFC7" (SEQ ID No:9) or a functionally active derivative thereof, or a functionally active fragment thereof, or a homologue thereof, or a variant of "TFC7", the variant being encoded by a nucleic acid that hybridizes to the "TFC7" nucleic acid (SEQ ID No:10 ) or its complement under low stringency conditions, and/or (xxiv) "VMA1" (SEQ ID No:275) or a functionally active derivative thereof, or a functionally active fragment thereof, or a homologue thereof, or a variant of "VMAI1", the variant being encoded by a nucleic acid that hybridizes to the "VMAI" nucleic acid (SEQ ID No:276 ) or its complement under low stringency conditions, and/or (xxv) "YDR214W" (SEQ ID No:337) or a functionally active derivative thereof, or a functionally active fragment thereof, or a homologue thereof, or a variant of "YDR214W", the variant being encoded by a nucleic acid that hybridizes to the "YDR214W" nucleic acid (SEQ ID No:338) or its complement under low stringency conditions, and/or WO 03/072602 PCT/EPO2/50003 285 (xxvi) "YRAI" (SEQ ID No:1195) or a functionally active derivative thereof, or a functionally active fragment thereof, or a homologue thereof, or a variant of "YRAI", the variant being encoded by a nucleicacid that hybridizes to the "YRA1" nucleic acid (SEQ ID No:1196) or its complement under low stringency conditions, is present in the complex. 40. The complex of any one of No. 1 - 7, or proteins of No. 12 or the antibody or fragment of No. 16, for use in a method of diagnosing a disease or disorder such as cancer such as leukemia, prostate cancer; target for affecting the regulation of aging processes. 41. A method for treating or preventing a disease or disorder characterized by an aberrant amount of, activity or component composition of or intracellular localization of, the complex of anyone of No. 1 - 7, comprising administering to a subject in need of such treatment or prevention a therapeutically effective amount of one or more molecules that modulate the amount of, DNA endonuclease activity and/or DNA helicase activity and/or RNAse activity, or protein composition of, said complex. 42. The method according to No. 41, wherein said disease or disorder involves decreased levels of the amount or activity of said complex. 43. The method according to No. 41 , wherein said disease or disorder involves increased levels of the amount or activity of said complex. 44. Complex of any of No. 1 - 7 and/or protein selected from the following proteins (i) "ATP 11" (SEQ ID No:2607) or a functionally active derivative thereof, or a functionally active fragment thereof, or a homologue thereof, or a variant of "ATP11", the variant being encoded by a nucleic acid that hybridizes to the "ATP 11" nucleic acid (SEQ ID No:2608) or its complement under low stringency conditions,and (ii) "CAF130" (SEQ ID No:2609) or a functionally active derivative thereof, or a functionally active fragment thereof, or a homologue thereof, or a variant of "CAF130", the variant being encoded by a nucleic acid that hybridizes to the "CAF130" nucleic acid (SEQ ID No:2610 ) or its complement under low stringency conditions,and WO 03/072602 PCT/EPO2/50003 286 (iii) "CAF40" (SEQ ID No:2611) or a functionally active derivative thereof, or a functionally active fragment thereof, or a homologue thereof, or a variant of "CAF40", the variant being encoded by a nucleic acid that hybridizes to the "CAF40" nucleic acid (SEQ ID No:2612 ) or its complement under low stringency conditions,and (iv) "CCR4" (SEQ ID No:2587) or a functionally active derivative thereof, or a functionally active fragment thereof, or a homologue thereof, or a variant of "CCR4", the variant being encoded by a nucleic acid that hybridizes to the "CCR4" nucleic acid (SEQ ID No:2588 ) or its complement under low stringency conditions,and (v) "CCT6" (SEQ ID No:347) or a functionally active derivative thereof, or a functionally active fragment thereof, or a homologue thereof, or a variant of "CCT6", the variant being encoded by a nucleic acid that hybridizes to the "CCT6" nucleic acid (SEQ ID No:348 ) or its complement under low stringency conditions,and (vi) "CDC36" (SEQ ID No:2589) or a functionally active derivative thereof, or a functionally active fragment thereof, or a homologue thereof, or a variant of "CDC36", the variant being encoded by a nucleic acid that hybridizes to the "CDC36" nucleic acid (SEQ ID No:2590 ) or its complement under low stringency conditions,and (vii) "CDC39" (SEQ ID No:1695) or a functionally active derivative thereof, or a functionally active fragment thereof, or a homologue thereof, or a variant of "CDC39", the variant being encoded by a nucleic acid that hybridizes to the "CDC39" nucleic acid (SEQ ID No:1696 ) or its complement under low stringency conditions,and (viii) "COP1" (SEQ ID No:2379) or a functionally active derivative thereof, or a functionally active fragment thereof, or a homologue thereof, or a variant of "COP1", the variant being encoded by a nucleic acid that hybridizes to the "COP1" nucleic acid (SEQ ID No:2380 ) or its complement under low stringency conditions,and (ix) "FAS2" (SEQ ID No:573) or a functionally active derivative thereof, or a functionally active fragment thereof, or a homologue thereof, or a variant of "FAS2", the variant being encoded by a nucleic acid that hybridizes to the "FAS2" nucleic acid (SEQ ID No:574 ) or its complement under low stringency conditions,and (x) "GCNI" (SEQ ID No:853) or a functionally active derivative thereof, or a functionally active fragment thereof, or a homologue thereof, or a variant of "GCN1", the variant being encoded by a nucleic acid that hybridizes to the "GCNI" nucleic acid (SEQ ID No:854) or its complement under low stringency conditions,and (xi) "NOT3" (SEQ ID No:2591) or a functionally active derivative thereof, or a functionally active fragment thereof, or a homologue thereof, or a variant of "NOT3", the variant being WO 03/072602 PCT/EPO2/50003 287 encoded by a nucleic acid that hybridizes to the "NOT3" nucleic acid (SEQ ID No:2592) or its complement under low stringency conditions,and (xii) "NOT5" (SEQ ID No:2593) or a functionally active derivative thereof, or a functionally active fragment thereof, or a homologue thereof, or a variant of "NOT5", the variant being encoded by a nucleic acid that hybridizes to the "NOT5" nucleic acid (SEQ ID No:2594) or its complement under low stringency conditions,and (xiii) "PDCI" (SEQ ID No:359) or a functionally active derivative thereof, or a functionally active fragment thereof, or a homologue thereof, or a variant of "PDCI ", the variant being encoded by a nucleic acid that hybridizes to the "PDCI" nucleic acid (SEQ ID No:360) or its complement under low stringency conditions,and (xiv) "POLl" (SEQ ID No:2595) or a functionally active derivative thereof, or a functionally active fragment thereof, or a homologue thereof, or a variant of "POLl", the variant being encoded by a nucleic acid that hybridizes to the "POLl" nucleic acid (SEQ ID No:2596 ) or its complement under low stringency conditions,and (xv) "POLl2" (SEQ ID No:2597) or a functionally active derivative thereof, or a functionally active fragment thereof, or a homologue thereof, or a variant of "POL12", the variant being encoded by a nucleic acid that hybridizes to the "POL12" nucleic acid (SEQ ID No:2598 ) or its complement under low stringency conditions,and (xvi) "POP2" (SEQ ID No:2599) or a functionally active derivative thereof, or a functionally active fragment thereof, or a homologue thereof, or a variant of "POP2", the variant being encoded by a nucleic acid that hybridizes to the "POP2" nucleic acid (SEQ ID No:2600 ) or its complement under low stringency conditions,and (xvii) "PRII" (SEQ ID No:2601) or a functionally active derivative thereof, or a functionally active fragment thereof, or a homologue thereof, or a variant of "PRII", the variant being encoded by a nucleic acid that hybriizes to the "PRII" nucleic acid (SEQ ID No:2602) or its complement under low stringency conditions,and (xviii) "PRI2" (SEQ ID No:2603) or a functionally active derivative thereof, or a functionally active fragment thereof, or a homologue thereof, or a variant of "PRI2", the variant being encoded by a nucleic acid that hybridizes to the "PRI2" nucleic acid (SEQ ID No:2604) or its complement under low stringency conditions,and (xix) "RVB2" (SEQ ID No:515) or a functionally active derivative thereof, or a functionally active fragment thereof, or a homologue thereof, or a variant of "RVB2", the variant being encoded by a nucleic acid that hybridizes to the "RVB2" nucleic acid (SEQ ID No:516 ) or its complement under low stringency conditions,and WO 03/072602 PCT/EPO2/50003 288 (xx) "SAM1" (SEQ ID No:449) or a functionally active derivative thereof, or a functionally active fragment thereof, or a homologue thereof, or a variant of "SAM1", the variant being encoded by a nucleic acid that hybridizes to the "SAM1" nucleic acid (SEQ ID No:450 ) or its complement under low stringency conditions,and (xxi) "SEC27" (SEQ ID No:1245) or a functionally active derivative thereof, or a functionally active fragment thereof, or a homologue thereof, or a variant of "SEC27", the variant being encoded by a nucleic acid that hybridizes to the "SEC27" nucleic acid (SEQ ID No:1246 ) or its complement under low stringency conditions,and (xxii) "SIGI" (SEQ ID No:2605) or a functionally active derivative thereof, or a functionally active fragment thereof, or a homologue thereof, or a variant of "SIGI", the variant being encoded by a nucleic acid that hybridizes to the "SIGI" nucleic acid (SEQ ID No:2606 ) or its complement under low stringency conditions,and (xxiii) "TFC7" (SEQ ID No:9) or a functionally active derivative thereof, or a functionally active fragment thereof, or a homologue thereof, or a variant of "TFC7", the variant being encoded by a nucleic acid that hybridizes to the "TFC7" nucleic acid (SEQ ID No:10 ) or its complement under low stringency conditions,and (xxiv) "VMAI" (SEQ ID No:275) or a functionally active derivative thereof, or a functionally active fragment thereof, or a homologue thereof, or a variant of "VMAI", the variant being encoded by a nucleic acid that hybridizes to the "VMAI" nucleic acid (SEQ ID No:276) or its complement under low stringency conditions,and (xxv) "YDR214W" (SEQ ID No:337) or a functionally active derivative thereof, or a functionally active fragment thereof, or a homologue thereof, or a variant of "YDR214W", the variant being encoded by a nucleic acid that hybridizes to the "YDR214W" nucleic acid (SEQ ID No:338 ) or its complement under low stringency conditions, and/or (xxvi) "YRA1" (SEQ ID No:1195) or a functionally active derivative thereof, or a functionally active fragment thereof, or a homologue thereof, or a variant of "YRAI", the variant being encoded by a nucleic acid that hybridizes to the "YRAI" nucleic acid (SEQ ID No:1196) or its complement under low stringency conditions, as a target for an active agent of a pharmaceutical, preferably a drug target in the treatment or prevention of a disease or disorder such as cancer such as leukemia, prostate cancer; target for affecting the regulation of aging processes. The present invention further relates to complex 149b WO 03/072602 PCT/EPO2/50003 289 1. A protein complex selected from complex (I) and comprising (a) at least one first protein selected from the group consisting of: (i) "CCR4" (SEQ ID No:2587) or a functionally active derivative thereof, or a functionally active fragment thereof, or a homologue thereof, or a variant of "CCR4", the variant being encoded by a nucleic acid that hybridizes to the "CCR4" nucleic acid (SEQ ID No:2588) or its complement under low stringency conditions, (ii) "CDC39" (SEQ ID No:1695) or a functionally active derivative thereof, or a functionally active fragment thereof, or a homologue thereof, or a variant of "CDC39", the variant being encoded by a nucleic acid that hybridizes to the "CDC39" nucleic acid (SEQ ID No:1696) or its complement under low stringency conditions, (iii) "NOT3" (SEQ ID No:2591) or a functionally active derivative thereof, or a functionally active fragment thereof, or a homologue thereof, or a variant of "NOT3", the variant being encoded by a nucleic acid that hybridizes to the "NOT3" nucleic acid (SEQ ID No:2592) or its complement under low stringency conditions, (iv) "POLl" (SEQ ID No:2595) or a functionally active derivative thereof, or a functionally active fragment thereof, or a homologue thereof, or a variant of "POLl", the variant being encoded by a nucleic acid that hybridizes to the "POLl" nucleic acid (SEQ ID No:2596) or its complement under low stringency conditions, (v) "POL12" (SEQ ID No:2597) or a functionally active derivative thereof, or a functionally active fragment thereof, or a homologue thereof, or a variant of "POL12", the variant being encoded by a nucleic acid that hybridizes to the "POL12" nucleic acid (SEQ ID No:2598) or its complement under low stringency conditions, (vi) "POP2" (SEQ ID No:2599) or a functionally active derivative thereof, or a functionally active fragment thereof, or a homologue thereof, or a variant of "POP2", the variant being encoded by a nucleic acid that hybridizes to the "POP2" nucleic acid (SEQ ID No:2600) or its complement under low stringency conditions, (vii) "PRIl" (SEQ ID No:2601) or a functionally active derivative thereof, or a functionally active fragment thereof, or a homologue thereof, or a variant of "PRII", the variant being encoded by a nucleic acid that hybridizes to the "PRIl" nucleic acid (SEQ ID No:2602) or its complement under low stringency conditions, (viii) "PRI2" (SEQ ID No:2603) or a functionally active derivative thereof, or a functionally active fragment thereof, or a homologue thereof, or a variant of "PRI2", the variant being encoded by a nucleic acid that hybridizes to the "PRI2" nucleic acid (SEQ ID No:2604) or its complement under low stringency conditions, and WO 03/072602 PCT/EPO2/50003 290 (ix) "SIGI" (SEQ ID No:2605) or a functionally active derivative thereof, or a functionally active fragment thereof, or a homologue thereof, or a variant of "SIGI", the variant being encoded by a nucleic acid that hybridizes to the "SIGI" nucleic acid (SEQ ID No:2606) or its complement under low stringency conditions, and (b) at least one second protein, which second protein is selected from the group consisting of: (i) "APG9" (SEQ ID No:2323) or a functionally active derivative thereof, or a functionally active fragment thereof, or a homologue thereof, or a variant of "APG9", the variant being encoded by a nucleic acid that hybridizes to the "APG9" nucleic acid (SEQ ID No:2324) or its complement under low stringency conditions, (ii) "CAF130" (SEQ ID No:2609) or a functionally active derivative thereof, or a functionally active fragment thereof, or a homologue thereof, or a variant of "CAF130", the variant being encoded by a nucleic acid that hybridizes to the "CAF130" nucleic acid (SEQ ID No:2610 ) or its complement under low stringency conditions, (iii) "CAF40" (SEQ ID No:2611) or a functionally active derivative thereof, or a functionally active fragment thereof, or a homologue thereof, or a variant of "CAF40", the variant being encoded by a nucleic acid that hybridizes to the "CAF40" nucleic acid (SEQ ID No:2612 ) or its complement under low stringency conditions, (iv) "CCT6" (SEQ ID No:347) or a functionally active derivative thereof, or a functionally active fragment thereof, or a homologue thereof, or a variant of "CCT6", the variant being encoded by a nucleic acid that hybridizes to the "CCT6" nucleic acid (SEQ ID No:348 ) or its complement under low stringency conditions, (v) "FAS2" (SEQ ID No:573) or a functionally active derivative thereof, or a functionally active fragment thereof, or a homologue thereof, or a variant of "FAS2", the variant being encoded by a nucleic acid that hybridizes to the "FAS2" nucleic acid (SEQ ID No:574 ) or its complement under low stringency conditions, (vi) "GBP2" (SEQ ID No:189) or a functionally active derivative thereof, or a functionally active fragment thereof, or a homologue thereof, or a variant of "GBP2", the variant being encoded by a nucleic acid that hybridizes to the "GBP2" nucleic acid (SEQ ID No:190) or its complement under low stringency conditions, (vii) "KEMI" (SEQ ID No:141) or a functionally active derivative thereof, or a functionally active fragment thereof, or a homologue thereof, or a variant of "KEM1", the variant WO 03/072602 PCT/EPO2/50003 291 being encoded by a nucleic acid that hybridizes to the "KEM1" nucleic acid (SEQ ID No:142) or its complement under low stringency conditions, (viii) "SAM1" (SEQ ID No:449) or a functionally active derivative thereof, or a functionally active fragment thereof, or a homologue thereof, or a variant of "SAM1", the variant being encoded by a nucleic acid that hybridizes to the "SAM1" nucleic acid (SEQ ID No:450 ) or its complement under low stringency conditions, (ix) "TFC7" (SEQ ID No:9) or a functionally active derivative thereof, or a functionally active fragment thereof, or a homologue thereof, or a variant of "TFC7", the variant being encoded by a nucleic acid that hybridizes to the "TFC7" nucleic acid (SEQ ID No:10 ) or its complement under low stringency conditions, (x) "VMAI" (SEQ ID No:275) or a functionally active derivative thereof, or a functionally active fragment thereof, or a homologue thereof, or a variant of "VMAI", the variant being encoded by a nucleic acid that hybridizes to the "VMAI" nucleic acid (SEQ ID No:276 ) or its complement under low stringency conditions, (xi) "YDR214W" (SEQ ID No:337) or a functionally active derivative thereof, or a functionally active fragment thereof, or a homologue thereof, or a variant of "YDR214W", the variant being encoded by a nucleic acid that hybridizes to the "YDR214W" nucleic acid (SEQ ID No:338 ) or its complement under low stringency conditions, and (xii) "YRAI" (SEQ ID No:1195) or a functionally active derivative thereof, or a functionally active fragment thereof, or a homologue thereof, or a variant of "YRA1", the variant being encoded by a nucleic acid that hybridizes to the "YRAI" nucleic acid (SEQ ID No:1196) or its complement under low stringency conditions, and a complex (11) comprising at least two of said second proteins, wherein said low stringency conditions comprise hybridization in a buffer comprising 35% formamide, 5X SSC, 50 mM Tris-HCI (pH 7.5), 5 mM EDTA, 0.02% PVP, 0.02% Ficoll, 0.2% BSA, 100 ug/ml denatured salmon sperm DNA, and 10% (wt/vol) dextran sulfate for 18-20 hours at 400 C, washing in a buffer consisting of 2X SSC, 25 mM Tris-HCI (pH 7.4), 5 mM EDTA, and 0.1 % SDS for 1.5 hours at 550 C, and washing in a buffer consisting of 2X SSC, 25 mM Tris-HCI (pH 7.4), 5 mM EDTA, and 0.1% SDS for 1.5 hours at 600 C. 2. The protein complex comprising the following proteins: (i) "APG9" (SEQ ID No:2323) or a functionally active derivative thereof, or a functionally active fragment thereof, or a homologue thereof, or a variant of "APG9", the variant being WO 03/072602 PCT/EPO2/50003 292 encoded by a nucleic acid that hybridizes to the "APG9" nucleic acid (SEQ ID No:2324) or its complement under low stringency conditions, (ii) "CAF130" (SEQ ID No:2609) or a functionally active derivative thereof, or a functionally active fragment thereof, or a homologue thereof, or a variant of "CAF130", the variant being encoded by a nucleic acid that hybridizes to the "CAF130" nucleic acid (SEQ ID No:2610 ) or its complement under low stringency conditions, (iii) "CAF40" (SEQ ID No:2611) or a functionally active derivative thereof, or a functionally active fragment thereof, or a homologue thereof, or a variant of "CAF40", the variant being encoded by a nucleic acid that hybridizes to the "CAF40" nucleic acid (SEQ ID No:2612) or its complement under low stringency conditions, (iv) "CCR4" (SEQ ID No:2587) or a functionally active derivative thereof, or a functionally active fragment thereof, or a homologue thereof, or a variant of "CCR4", the variant being encoded by a nucleic acid that hybridizes to the "CCR4" nucleic acid (SEQ ID No:2588) or its complement under low stringency conditions, (v) "CCT6" (SEQ ID No:347) or a functionally active derivative thereof, or a functionally active fragment thereof, or a homologue thereof, or a variant of "CCT6", the variant being encoded by a nucleic acid that hybridizes to the "CCT6" nucleic acid (SEQ ID No:348 ) or its complement under low stringency conditions, (vi) "CDC39" (SEQ ID No:1695) or a functionally active derivative thereof, or a functionally active fragment thereof, or a homologue thereof, or a variant of "CDC39", the variant being encoded by a nucleic acid that hybridizes to the "CDC39" nucleic acid (SEQ ID No:1696 ) or its complement under low stringency conditions, (vii) "FAS2" (SEQ ID No:573) or a functionally active derivative thereof, or a functionally active fragment thereof, or a homologue thereof, or a variant of "FAS2", the variant being encoded by a nucleic acid that hybridizes to the "FAS2" nucleic acid (SEQ ID No:574 ) or its complement under low stringency conditions, (viii) "GBP2" (SEQ ID No:189) or a functionally active derivative thereof, or a functionally active fragment thereof, or a homologue thereof, or a variant of "GBP2", the variant being encoded by a nucleic acid that hybridizes to the "GBP2" nucleic acid (SEQ ID No:190) or its complement under low stringency conditions, (ix) "KEMI" (SEQ ID No:141) or a functionally active derivative thereof, or a functionally active fragment thereof, or a homologue thereof, or a variant of "KEM 1", the variant being encoded by a nucleic acid that hybridizes to the "KEMI" nucleic acid (SEQ ID No:142) or its complement under low stringency conditions, WO 03/072602 PCT/EPO2/50003 293 (x) "NOT3" (SEQ ID No:2591) or a functionally active derivative thereof, or a functionally active fragment thereof, or a homologue thereof, or a variant of "NOT3", the variant being encoded by a nucleic acid that hybridizes to the "NOT3" nucleic acid (SEQ ID No:2592) or its complement under low stringency conditions, (xi) "POLl" (SEQ ID No:2595) or a functionally active derivative thereof, or a functionally active fragment thereof, or a homologue thereof, or a variant of "POLl", the variant being encoded by a nucleic acid that hybridizes to the "POLl" nucleic acid (SEQ ID No:2596) or its complement under low stringency conditions, (xii) "POL12" (SEQ ID No:2597) or a functionally active derivative thereof, or a functionally active fragment thereof, or a homologue thereof, or a variant of "POL12", the variant being encoded by a nucleic acid that hybridizes to the "POL12" nucleic acid (SEQ ID No:2598 ) or its complement under low stringency conditions, (xiii) "POP2" (SEQ ID No:2599) or a functionally active derivative thereof, or a functionally active fragment thereof, or a homologue thereof, or a variant of "POP2", the variant being encoded by a nucleic acid that hybridizes to the "POP2" nucleic acid (SEQ ID No:2600 ) or its complement under low stringency conditions, (xiv) "PRII" (SEQ ID No:2601) or a functionally active derivative thereof, or a functionally active fragment thereof, or a homologue thereof, or a variant of "PRII", the variant being encoded by a nucleic acid that hybridizes to the "PRII" nucleic acid (SEQ ID No:2602) or its complement under low stringency conditions, (xv) "PRI2" (SEQ ID No:2603) or a functionally active derivative thereof, or a functionally active fragment thereof, or a homologue thereof, or a variant of "PRI2", the variant being encoded by a nucleic acid that hybridizes to the "PRI2" nucleic acid (SEQ ID No:2604) or its complement under low stringency conditions, (xvi) "SAM1" (SEQ ID No:449) or a functionally active derivative thereof, or a functionally active fragment thereof, or a homologue thereof, or a variant of "SAM1", the variant being encoded by a nucleic acid that hybridizes to the "SAM1" nucleic acid (SEQ ID No:450 ) or its complement under low stringency conditions, (xvii) "SIGI" (SEQ ID No:2605) or a functionally active derivative thereof, or a functionally active fragment thereof, or a homologue thereof, or a variant of "SIG1I", the variant being encoded by a nucleic acid that hybridizes to the "SIG " nucleic acid (SEQ ID No:2606 ) or its complement under low stringency conditions, (xviii) "TFC7" (SEQ ID No:9) or a functionally active derivative thereof, or a functionally active fragment thereof, or a homologue thereof, or a variant of "TFC7", the variant being WO 03/072602 PCT/EPO2/50003 294 encoded by a nucleic acid that hybridizes to the "TFC7" nucleic acid (SEQ ID No:10 ) or its complement under low stringency conditions, (xix) "VMAI" (SEQ ID No:275) or a functionally active derivative thereof, or a functionally active fragment thereof, or a homologue thereof, or a variant of "VMAI ", the variant being encoded by a nucleic acid that hybridizes to the "VMAI" nucleic acid (SEQ ID No:276) or its complement under low stringency conditions, (xx) "YDR214W" (SEQ ID No:337) or a functionally active derivative thereof, or a functionally active fragment thereof, or a homologue thereof, or a variant of "YDR214W", the variant being encoded by a nucleic acid that hybridizes to the "YDR214W" nucleic acid (SEQ ID No:338 ) or its complement under low stringency conditions, and (xxi) "YRAI" (SEQ ID No:1195) or a functionally active derivative thereof, or a functionally active fragment thereof, or a homologue thereof, or a variant of "YRAI", the variant being encoded by a nucleic acid that hybridizes to the "YRAI" nucleic acid (SEQ ID No:1196 ) or its complement under low stringency conditions,. 3. The protein complex according to No. 1 comprising all but 1 - 11 of the following proteins: (i) "APG9" (SEQ ID No:2323) or a functionally active derivative thereof, or a functionally active fragment thereof, or a homologue thereof, or a variant of "APG9", the variant being encoded by a nucleic acid that hybridizes to the "APG9" nucleic acid (SEQ ID No:2324) or its complement under low stringency conditions, (ii) "CAF130" (SEQ ID No:2609) or a functionally active derivative thereof, or a functionally active fragment thereof, or a homologue thereof, or a variant of "CAF130", the variant being encoded by a nucleic acid that hybridizes to the "CAF130" nucleic acid (SEQ ID No:2610 ) or its complement under low stringency conditions, (iii) "CAF40" (SEQ ID No:2611) or a functionally active derivative thereof, or a functionally active fragment thereof, or a homologue thereof, or a variant of "CAF40", the variant being encoded by a nucleic acid that hybridizes to the "CAF40" nucleic acid (SEQ ID No:2612 ) or its complement under low stringency conditions, (iv) "CCR4" (SEQ ID No:2587) or a functionally active derivative thereof, or a functionally active fragment thereof, or a homologue thereof, or a variant of "CCR4", the variant being encoded by a nucleic acid that hybridizes to the "CCR4" nucleic acid (SEQ ID No:2588) or its complement under low stringency conditions, WO 03/072602 PCT/EPO2/50003 295 (v) "CCT6" (SEQ ID No:347) or a functionally active derivative thereof, or a functionally active fragment thereof, or a homologue thereof, or a variant of "CCT6", the variant being encoded by a nucleic acid that hybridizes to the "CCT6" nucleic acid (SEQ ID No:348) or its complement under low stringency conditions, (vi) "CDC39" (SEQ ID No:1695) or a functionally active derivative thereof, or a functionally active fragment thereof, or a homologue thereof, or a variant of "CDC39", the variant being encoded by a nucleic acid that hybridizes to the "CDC39" nucleic acid (SEQ ID No:1696) or its complement under low stringency conditions, (vii) "FAS2" (SEQ ID No:573) or a functionally active derivative thereof, or a functionally active fragment thereof, or a homologue thereof, or a variant of "FAS2", the variant being encoded by a nucleic acid that hybridizes to the "FAS2" nucleic acid (SEQ ID No:574) or its complement under low stringency conditions, (viii) "GBP2" (SEQ ID No:189) or a functionally active derivative thereof, or a functionally active fragment thereof, or a homologue thereof, or a variant of "GBP2", the variant being encoded by a nucleic acid that hybridizes to the "GBP2" nucleic acid (SEQ ID No:190) or its complement under low stringency conditions, (ix) "KEMI" (SEQ ID No:141) or a functionally active derivative thereof, or a functionally active fragment thereof, or a homologue thereof, or a variant of "KEM1", the variant being encoded by a nucleic acid that hybridizes to the "KEM 1" nucleic acid (SEQ ID No:142) or its complement under low stringency conditions, (x) "NOT3" (SEQ ID No:2591) or a functionally active derivative thereof, or a functionally active fragment thereof, or a homologue thereof, or a variant of "NOT3", the variant being encoded by a nucleic acid that hybridizes to the "NOT3" nucleic acid (SEQ ID No:2592) or its complement under low stringency conditions, (xi) "POLl" (SEQ ID No:2595) or a functionally active derivative thereof, or a functionally active fragment thereof, or a homologue thereof, or a variant of "POLl", the variant being encoded by a nucleic acid that hybridizes to the "POLl" nucleic acid (SEQ ID No:2596) or its complement under low stringency conditions, (xii) "POL12" (SEQ ID No:2597) or a functionally active derivative thereof, or a functionally active fragment thereof, or a homologue thereof, or a variant of "POLl 2", the variant being encoded by a nucleic acid that hybridizes to the "POLI2" nucleic acid (SEQ ID No:2598) or its complement under low stringency conditions, (xiii) "POP2" (SEQ ID No:2599) or a functionally active derivative thereof, or a functionally active fragment thereof, or a homologue thereof, or a variant of "POP2", the WO 03/072602 PCT/EPO2/50003 296 variant being encoded by a nucleic acid that hybridizes to the "POP2" nucleic acid (SEQ ID No:2600 ) or its complement under low stringency conditions, (xiv) "PRII" (SEQ ID No:2601) or a functionally active derivative thereof, or a functionally active fragment thereof, or a homologue thereof, or a variant of "PRII", the variant being encoded by a nucleic acid that hybridizes to the "PRII" nucleic acid (SEQ ID No:2602) or its complement under low stringency conditions, (xv) "PRI2" (SEQ ID No:2603) or a functionally active derivative thereof, or a functionally active fragment thereof, or a homologue thereof, or a variant of "PRI2", the variant being encoded by a nucleic acid that hybridizes to the "PRI2" nucleic acid (SEQ ID No:2604) or its complement under low stringency conditions, (xvi) "SAM1" (SEQ ID No:449) or a functionally active derivative thereof, or a functionally active fragment thereof, or a homologue thereof, or a variant of "SAM1", the variant being encoded by a nucleic acid that hybridizes to the "SAM1" nucleic acid (SEQ ID No:450 ) or its complement under low stringency conditions, (xvii) "SIG1" (SEQ ID No:2605) or a functionally active derivative thereof, or a functionally active fragment thereof, or a homologue thereof, or a variant of "SIG1", the variant being encoded by a nucleic acid that hybridizes to the "SIGI1" nucleic acid (SEQ ID No:2606 ) or its complement under low stringency conditions, (xviii) "TFC7" (SEQ ID No:9) or a functionally active derivative thereof, or a functionally active fragment thereof, or a homologue thereof, or a variant of "TFC7", the variant being encoded by a nucleic acid that hybridizes to the "TFC7" nucleic acid (SEQ ID No:10 ) or its complement under low stringency conditions, (xix) "VMAI" (SEQ ID No:275) or a functionally active derivative thereof, or a functionally active fragment thereof, or a homologue thereof, or a variant of "VMAI", the variant being encoded by a nucleic acid that hybridizes to the "VMAI" nucleic acid (SEQ ID No:276 ) or its complement under low stringency conditions, (xx) "YDR214W" (SEQ ID No:337) or a functionally active derivative thereof, or a functionally active fragment thereof, or a homologue thereof, or a variant of "YDR214W", the variant being encoded by a nucleic acid that hybridizes to the "YDR214W" nucleic acid (SEQ ID No:338) or its complement under low stringency conditions, and (xxi) "YRAI" (SEQ ID No:1195) or a functionally active derivative thereof, or a functionally active fragment thereof, or a homologue thereof, or a variant of "YRA1", the variant being encoded by a nucleic acid that hybridizes to the "YRA1" nucleic acid (SEQ ID No:1196 ) or its complement under low stringency conditions.

WO 03/072602 PCT/EPO2/50003 297 4. The complex of any of No. 1 - 3 comprising a functionally active derivative of said first protein and/or a functionally active derivative of said second protein, wherein the functionally active derivative is a fusion protein comprising said first protein or said second protein fused to an amino acid sequence different from the first protein or second protein, respectively. 5. The complex of No. 4 wherein the functionally active derivative is a fusion protein comprising said first protein or said second protein fused to an affinity tag or label. 6. The complex of any of No. 1 - 3 comprising a fragment of said first protein and/or a fragment of said second protein, which fragment binds to another protein component of said complex. 7. The complex of any of No. 1 -6 that is involved in the DNA endonuclease activity; DNA helicase activity; RNAse activity. 8. A process for preparing complex of any of No. 1 - 7 and optionally the components thereof comprising the following steps: Expressing a protein (bait) of the complex, preferably the tagged protein, in a target cell, or a tissue or an organ, isolating the protein complex which is attached to the bait protein, and optionally disassociating the protein complex and isolating the individual complex members. 9. The process according to No. 8 wherein the tagged protein comprises two different tags which allow two separate affinity purification steps. 10. The process according to any of No. 8 - 9 wherein the two tags are separated by a cleavage site for a protease. 11. Component of the CCR4/NOT-sub- complex obtainable by a process according to any of No. 8 - 10. 12. Protein of the CCR4/NOT-sub- complex selected from WO 03/072602 PCT/EPO2/50003 298 (i) "YDR214W" (SEQ ID No:337) or a functionally active derivative thereof, or a functionally active fragment thereof, or a homologue thereof, or a variant of "YDR214W", the variant being encoded by a nucleic acid that hybridizes to the "YDR214W" nucleic acid (SEQ ID No:338) or its complement under low stringency conditions, wherein said low stringency conditions comprise hybridization in a buffer comprising 35% formamide, 5X SSC, 50 mM Tris-HCI (pH 7.5), 5 mM EDTA, 0.02% PVP, 0.02% Ficoll, 0.2% BSA, 100 ug/ml denatured salmon sperm DNA, and 10% (wt/vol) dextran sulfate for 18-20 hours at 400 C, washing in a buffer consisting of 2X SSC, 25 mM Tris-HCI (pH 7.4), 5 mM EDTA, and 0.1 % SDS for 1.5 hours at 550 C, and washing in a buffer consisting of 2X SSC, 25 mM Tris-HCI (pH 7.4), 5 mM EDTA, and 0.1% SDS for 1.5 hours at 600 C. 13. Nucleic acid encoding a protein according to No. 12. 14. Construct, preferably a vector construct, comprising (a) a nucleic acid according to No. 13 and at least one further nucleic acid which is normally not associated with said nucleic acid, or (b) at least two separate nucleic acid sequences each encoding a different protein, or a functionally active fragment or a functionally active derivative thereof at least one of said proteins, or functionally active fragments or functionally active derivative thereof being selected from the first group of proteins according to No. 1 (a) and at least one of said proteins, or functionally active fragments or functionally active derivative thereof being selected from the second group of proteins according to No. 1 (b) or (c)at least two separate nucleic acid sequences each encoding a different protein, or a functionally active fragment or a functionally active derivative thereof, or a homologue or a variant thereof, said proteins being selected from the proteins of complex (11) according to No. 1. 15. Host cell containing a vector comprising at least the nucleic acid of No. 13 and/or a construct of No. 14 or containing several vectors each comprising at least one nucleic acid sequence encoding at least one of the proteins, or functionally active fragments or functionally active derivatives thereof selected from the first group of proteins according to No. 1(a) and the proteins, or functionally active fragments or functionally active derivatives thereof selected from the second group of proteins according to No. 1(b).

WO 03/072602 PCT/EPO2/50003 299 16. An antibody or a fragment of said antibody containing the binding domain thereof, selected from an antibody or fragment thereof, which binds the complex of any of No. 1 7 and which does not bind any of the proteins of said complex when uncomplexed and an antibody or a fragment of said antibody which binds to any of the proteins according to No. 12. 17. A kit comprising in one or more container: (a) the complex of any of No. 1 - 7 and/or the proteins of No. 12 and/or (b) an antibody according to No. 16 and/or (c) a nucleic acid encoding a protein of the complex of any of No. 1 - 7 and/or a protein of No. 12 and/or (d) cells expressing the complex of any of No. 1 - 7 and/or the proteins of No. 12 and optionally (e) further components such as reagents and working instructions. 18. A kit according to No. 17 for processing a substrate of said complex. 19. A kit according to No. 17 for the diagnosis or prognosis of a disease or a disease risk, preferentially for a disease or disorder such as cancer such as leukemia, prostate cancer. 20. Array, preferably a microarray, in which at least a complex according to any of No. 1 7 and/or at least one antibody according to No. 16 is attached to a solid carrier. 21. A process for modifying a physiological substrate of the complex comprising the step of bringing into contact a complex of any of No. 1 - 7 with said substrate, such that said substrate is modified. 22. A pharmaceutical composition comprising the protein complex of any of No. 1 - 7 and/or any of the following the proteins: (i) "YDR214W" (SEQ ID No:337) or a functionally active derivative thereof, or a functionally active fragment thereof, or a homologue thereof, or a variant of "YDR214W", the variant being encoded by a nucleic acid that hybridizes to the "YDR214W" nucleic acid (SEQ ID No:338 ) or its complement under low stringency conditions, WO 03/072602 PCT/EPO2/50003 300 and a pharmaceutical acceptable carrier. 23. A pharmaceutical composition according to No. 22 for the treatment of diseases and disorders such as cancer such as leukemia, prostate cancer. 24. A method for screening for a molecule that binds to a complex of anyone of No. 1 - 7 and/or any of the following proteins: (i) "YDR214W" (SEQ ID No:337) or a functionally active derivative thereof, or a functionally active fragment thereof, or a homologue thereof, or a variant of "YDR214W", the variant being encoded by a nucleic acid that hybridizes to the "YDR214W" nucleic acid (SEQ ID No:338 ) or its complement under low stringency conditions, comprising the steps of (a) exposing said complex, or a cell or organism containing same to one or more candidate molecules; and (b) determining whether said candidate molecule is bound to the complex or protein. 25. A method for screening for a molecule that modulates directly or indirectly the function, activity, composition or formation of the complex of any one of No. 1 - 7 comprising the steps of (a) exposing said complex, or a cell or organism containing CCR4/NOT-sub- complex to one or more candidate molecules; and (b) determining the amount of activity of protein components of, and/or intracellular localization of, said complex and/or the transcription level of a gene regulated by the complex and/or the abundance and/or activity of a protein or protein complex dependend on the function of the complex and/or product of a gene dependent on the complex in the presence of the one or more candidate molecules, wherein a change in said amount, activity, protein components or intracellular localization relative to said amount, activity, protein components and/or intracellular localization and/or a change in the transcription level of a gene dependend on the complex and/or the abundance and/or activity of a protein or protein complex dependent on the function of the complex and/or product of a gene dependent on the complex in the absence of said candidate molecules indicates that the molecule modulates function, activity or composition of said complex. 26. The method of No. 25, wherein the amount of said complex is determined.

WO 03/072602 PCT/EPO2/50003 301 27. The method of No. 25, wherein the activity of said complex is determined. 28. The method of No. 27, wherein said determining step comprises isolating from the cell or organism said complex to produce said isolated complex and contacting said isolated complex in the presence or absence of a candidate molecule with a substrate of said complex and determining the processing of said substrate is modified in the presence of said candidate molecule. 29. The method of No. 25, wherein the amount of the individual protein components of said complex are determined. 30. The method of No. 29, wherein said determining step comprises determining whether (i) "APG9" (SEQ ID No:2323) or a functionally active derivative thereof, or a functionally active fragment thereof, or a homologue thereof, or a variant of "APG9", the variant being encoded by a nucleic acid that hybridizes to the "APG9" nucleic acid (SEQ ID No:2324) or its complement under low stringency conditions,and/or (ii) "CAF130" (SEQ ID No:2609) or a functionally active derivative thereof, or a functionally active fragment thereof, or a homologue thereof, or a variant of "CAF130", the variant being encoded by a nucleic acid that hybridizes to the "CAF130" nucleic acid (SEQ ID No:2610 ) or its complement under low stringency conditions,and/or (iii) "CAF40" (SEQ ID No:2611) or a functionally active derivative thereof, or a functionally active fragment thereof, or a homologue thereof, or a variant of "CAF40", the variant being encoded by a nucleic acid that hybridizes to the "CAF40" nucleic acid (SEQ ID No:2612 ) or its complement under low stringency conditions,and/or (iv) "CCR4" (SEQ ID No:2587) or a functionally active derivative thereof, or a functionally active fragment thereof, or a homologue thereof, or a variant of "CCR4", the variant being encoded by a nucleic acid that hybridizes to the "CCR4" nucleic acid (SEQ ID No:2588) or its complement under low stringency conditions,and/or (v) "CCT6" (SEQ ID No:347) or a functionally active derivative thereof, or a functionally active fragment thereof, or a homologue thereof, or a variant of "CCT6", the variant being encoded by a nucleic acid that hybridizes to the "CCT6" nucleic acid (SEQ ID No:348 ) or its complement under low stringency conditions,and/or WO 03/072602 PCT/EPO2/50003 302 (vi) "CDC39" (SEQ ID No:1695) or a functionally active derivative thereof, or a functionally active fragment thereof, or a homologue thereof, or a variant of "CDC39", the variant being encoded by a nucleic acid that hybridizes to the "CDC39" nucleic acid (SEQ ID No:1696 ) or its complement under low stringency conditions,and/or (vii) "FAS2" (SEQ ID No:573) or a functionally active derivative thereof, or a functionally active fragment thereof, or a homologue thereof, or a variant of "FAS2", the variant being encoded by a nucleic acid that hybridizes to the "FAS2" nucleic acid (SEQ ID No:574) or its complement under low stringency conditions,and/or (viii) "GBP2" (SEQ ID No:189) or a functionally active derivative thereof, or a functionally active fragment thereof, or a homologue thereof, or a variant of "GBP2", the variant being encoded by a nucleic acid that hybridizes to the "GBP2" nucleic acid (SEQ ID No:190) or its complement under low stringency conditions,and/or (ix) "KEMI" (SEQ ID No:141) or a functionally active derivative thereof, or a functionally active fragment thereof, or a homologue thereof, or a variant of "KEM1", the variant being encoded by a nucleic acid that hybridizes to the "KEMI" nucleic acid (SEQ ID No:142 ) or its complement under low stringency conditions,and/or (x) "NOT3" (SEQ ID No:2591) or a functionally active derivative thereof, or a functionally active fragment thereof, or a homologue thereof, or a variant of "NOT3", the variant being encoded by a nucleic acid that hybridizes to the "NOT3" nucleic acid (SEQ ID No:2592) or its complement under low stringency conditions,andlor (xi) "POLl" (SEQ ID No:2595) or a functionally active derivative thereof, or a functionally active fragment thereof, or a homologue thereof, or a variant of "POLl", the variant being encoded by a nucleic acid that hybridizes to the "POLl" nucleic acid (SEQ ID No:2596) or its complement under low stringency conditions,and/or (xii) "POL12" (SEQ ID No:2597) or a functionally active derivative thereof, or a functionally active fragment thereof, or a homologue thereof, or a variant of "POLl 2", the variant being encoded by a nucleic acid that hybridizes to the "POL12" nucleic acid (SEQ ID No:2598) or its complement under low stringency conditions,and/or (xiii) "POP2" (SEQ ID No:2599) or a functionally active derivative thereof, or a functionally active fragment thereof, or a homologue thereof, or a variant of "POP2", the variant being encoded by a nucleic acid that hybridizes to the "POP2" nucleic acid (SEQ ID No:2600) or its complement under low stringency conditions,and/or (xiv) "PRII" (SEQ ID No:2601) or a functionally active derivative thereof, or a functionally active fragment thereof, or a homologue thereof, or a variant of "PRII", the variant being WO 03/072602 PCT/EPO2/50003 303 encoded by a nucleic acid that hybridizes to the "PRII" nucleic acid (SEQ ID No:2602) or its complement under low stringency conditions,and/or (xv) "PRI2" (SEQ ID No:2603) or a functionally active derivative thereof, or a functionally active fragment thereof, or a homologue thereof, or a variant of "PRI2", the variant being encoded by a nucleic acid that hybridizes to the "PRI2" nucleic acid (SEQ ID No:2604) or its complement under low stringency conditions,and/or (xvi) "SAM I" (SEQ ID No:449) or a functionally active derivative thereof, or a functionally active fragment thereof, or a homologue thereof, or a variant of "SAM1", the variant being encoded by a nucleic acid that hybridizes to the "SAM1" nucleic acid (SEQ ID No:450 ) or its complement under low stringency conditions,and/or (xvii) "SIGI" (SEQ ID No:2605) or a functionally active derivative thereof, or a functionally active fragment thereof, or a homologue thereof, or a variant of "SIG1", the variant being encoded by a nucleic acid that hybridizes to the "SIGI" nucleic acid (SEQ ID No:2606 ) or its complement under low stringency conditions,and/or (xviii) "TFC7" (SEQ ID No:9) or a functionally active derivative thereof, or a functionally active fragment thereof, or a homologue thereof, or a variant of "TFC7", the variant being encoded by a nucleic acid that hybridizes to the "TFC7" nucleic acid (SEQ ID No:10 ) or its complement under low stringency conditions,and/or (xix) "VMAI" (SEQ ID No:275) or a functionally active derivative thereof, or a functionally active fragment thereof, or a homologue thereof, or a variant of "VMAI", the variant being encoded by a nucleic acid that hybridizes to the "VMAI" nucleic acid (SEQ ID No:276 ) or its complement under low stringency conditions,and/or (xx) "YDR214W" (SEQ ID No:337) or a functionally active derivative thereof, or a functionally active fragment thereof, or a homologue thereof, or a variant of "YDR214W", the variant being encoded by a nucleic acid that hybridizes to the "YDR214W" nucleic acid (SEQ ID No:338) or its complement under low stringency conditions, and/or (xxi) "YRAI" (SEQ ID No:1195) or a functionally active derivative thereof, or a functionally active fragment thereof, or a homologue thereof, or a variant of "YRAI", the variant being encoded by a nucleic acid that hybridizes to the "YRAI" nucleic acid (SEQ ID No:1196) or its complement under low stringency conditions, is present in the complex.

WO 03/072602 PCT/EPO2/50003 304 31. The method of any of No. 25 - 30, wherein said method is a method of screening for a drug for treatment or prevention of a disease or disorder such as cancer such as leukemia, prostate cancer. 32. Use of a molecule that modulates the amount of, activity of, or the protein components of the complex of any one of No. 1 - 7 for the manufacture of a medicament for the treatment or prevention of a disease or disorder such as cancer such as leukemia, prostate cancer. 33. A method for the production of a pharmaceutical composition comprising carrying out the method of any of No. 1 - 7 to identify a molecule that modulates the function, activity, composition or formation of said complex, and further comprising mixing the identified molecule with a pharmaceutically acceptable carrier. 34. A method for diagnosing or screening for the presence of a disease or disorder or a predisposition for developing a disease or disorder in a subject, which disease or disorder is characterized by an aberrant amount of, activity of, or component composition of, or intracellular localization of the complex of any one of the No. 1 - 7, comprising determining the amount of, activity of, protein components of, and/or intracellular localization of, said complex and/or the transcription level of a gene dependend on the complex and/or the abundance and/or activity of a protein or protein complex dependend on the function of the complex and/or product of a gene dependent on the complex in a comparative sample derived from a subject, wherein a difference in said amount, activity, or protein components of, said complex in a corresponding sample from a subject not having the disease or disorder or predisposition indicates the presence in the subject of the disease or disorder or predisposition in the subject. 35. The method of No. 34, wherein the amount of said complex is determined. 36. The method of No. 34, wherein the activity of said complex is determined. 37. The method of No. 36, wherein said determining step comprises isolating from the subject said complex to produce said isolated complex and contacting said isolated complex in the presence or absence of a candidate molecule with a substrate of said WO 03/072602 PCT/EPO2/50003 305 complex and determining whether said substrate is processed in the absence of the candidate molecule and whether the processing of said substrate is modified in the presence of said candidate molecule. 38. The method of No. 34, wherein the amount of the individual protein components of said complex are determined. 39. The method of No. 38, wherein said determining step comprises determining whether (i) "APG9" (SEQ ID No:2323) or a functionally active derivative thereof, or a functionally active fragment thereof, or a homologue thereof, or a variant of "APG9", the variant being encoded by a nucleic acid that hybridizes to the "APG9" nucleic acid (SEQ ID No:2324) or its complement under low stringency conditions, and/or (ii) "CAF130" (SEQ ID No:2609) or a functionally active derivative thereof, or a functionally active fragment thereof, or a homologue thereof, or a variant of "CAF130", the variant being encoded by a nucleic acid that hybridizes to the "CAF130" nucleic acid (SEQ ID No:2610 ) or its complement under low stringency conditions, and/or (iii) "CAF40" (SEQ ID No:2611) or a functionally active derivative thereof, or a functionally active fragment thereof, or a homologue thereof, or a variant of "CAF40", the variant being encoded by a nucleic acid that hybridizes to the "CAF40" nucleic acid (SEQ ID No:2612) or its complement under low stringency conditions, and/or (iv) "CCR4" (SEQ ID No:2587) or a functionally active derivative thereof, or a functionally active fragment thereof, or a homologue thereof, or a variant of "CCR4", the variant being encoded by a nucleic acid that hybridizes to the "CCR4" nucleic acid (SEQ ID No:2588 ) or its complement under low stringency conditions, and/or (v) "CCT6" (SEQ ID No:347) or a functionally active derivative thereof, or a functionally active fragment thereof, or a homologue thereof, or a variant of "CCT6", the variant being encoded by a nucleic acid that hybridizes to the "CCT6" nucleic acid (SEQ ID No:348 ) or its complement under low stringency conditions, and/or (vi) "CDC39" (SEQ ID No:1695) or a functionally active derivative thereof, or a functionally active fragment thereof, or a homologue thereof, or a variant of "CDC39", the variant being encoded by a nucleic acid that hybridizes to the "CDC39" nucleic acid (SEQ ID No:1696 ) or its complement under low stringency conditions, and/or WO 03/072602 PCT/EPO2/50003 306 (vii) "FAS2" (SEQ ID No:573) or a functionally active derivative thereof, or a functionally active fragment thereof, or a homologue thereof, or a variant of "FAS2", the variant being encoded by a nucleic acid that hybridizes to the "FAS2" nucleic acid (SEQ ID No:574) or its complement under low stringency conditions, and/or (viii) "GBP2" (SEQ ID No:189) or a functionally active derivative thereof, or a functionally active fragment thereof, or a homologue thereof, or a variant of "GBP2", the variant being encoded by a nucleic acid that hybridizes to the "GBP2" nucleic acid (SEQ ID No:190) or its complement under low stringency conditions, and/or (ix) "KEMI" (SEQ ID No:141) or a functionally active derivative thereof, or a functionally active fragment thereof, or a homologue thereof, or a variant of "KEM1", the variant being encoded by a nucleic acid that hybridizes to the "KEMI" nucleic acid (SEQ ID No:142 ) or its complement under low stringency conditions, andlor (x) "NOT3" (SEQ ID No:2591) or a functionally active derivative thereof, or a functionally active fragment thereof, or a homologue thereof, or a variant of "NOT3", the variant being encoded by a nucleic acid that hybridizes to the "NOT3" nucleic acid (SEQ ID No:2592) or its complement under low stringency conditions, and/or (xi) "POLl" (SEQ ID No:2595) or a functionally active derivative thereof, or a functionally active fragment thereof, or a homologue thereof, or a variant of "POLl", the variant being encoded by a nucleic acid that hybridizes to the "POLl" nucleic acid (SEQ ID No:2596) or its complement under low stringency conditions, and/or (xii) "POLI2" (SEQ ID No:2597) or a functionally active derivative thereof, or a functionally active fragment thereof, or a homologue thereof, or a variant of "POLl12", the variant being encoded by a nucleic acid that hybridizes to the "POLl12" nucleic acid (SEQ ID No:2598) or its complement under low stringency conditions, and/or (xiii) "POP2" (SEQ ID No:2599) or a functionally active derivative thereof, or a functionally active fragment thereof, or a homologue thereof, or a variant of "POP2", the variant being encoded by a nucleic acid that hybridizes to the "POP2" nucleic acid (SEQ ID No:2600 ) or its complement under low stringency conditions, and/or (xiv) "PRII" (SEQ ID No:2601) or a functionally active derivative thereof, or a functionally active fragment thereof, or a homologue thereof, or a variant of "PRII", the variant being encoded by a nucleic acid that hybridizes to the "PRII" nucleic acid (SEQ ID No:2602) or its complement under low stringency conditions, and/or (xv) "PRI2" (SEQ ID No:2603) or a functionally active derivative thereof, or a functionally active fragment thereof, or a homologue thereof, or a variant of "PRI2", the variant being WO 03/072602 PCT/EPO2/50003 307 encoded by a nucleic acid that hybridizes to the "PRI2" nucleic acid (SEQ ID No:2604) or its complement under low stringency conditions, and/or (xvi) "SAM1" (SEQ ID No:449) or a functionally active derivative thereof, or a functionally active fragment thereof, or a homologue thereof, or a variant of "SAM1", the variant being encoded by a nucleic acid that hybridizes to the "SAM1" nucleic acid (SEQ ID No:450 ) or its complement under low stringency conditions, and/or (xvii) "SIG1" (SEQ ID No:2605) or a functionally active derivative thereof, or a functionally active fragment thereof, or a homologue thereof, or a variant of "SIGI1", the variant being encoded by a nucleic acid that hybridizes to the "SIGI" nucleic acid (SEQ ID No:2606 ) or its complement under low stringency conditions, and/or (xviii) "TFC7" (SEQ ID No:9) or a functionally active derivative thereof, or a functionally active fragment thereof, or a homologue thereof, or a variant of "TFC7", the variant being encoded by a nucleic acid that hybridizes to the "TFC7" nucleic acid (SEQ ID No:10 ) or its complement under low stringency conditions, and/or (xix) "VMAI" (SEQ ID No:275) or a functionally active derivative thereof, or a functionally active fragment thereof, or a homologue thereof, or a variant of "VMAI", the variant being encoded by a nucleic acid that hybridizes to the "VMAI" nucleic acid (SEQ ID No:276 ) or its complement under low stringency conditions, andlor (xx) "YDR214W" (SEQ ID No:337) or a functionally active derivative thereof, or a functionally active fragment thereof, or a homologue thereof, or a variant of "YDR214W", the variant being encoded by a nucleic acid that hybridizes to the "YDR214W" nucleic acid (SEQ ID No:338 ) or its complement under low stringency conditions, and/or (xxi) "YRAI" (SEQ ID No:1195) or a functionally active derivative thereof, or a functionally active fragment thereof, or a homologue thereof, or a variant of "YRAI", the variant being encoded by a nucleic acid that hybridizes to the "YRAI" nucleic acid (SEQ ID No:1196 ) or its complement under low stringency conditions, is present in the complex. 40. The complex of any one of No. 1 - 7, or proteins of No. 12 or the antibody or fragment of No. 16, for use in a method of diagnosing a disease or disorder such as cancer such as leukemia, prostate cancer. 41. A method for treating or preventing a disease or disorder characterized by an aberrant amount of, activity or component composition of or intracellular localization of, WO 03/072602 PCT/EPO2/50003 308 the complex of anyone of No. 1 - 7, comprising administering to a subject in need of such treatment or prevention a therapeutically effective amount of one or more molecules that modulate the amount of, DNA endonuclease activity; DNA helicase activity; RNAse activity, or protein composition of, said complex. 42. The method according to No. 41, wherein said disease or disorder involves decreased levels of the amount or activity of said complex. 43. The method according to No. 41, wherein said disease or disorder involves increased levels of the amount or activity of said complex. 44. Complex of any of No. 1 - 7 and/or protein selected from the following proteins (i) "APG9" (SEQ ID No:2323) or a functionally active derivative thereof, or a functionally active fragment thereof, or a homologue thereof, or a variant of "APG9", the variant being encoded by a nucleic acid that hybridizes to the "APG9" nucleic acid (SEQ ID No:2324) or its complement under low stringency conditions,and (ii) "CAF130" (SEQ ID No:2609) or a functionally active derivative thereof, or a functionally active fragment thereof, or a homologue thereof, or a variant of "CAF130", the variant being encoded by a nucleic acid that hybridizes to the "CAF130'" nucleic acid (SEQ ID No:2610 ) or its complement under low stringency conditions,and (iii) "CAF40" (SEQ ID No:2611) or a functionally active derivative thereof, or a functionally active fragment thereof, or a homologue thereof, or a variant of "CAF40", the variant being encoded by a nucleic acid that hybridizes to the "CAF40" nucleic acid (SEQ ID No:2612 ) or its complement under low stringency conditions,and (iv) "CCR4" (SEQ ID No:2587) or a functionally active derivative thereof, or a functionally active fragment thereof, or a homologue thereof, or a variant of "CCR4", the variant being encoded by a nucleic acid that hybridizes to the "CCR4" nucleic acid (SEQ ID No:2588) or its complement under low stringency conditions,and (v) "CCT6" (SEQ ID No:347) or a functionally active derivative thereof, or a functionally active fragment thereof, or a homologue thereof, or a variant of "CCT6", the variant being encoded by a nucleic acid that hybridizes to the "CCT6" nucleic acid (SEQ ID No:348 ) or its complement under low stringency conditions,and (vi) "CDC39" (SEQ ID No:1695) or a functionally active derivative thereof, or a functionally active fragment thereof, or a homologue thereof, or a variant of "CDC39", the WO 03/072602 PCT/EPO2/50003 309 variant being encoded by a nucleic acid that hybridizes to the "CDC39" nucleic acid (SEQ ID No:1696 ) or its complement under low stringency conditions,and (vii) "FAS2" (SEQ ID No:573) or a functionally active derivative thereof, or a functionally active fragment thereof, or a homologue thereof, or a variant of "FAS2", the variant being encoded by a nucleic acid that hybridizes to the "FAS2" nucleic acid (SEQ ID No:574 ) or its complement under low stringency conditions,and (viii) "GBP2" (SEQ ID No:189) or a functionally active derivative thereof, or a functionally active fragment thereof, or a homologue thereof, or a variant of "GBP2", the variant being encoded by a nucleic acid that hybridizes to the "GBP2" nucleic acid (SEQ ID No:190) or its complement under low stringency conditions,and (ix) "KEM1" (SEQ ID No:141) or a functionally active derivative thereof, or a functionally active fragment thereof, or a homologue thereof, or a variant of "KEM1", the variant being encoded by a nucleic acid that hybridizes to the "KEM1" nucleic acid (SEQ ID No:142) or its complement under low stringency conditions,and (x) "NOT3" (SEQ ID No:2591) or a functionally active derivative thereof, or a functionally active fragment thereof, or a homologue thereof, or a variant of "NOT3", the variant being encoded by a nucleic acid that hybridizes to the "NOT3" nucleic acid (SEQ ID No:2592) or its complement under low stringency conditions,and (xi) "POLl" (SEQ ID No:2595) or a functionally active derivative thereof, or a functionally active fragment thereof, or a homologue thereof, or a variant of "POLl", the variant being encoded by a nucleic acid that hybridizes to the "POLl" nucleic acid (SEQ ID No:2596) or its complement under low stringency conditions,and (xii) "POLl 2" (SEQ ID No:2597) or a functionally active derivative thereof, or a functionally active fragment thereof, or a homologue thereof, or a variant of "POLl12", the variant being encoded by a nucleic acid that hybridizes to the "POL12" nucleic acid (SEQ ID No:2598 ) or its complement under low stringency conditions,and (xiii) "POP2" (SEQ ID No:2599) or a functionally active derivative thereof, or a functionally active fragment thereof, or a homologue thereof, or a variant of "POP2", the variant being encoded by a nucleic acid that hybridizes to the "POP2" nucleic acid (SEQ ID No:2600 ) or its complement under low stringency conditions,aeind (xiv) "PRII" (SEQ ID No:2601) or a functionally active derivative thereof, or a functionally active fragment thereof, or a homologue thereof, or a variant of "PRII ", the variant being encoded by a nucleic acid that hybridizes to the "PRII" nucleic acid (SEQ ID No:2602) or its complement under low stringency conditions,and WO 03/072602 PCT/EPO2/50003 310 (xv) "PRI2" (SEQ ID No:2603) or a functionally active derivative thereof, or a functionally active fragment thereof, or a homologue thereof, or a variant of "PRI2", the variant being encoded by a nucleic acid that hybridizes to the "PRI2" nucleic acid (SEQ ID No:2604) or its complement under low stringency conditions,and (xvi) "SAM1" (SEQ ID No:449) or a functionally active derivative thereof, or a functionally active fragment thereof, or a homologue thereof, or a variant of "SAM1", the variant being encoded by a nucleic acid that hybridizes to the "SAM1" nucleic acid (SEQ ID No:450) or its complement under low stringency conditions,and (xvii) "SIG1" (SEQ ID No:2605) or a functionally active derivative thereof, or a functionally active fragment thereof, or a homologue thereof, or a variant of "SIGI", the variant being encoded by a nucleic acid that hybridizes to the "SIGI" nucleic acid (SEQ ID No:2606 ) or its complement under low stringency conditions,and (xviii) "TFC7" (SEQ ID No:9) or a functionally active derivative thereof, or a functionally active fragment thereof, or a homologue thereof, or a variant of "TFC7", the variant being encoded by a nucleic acid that hybridizes to the "TFC7" nucleic acid (SEQ ID No:10 ) or its complement under low stringency conditions,and (xix) "VMAI" (SEQ ID No:275) or a functionally active derivative thereof, or a functionally active fragment thereof, or a homologue thereof, or a variant of "VMAI", the variant being encoded by a nucleic acid that hybridizes to the "VMAI" nucleic acid (SEQ ID No:276 ) or its complement under low stringency conditions,and (xx) "YDR214W" (SEQ ID No:337) or a functionally active derivative thereof, or a functionally active fragment thereof, or a homologue thereof, or a variant of "YDR214W", the variant being encoded by a nucleic acid that hybridizes to the "YDR214W" nucleic acid (SEQ ID No:338 ) or its complement under low stringency conditions, and/or (xxi) "YRAI" (SEQ ID No:1195) or a functionally active derivative thereof, or a functionally active fragment thereof, or a homologue thereof, or a variant of "YRAI", the variant being encoded by a nucleic acid that hybridizes to the "YRAI" nucleic acid (SEQ ID No:1196 ) or its complement under low stringency conditions, as a target for an active agent of a pharmaceutical, preferably a drug target in the treatment or prevention of a disease or disorder such as cancer such as leukemia, prostate cancer.

WO 03/072602 PCT/EPO2/50003 311 More preferably, the present invention further relates to further following embodiments of the Ccr4-Not-complex 1. A protein complex selected from complex (I) and comprising (a) at least one first protein selected from the group consisting of: (i) "Kiaal 194" (SEQ ID No: 3271) or a functionally active derivative thereof, or a functionally active fragment thereof, or a homologue thereof, or a variant of "Kiaal 194", the variant being encoded by a nucleic acid that hybridizes to the "Kiaall94" nucleic acid (SEQ ID No: 3272) or its complement under low stringency conditions, and (i i) "Calif" (SEQ ID No:3275) or a functionally active derivative thereof, or a functionally active fragment thereof, or a homologue thereof, or a variant of "Calif ", the variant being encoded by a nucleic acid that hybridizes to the "Calif" nucleic acid (SEQ ID No: 3276) or its complement under low stringency conditions, and (ii i) "Hnot2" (SEQ ID No: 3281) or a functionally active derivative thereof, or a functionally active fragment thereof, or a homologue thereof, or a variant of "Hnot2", the variant being encoded by a nucleic acid that hybridizes to the "Hnot2" nucleic acid (SEQ ID No: 3282) or its complement under low stringency conditions, and (b) at least one second protein, which second protein is selected from the group consisting of: (i) "Kiaal007" (SEQ ID No: 3269) or a functionally active derivative thereof, or a functionally active fragment thereof, or a homologue thereof, or a variant of "Kiaal007", the variant being encoded by a nucleic acid that hybridizes to the "Kiaa1007" nucleic acid (SEQ ID No: 3270) or its complement under low stringency conditions, (ii) "Hcafl" (SEQ ID No: 3273) or a functionally active derivative thereof, or a functionally active fragment thereof, or a homologue thereof, or a variant of "Hcafl", the variant being encoded by a nucleic acid that hybridizes to the "Hcafl" nucleic acid (SEQ ID No:3274) or its complement under low stringency conditions, (iii) "Rqcd" (SEQ ID No:3277) or a functionally active derivative thereof, or a functionally active fragment thereof, or a homologue thereof, or a variant of "Rqcd ", the variant being encoded by a nucleic acid that hybridizes to the "Rqcd" nucleic acid (SEQ ID No:3278 ) or its complement under low stringency conditions, WO 03/072602 PCT/EPO2/50003 312 (iv) "Aah02928" (SEQ ID No: 3279) or a functionally active derivative thereof, or a functionally active fragment thereof, or a homologue thereof, or a variant of "Aah02928", the variant being encoded by a nucleic acid that hybridizes to the "Aah02928" nucleic acid (SEQ ID No: 3280) or its complement under low stringency conditions, and a complex (11) comprising at least two of said second proteins, wherein said low stringency conditions comprise hybridization in a buffer comprising 35% formamide, 5X SSC, 50 mM Tris-HCI (pH 7.5), 5 mM EDTA, 0.02% PVP, 0.02% Ficoll, 0.2% BSA, 100 ug/ml denatured salmon sperm DNA, and 10% (wt/vol) dextran sulfate for 18-20 hours at 40' C, washing in a buffer consisting of 2X SSC, 25 mM Tris-HCI (pH 7.4), 5 mM EDTA, and 0.1 % SDS for 1.5 hours at 55' C, and washing in a buffer consisting of 2X SSC, 25 mM Tris-HCI (pH 7.4), 5 mM EDTA, and 0.1% SDS for 1.5 hours at 600 C. 2. The protein complex comprising the following proteins: (i) "Kiaal007" (SEQ ID No: 3269) or a functionally active derivative thereof, or a functionally active fragment thereof, or a homologue thereof, or a variant of "Kiaal007", the variant being encoded by a nucleic acid that hybridizes to the "Kiaal 007" nucleic acid (SEQ ID No: 3270) or its complement under low stringency conditions, (ii) "Kiaal 194" (SEQ ID No: 3271) or a functionally active derivative thereof, or a functionally active fragment thereof, or a homologue thereof, or a variant of "Kiaal 194", the variant being encoded by a nucleic acid that hybridizes to the "Kiaal 194" nucleic acid (SEQ ID No: 3272) or its complement under low stringency conditions, (iii) "Hcafl" (SEQ ID No: 3273) or a functionally active derivative thereof, or a functionally active fragment thereof, or a homologue thereof, or a variant of "Hcafl", the variant being encoded by a nucleic acid that hybridizes to the "Hcafl" nucleic acid (SEQ ID No: 3274) or its complement under low stringency conditions, (iv) "Calif" (SEQ ID No: 3275) or a functionally active derivative thereof, or a functionally active fragment thereof, or a homologue thereof, or a variant of"Calif ", the variant being encoded by a nucleic acid that hybridizes to the "Calif" nucleic acid (SEQ ID No: 3276) or its complement under low stringency conditions, (v) "Rqcd "(SEQ ID No:3277) or a functionally active derivative thereof, or a functionally active fragment thereof, or a homologue thereof, or a variant of "Rqcd ", the variant being encoded by a nucleic acid that hybridizes to the "Rqcd" nucleic acid (SEQ ID No: 3278) or its complement under low stringency conditions, WO 03/072602 PCT/EPO2/50003 313 (vi) "Aah02928" (SEQ ID No: 3279) or a functionally active derivative thereof, or a functionally active fragment thereof, or a homologue thereof, or a variant of "Aah02928", the variant being encoded by a nucleic acid that hybridizes to the "Aah02928" nucleic acid (SEQ ID No:3280) or its complement under low stringency conditions, (vii) "Hnot2" (SEQ ID No: 3281) or a functionally active derivative thereof, or a functionally active fragment thereof, or a homologue thereof, or a variant of "Hnot2", the variant being encoded by a nucleic acid that hybridizes to the "Hnot2" nucleic acid (SEQ ID No: 3282) or its complement under low stringency conditions. 3. The protein complex according to No. 1 comprising all but 1 - 3 of the following proteins: (i) "Kiaal007" (SEQ ID No: 3269) or a functionally active derivative thereof, or a functionally active fragment thereof, or a homologue thereof, or a variant of "Kiaal007", the variant being encoded by a nucleic acid that hybridizes to the "Kiaa1 007" nucleic acid (SEQ ID No: 3270) or its complement under low stringency conditions, (ii) "Kiaal 194" (SEQ ID No: 3271) or a functionally active derivative thereof, or a functionally active fragment thereof, or a homologue thereof, or a variant of "Kiaal 194", the variant being encoded by a nucleic acid that hybridizes to the "Kiaa1194" nucleic acid (SEQ ID No: 3272) or its complement under low stringency conditions, (iii) "Hcafl" (SEQ ID No: 3273) or a functionally active derivative thereof, or a functionally active fragment thereof, or a homologue thereof, or a variant of "Hcafl", the variant being encoded by a nucleic acid that hybridizes to the "Hcafl" nucleic acid (SEQ ID No: 3274) or its complement under low stringency conditions, (iv) "Calif" (SEQ ID No: 3275) or a functionally active derivative thereof, or a functionally active fragment thereof, or a homologue thereof, or a variant of "Calif ", the variant being encoded by a nucleic acid that hybridizes to the "Calif" nucleic acid (SEQ ID No: 3276) or its complement under low stringency conditions, (v) "Rqcd " (SEQ ID No:3277) or a functionally active derivative thereof, or a functionally active fragment thereof, or a homologue thereof, or a variant of "Rqcd ", the variant being encoded by a nucleic acid that hybridizes to the "Rqcd" nucleic acid (SEQ ID No: 3278) or its complement under low stringency conditions, (vi) "Aah02928" (SEQ ID No: 3279) or a functionally active derivative thereof, or a functionally active fragment thereof, or a homologue thereof, or a variant of "Aah02928", WO 03/072602 PCT/EPO2/50003 314 the variant being encoded by a nucleic acid that hybridizes to the "Aah02928" nucleic acid (SEQ ID No:3280) or its complement under low stringency conditions, (vii) "Hnot2" (SEQ ID No: 3281) or a functionally active derivative thereof, or a functionally active fragment thereof, or a homologue thereof, or a variant of "Hnot2", the variant being encoded by a nucleic acid that hybridizes to the "Hnot2" nucleic acid (SEQ ID No: 3282) or its complement under low stringency conditions. 4. The complex of any of No. 1 - 3 comprising a functionally active derivative of said first protein and/or a functionally active derivative of said second protein, wherein the functionally active derivative is a fusion protein comprising said first protein or said second protein fused to an amino acid sequence different from the first protein or second protein, respectively. 5. The complex of No. 4 wherein the functionally active derivative is a fusion protein comprising said first protein or said second protein fused to an affinity tag or label. 6. The complex of any of No. 1 - 3 comprising a fragment of said first protein and/or a fragment of said second protein, which fragment binds to another protein component of said complex. 7. The complex of any of No. 1 -6 that is involved in DNA endonuclease activity and/or DNA helicase activity and/or RNAse activity. 8. A process for preparing complex of any of No. 1 - 7 and optionally the components thereof comprising the following steps: Expressing a protein (bait) of the complex, preferably the tagged protein, in a target cell, or a tissue or an organ, isolating the protein complex which is attached to the bait protein, and optionally disassociating the protein complex and isolating the individual complex members. 9. The process according to No. 8 wherein the tagged protein comprises two different tags which allow two separate affinity purification steps.

WO 03/072602 PCT/EPO2/50003 315 10. The process according to any of No. 8 - 9 wherein the two tags are separated by a cleavage site for a protease. 11. Component of the CCR4-NOT-subcomplex obtainable by a process according to any of No. 8-10. 12. Construct, preferably a vector construct, comprising (a) at least two separate nucleic acid sequences each encoding a different protein, or a functionally active fragment or a functionally active derivative thereof at least one of said proteins, or functionally active fragments or functionally active derivative thereof being selected from the first group of proteins according to No. 1 (a) and at least one of said proteins, or functionally active fragments or functionally active derivative thereof being selected from the second group of proteins according to No. 1 (b) or (b)at least two separate nucleic acid sequences each encoding a different protein, or a functionally active fragment or a functionally active derivative thereof, or a homologue or a variant thereof, said proteins being selected from the proteins of complex (11) according to No. 1. 13. Host cell containing a vector comprising a construct of No. 14 or containing several vectors each comprising at least one nucleic acid sequence encoding at least one of the proteins, or functionally active fragments or functionally active derivatives thereof selected from the first group of proteins according to No. 1(a) and the proteins, or functionally active fragments or functionally active derivatives thereof selected from the second group of proteins according to No. 1(b). 14. An antibody or a fragment of said antibody containing the binding domain thereof, selected from an antibody or fragment thereof, which binds the complex of any of No. 1 7 and which does not bind any of the proteins of said complex when uncomplexed. 15. A kit comprising in one or more container: (a) the complex of any of No. 1 - 7 (b) an antibody according to No. 14 andlor (c) a nucleic acid encoding a protein of the complex of any of No. 1 - 7 (d) cells expressing the complex of any of No. 1 - 7 WO 03/072602 PCT/EPO2/50003 316 and optionally (e) further components such as reagents and working instructions. 16. A kit according to No. 15 for processing a substrate of said complex. 17. A kit according to No. 15 for the diagnosis or prognosis of a disease or a disease risk, preferentially for a disease or disorder such as cancer such as leukemia, prostate cancer; target for affecting the regulation of aging processes. 18. Array, preferably a microarray, in which at least a complex according to any of No. 1 - 7 and/or at least one antibody according to No. 14 is attached to a solid carrier. 19. A process for modifying a physiological substrate of the complex comprising the step of bringing into contact a complex of any of No. 1 - 7 with said substrate, such that said substrate is modified. 20. A pharmaceutical composition comprising the protein complex of any of No. 1 - 7 and a pharmaceutical acceptable carrier. 21. A pharmaceutical composition according to No. 20 for the treatment of diseases and disorders such cancer such as leukemia, prostate cancer; target for affecting the regulation of aging processes. 22. A method for screening for a molecule that binds to a complex of anyone of No. 1 - 7 comprising the steps of (a) exposing said complex, or a cell or organism containing same to one or more candidate molecules; and (b) determining whether said candidate molecule is bound to the complex or protein. 23. A method for screening for a molecule that modulates directly or indirectly the function, activity, composition or formation of the complex of any one of No. 1 - 7 comprising the steps of (a) exposing said complex, or a cell or organism containing CCR4-NOT-subcomplex to one or more candidate molecules; and WO 03/072602 PCT/EPO2/50003 317 (b) determining the amount of activity of protein components of, and/or intracellular localization of, said complex and/or the transcription level of a gene regulated by the complex and/or the abundance and/or activity of a protein or protein complex dependent on the function of the complex and/or product of a gene dependent on the complex in the presence of the one or more candidate molecules, wherein a change in said amount, activity, protein components or intracellular localization relative to said amount, activity, protein components and/or intracellular localization and/or a change in the transcription level of a gene dependent on the complex and/or the abundance and/or activity of a protein or protein complex dependent on the function of the complex and/or product of a gene dependent on the complex in the absence of said candidate molecules indicates that the molecule modulates function, activity or composition of said complex. 24. The method of No. 23, wherein the amount of said complex is determined. 25. The method of No. 24, wherein the activity of said complex is determined. 26. The method of No. 25, wherein said determining step comprises isolating from the cell or organism said complex to produce said isolated complex and contacting said isolated complex in the presence or absence of a candidate molecule with a substrate of said complex and determining the processing of said substrate is modified in the presence of said candidate molecule. 27. The method of No. 23, wherein the amount of the individual protein components of said complex are determined. 28. The method of No. 27, wherein said determining step comprises determining whether (i) "Kiaal007" (SEQ ID No: 3269) or a functionally active derivative thereof, or a functionally active fragment thereof, or a homologue thereof, or a variant of "Kiaa1007", the variant being encoded by a nucleic acid that hybridizes to the "Kiaa1 007" nucleic acid (SEQ ID No: 3270) or its complement under low stringency conditions, and/or (ii) "Kiaall94" (SEQ ID No: 3271) or a functionally active derivative thereof, or a functionally active fragment thereof, or a homologue thereof, or a variant of "Kiaall94", WO 03/072602 PCT/EPO2/50003 318 the variant being encoded by a nucleic acid that hybridizes to the "Kiaal 194" nucleic acid (SEQ ID No: 3272) or its complement under low stringency conditions, and/or (iii) "Hcafl" (SEQ ID No: 3273) or a functionally active derivative thereof, or a functionally active fragment thereof, or a homologue thereof, or a variant of "Hcafl", the variant being encoded by a nucleic acid that hybridizes to the "Hcafl" nucleic acid (SEQ ID No: 3274) or its complement under low stringency conditions, and/or (iv) "Calif" (SEQ ID No: 3275) or a functionally active derivative thereof, or a functionally active fragment thereof, or a homologue thereof, or a variant of "Calif ", the variant being encoded by a nucleic acid that hybridizes to the "Calif" nucleic acid (SEQ ID No: 3276) or its complement under low stringency conditions, and/or (v) "Rqcd" (SEQ ID No:3277) or a functionally active derivative thereof, or a functionally active fragment thereof, or a homologue thereof, or a variant of "Rqcd ", the variant being encoded by a nucleic acid that hybridizes to the "Rqcd" nucleic acid (SEQ ID No: 3278) or its complement under low stringency conditions, and/or (vi) "Aah02928" (SEQ ID No: 3279) or a functionally active derivative thereof, or a functionally active fragment thereof, or a homologue thereof, or a variant of "Aah02928", the variant being encoded by a nucleic acid that hybridizes to the "Aah02928" nucleic acid (SEQ ID No:3280) or its complement under low stringency conditions, and/or (vii) "Hnot2" (SEQ ID No: 3281) or a functionally active derivative thereof, or a functionally active fragment thereof, or a homologue thereof, or a variant of "Hnot2", the variant being encoded by a nucleic acid that hybridizes to the "Hnot2" nucleic acid (SEQ ID No: 3282) or its complement under low stringency conditions, is present in the complex. 29. The method of any of No. 23 - 28, wherein said method is a method of screening for a drug for treatment or prevention of a disease or disorder such as cancer such as leukemia, prostate cancer; target for affecting the regulation of aging processes. 30. Use of a molecule that modulates the amount of, activity of, or the protein components of the complex of any one of No. 1 - 7 for the manufacture of a medicament for the treatment or prevention of a disease or disorder such as cancer such as leukemia, prostate cancer; target for affecting the regulation of aging processes.

WO 03/072602 PCT/EPO2/50003 319 31. A method for the production of a pharmaceutical composition comprising carrying out the method of any of No. 1 - 7 to identify a molecule that modulates the function, activity, composition or formation of said complex, and further comprising mixing the identified molecule with a pharmaceutically acceptable carrier. 32. A method for diagnosing or screening for the presence of a disease or disorder or a predisposition for developing a disease or disorder in a subject, which disease or disorder is characterized by an aberrant amount of, activity of, or component composition of, or intracellular localization of the complex of any one of the No. 1 - 7, comprising determining the amount of, activity of, protein components of, and/or intracellular localization of, said complex and/or the transcription level of a gene dependent on the complex and/or the abundance and/or activity of a protein or protein complex dependent on the function of the complex and/or product of a gene dependent on the complex in a comparative sample derived from a subject, wherein a difference in said amount, activity, or protein components of, said complex in a corresponding sample from a subject not having the disease or disorder or predisposition indicates the presence in the subject of the disease or disorder or predisposition in the subject. 33. The method of No. 32, wherein the amount of said complex is determined. 34. The method of No. 32, wherein the activity of said complex is determined. 35. The method of No. 34, wherein said determining step comprises isolating from the subject said complex to produce said isolated complex and contacting said isolated complex in the presence or absence of a candidate molecule with a substrate of said complex and determining whether said substrate is processed in the absence of the candidate molecule and whether the processing of said substrate is modified in the presence of said candidate molecule. 36. The method of No. 32, wherein the amount of the individual protein components of said complex are determined.

WO 03/072602 PCT/EPO2/50003 320 37. The method of No. 36, wherein said determining step comprises determining whether (i) "Kiaal007" (SEQ ID No: 3269) or a functionally active derivative thereof, or a functionally active fragment thereof, or a homologue thereof, or a variant of "Kiaal007", the variant being encoded by a nucleic acid that hybridizes to the "Kiaal1007" nucleic acid (SEQ ID No: 3270) or its complement under low stringency conditions, and/or (ii) "Kiaal 194" (SEQ ID No: 3271) or a functionally active derivative thereof, or a functionally active fragment thereof, or a homologue thereof, or a variant of "Kiaal 194", the variant being encoded by a nucleic acid that hybridizes to the "Kiaall94" nucleic acid (SEQ ID No: 3272) or its complement under low stringency conditions, and/or (iii) "Hcafl" (SEQ ID No: 3273) or a functionally active derivative thereof, or a functionally active fragment thereof, or a homologue thereof, or a variant of "Hcafl", the variant being encoded by a nucleic acid that hybridizes to the "Hcafl" nucleic acid (SEQ ID No: 3274 ) or its complement under low stringency conditions, and/or (iv) "Calif" (SEQ ID No: 3275) or a functionally active derivative thereof, or a functionally active fragment thereof, or a homologue thereof, or a variant of "Calif ", the variant being encoded by a nucleic acid that hybridizes to the "Calif" nucleic acid (SEQ ID No: 3276) or its complement under low stringency conditions, and/or (v) "Rqcd " (SEQ ID No:3277) or a functionally active derivative thereof, or a functionally active fragment thereof, or a homologue thereof, or a variant of "Rqcd ", the variant being encoded by a nucleic acid that hybridizes to the "Rqcd" nucleic acid (SEQ ID No: 3278) or its complement under low stringency conditions, and/or (vi) "Aah02928" (SEQ ID No: 3279) or a functionally active derivative thereof, or a functionally active fragment thereof, or a homologue thereof, or a variant of "Aah02928", the variant being encoded by a nucleic acid that hybridizes to the "Aah02928" nucleic acid (SEQ ID No:3280) or its complement under low stringency conditions, and/or (vii) "Hnot2" (SEQ ID No: 3281) or a functionally active derivative thereof, or a functionally active fragment thereof, or a homologue thereof, or a variant of "Hnot2", the variant being encoded by a nucleic acid that hybridizes to the "Hnot2" nucleic acid (SEQ ID No: 3282) or its complement under low stringency conditions. "RRP13" nucleic acid (SEQ ID No:68 ) or its complement under low stringency conditions, is present in the complex.

WO 03/072602 PCT/EPO2/50003 321 38. The complex of any one of No. 1 - 7, or the antibody or fragment of No. 16, for use in a method of diagnosing a disease or disorder such as inherited developmental diseases such as X-linked spondyloepiphyseal dysplasia tarda. 39. A method for treating or preventing a disease or disorder characterized by an aberrant amount of, activity or component composition of or intracellular localization of, the complex of anyone of No. 1 - 7, comprising administering to a subject in need of such treatment or prevention a therapeutically effective amount of one or more molecules that modulate the amount of, biochemical activity, or protein composition of, said complex. 40. The method according to No. 39, wherein said disease or disorder involves decreased levels of the amount or activity of said complex. 41. The method according to No. 39 , wherein said disease or disorder involves increased levels of the amount or activity of said complex. 42. Complex of any of No. 1 - 7 and/or protein selected from the following proteins (i) "Kiaal007" (SEQ ID No: 3269) or a functionally active derivative thereof, or a functionally active fragment thereof, or a homologue thereof, or a variant of "Kiaal007", the variant being encoded by a nucleic acid that hybridizes to the "Kiaa1007" nucleic acid (SEQ ID No: 3270) or its complement under low stringency conditions, (ii) "Kiaall94" (SEQ ID No: 3271) or a functionally active derivative thereof, or a functionally active fragment thereof, or a homologue thereof, or a variant of "Kiaal194", the variant being encoded by a nucleic acid that hybridizes to the "Kiaal 194" nucleic acid (SEQ ID No: 3272) or its complement under low stringency conditions, (iii) "Hcafl" (SEQ ID No: 3273) or a functionally active derivative thereof, or a functionally active fragment thereof, or a homologue thereof, or a variant of "Hcafl", the variant being encoded by a nucleic acid that hybridizes to the "Hcafl" nucleic acid (SEQ ID No: 3274 ) or its complement under low stringency conditions, (iv) "Calif" (SEQ ID No: 3275) or a functionally active derivative thereof, or a functionally active fragment thereof, or a homologue thereof, or a variant of "Calif ", the variant being encoded by a nucleic acid that hybridizes to the "Calif" nucleic acid (SEQ ID No: 3276) or its complement under low stringency conditions, WO 03/072602 PCT/EPO2/50003 322 (v) "Rqcd " (SEQ ID No:3277) or a functionally active derivative thereof, or a functionally active fragment thereof, or a homologue thereof, or a variant of "Rqcd ", the variant being encoded by a nucleic acid that hybridizes to the "Rqcd" nucleic acid (SEQ ID No: 3278) or its complement under low stringency conditions, (vi) "Aah02928" (SEQ ID No: 3279) or a functionally active derivative thereof, or a functionally active fragment thereof, or a homologue thereof, or a variant of "Aah02928", the variant being encoded by a nucleic acid that hybridizes to the "Aah02928" nucleic acid (SEQ ID No:3280) or its complement under low stringency conditions, (vii) "Hnot2" (SEQ ID No: 3281) or a functionally active derivative thereof, or a functionally active fragment thereof, or a homologue thereof, or a variant of "Hnot2", the variant being encoded by a nucleic acid that hybridizes to the "Hnot2" nucleic acid (SEQ ID No: 3282) or its complement under low stringency conditions. "RRP13" nucleic acid (SEQ ID No:68 ) or its complement under low stringency conditions as a target for an active agent of a pharmaceutical, preferably a drug target in the treatment or prevention of a disease or disorder such as cancer such as leukemia, prostate cancer; target for affecting the regulation of aging processes. In a preferred embodiment of the present invention, the protein components of the complex are vertebrate homologs of the yeast proteins, or a mixture of yeast and vertebrate homolog proteins. In a more preferred embodiment, the protein components of the complex are mammalian homologs of the yeast proteins, or a mixture of yeast and mammalian homolog proteins. In particular aspects,n the native component proteins, or derivatives or fragments of the complex are obtained from a mammal such as mouse, rat, pig, cow, dog, monkey, human, sheep or horse. In another preferred embodiment, the protein components of the complex are human homologs of the yeast proteins, or a mixture of yeast and human homolog proteins. In yet another preferred embodiment, the protein components of the complex are a mixture of yeast, vertebrate, mammalian and/or human proteins. As used herein, a "functionally active complex" refers to that material displaying one or more known functional attributes of a wild type complex, including but not limited to binding to a complex-specific antibody or physiological function (for physiological functions of the protein complexes of the present invention.

WO 03/072602 PCT/EPO2/50003 323 A specific embodiment of the present invention is directed to a complex comprising of a fragment of a component protein that can be bound by an anti component protein antibody or bound by an antibody specific for the protein complex or wherein the fragment is able to bind another component protein of the complex. In another specific embodiments, the present invention is directed to a complex comprising a fragment of one or more members of the complex. Fragments, or proteins comprising fragments, lacking a region of a member of the complex, are also provided. Nucleic acids encoding the foregoing are also provided in the present invention. The present invention is also directed to methods for production of a protein complex of the present invention and derivatives of the complex and/or fragments and/or derivatives of individual component proteins or the complex e. g. by the TAP method described further below. Pharmaceutical compositions are also provided. The present invention is further directed to complexes comprising a fusion protein which comprises a component of the complex or a fragment thereof linked via a covalent bond to an amino acid sequence different from said component protein, as well as nucleic acids encoding the protein, fusions and fragments thereof. For example, the non-component protein portion of the fusion protein, which can be added to the N terminal, the C-terminal or inserted into the amino acid sequence of the complex component can comprise a few amino acids, which provide an epitope that is used as a target for affinity purification of the fusion protein and/or complex. The invention is further directed to methods for modulating (i.e., inhibiting or enhancing) the amount of, activity of, or the identity of the protein components of, a complex of the present invention. The protein components of a complex of the present invention have been implicated in many physiological processes. The present invention is also directed to methods for screening a complex, as well as a derivative of the complex, for the ability to alter a cell function, particularly a cell function in which the complex and/or a component protein of the complex has been implicated. Moreover, the present invention provides a process for the identification and/or preparation of an effector of a composition according to the invention which process comprises the steps of bringing into contact the composition of the invention or of a component thereof with a compound, a mixture of compounds or a library of compounds and determining whether the compounds or certain compounds of the mixture or library bind to the composition of the invention and/or a component thereof WO 03/072602 PCT/EPO2/50003 324 and/or affects the biological activity of such a composition or component and then optionally further purifying the compound positively tested as effector by such a process. A major application of the composition according to the invention results in the identification of an active agent capable of binding thereto. Hence, the compositions of the invention are useful tools in screening for new pharmaceutical drugs. The present invention is also directed to a method for isolating the complex and the component proteins comprising tagging a protein of the complex with a sequence that allows affinity purification of the tagged protein, expressing such protein in a target cell, isolating the protein complex which is attached to the tagged protein, and optionally disassociating the protein complex and isolating the individual complex members. The present invention further relates to a composition, preferably a protein complex, which is obtainable by the method comprising the following steps: tagging a protein as defined above, i.e. a protein which forms part of a protein complex, with a moiety, preferably an amino acid sequence, that allows affinity purification of the tagged protein and expressing such protein in a target cell and isolating the protein complex which is attached to the tagged protein. The details of such purification are described in WO 00/09716 and in Rigaut, G. et al. (1999), Nature Biotechnology, Vol. 17 (10): 1030 1032 and further herein below. The tagging can essentially be performed with any moiety which is capable of providing a specific interaction with a further moiety, e.g. in the sense of a ligand receptor interaction, antigen antibody interaction or the like. The tagged protein can also be expressed in an amount in the target cell which comes close to the physiological concentration in order to avoid a complex formation merely due to high concentration of the expressed protein but not reflecting the natural occurring complex. In a further preferred embodiment, the composition is obtained by using a tagged protein which comprises two different tags which allow two different affinity purification steps. This measure allows a higher degree of purification of the composition in question. In a further preferred embodiment the tagged protein comprises two tags that are separated by a cleavage site for a protease. This allows a step-by-step purification on affinity columns. The present invention is also directed to therapeutic and prophylactic, as well as diagnostic, prognostic, and screening methods and compositions based upon the WO 03/072602 PCT/EPO2/50003 325 complex (and the nucleic acids encoding the individual proteins that participate in the complex). Therapeutic compounds of the invention include, but are not limited to, a complex of the invention, and a complex where one or more members of the complex is a derivative or fragment thereof. The present invention is also directed to complex specific antibodies to and nucleic acids encoding the foregoing; and antisense nucleic acids to the nucleotide sequences encoding the complex components. Diagnostic, prognostic and screening kits are also provided. The present invention further relates to a kit comprising a composition as described above, optionally together with further reagents and working instructions. The further reagents may be, for example, buffers, substrates for enzymes but also carrier material such as beads, filters, microarrays and other solid carries. The working instructions may indicate how to use the ingredients of the kit in order to perform a desired assay. The present invention further relates to a nucleic acid encoding a component of a composition as defined above. Such a nucleic acid may be used for example to express a desired tagged protein in a given cell for the isolation of a complex or component according to the invention. Such a nucleic acid may also be used for the identification and isolation of genes from other organisms by cross species hybridization. The present invention further relates to a construct, preferably a vector construct, which comprises a nucleic acid as described above. Such constructs may comprise expression controlling elements such as promoters, enhancers and terminators in order to express the nucleic acids in a given host cell, preferably under conditions which resemble the physiological concentrations. The present invention further relates to a host cell containing a construct as defined above. Such a host cell can be, e.g., any eukaryotic cell such as yeast, plant or mammalian, whereas human cells are preferred. Such host cells may form the starting material for isolation of a complex according to the present invention. Animal models and methods of screening for modulators (i.e., agonists, and antagonists) of the amount of, activity of, or protein component composition of, a complex of the present invention are also provided. The present invention further relates to a kit comprising a composition as described above, optionally together with further reagents and working instructions. The further reagents may be, for example, buffers, substrates for enzymes but also carrier material such as beads, filters, microarrays and other solid carries. The working WO 03/072602 PCT/EPO2/50003 326 instructions may indicate how to use the ingredients of the kit in order to perform a desired assay. The TRAPP-complex (complex 102) The present invention further relates to components of the transport protein particle (TRAPP) complex, the complete protein complex, uses of said components and complex as well as to methods of preparing same. Membrane traffic along the secretory or endocytic pathways is a multistage process, which is mediated by vesicular carriers. Membrane traffic can be subdivided in three steps: i) the formation or budding of a transport vesicle, ii) vesicle recognition by the target organelle (targeting/tethering) and iii) fusion of the vesicle with the target organelle. Transport vesicles are tethered and fused to target membranes in a highly regulated way. Transport specificity might be mediated by multiple, large multiprotein complexes, such as the transport protein particle (TRAPP), that act in a stage-dependent manner in the secretory andlor endocytic pathway (reviewed in .Lowe, M. (2000). Membrane transport: tethers and TRAPPs. Curr. Biol. 10, 407-409. The transport protein particle (TRAPP) was initially identified and characterized in Saccharomyces cerevisiae as a multiprotein complex containing following 10 polypeptides, Bet3p, Bet5p, Trs20p, Trs23p, Trs31p, Trs33p, Trs65p (KRE11), Trs85p (GSG1), Trsl20p and Trsl30p. TRAPP is required early in the secretory pathway for the docking of endoplasmic reticulum (ER)-derived transport vesicles to cis-Golgi membranes, prior to the SNARE-mediated fusion event. TRAPP was originally identified by genetics and biochemical methods. All complex components were identified by mass spectrometric analysis of a Bet3p-immunopurified complex. TRAPP is a peripheral membrane complex and has been localized by subcellular fractionation and light microscopy to the cis-Golgi. Seven of the TRAPP components are essential for vegetative growth in yeast. In yeast, two distinct TRAPP complexes exist, termed TRAPP I and II that have different subunit compositions and which, mediate different transport events. TRAPP I, which contains seven subunits, Bet3p, Bet5p, Trs20p, Trs23p, Trs31p, Trs33p and Trs85p, is required for membrane traffic between the ER and the Golgi. TRAPP II, which corresponds to the originally identified 10 subunit complex, functions in WO 03/072602 PCT/EPO2/50003 327 Golgi traffic or in exit from the Golgi. Both TRAPP I and TRAPP II can act as Guanine nucleotide Exchange Factors (GEFs) for Ypt small GTPases, Yptl p and Ypt31132, which have been implicated in vesicle docking in ER-Golgi and trans-Golgi transport, respectively. Despite the large body of information already available from the prior art concerning the TRAPP-complex up to now not all components of the complex are known not to speak of the composition of the complex as a whole. By applying the process according to the invention to the isolation of the TRAPP complex from yeast three new proteins could be identified in said yeast complex. The proteins are listed below. The Accession-Number is the GenBank-Accession number for the protein. Fksl: Is a known and non-essential protein which has been described as a transferase and has been shown to be involved in carbohydrate metabolism and cell wall maintenance. It has been shown to be a component of the beta-l,3-glucan synthase. (GenBank Acc. No.: AAB67256.1) Rvb2: Is a known and essential protein which has been shown to be invoved in Pol II transcription and RNA processing/modification (GenBank Acc. No.: CAA97952.1) Skn1: Is a known and non-essential protein which has been proposed to have transferase activity and to be involved in beta-1,6-glucan synthesis (GenBank Acc. No. CAA97156.1) In addition, the invention relates to the human TRAPP-complex. For the mammalian system, various data have been presented which have given evidence both for a conserved mechanism and also showed some differences between the yeast and mammalian structures.

WO 03/072602 PCT/EPO2/50003 328 The composition and function of the mammalian complex based on the data to date is as follows: An analogous/orthologous human complex has been immunopurified using Bet3 antibodies as a Triton X-100 resistant ~670 kDa complex (Sacher, M., Jiang, Y., Barrowman, J., Scarpa, A., Burston, J., Zhang, L., Schieltz, D., Yates Ill, J.R., Abeliovich, H. And Ferro-Novick, S. (1998), EMBO J. 17, 1494-2503.). The human complex appears smaller in size than the larger TRAPP II complex in yeast, which is -1094 kDa. This difference could be accounted for by the smaller size of the individual subunits, but could also be due to different complex composition. Database searches have revealed that most of the yeast TRAPP components have mammalian counterparts, suggesting a conserved role for a human TRAPP complex in the secretory pathway. However, no comprehensive analysis of purified human TRAPP has been reported. Another difference is that in human cell extracts several TRAPP components are to large extent soluble monomers, suggesting a different regulation of complex assembly. The previously uncharacterised human TRAPP-complex was - by applying the protocols for protein complex isolation in mammalian cells as described in Section 'Protocols' (infra) and using hbet3 as a bait- found to be composed of the following proteins (see Fig. 8 and Tab. lb): hBet3 (homolog of ybet3): GenBank Acc. No. of protein NP_055223 hMum2 (homolog of ybet5): GenBank Acc. No. of protein NP_067033 R326112 (MGC2650) (homolog of ytrs33): GenBank Acc. No. of protein NP_077013 Sedlin (homolog of ytrs20): GenBank Acc. No. of protein NP056974 Ehoc-1 (homolog of ytrsl30): GenBank Acc. No. of protein NP_003265 KIAA1012 (homolog of ytrs85): GenBank Acc. No. of protein XP_035414 PTD009 (homolog of ytrs23): GenBank Acc. No. of protein NP_057230 So far, for the human complex, none of the interactions have been shown. There are diseases which involve defects in the function of components of the TRAPP complex (Gedeon, A. K. et al., 1999, Nat Genet 22, 400-4).

WO 03/072602 PCT/EPO2/50003 329 Spondyloephiphyseal dysplasia tarda is a rare X-linked recessive osteochondrodysplasia. This disorder is progressive and is manifested by short stature with short neck and trunk, barrel chest and absence of systemic complications. The genetic defect has been mapped to SEDL (Sedlin), which is a human homologue of Trs20 in yeast. However, SEDL has not yet been shown to be a constituent of a purified human TRAPP complex. But, if so, it implies that other components of the TRAPP complex might be involved in skeletal anomalies in a manner similar to SEDL. The present invention further relates to further following embodiments relating to the TRAPP-complex: Thus, the present invention relates to the following embodiments 1. A protein complex selected from complex (I) and comprising (a) at least one first protein selected from the group consisting of: (i) "BET3" (SEQ ID No:1299) or a functionally active derivative thereof, or a functionally active fragment thereof, or a homologue thereof, or a variant of "BET3", the variant being encoded by a nucleic acid that hybridizes to the "BET3" nucleic acid (SEQ ID No:1300) or its complement under low stringency conditions, (ii) "BET5" (SEQ ID No:1301) or a functionally active derivative thereof, or a functionally active fragment thereof, or a homologue thereof, or a variant of "BET5", the variant being encoded by a nucleic acid that hybridizes to the "BET5" nucleic acid (SEQ ID No:1302) or its complement under low stringency conditions, (iii) "GSGI" (SEQ ID No:1303) or a functionally active derivative thereof, or a functionally active fragment thereof, or a homologue thereof, or a variant of "GSGI", the variant being encoded by a nucleic acid that hybridizes to the "GSG1" nucleic acid (SEQ ID No:1304) or its complement under low stringency conditions, (iv) "KRE11" (SEQ ID No:1305) or a functionally active derivative thereof, or a functionally active fragment thereof, or a homologue thereof, or a variant of "KRE 11", the variant being encoded by a nucleic acid that hybridizes to the "KRE11" nucleic acid (SEQ ID No:1306 ) or its complement under low stringency conditions, (v) "TRS120" (SEQ ID No:1307) or a functionally active derivative thereof, or a functionally active fragment thereof, or a homologue thereof, or a variant of "TRS120", WO 03/072602 PCT/EPO2/50003 330 the variant being encoded by a nucleic acid that hybridizes to the "TRS120" nucleic acid (SEQ ID No:1308) or its complement under low stringency conditions, (vi) "TRS130" (SEQ ID No:1309) or a functionally active derivative thereof, or a functionally active fragment thereof, or a homologue thereof, or a variant of "TRS130", the variant being encoded by a nucleic acid that hybridizes to the "TRS130" nucleic acid (SEQ ID No:1310 ) or its complement under low stringency conditions, (vii) "TRS20" (SEQ ID No:1311) or a functionally active derivative thereof, or a functionally active fragment thereof, or a homologue thereof, or a variant of "TRS20", the variant being encoded by a nucleic acid that hybridizes to the "TRS20" nucleic acid (SEQ ID No:1312 ) or its complement under low stringency conditions, (viii) "TRS23" (SEQ ID No:1313) or a functionally active derivative thereof, or a functionally active fragment thereof, or a homologue thereof, or a variant of "TRS23", the variant being encoded by a nucleic acid that hybridizes to the "TRS23" nucleic acid (SEQ ID No:1314 ) or its complement under low stringency conditions, (ix) "TRS31" (SEQ ID No:1315) or a functionally active derivative thereof, or a functionally active fragment thereof, or a homologue thereof, or a variant of "TRS31", the variant being encoded by a nucleic acid that hybridizes to the "TRS31" nucleic acid (SEQ ID No:1316 ) or its complement under low stringency conditions, and (x) "TRS33" (SEQ ID No:1317) or a functionally active derivative thereof, or a functionally active fragment thereof, or a homologue thereof, or a variant of "TRS33", the variant being encoded by a nucleic acid that hybridizes to the "TRS33" nucleic acid (SEQ ID No:1318 ) or its complement under low stringency conditions, and (b) at least one second protein, which second protein is selected from the group consisting of: (i) "FKSI" (SEQ ID No:149) or a functionally active derivative thereof, or a functionally active fragment thereof, or a homologue thereof, or a variant of "FKSI", the variant being encoded by a nucleic acid that hybridizes to the "FKSI" nucleic acid (SEQ ID No:150 ) or its complement under low stringency conditions, (ii) "RVB2" (SEQ ID No:515) or a functionally active derivative thereof, or a functionally active fragment thereof, or a homologue thereof, or a variant of "RVB2", the variant being encoded by a nucleic acid that hybridizes to the "RVB2" nucleic acid (SEQ ID No:516 ) or its complement under low stringency conditions, and WO 03/072602 PCT/EPO2/50003 331 (iii) "SKN1" (SEQ ID No:1319) or a functionally active derivative thereof, or a functionally active fragment thereof, or a homologue thereof, or a variant of "SKN1", the variant being encoded by a nucleic acid that hybridizes to the "SKNI" nucleic acid (SEQ ID No:1320) or its complement under low stringency conditions, and a complex (11) comprising at least two of said second proteins, wherein said low stringency conditions comprise hybridization in a buffer comprising 35% formamide, 5X SSC, 50 mM Tris-HCI (pH 7.5), 5 mM EDTA, 0.02% PVP, 0.02% Ficoll, 0.2% BSA, 100 ug/ml denatured salmon sperm DNA, and 10% (wt/vol) dextran sulfate for 18-20 hours at 400 C, washing in a buffer consisting of 2X SSC, 25 mM Tris-HCI (pH 7.4), 5 mM EDTA, and 0.1 % SDS for 1.5 hours at 550 C, and washing in a buffer consisting of 2X SSC, 25 mM Tris-HCI (pH 7.4), 5 mM EDTA, and 0.1% SDS for 1.5 hours at 600 C. 2. The protein complex selected from complex (I) and comprising the following proteins: (i) "BET3" (SEQ ID No:1299) or a functionally active derivative thereof, or a functionally active fragment thereof, or a homologue thereof, or a variant of "BET3", the variant being encoded by a nucleic acid that hybridizes to the "BET3" nucleic acid (SEQ ID No:1300) or its complement under low stringency conditions, (ii) "BET5" (SEQ ID No:1301) or a functionally active derivative thereof, or a functionally active fragment thereof, or a homologue thereof, or a variant of "BET5", the variant being encoded by a nucleic acid that hybridizes to the "BET5" nucleic acid (SEQ ID No:1302) or its complement under low stringency conditions, (iii) "FKSI" (SEQ ID No:149) or a functionally active derivative thereof, or a functionally active fragment thereof, or a homologue thereof, or a variant of "FKSI", the variant being encoded by a nucleic acid that hybridizes to the "FKSI" nucleic acid (SEQ ID No:150 ) or its complement under low stringency conditions, (iv) "GSGI" (SEQ ID No:1303) or a functionally active derivative thereof, or a functionally active fragment thereof, or a homologue thereof, or a variant of "GSGI", the variant being encoded by a nucleic acid that hybridizes to the "GSG1" nucleic acid (SEQ ID No:1304) or its complement under low stringency conditions, (v) "KRE1 1" (SEQ ID No:1305) or a functionally active derivative thereof, or a functionally active fragment thereof, or a homologue thereof, or a variant of "KRE11", the variant being encoded by a nucleic acid that hybridizes to the "KRE11" nucleic acid (SEQ ID No:1306) or its complement under low stringency conditions, WO 03/072602 PCT/EPO2/50003 332 (vi) "RVB2" (SEQ ID No:515) or a functionally active derivative thereof, or a functionally active fragment thereof, or a homologue thereof, or a variant of "RVB2", the variant being encoded by a nucleic acid that hybridizes to the "RVB2" nucleic acid (SEQ ID No:516 ) or its complement under low stringency conditions, (vii) "SKNI" (SEQ ID No:1319) or a functionally active derivative thereof, or a functionally active fragment thereof, or a homologue thereof, or a variant of "SKNI", the variant being encoded by a nucleic acid that hybridizes to the "SKN1" nucleic acid (SEQ ID No:1320) or its complement under low stringency conditions, (viii) "TRS120" (SEQ ID No:1307) or a functionally active derivative thereof, or a functionally active fragment thereof, or a homologue thereof, or a variant of "TRS120", the variant being encoded by a nucleic acid that hybridizes to the "TRS120" nucleic acid (SEQ ID No:1308) or its complement under low stringency conditions, (ix) "TRS130" (SEQ ID No:1309) or a functionally active derivative thereof, or a functionally active fragment thereof, or a homologue thereof, or a variant of "TRS130", the variant being encoded by a nucleic acid that hybridizes to the "TRS130" nucleic acid (SEQ ID No:1310 ) or its complement under low stringency conditions, (x) "TRS20" (SEQ ID No:1311) or a functionally active derivative thereof, or a functionally active fragment thereof, or a homologue thereof, or a variant of "TRS20", the variant being encoded by a nucleic acid that hybridizes to the "TRS20" nucleic acid (SEQ ID No:1312 ) or its complement under low stringency conditions, (xi) "TRS23" (SEQ ID No:1313) or a functionally active derivative thereof, or a functionally active fragment thereof, or a homologue thereof, or a variant of "TRS23", the variant being encoded by a nucleic acid that hybridizes to the "TRS23" nucleic acid (SEQ ID No:1314 ) or its complement under low stringency conditions, (xii) "TRS31" (SEQ ID No:1315) or a functionally active derivative thereof, or a functionally active fragment thereof, or a homologue thereof, or a variant of "TRS31", the variant being encoded by a nucleic acid that hybridizes to the "TRS31" nucleic acid (SEQ ID No:1316) or its complement under low stringency conditions, and (xiii) "TRS33" (SEQ ID No:1317) or a functionally active derivative thereof, or a functionally active fragment thereof, or a homologue thereof, or a variant of "TRS33", the variant being encoded by a nucleic acid that hybridizes to the "TRS33" nucleic acid (SEQ ID No:1318 ) or its complement under low stringency conditions, and a protein complex selected from complex (II) and comprising the following proteins: WO 03/072602 PCT/EPO2/50003 333 (i) "BET3" (SEQ ID No:1299) or a functionally active derivative thereof, or a functionally active fragment thereof, or a homologue thereof, or a variant of "BET3", the variant being encoded by a nucleic acid that hybridizes to the "BET3" nucleic acid (SEQ ID No:1300) or its complement under low stringency conditions, (ii) "BET5" (SEQ ID No:1301) or a functionally active derivative thereof, or a functionally active fragment thereof, or a homologue thereof, or a variant of "BET5", the variant being encoded by a nucleic acid that hybridizes to the "BET5" nucleic acid (SEQ ID No:1302) or its complement under low stringency conditions, (iii) "GSGI" (SEQ ID No:1303) or a functionally active derivative thereof, or a functionally active fragment thereof, or a homologue thereof, or a variant of "GSG 1", the variant being encoded by a nucleic acid that hybridizes to the "GSG1" nucleic acid (SEQ ID No:1304 ) or its complement under low stringency conditions, (iv) "KRE11" (SEQ ID No:1305) or a functionally active derivative thereof, or a functionally active fragment thereof, or a homologue thereof, or a variant of "KRE 11", the variant being encoded by a nucleic acid that hybridizes to the "KRE11" nucleic acid (SEQ ID No:1306 ) or its complement under low stringency conditions, (v) "SKNI" (SEQ ID No:1319) or a functionally active derivative thereof, or a functionally active fragment thereof, or a homologue thereof, or a variant of "SKN 1", the variant being encoded by a nucleic acid that hybridizes to the "SKNI" nucleic acid (SEQ ID No:1320) or its complement under low stringency conditions, (vi) "TRS120" (SEQ ID No:1307) or a functionally active derivative thereof, or a functionally active fragment thereof, or a homologue thereof, or a variant of "TRS120", the variant being encoded by a nucleic acid that hybridizes to the "TRS120" nucleic acid (SEQ ID No:1308 ) or its complement under low stringency conditions, (vii) "TRS130" (SEQ ID No:1309) or a functionally active derivative thereof, or a functionally active fragment thereof, or a homologue thereof, or a variant of "TRS130", the variant being encoded by a nucleic acid that hybridizes to the "TRS130" nucleic acid (SEQ ID No:1310) or its complement under low stringency conditions, (viii) "TRS20" (SEQ ID No:1311) or a functionally active derivative thereof, or a functionally active fragment thereof, or a homologue thereof, or a variant of "TRS20", the variant being encoded by a nucleic acid that hybridizes to the "TRS20" nucleic acid (SEQ ID No:1312 ) or its complement under low stringency conditions, (ix) "TRS23" (SEQ ID No:1313) or a functionally active derivative thereof, or a functionally active fragment thereof, or a homologue thereof, or a variant of "TRS23", the WO 03/072602 PCT/EPO2/50003 334 variant being encoded by a nucleic acid that hybridizes to the "TRS23" nucleic acid (SEQ ID No:1314 ) or its complement under low stringency conditions, (x) "TRS31" (SEQ ID No:1315) or a functionally active derivative thereof, or a functionally active fragment thereof, or a homologue thereof, or a variant of "TRS31", the variant being encoded by a nucleic acid that hybridizes to the "TRS31" nucleic acid (SEQ ID No:1316) or its complement under low stringency conditions, and (xi) "TRS33" (SEQ ID No:1317) or a functionally active derivative thereof, or a functionally active fragment thereof, or a homologue thereof, or a variant of "TRS33", the variant being encoded by a nucleic acid that hybridizes to the "TRS33" nucleic acid (SEQ ID No:1318 ) or its complement under low stringency conditions, 3. The protein complex according to No. 1 comprising all but 1 - 2 of the following proteins: (i) "BET3" (SEQ ID No:1299) or a functionally active derivative thereof, or a functionally active fragment thereof, or a homologue thereof, or a variant of "BET3", the variant being encoded by a nucleic acid that hybridizes to the "BET3" nucleic acid (SEQ ID No:1300) or its complement under low stringency conditions, (ii) "BET5" (SEQ ID No:1301) or a functionally active derivative thereof, or a functionally active fragment thereof, or a homologue thereof, or a variant of "BET5", the variant being encoded by a nucleic acid that hybridizes to the "BET5" nucleic acid (SEQ ID No:1302) or its complement under low stringency conditions, (iii) "FKSI" (SEQ ID No:149) or a functionally active derivative thereof, or a functionally active fragment thereof, or a homologue thereof, or a variant of "FKSI", the variant being encoded by a nucleic acid that hybridizes to the "FKSI" nucleic acid (SEQ ID No:150 ) or its complement under low stringency conditions, (iv) "GSGI" (SEQ ID No:1303) or a functionally active derivative thereof, or a functionally active fragment thereof, or a homologue thereof, or a variant of "GSG I", the variant being encoded by a nucleic acid that hybridizes to the "GSG1" nucleic acid (SEQ ID No:1304) or its complement under low stringency conditions, (v) "KRE11" (SEQ ID No:1305) or a functionally active derivative thereof, or a functionally active fragment thereof, or a homologue thereof, or a variant of "KRE11", the variant being encoded by a nucleic acid that hybridizes to the "KRE1 1" nucleic acid (SEQ ID No:1306) or its complement under low stringency conditions, WO 03/072602 PCT/EPO2/50003 335 (vi) "RVB2" (SEQ ID No:515) or a functionally active derivative thereof, or a functionally active fragment thereof, or a homologue thereof, or a variant of "RVB2", the variant being encoded by a nucleic acid that hybridizes to the "RVB2" nucleic acid (SEQ ID No:516) or its complement under low stringency conditions, (vii) "SKNI" (SEQ ID No:1319) or a functionally active derivative thereof, or a functionally active fragment thereof, or a homologue thereof, or a variant of "SKNI1", the variant being encoded by a nucleic acid that hybridizes to the "SKN 1" nucleic acid (SEQ ID No:1320) or its complement under low stringency conditions, (viii) "TRS120" (SEQ ID No:1307) or a functionally active derivative thereof, or a functionally active fragment thereof, or a homologue thereof, or a variant of "TRS120", the variant being encoded by a nucleic acid that hybridizes to the "TRS120" nucleic acid (SEQ ID No:1308 ) or its complement under low stringency conditions, (ix) "TRS130" (SEQ ID No:1309) or a functionally active derivative thereof, or a functionally active fragment thereof, or a homologue thereof, or a variant of "TRS130", the variant being encoded by a nucleic acid that hybridizes to the "TRS130" nucleic acid (SEQ ID No:1310 ) or its complement under low stringency conditions, (x) "TRS20" (SEQ ID No:1311) or a functionally active derivative thereof, or a functionally active fragment thereof, or a homologue thereof, or a variant of "TRS20", the variant being encoded by a nucleic acid that hybridizes to the "TRS20" nucleic acid (SEQ ID No:1312) or its complement under low stringency conditions, (xi) "TRS23" (SEQ ID No:1313) or a functionally active derivative thereof, or a functionally active fragment thereof, or a homologue thereof, or a variant of "TRS23", the variant being encoded by a nucleic acid that hybridizes to the "TRS23" nucleic acid (SEQ ID No:1314) or its complement under low stringency conditions, (xii) "TRS31" (SEQ ID No:1315) or a functionally active derivative thereof, or a functionally active fragment thereof, or a homologue thereof, or a variant of "TRS31", the variant being encoded by a nucleic acid that hybridizes to the "TRS31" nucleic acid (SEQ ID No:1316) or its complement under low stringency conditions, and (xiii) "TRS33" (SEQ ID No:1317) or a functionally active derivative thereof, or a functionally active fragment thereof, or a homologue thereof, or a variant of "TRS33", the variant being encoded by a nucleic acid that hybridizes to the "TRS33" nucleic acid (SEQ ID No:1318) or its complement under low stringency conditions.

WO 03/072602 PCT/EPO2/50003 336 4. The complex of any of No. 1 - 3 comprising a functionally active derivative of said first protein and/or a functionally active derivative of said second protein, wherein the functionally active derivative is a fusion protein comprising said first protein or said second protein fused to an amino acid sequence different from the first protein or second protein, respectively. 5. The complex of No. 4 wherein the functionally active derivative is a fusion protein comprising said first protein or said second protein fused to an affinity tag or label. 6. The complex of any of No. 1 - 3 comprising a fragment of said first protein and/or a fragment of said second protein, which fragment binds to another protein component of said complex. 7. The complex of any of No. 1 -6 that is involved in the vesicle targeting activity and/or the effect on ER to Golgi transport. 8. A process for preparing complex of any of No. 1 - 7 and optionally the components thereof comprising the following steps: Expressing a protein (bait) of the complex, preferably the tagged protein, in a target cell, or a tissue or an organ, isolating the protein complex which is attached to the bait protein, and optionally disassociating the protein complex and isolating the individual complex members. 9. The process according to No. 8 wherein the tagged protein comprises two different tags which allow two separate affinity purification steps. 10. The process according to any of No. 8 - 9 wherein the two tags are separated by a cleavage site for a protease. 11. Component of the TRAPP-complex obtainable by a process according to any of No. 8-10. 12. Construct, preferably a vector construct, comprising at least two separate nucleic acid sequences each encoding a different protein, or a functionally active fragment or a WO 03/072602 PCT/EPO2/50003 337 functionally active derivative thereof at least one of said proteins, or functionally active fragments or functionally active derivative thereof being selected from the first group of proteins according to No. 1 (a) and at least one of said proteins, or functionally active fragments or functionally active derivative thereof being selected from the second group of proteins according to No. 1 (b) or (c)at least two separate nucleic acid sequences each encoding a different protein, or a functionally active fragment or a functionally active derivative thereof, or a homologue or a variant thereof, said proteins being selected from the proteins of complex (11) according to No. 1. 13. Host cell containing a vector comprising at least the nucleic acid of No. or containing several vectors each comprising at least one nucleic acid sequence encoding at least one of the proteins, or functionally active fragments or functionally active derivatives thereof selected from the first group of proteins according to No. 1(a) and the proteins, or functionally active fragments or functionally active derivatives thereof selected from the second group of proteins according to No. 1(b). 14. An antibody or a fragment of said antibody containing the binding domain thereof, selected from an antibody or fragment thereof, which binds the complex of any of No. 1 7 and which does not bind any of the proteins of said complex when uncomplexed. 15. A kit comprising in one or more container: (a) the complex of any of No. 1 - 7 and/or (b) an antibody according to No. 14 and/or (c) a nucleic acid encoding a protein of the complex of any of No. 1 - 7 and/or (d) cells expressing the complex of any of No. 1 - 7 and optionally (e) further components such as reagents and working instructions. 16. A kit according to No. 15 for processing a substrate of said complex. 17. A kit according to No. 15 for the diagnosis or prognosis of a disease or a disease risk, preferentially for a disease or disorder such as inherited developmental diseases such as X-linked spondyloepiphyseal dysplasia tarda.

WO 03/072602 PCT/EPO2/50003 338 18. Array, preferably a microarray, in which at least a complex according to any of No. 1 7 and/or at least one antibody according to No. 14 is attached to a solid carrier. 19. A process for modifying a physiological substrate of the complex comprising the step of bringing into contact a complex of any of No. 1 - 7 with said substrate, such that said substrate is modified. 20. A pharmaceutical composition comprising the protein complex of any of No. 1 - 7 and a pharmaceutical acceptable carrier. 21. A pharmaceutical composition according to No. 20 for the treatment of diseases and disorders such as inherited developmental diseases such as X-linked spondyloepiphyseal dysplasia tarda. 22. A method for screening for a molecule that binds to a complex of anyone of No. 1 - 7 comprising the steps of (a) exposing said complex, or a cell or organism containing same to one or more candidate molecules; and (b) determining whether said candidate molecule is bound to the complex or protein. 23. A method for screening for a molecule that modulates directly or indirectly the function, activity, composition or formation of the complex of any one of No. 1 - 7 comprising the steps of (a) exposing said complex, or a cell or organism containing TRAPP-complex to one or more candidate molecules; and (b) determining the amount of activity of protein components of, and/or intracellular localization of, said complex and/or the transcription level of a gene regulated by the complex and/or the abundance and/or activity of a protein or protein complex dependend on the function of the complex and/or product of a gene dependent on the complex in the presence of the one or more candidate molecules, wherein a change in said amount, activity, protein components or intracellular localization relative to said amount, activity, protein components and/or intracellular localization and/or a change in the transcription level of a gene dependend on the complex and/or the abundance and/or activity of a protein or protein complex dependent on the function of the complex and/or product of a WO 03/072602 PCT/EPO2/50003 339 gene dependent on the complex in the absence of said candidate molecules indicates that the molecule modulates function, activity or composition of said complex. 24. The method of No. 23, wherein the amount of said complex is determined. 25. The method of No. 23, wherein the activity of said complex is determined. 26. The method of No. 25, wherein said determining step comprises isolating from the cell or organism said complex to produce said isolated complex and contacting said isolated complex in the presence or absence of a candidate molecule with a substrate of said complex and determining the processing of said substrate is modified in the presence of said candidate molecule. 27. The method of No. 23, wherein the amount of the individual protein components of said complex are determined. 28. The method of No. 27, wherein said determining step comprises determining whether (i) "BET3" (SEQ ID No:1299) or a functionally active derivative thereof, or a functionally active fragment thereof, or a homologue thereof, or a variant of "BET3", the variant being encoded by a nucleic acid that hybridizes to the "BET3" nucleic acid (SEQ ID No:1300) or its complement under low stringency conditions,and/or (ii) "BET5" (SEQ ID No:1301) or a functionally active derivative thereof, or a functionally active fragment thereof, or a homologue thereof, or a variant of "BET5", the variant being encoded by a nucleic acid that hybridizes to the "BET5" nucleic acid (SEQ ID No:1302) or its complement under low stringency conditions,and/or (iii) "FKSI1" (SEQ ID No:149) or a functionally active derivative thereof, or a functionally active fragment thereof, or a homologue thereof, or a variant of "FKS1", the variant being encoded by a nucleic acid that hybridizes to the "FKS1" nucleic acid (SEQ ID No:150 ) or its complement under low stringency conditions,and/or (iv) "GSGI" (SEQ ID No:1303) or a functionally active derivative thereof, or a functionally active fragment thereof, or a homologue thereof, or a variant of "GSG 1", the variant being encoded by a nucleic acid that hybridizes to the "GSG1" nucleic acid (SEQ ID No:1304) or its complement under low stringency conditions,and/or WO 03/072602 PCT/EPO2/50003 340 (v) "KRE 11" (SEQ ID No:1305) or a functionally active derivative thereof, or a functionally active fragment thereof, or a homologue thereof, or a variant of "KRE1 1", the variant being encoded by a nucleic acid that hybridizes to the "KRE11" nucleic acid (SEQ ID No:1306) or its complement under low stringency conditions,and/or (vi) "RVB2" (SEQ ID No:515) or a functionally active derivative thereof, or a functionally active fragment thereof, or a homologue thereof, or a variant of "RVB2", the variant being encoded by a nucleic acid that hybridizes to the "RVB2" nucleic acid (SEQ ID No:516 ) or its complement under low stringency conditions,and/or (vii) "SKN1" (SEQ ID No:1319) or a functionally active derivative thereof, or a functionally active fragment thereof, or a homologue thereof, or a variant of "SKNI1", the variant being encoded by a nucleic acid that hybridizes to the "SKNI" nucleic acid (SEQ ID No:1320) or its complement under low stringency conditions,andlor (viii) "TRS120" (SEQ ID No:1307) or a functionally active derivative thereof, or a functionally active fragment thereof, or a homologue thereof, or a variant of "TRS120", the variant being encoded by a nucleic acid that hybridizes to the "TRS120" nucleic acid (SEQ ID No:1308 ) or its complement under low stringency conditions,and/or (ix) "TRS130" (SEQ ID No:1309) or a functionally active derivative thereof, or a functionally active fragment thereof, or a homologue thereof, or a variant of "TRS130", the variant being encoded by a nucleic acid that hybridizes to the "TRS130" nucleic acid (SEQ ID No:1310 ) or its complement under low stringency conditions,and/or (x) "TRS20" (SEQ ID No:1311) or a functionally active derivative thereof, or a functionally active fragment thereof, or a homologue thereof, or a variant of "TRS20", the variant being encoded by a nucleic acid that hybridizes to the "TRS20" nucleic acid (SEQ ID No:1312 ) or its complement under low stringency conditions,and/or (xi) "TRS23" (SEQ ID No:1313) or a functionally active derivative thereof, or a functionally active fragment thereof, or a homologue thereof, or a variant of "TRS23", the variant being encoded by a nucleic acid that hybridizes to the "TRS23" nucleic acid (SEQ ID No:1314) or its complement under low stringency conditions,and/or (xii) "TRS31" (SEQ ID No:1315) or a functionally active derivative thereof, or a functionally active fragment thereof, or a homologue thereof, or a variant of "TRS31", the variant being encoded by a nucleic acid that hybridizes to the "TRS31" nucleic acid (SEQ ID No:1316) or its complement under low stringency conditions, and/or (xiii) "TRS33" (SEQ ID No:1317) or a functionally active derivative thereof, or a functionally active fragment thereof, or a homologue thereof, or a variant of "TRS33", the variant being WO 03/072602 PCT/EPO2/50003 341 encoded by a nucleic acid that hybridizes to the "TRS33" nucleic acid (SEQ ID No:1318) or its complement under low stringency conditions, is present in the complex. 29. The method of any of No. 23 - 28, wherein said method is a method of screening for a drug for treatment or prevention of a disease or disorder such as inherited developmental diseases such as X-linked spondyloepiphyseal dysplasia tarda. 30. Use of a molecule that modulates the amount of, activity of, or the protein components of the complex of any one of No. 1 - 7 for the manufacture of a medicament for the treatment or prevention of a disease or disorder such as inherited developmental diseases such as X-linked spondyloepiphyseal dysplasiatarda. 31. A method for the production of a pharmaceutical composition comprising carrying out the method of any of No. 1 - 7 to identify a molecule that modulates the function, activity, composition or formation of said complex, and further comprising mixing the identified molecule with a pharmaceutically acceptable carrier. 32. A method for diagnosing or screening for the presence of a disease or disorder or a predisposition for developing a disease or disorder in a subject, which disease or disorder is characterized by an aberrant amount of, activity of, or component composition of, or intracellular localization of the complex of any one of the No. 1 - 7, comprising determining the amount of, activity of, protein components of, andlor intracellular localization of, said complex and/or the transcription level of a gene dependend on the complex and/or the abundance and/or activity of a protein or protein complex dependend on the function of the complex and/or product of a gene dependent on the complex in a comparative sample derived from a subject, wherein a difference in said amount, activity, or protein components of, said complex in a corresponding sample from a subject not having the disease or disorder or predisposition indicates the presence in the subject of the disease or disorder or predisposition in the subject. 33. The method of No. 32, wherein the amount of said complex is determined. 34. The method of No. 32, wherein the activity of said complex is determined.

WO 03/072602 PCT/EPO2/50003 342 35. The method of No. 34, wherein said determining step comprises isolating from the subject said complex to produce said isolated complex and contacting said isolated complex in the presence or absence of a candidate molecule with a substrate of said complex and determining whether said substrate is processed in the absence of the candidate molecule and whether the processing of said substrate is modified in the presence of said candidate molecule. 36. The method of No. 32, wherein the amount of the individual protein components of said complex are determined. 37. The method of No. 36, wherein said determining step comprises determining whether (i) "BET3" (SEQ ID No:1299) or a functionally active derivative thereof, or a functionally active fragment thereof, or a homologue thereof, or a variant of "BET3", the variant being encoded by a nucleic acid that hybridizes to the "BET3" nucleic acid (SEQ ID No:1300) or its complement under low stringency conditions, and/or (ii) "BET5" (SEQ ID No:1301) or a functionally active derivative thereof, or a functionally active fragment thereof, or a homologue thereof, or a variant of "BET5", the variant being encoded by a nucleic acid that hybridizes to the "BET5" nucleic acid (SEQ ID No:1302) or its complement under low stringency conditions, and/or (iii) "FKSI" (SEQ ID No:149) or a functionally active derivative thereof, or a functionally active fragment thereof, or a homologue thereof, or a variant of "FKSI", the variant being encoded by a nucleic acid that hybridizes to the "FKSI" nucleic acid (SEQ ID No:150 ) or its complement under low stringency conditions, and/or (iv) "GSGI" (SEQ ID No:1303) or a functionally active derivative thereof, or a functionally active fragment thereof, or a homologue thereof, or a variant of "GSGI1", the variant being encoded by a nucleic acid that hybridizes to the "GSG1" nucleic acid (SEQ ID No:1304) or its complement under low stringency conditions, and/or (v) "KRE11" (SEQ ID No:1305) or a functionally active derivative thereof, or a functionally active fragment thereof, or a homologue thereof, or a variant of "KRE1 1", the variant being encoded by a nucleic acid that hybridizes to the "KRE11" nucleic acid (SEQ ID No:1306) or its complement under low stringency conditions, and/or WO 03/072602 PCT/EPO2/50003 343 (vi) "RVB2" (SEQ ID No:515) or a functionally active derivative thereof, or a functionally active fragment thereof, or a homologue thereof, or a variant of "RVB2", the variant being encoded by a nucleic acid that hybridizes to the "RVB2" nucleic acid (SEQ ID No:516 ) or its complement under low stringency conditions, and/or (vii) "SKNI" (SEQ ID No:1319) or a functionally active derivative thereof, or a functionally active fragment thereof, or a homologue thereof, or a variant of "SKNI", the variant being encoded by a nucleic acid that hybridizes to the "SKNI" nucleic acid (SEQ ID No:1320) or its complement under low stringency conditions, and/or (viii) "TRS120" (SEQ ID No:1307) or a functionally active derivative thereof, or a functionally active fragment thereof, or a homologue thereof, or a variant of "TRS120", the variant being encoded by a nucleic acid that hybridizes to the "TRS120" nucleic acid (SEQ ID No:1308 ) or its complement under low stringency conditions, and/or (ix) "TRS130" (SEQ ID No:1309) or a functionally active derivative thereof, or a functionally active fragment thereof, or a homologue thereof, or a variant of "TRS130", the variant being encoded by a nucleic acid that hybridizes to the "TRS130" nucleic acid (SEQ ID No:1310 ) or its complement under low stringency conditions, and/or (x) "TRS20" (SEQ ID No:1311) or a functionally active derivative thereof, or a functionally active fragment thereof, or a homologue thereof, or a variant of "TRS20", the variant being encoded by a nucleic acid that hybridizes to the "TRS20" nucleic acid (SEQ ID No:1312 ) or its complement under low stringency conditions, and/or (xi) "TRS23" (SEQ ID No:1313) or a functionally active derivative thereof, or a functionally active fragment thereof, or a homologue thereof, or a variant of "TRS23", the variant being encoded by a nucleic acid that hybridizes to the "TRS23" nucleic acid (SEQ ID No:1314) or its complement under low stringency conditions, and/or (xii) "TRS31" (SEQ ID No:1315) or a functionally active derivative thereof, or a functionally active fragment thereof, or a homologue thereof, or a variant of "TRS31", the variant being encoded by a nucleic acid that hybridizes to the "TRS31" nucleic acid (SEQ ID No:1316 ) or its complement under low stringency conditions, and/or (xiii) "TRS33" (SEQ ID No:1317) or a functionally active derivative thereof, or a functionally active fragment thereof, or a homologue thereof, or a variant of "TRS33", the variant being encoded by a nucleic acid that hybridizes to the "TRS33" nucleic acid (SEQ ID No:1318 ) or its complement under low stringency conditions, is present in the complex.

WO 03/072602 PCT/EPO2/50003 344 38. The complex of any one of No. 1 - 7 or the antibody or fragment of No. 14, for use in a method of diagnosing a disease or disorder such as inherited developmental diseases such as X-linked spondyloepiphyseal dysplasia tarda. 39. A method for treating or preventing a disease or disorder characterized by an aberrant amount of, activity or component composition of or intracellular localization of, the complex of anyone of No. 1 - 7, comprising administering to a subject in need of such treatment or prevention a therapeutically effective amount of one or more molecules that modulate the amount of, vesicle targeting activity and/or the effect on ER to Golgi transport, or protein composition of, said complex. 40. The method according to No. 39, wherein said disease or disorder involves decreased levels of the amount or activity of said complex. 41. The method according to No. 39 , wherein said disease or disorder involves increased levels of the amount or activity of said complex. 42. Complex of any of No. 1 - 7 and/or protein selected from the following proteins (i) "BET3" (SEQ ID No:1299) or a functionally active derivative thereof, or a functionally active fragment thereof, or a homologue thereof, or a variant of "BET3", the variant being encoded by a nucleic acid that hybridizes to the "BET3" nucleic acid (SEQ ID No:1300) or its complement under low stringency conditions,and (ii) "BET5" (SEQ ID No:1301) or a functionally active derivative thereof, or a functionally active fragment thereof, or a homologue thereof, or a variant of "BET5", the variant being encoded by a nucleic acid that hybridizes to the "BET5" nucleic acid (SEQ ID No:1302) or its complement under low stringency conditions,and (iii) "FKS1" (SEQ ID No:149) or a functionally active derivative thereof, or a functionally active fragment thereof, or a homologue thereof, or a variant of "FKS1", the variant being encoded by a nucleic acid that hybridizes to the "FKS1" nucleic acid (SEQ ID No:150 ) or its complement under low stringency conditions,and (iv) "GSG1" (SEQ ID No:1303) or a functionally active derivative thereof, or a functionally active fragment thereof, or a homologue thereof, or a variant of "GSGI", the variant being encoded by a nucleic acid that hybridizes to the "GSG1" nucleic acid (SEQ ID No:1304) or its complement under low stringency conditions,and WO 03/072602 PCT/EPO2/50003 345 (v) "KRE11" (SEQ ID No:1305) or a functionally active derivative thereof, or a functionally active fragment thereof, or a homologue thereof, or a variant of "KRE11", the variant being encoded by a nucleic acid that hybridizes to the "KRE 11" nucleic acid (SEQ ID No:1306) or its complement under low stringency conditions,and (vi) "RVB2" (SEQ ID No:515) or a functionally active derivative thereof, or a functionally active fragment thereof, or a homologue thereof, or a variant of "RVB2", the variant being encoded by a nucleic acid that hybridizes to the "RVB2" nucleic acid (SEQ ID No:516 ) or its complement under low stringency conditions,and (vii) "SKNI" (SEQ ID No:1319) or a functionally active derivative thereof, or a functionally active fragment thereof, or a homologue thereof, or a variant of "SKN1", the variant being encoded by a nucleic acid that hybridizes to the "SKN1" nucleic acid (SEQ ID No:1320) or its complement under low stringency conditions,and (viii) "TRS120" (SEQ ID No:1307) or a functionally active derivative thereof, or a functionally active fragment thereof, or a homologue thereof, or a variant of "TRS120", the variant being encoded by a nucleic acid that hybridizes to the "TRS120" nucleic acid (SEQ ID No:1308) or its complement under low stringency conditions,and (ix) "TRS130" (SEQ ID No:1309) or a functionally active derivative thereof, or a functionally active fragment thereof, or a homologue thereof, or a variant of "TRS130", the variant being encoded by a nucleic acid that hybridizes to the "TRS130" nucleic acid (SEQ ID No:1310) or its complement under low stringency conditions,and (x) "TRS20" (SEQ ID No:1311) or a functionally active derivative thereof, or a functionally active fragment thereof, or a homologue thereof, or a variant of "TRS20", the variant being encoded by a nucleic acid that hybridizes to the "TRS20" nucleic acid (SEQ ID No:1312 ) or its complement under low stringency conditions,and (xi) "TRS23" (SEQ ID No:1313) or a functionally active derivative thereof, or a functionally active fragment thereof, or a homologue thereof, or a variant of "TRS23", the variant being encoded by a nucleic acid that hybridizes to the "TRS23" nucleic acid (SEQ ID No:1314) or its complement under low stringency conditions,and (xii) "TRS31" (SEQ ID No:1315) or a functionally active derivative thereof, or a functionally active fragment thereof, or a homologue thereof, or a variant of "TRS31", the variant being encoded by a nucleic acid that hybridizes to the "TRS31" nucleic acid (SEQ ID No:1316 ) or its complement under low stringency conditions, and/or (xiii) "TRS33" (SEQ ID No:1317) or a functionally active derivative thereof, or a functionally active fragment thereof, or a homologue thereof, or a variant of "TRS33", the WO 03/072602 PCT/EPO2/50003 346 variant being encoded by a nucleic acid that hybridizes to the "TRS33" nucleic acid (SEQ ID No:1318) or its complement under low stringency conditions, as a target for an active agent of a pharmaceutical, preferably a drug target in the treatment or prevention of a disease or disorder such as inherited developmental diseases such as X-linked spondyloepiphyseal dysplasia tarda. xxxxxxxx More preferntailly, The present invention relates to the following: 1. A protein complex selected from complex (I) and comprising (a) at least one first protein selected from the group consisting of: (i) "Hbet3" (SEQ ID No:3255) or a functionally active derivative thereof, or a functionally active fragment thereof, or a homologue thereof, or a variant of" Hbet3", the variant being encoded by a nucleic acid that hybridizes to the" Hbet3" nucleic acid (SEQ ID No:3256 ) or its complement under low stringency conditions, and (b) at least one second protein, which second protein is selected from the group consisting of: (i) "Hmum2" (SEQ ID No: 3257) or a functionally active derivative thereof, or a functionally active fragment thereof, or a homologue thereof, or a variant of ""Hmum2", the variant being encoded by a nucleic acid that hybridizes to the ""Hmum2" nucleic acid (SEQ ID No:3258) or its complement under low stringency conditions, (ii) "R32611_2"(MGC2650) (SEQ ID No:3259) or a functionally active derivative thereof, or a functionally active fragment thereof, or a homologue thereof, or a variant of "R32611_2"(MGC2650), the variant being encoded by a nucleic acid that hybridizes to the "R32611_2"(MGC2650) nucleic acid (SEQ ID No:3260) or its complement under low stringency conditions, (iii) "Sedlin" (SEQ ID No:3261) or a functionally active derivative thereof, or a functionally active fragment thereof, or a homologue thereof, or a variant of "Sedlin ", the variant being encoded by a nucleic acid that hybridizes to the "Sedlin " nucleic acid (SEQ ID No:3262) or its complement under low stringency conditions, (iv) "Ehoc-1" (SEQ ID No:3263) or a functionally active derivative thereof, or a functionally active fragment thereof, or a homologue thereof, or a variant of "Ehoc-1", the WO 03/072602 PCT/EPO2/50003 347 variant being encoded by a nucleic acid that hybridizes to the "Ehoc-1" nucleic acid (SEQ ID No:3264) or its complement under low stringency conditions, (v) "Kiaa1012" (SEQ ID No:3265) or a functionally active derivative thereof, or a functionally active fragment thereof, or a homologue thereof, or a variant of "Kiaal 012", the variant being encoded by a nucleic acid that hybridizes to the "Kiaal012" nucleic acid (SEQ ID No:3266 ) or its complement under low stringency conditions, (vi) "Ptd009" (SEQ ID No:3267) or a functionally active derivative thereof, or a functionally active fragment thereof, or a homologue thereof, or a variant of "Ptd009", the variant being encoded by a nucleic acid that hybridizes to the "Ptd009" nucleic acid (SEQ ID No:3268 ) or its complement under low stringency conditions, and a complex (11) comprising at least two of said second proteins, wherein said low stringency conditions comprise hybridization in a buffer comprising 35% formamide, 5X SSC, 50 mM Tris-HCI (pH 7.5), 5 mM EDTA, 0.02% PVP, 0.02% Ficoll, 0.2% BSA, 100 ug/ml denatured salmon sperm DNA, and 10% (wt/vol) dextran sulfate for 18-20 hours at 400 C, washing in a buffer consisting of 2X SSC, 25 mM Tris-HCI (pH 7.4), 5 mM EDTA, and 0.1 % SDS for 1.5 hours at 550 C, and washing in a buffer consisting of 2X SSC, 25 mM Tris-HCI (pH 7.4), 5 mM EDTA, and 0.1% SDS for 1.5 hours at 600 C. 2. The protein complex comprising the following proteins: (i) "Hbet3" (SEQ ID No:3255) or a functionally active derivative thereof, or a functionally active fragment thereof, or a homologue thereof, or a variant of "Hbet3", the variant being encoded by a nucleic acid that hybridizes to the "Hbet3" nucleic acid (SEQ ID No:3256) or its complement under low stringency conditions, (ii) "Hmum2" (SEQ ID No: 3257) or a functionally active derivative thereof, or a functionally active fragment thereof, or a homologue thereof, or a variant of "Hmum2", the variant being encoded by a nucleic acid that hybridizes to the "Hmum2" nucleic acid (SEQ ID No:3258 ) or its complement under low stringency conditions, (iii) "R32611_2"(MGC2650) (SEQ ID No:3259) or a functionally active derivative thereof, or a functionally active fragment thereof, or a homologue thereof, or a variant of "R32611_2"(MGC2650) the variant being encoded by a nucleic acid that hybridizes to the "R32611 2"(MGC2650) nucleic acid (SEQ ID No:3260) or its complement under low stringency conditions, (iv) "Sedlin " (SEQ ID No:3261) or a functionally active derivative thereof, or a functionally active fragment thereof, or a homologue thereof, or a variant of" Sedlin ", the WO 03/072602 PCT/EPO2/50003 348 variant being encoded by a nucleic acid that hybridizes to the "Sedlin " nucleic acid (SEQ ID No:3262) or its complement under low stringency conditions, (v)) "Ehoc-1" (SEQ ID No:3263) or a functionally active derivative thereof, or a functionally active fragment thereof, or a homologue thereof, or a variant of "Ehoc-1", the variant being encoded by a nucleic acid that hybridizes to the "Ehoc-1" nucleic acid (SEQ ID No:3264 ) or its complement under low stringency conditions, (vi)) "Kiaal012" (SEQ ID No:3265) or a functionally active derivative thereof, ora functionally active fragment thereof, or a homologue thereof, or a variant of "Kiaal012", the variant being encoded by a nucleic acid that hybridizes to the "Kiaa1 012" nucleic acid (SEQ ID No:3266 ) or its complement under low stringency conditions, (vii) "Ptd009" (SEQ ID No:3267) or a functionally active derivative thereof, or a functionally active fragment thereof, or a homologue thereof, or a variant of "Ptd009", the variant being encoded by a nucleic acid that hybridizes to the "Ptd009" nucleic acid (SEQ ID No:3268) or its complement under low stringency conditions. 3. The protein complex according to No. 1 comprising all but 1 - 5 of the following proteins: (i) "Hbet3" (SEQ ID No:3255) or a functionally active derivative thereof, or a functionally active fragment thereof, or a homologue thereof, or a variant of "Hbet3", the variant being encoded by a nucleic acid that hybridizes to the "Hbet3" nucleic acid (SEQ ID No:3256 ) or its complement under low stringency conditions, (ii) "Hmum2" (SEQ ID No: 3257) or a functionally active derivative thereof, or a functionally active fragment thereof, or a homologue thereof, or a variant of "Hmum2", the variant being encoded by a nucleic acid that hybridizes to the "Hmum2" nucleic acid (SEQ ID No:3258 ) or its complement under low stringency conditions, (iii) "R32611_2"(MGC2650) (SEQ ID No:3259) or a functionally active derivative thereof, or a functionally active fragment thereof, or a homologue thereof, or a variant of "R32611_2"(MGC2650), the variant being encoded by a nucleic acid that hybridizes to the "R32611_2"(MGC2650) nucleic acid (SEQ ID No:3260 ) or its complement under low stringency conditions, (iv) "Sedlin " (SEQ ID No:3261) or a functionally active derivative thereof, or a functionally active fragment thereof, or a homologue thereof, or a variant of "Sedlin ", the variant being encoded by a nucleic acid that hybridizes to the "Sedlin " nucleic acid (SEQ ID No:3262 ) or its complement under low stringency conditions, WO 03/072602 PCT/EPO2/50003 349 (v) "Ehoc-1" (SEQ ID No:3263) or a functionally active derivative thereof, or a functionally active fragment thereof, or a homologue thereof, or a variant of "Ehoc-1", the variant being encoded by a nucleic acid that hybridizes to the "Ehoc-l" nucleic acid (SEQ ID No:3264) or its complement under low stringency conditions, (vi) "Kiaal012" (SEQ ID No:3265) or a functionally active derivative thereof, or a functionally active fragment thereof, or a homologue thereof, or a variant of "Kiaal012", the variant being encoded by a nucleic acid that hybridizes to the "Kiaa1012" nucleic acid (SEQ ID No:3266 ) or its complement under low stringency conditions, (vii) "Ptd009" (SEQ ID No:3267) or a functionally active derivative thereof, or a functionally active fragment thereof, or a homologue thereof, or a variant of "Ptd009", the variant being encoded by a nucleic acid that hybridizes to the "Ptd009" nucleic acid (SEQ ID No:3268) or its complement under low stringency conditions. 4. The complex of any of No. 1 - 3 comprising a functionally active derivative of said first protein and/or a functionally active derivative of said second protein, wherein the functionally active derivative is a fusion protein comprising said first protein or said second protein fused to an amino acid sequence different from the first protein or second protein, respectively. 5. The complex of No. 4 wherein the functionally active derivative is a fusion protein comprising said first protein or said second protein fused to an affinity tag or label. 6. The complex of any of No. 1 - 3 comprising a fragment of said first protein and/or a fragment of said second protein, which fragment binds to another protein component of said complex. 7. The complex of any of No. 1 -6 that is involved in vesicle targeting activity and/or the effect on ER to Golgi transport. 8. A process for preparing complex of any of No. 1 - 7 and optionally the components thereof comprising the following steps: Expressing a protein (bait) of the complex, preferably the tagged protein, in a target cell, or a tissue or an organ, isolating the protein complex which is attached to the bait WO 03/072602 PCT/EPO2/50003 350 protein, and optionally disassociating the protein complex and isolating the individual complex members. 9. The process according to No. 8 wherein the tagged protein comprises two different tags which allow two separate affinity purification steps. 10. The process according to any of No. 8 - 9 wherein the two tags are separated by a cleavage site for a protease. 11. Components of the complex involved in the vesicle targeting activity and/or the effect on ER to Golgi transport obtainable by a process according to any of No. 8 - 10. 12. Construct, preferably a vector construct, comprising (a) at least two separate nucleic acid sequences each encoding a different protein, or a functionally active fragment or a functionally active derivative thereof at least one of said proteins, or functionally active fragments or functionally active derivative thereof being selected from the first group of proteins according to No. 1 (a) and at least one of said proteins, or functionally active fragments or functionally active derivative thereof being selected from the second group of proteins according to No. 1 (b) or (b)at least two separate nucleic acid sequences each encoding a different protein, or a functionally active fragment or a functionally active derivative thereof, or a homologue or a variant thereof, said proteins being selected from the proteins of complex (II) according to No. 1. 13. Host cell containing a vector comprising a construct of No. 12 or containing several vectors each comprising at least one nucleic acid sequence encoding at least one of the proteins, or functionally active fragments or functionally active derivatives thereof selected from the first group of proteins according to No. 1(a) and the proteins, or functionally active fragments or functionally active derivatives thereof selected from the second group of proteins according to No. 1(b). 14. An antibody or a fragment of said antibody containing the binding domain thereof, selected from an antibody or fragment thereof, which binds the complex of any of No. 1 7 and which does not bind any of the proteins of said complex when uncomplexed.

WO 03/072602 PCT/EPO2/50003 351 15. A kit comprising in one or more container: (a) the complex of any of No. 1 - 7 (b) an antibody according to No. 14 and/or (c) a nucleic acid encoding a protein of the complex of any of No. 1 - 7 (d) cells expressing the complex of any of No. 1 - 7 and optionally (e) further components such as reagents and working instructions. 16. A kit according to No. 15 for processing a substrate of said complex. 17. A kit according to No. 16 for the diagnosis or prognosis of a disease or a disease risk, preferentially for a disease or disorder such as inherited developmental diseases such as X-linked spondyloepiphyseal dysplasia tarda. 18. Array, preferably a microarray, in which at least a complex according to any of No. 1 - 7 and/or at least one antibody according to No. 16 is attached to a solid carrier. 19. A process for modifying a physiological substrate of the complex comprising the step of bringing into contact a complex of any of No. 1 - 7 with said substrate, such that said substrate is modified. 20. A pharmaceutical composition comprising the protein complex of any of No. 1 - 7 and a pharmaceutical acceptable carrier. 21. A pharmaceutical composition according to No. 20 for the treatment of diseases and disorders such as inherited developmental diseases such as X-linked spondyloepiphyseal dysplasia tarda. 22. A method for screening for a molecule that binds to a complex of anyone of No. 1 - 7 comprising the steps of (a) exposing said complex, or a cell or organism containing same to one or more candidate molecules; and (b) determining whether said candidate molecule is bound to the complex or protein.

WO 03/072602 PCT/EPO2/50003 352 23. A method for screening for a molecule that modulates directly or indirectly the function, activity, composition or formation of the complex of any one of No. 1 - 7 comprising the steps of (a) exposing said complex, or a cell or organism containing TRAPP-complex to one or more candidate molecules; and (b) determining the amount of activity of protein components of, and/or intracellular localization of, said complex and/or the transcription level of a gene regulated by the complex and/or the abundance and/or activity of a protein or protein complex dependent on the function of the complex and/or product of a gene dependent on the complex in the presence of the one or more candidate molecules, wherein a change in said amount, activity, protein components or intracellular localization relative to said amount, activity, protein components and/or intracellular localization and/or a change in the transcription level of a gene dependent on the complex and/or the abundance and/or activity of a protein or protein complex dependent on the function of the complex and/or product of a gene dependent on the complex in the absence of said candidate molecules indicates that the molecule modulates function, activity or composition of said complex. 24. The method of No. 23, wherein the amount of said complex is determined. 25. The method of No. 23, wherein the activity of said complex is determined. 26. The method of No. 25, wherein said determining step comprises isolating from the cell or organism said complex to produce said isolated complex and contacting said isolated complex in the presence or absence of a candidate molecule with a substrate of said complex and determining the processing of said substrate is modified in the presence of said candidate molecule. 27. The method of No. 23, wherein the amount of the individual protein components of said complex are determined. 28. The method of No. 27, wherein said determining step comprises determining whether (i) "Hbet3" (SEQ ID No:3255) or a functionally active derivative thereof, or a functionally active fragment thereof, or a homologue thereof, or a variant of" Hbet3", the variant WO 03/072602 PCT/EPO2/50003 353 being encoded by a nucleic acid that hybridizes to the" Hbet3" nucleic acid (SEQ ID No:3256) or its complement under low stringency conditions, and/or (ii) "Hmum2" (SEQ ID No: 3257) or a functionally active derivative thereof, or a functionally active fragment thereof, or a homologue thereof, or a variant of" Hmum2", the variant being encoded by a nucleic acid that hybridizes to the" Hmum2" nucleic acid (SEQ ID No:3258 ) or its complement under low stringency conditions, and/or (iii) "R32611 2"(MGC2650) (SEQ ID No:3259) or a functionally active derivative thereof, or a functionally active fragment thereof, or a homologue thereof, or a variant of "R32611_2"(MGC2650) the variant being encoded by a nucleic acid that hybridizes to the "R32611_2"(MGC2650) nucleic acid (SEQ ID No:3260 ) or its complement under low stringency conditions, and/or (iv) "Sedlin "(SEQ ID No:3261) or a functionally active derivative thereof, or a functionally active fragment thereof, or a homologue thereof, or a variant of" Sedlin ", the variant being encoded by a nucleic acid that hybridizes to the " Sedlin " nucleic acid (SEQ ID No:3262 ) or its complement under low stringency conditions, and/or (v)) "Ehoc-1" (SEQ ID No:3263) or a functionally active derivative thereof, or a functionally active fragment thereof, or a homologue thereof, or a variant of" Ehoc-1", the variant being encoded by a nucleic acid that hybridizes to the" Ehoc-1" nucleic acid (SEQ ID No:3264 ) or its complement under low stringency conditions, and/or (vi)) "Kiaa1012" (SEQ ID No:3265) ora functionally active derivative thereof, or a functionally active fragment thereof, or a homologue thereof, or a variant of "Kiaa1012", the variant being encoded by a nucleic acid that hybridizes to the "Kiaal 012" nucleic acid (SEQ ID No:3266 ) or its complement under low stringency conditions, and/or (vii) "Ptd009" (SEQ ID No:3267) or a functionally active derivative thereof, or a functionally active fragment thereof, or a homologue thereof, or a variant of "Ptd009", the variant being encoded by a nucleic acid that hybridizes to the "Ptd009" nucleic acid (SEQ ID No:3268) or its complement under low stringency conditions, is present in the complex. 29. The method of any of No. 23 - 28, wherein said method is a method of screening for a drug for treatment or prevention of a disease or disorder such as inherited developmental diseases such as X-linked spondyloepiphyseal dysplasia tarda.

WO 03/072602 PCT/EPO2/50003 354 30. Use of a molecule that modulates the amount of, activity of, or the protein components of the complex of any one of No. 1 - 7 for the manufacture of a medicament for the treatment or prevention of a disease or disorder such as inherited developmental diseases such as X-linked spondyloepiphyseal dysplasia tarda. 31. A method for the production of a pharmaceutical composition comprising carrying out the method of any of No. 1 - 7 to identify a molecule that modulates the function, activity, composition or formation of said complex, and further comprising mixing the identified molecule with a pharmaceutically acceptable carrier. 32. A method for diagnosing or screening for the presence of a disease or disorder or a predisposition for developing a disease or disorder in a subject, which disease or disorder is characterized by an aberrant amount of, activity of, or component composition of, or intracellular localization of the complex of any one of the No. 1 - 7, comprising determining the amount of, activity of, protein components of, and/or intracellular localization of, said complex and/or the transcription level of a gene dependend on the complex and/or the abundance and/or activity of a protein or protein complex dependend on the function of the complex andlor product of a gene dependent on the complex in a comparative sample derived from a subject, wherein a difference in said amount, activity, or protein components of, said complex in a corresponding sample from a subject not having the disease or disorder or predisposition indicates the presence in the subject of the disease or disorder or predisposition in the subject. 33. The method of No. 32, wherein the amount of said complex is determined. 34. The method of No. 32, wherein the activity of said complex is determined. 35. The method of No. 34, wherein said determining step comprises isolating from the subject said complex to produce said isolated complex and contacting said isolated complex in the presence or absence of a candidate molecule with a substrate of said complex and determining whether said substrate is processed in the absence of the candidate molecule and whether the processing of said substrate is modified in the presence of said candidate molecule.

WO 03/072602 PCT/EPO2/50003 355 36. The method of No. 32, wherein the amount of the individual protein components of said complex are determined. 37. The method of No. 36, wherein said determining step comprises determining whether (i) "Hbet3" (SEQ ID No:3255) or a functionally active derivative thereof, or a functionally active fragment thereof, or a homologue thereof, or a variant of "Hbet3", the variant being encoded by a nucleic acid that hybridizes to the "Hbet3" nucleic acid (SEQ ID No:3256) or its complement under low stringency conditions, and/or (ii) "Hmum2" (SEQ ID No: 3257) or a functionally active derivative thereof, or a functionally active fragment thereof, or a homologue thereof, or a variant of "Hmum2", the variant being encoded by a nucleic acid that hybridizes to the "Hmum2" nucleic acid (SEQ ID No:3258 ) or its complement under low stringency conditions, and/or (iii) "R32611_2"(MGC2650) (SEQ ID No:3259) or a functionally active derivative thereof, or a functionally active fragment thereof, or a homologue thereof, or a variant of "R32611_2"(MGC2650) the variant being encoded by a nucleic acid that hybridizes to the "R32611 2"(MGC2650) nucleic acid (SEQ ID No:3260) or its complement under low stringency conditions, and/or (iv) "Sedlin " (SEQ ID No:3261) or a functionally active derivative thereof, or a functionally active fragment thereof, or a homologue thereof, or a variant of "Sedlin ", the variant being encoded by a nucleic acid that hybridizes to the "Sedlin" nucleic acid (SEQ ID No:3262 ) or its complement under low stringency conditions, and/or (v) "Ehoc-1" (SEQ ID No:3263) or a functionally active derivative thereof, or a functionally active fragment thereof, or a homologue thereof, or a variant of "Ehoc-1", the variant being encoded by a nucleic acid that hybridizes to the "Ehoc-1" nucleic acid (SEQ ID No:3264) or its complement under low stringency conditions, and/or (vi)) "Kiaal012" (SEQ ID No:3265) or a functionally active derivative thereof, or a functionally active fragment thereof, or a homologue thereof, or a variant of "Kiaal1012", the variant being encoded by a nucleic acid that hybridizes to the "Kiaa1012" nucleic acid (SEQ ID No:3266 ) or its complement under low stringency conditions, and/or (vii) "Ptd009" (SEQ ID No:3267) or a functionally active derivative thereof, or a functionally active fragment thereof, or a homologue thereof, or a variant of "Ptd009", the variant being encoded by a nucleic acid that hybridizes to the "Ptd009" nucleic acid (SEQ ID No:3268) or its complement under low stringency conditions, WO 03/072602 PCT/EPO2/50003 356 is present in the complex. 38. The complex of any one of No. 1 - 7, or the antibody or fragment of No. 16, for use in a method of diagnosing a disease or disorder such as inherited developmental diseases such as X-linked spondyloepiphyseal dysplasia tarda. 39. A method for treating or preventing a disease or disorder characterized by an aberrant amount of, activity or component composition of or intracellular localization of, the complex of anyone of No. 1 - 7, comprising administering to a subject in need of such treatment or prevention a therapeutically effective amount of one or more molecules that modulate the amount of, the biochemical activity, or protein composition of, said complex. 40. The method according to No. 39, wherein said disease or disorder involves decreased levels of the amount or activity of said complex. 41. The method according to No. 39 , wherein said disease or disorder involves increased levels of the amount or activity of said complex. 42. Complex of any of No. 1 - 7 and/or protein selected from the following proteins (i) "Hbet3" (SEQ ID No:3255) or a functionally active derivative thereof, or a functionally active fragment thereof, or a homologue thereof, or a variant of "Hbet3", the variant being encoded by a nucleic acid that hybridizes to the "Hbet3" nucleic acid (SEQ ID No:3256) or its complement under low stringency conditions, (ii) "Hmum2" (SEQ ID No: 3257) or a functionally active derivative thereof, or a functionally active fragment thereof, or a homologue thereof, or a variant of "Hmum2", the variant being encoded by a nucleic acid that hybridizes to the "Hmum2" nucleic acid (SEQ ID No:3258 ) or its complement under low stringency conditions, (iii) "R32611_2"(MGC2650) (SEQ ID No:3259) or a functionally active derivative thereof, or a functionally active fragment thereof, or a homologue thereof, or a variant of "R32611_2"(MGC2650) the variant being encoded by a nucleic acid that hybridizes to the "R32611_2"(MGC2650) nucleic acid (SEQ ID No:3260) or its complement under low stringency conditions, WO 03/072602 PCT/EPO2/50003 357 (iv) "Sedlin " (SEQ ID No:3261) or a functionally active derivative thereof, or a functionally active fragment thereof, or a homologue thereof, or a variant of "Sedlin ", the variant being encoded by a nucleic acid that hybridizes to the "Sedlin " nucleic acid (SEQ ID No:3262 ) or its complement under low stringency conditions, (v) "Ehoc-1" (SEQ ID No:3263) or a functionally active derivative thereof, or a functionally active fragment thereof, or a homologue thereof, or a variant of "Ehoc-1", the variant being encoded by a nucleic acid that hybridizes to the "Ehoc-1" nucleic acid (SEQ ID No:3264 ) or its complement under low stringency conditions, (vi)) "Kiaal1012" (SEQ ID No:3265) or a functionally active derivative thereof, or a functionally active fragment thereof, or a homologue thereof, or a variant of "Kiaal012", the variant being encoded by a nucleic acid that hybridizes to the "Kiaal 012" nucleic acid (SEQ ID No:3266 ) or its complement under low stringency conditions, (vii) "Ptd009" (SEQ ID No:3267) or a functionally active derivative thereof, or a functionally active fragment thereof, or a homologue thereof, or a variant of "Ptd009", the variant being encoded by a nucleic acid that hybridizes to the "Ptd009" nucleic acid (SEQ ID No:3268) or its complement under low stringency conditions is present in the complex as a target for an active agent of a pharmaceutical, preferably a drug target in the treatment or prevention of a disease or disorder such as inherited developmental diseases such as X-linked spondyloepiphyseal dysplasia tarda. In a preferred embodiment of the present invention, the protein components of the complex are vertebrate homologs of the yeast proteins, or a mixture of yeast and vertebrate homolog proteins. In a more preferred embodiment, the protein components of the complex are mammalian homologs of the yeast proteins, or a mixture of yeast and mammalian homolog proteins. In particular aspects,n the native component proteins, or derivatives or fragments of the complex are obtained from a mammal such as mouse, rat, pig, cow, dog, monkey, human, sheep or horse. In another preferred embodiment, the protein components of the complex are human homologs of the yeast proteins, or a mixture of yeast and human homolog proteins. In yet another preferred embodiment, the protein components of the complex are a mixture of yeast, vertebrate, mammalian and/or human proteins. As used herein, a "functionally active complex" refers to that material displaying one or more known functional attributes of a wild type complex, including but WO 03/072602 PCT/EPO2/50003 358 not limited to binding to a complex-specific antibody or physiological function (for physiological functions of the protein complexes of the present inventio A specific embodiment of the present invention is directed to a complex comprising of a fragment of a component protein that can be bound by an anti component protein antibody or bound by an antibody specific for the protein complex or wherein the fragment is able to bind another component protein of the complex. In another specific embodiments, the present invention is directed to a complex comprising a fragment of one or more members of the complex. Fragments, or proteins comprising fragments, lacking a region of a member of the complex, are also provided. Nucleic acids encoding the foregoing are also provided in the present invention. The present invention is also directed to methods for production of a protein complex of the present invention and derivatives of the complex and/or fragments and/or derivatives of individual component proteins or the complex e. g. by the TAP method described further below. Pharmaceutical compositions are also provided. The present invention is further directed to complexes comprising a fusion protein which comprises a component of the complex or a fragment thereof linked via a covalent bond to an amino acid sequence different from said component protein, as well as nucleic acids encoding the protein, fusions and fragments thereof. For example, the non-component protein portion of the fusion protein, which can be added to the N terminal, the C-terminal or inserted into the amino acid sequence of the complex component can comprise a few amino acids, which provide an epitope that is used as a target for affinity purification of the fusion protein and/or complex. The invention is further directed to methods for modulating (i.e., inhibiting or enhancing) the amount of, activity of, or the identity of the protein components of, a complex of the present invention. The protein components of a complex of the present invention have been implicated in many physiological processes. The present invention is also directed to methods for screening a complex, as well as a derivative of the complex, for the ability to alter a cell function, particularly a cell function in which the complex and/or a component protein of the complex has been implicated. Moreover, the present invention provides a process for the identification and/or preparation of an effector of a composition according to the invention which process comprises the steps of bringing into contact the composition of the invention or of a component thereof with a compound, a mixture of compounds or a library of compounds and determining whether the compounds or certain compounds of the WO 03/072602 PCT/EPO2/50003 359 mixture or library bind to the composition of the invention and/or a component thereof and/or affects the biological activity of such a composition or component and then optionally further purifying the compound positively tested as effector by such a process. A major application of the composition according to the invention results in the identification of an active agent capable of binding thereto. Hence, the compositions of the invention are useful tools in screening for new pharmaceutical drugs. The present invention is also directed to a method for isolating the complex and the component proteins comprising tagging a protein of the complex with a sequence that allows affinity purification of the tagged protein, expressing such protein in a target cell, isolating the protein complex which is attached to the tagged protein, and optionally disassociating the protein complex and isolating the individual complex members. The present invention further relates to a composition, preferably a protein complex, which is obtainable by the method comprising the following steps: tagging a protein as defined above, i.e. a protein which forms part of a protein complex, with a moiety, preferably an amino acid sequence, that allows affinity purification of the tagged protein and expressing such protein in a target cell and isolating the protein complex which is attached to the tagged protein. The details of such purification are described in WO 00/09716 and in Rigaut, G. et al. (1999), Nature Biotechnology, Vol. 17 (10): 1030 1032 and further herein below. The tagging can essentially be performed with any moiety which is capable of providing a specific interaction with a further moiety, e.g. in the sense of a ligand receptor interaction, antigen antibody interaction or the like. The tagged protein can also be expressed in an amount in the target cell which comes close to the physiological concentration in order to avoid a complex formation merely due to high concentration of the expressed protein but not reflecting the natural occurring complex. In a further preferred embodiment, the composition is obtained by using a tagged protein which comprises two different tags which allow two different affinity purification steps. This measure allows a higher degree of purification of the composition in question. In a further preferred embodiment the tagged protein comprises two tags that are separated by a cleavage site for a protease. This allows a step-by-step purification on affinity columns.

WO 03/072602 PCT/EPO2/50003 360 The present invention is also directed to therapeutic and prophylactic, as well as diagnostic, prognostic, and screening methods and compositions based upon the complex (and the nucleic acids encoding the individual proteins that participate in the complex). Therapeutic compounds of the invention include, but are not limited to, a complex of the invention, and a complex where one or more members of the complex is a derivative or fragment thereof. The present invention is also directed to complex specific antibodies to and nucleic acids encoding the foregoing; and antisense nucleic acids to the nucleotide sequences encoding the complex components. Diagnostic, prognostic and screening kits are also provided. The present invention further relates to a kit comprising a composition as described above, optionally together with further reagents and working instructions. The further reagents may be, for example, buffers, substrates for enzymes but also carrier material such as beads, filters, microarrays and other solid carries. The working instructions may indicate how to use the ingredients of the kit in order to perform a desired assay. The present invention further relates to a nucleic acid encoding a component of a composition as defined above. Such a nucleic acid may be used for example to express a desired tagged protein in a given cell for the isolation of a complex or component according to the invention. Such a nucleic acid may also be used for the identification and isolation of genes from other organisms by cross species hybridization. The present invention further relates to a construct, preferably a vector construct, which comprises a nucleic acid as described above. Such constructs may comprise expression controlling elements such as promoters, enhancers and terminators in order to express the nucleic acids in a given host cell, preferably under conditions which resemble the physiological concentrations. The present invention further relates to a host cell containing a construct as defined above. Such a host cell can be, e.g., any eukaryotic cell such as yeast, plant or mammalian, whereas human cells are preferred. Such host cells may form the starting material for isolation of a complex according to the present invention. Animal models and methods of screening for modulators (i.e., agonists, and antagonists) of the amount of, activity of, or protein component composition of, a complex of the present invention are also provided. The present invention further relates to a kit comprising a composition as described above, optionally together with further reagents and working instructions. The WO 03/072602 PCT/EPO2/50003 361 further reagents may be, for example, buffers, substrates for enzymes but also carrier material such as beads, filters, microarrays and other solid carries. The working instructions may indicate how to use the ingredients of the kit in order to perform a desired assay. PROTOCOLS: ISOLATION OF PROTEIN COMPLEXES: a) ISOLATION OF COMPLEXES FROM YEAST: Yeast strain construction: Yeast strains expressing TAP-tagged ORFs were constructed in a semi-automated way essentially according to Rigaut et al. (Rigaut, G. et al., Nat Biotechnol 17, 1030-2. (1999)) and Puig et al. (Puig, O. et al., Methods 24, 218-29. (2001)). TAP-purification of soluble proteins: The purification was done from 2 liters of yeast cells grown to late log phase (OD600 ~3 - 4). Cells were harvested and the pellet was frozen in liquid nitrogen and stored at -80 oC. All steps were done at 49C. For preparation of protein lysates the cells were resuspended in buffer A (50 mM Tris-HCI pH 7.5, 100 mM NaCI, 0.15 % NP 40, 1.5 mM MgCt, 0.5 mM DTT, protease inhibitors) and subjected to mechanical disruption with glass beads. Lysates were clarified by two successive centrifugation steps at 20.000 x g for 10 min and 100,000 x g for 1 hour. After addition of glycerol to 5 % final concentration the lysates were frozen in liquid nitrogen and stored at -80 0 C. For the first purification step 500 pI of rabbit IgG-Agarose (50:50 slurry, Sigma A2909) pre-equilibrated in buffer A were added to the lysate and the sample was rotated for 1 hour. The unbound fraction was discarded and the beads with the bound material were transferred to a 0.8 ml column (MoBiTec M1002, 90 pm filter). The beads were washed with 10 ml of buffer A. 150 ptl of buffer A and 4 gl of TEV protease (1 mg/ml) were added to the column and the sample was incubated on a shaker at 16 0 C for 1 hour. The eluate was recovered by pressing with a syringe.

WO 03/072602 PCT/EPO2/50003 362 150 p.1 of buffer A containing 4 mM CaCl 2 was added to the previous eluate and this mixture was transferred to a MoBiTec column containing 300 p1 (bead volume) of Calmodulin affinity resin (Stratagene #214303) which was prewashed in buffer A containing 2 mM CaC 2 . The samples were rotated for 1 hour at 4 0 C. After washing of the beads with 5 ml of buffer A containing 2 mM CaCI 2 , protein complexes were eluted wth 600 pl of elution buffer (10 mM Tris-HCI pH 8.0, 5 mM EGTA). The samples were concentrated in siliconized tubes in a speed vac. Proteins were detected by polyacrylamide gel electrophoresis followed by staining with colloidal Coomassie blue. TAP-purification of membrane proteins: The purification was done from 2 liters of yeast cells grown to late log phase (OD 60 0 ~3 4). Cells were harvested and the pellet was frozen in liquid nitrogen and stored at -80 OC. All steps were done at 4 0 C. For the purification of TAP-tagged membrane proteins cells were lysed in buffer containing 50 mM Hepes/KOH pH 7.5, 150 mM KCI, 0.25 % NP-40, 2 mM MgCI 2 , 2 mM EDTA, 0.5 mM DTT and protease inhibitors. The extracts were spun at 20,000 x g for 10 min and the resulting supematant was adjusted to 1.5 % NP-40 and 5 % glycerol. Samples were incubated for 30 min with end-over-end shaking and then centrifuged at 180,000 x g for 30 min. The resulting supernatant was immediately used for TAP-purification. For the first purification step 500 p!l of rabbit IgG-Agarose (50:50 slurry, Sigma A2909) pre-equilibrated in buffer B (50 mM Tris-HCI pH 7.5, 100 mM NaCI, 0.5 % NP-40, 1.5 mM MgCI 2 , 0.5 mM DTT, protease inhibitors) was added to the lysate and the sample was rotated for 1 hour. The unbound fraction was discarded and the beads with the bound material were transferred to a 0.8 ml column (MoBiTec M1002, 90 pm filter). The beads were washed with 10 ml of buffer B. 150 p1 of buffer B and 8 p1 of TEV protease (1 mg/ml) were added to the column and the sample was incubated on a shaker at 16 0 C for 1 hour. The eluate was recovered by pressing with a syringe. 150 p1 of buffer B containing 4 mM CaCl 2 was added to the previous eluate and this mixture was transferred to a MoBiTec column containing 300 p1 (bead volume) of Calmodulin affinity resin (Stratagene #214303) which was prewashed in buffer B containing 2 mM CaCI 2 . The samples were rotated for 1 hour at 40C.

WO 03/072602 PCT/EPO2/50003 363 After washing of the beads with 5 ml of buffer B containing 2 mM CaCI 2 , protein complexes were eluted with 600 pl of elution buffer (10 mM Tris-HCI pH 8.0, 5 mM EGTA). The samples were concentrated in siliconized tubes in a speed vac. Proteins were detected by polyacrylamide gel electrophoresis followed by staining with colloidal Coomassie blue. b) ISOLATION OF COMPLEXES FROM MAMMALIAN CELLS Cells: Retroviral transduction vectors containing the TAP-cassette were generated by directional cloning of PCR-amplified ORFs into a modified version of a MmoLV-based vector via the Gateway site-specific recombination sstem (Life Technologies). Virus stocks were generated in a HEK293 gag-pol packaging cell line by pseudotyping with VSV-G. Cells were infected and complexe were purified after cell expansion and cultivation of 3-5 using a modified TAP-protocoll Standard lysis protocol: The medium was removed from the culture dish and the cells were scraped directly from the plate with help of a rubber policeman. The cells were collected on ice washed 3 times with PBS and resuspended in lysis buffer (50 mM Tris, pH: 7.5; 5 % glycerol; 0,2 % IGEPAL; 1.5 mM MgCI2; 1 mM DTT; 100 mM NaCI; 50 mM NaF; 1 mM Na3VO4 + protease inhibitors). The cells were lysed for 30 min on ice, spun for 10 min. at 20,000g and re-spun for I h at 100,000g. The supernatant was recovered, rapidly frozen in liquid nitrogen and stored at -80 °C. For pre-clearing the thawed lysate was incubated with 500 pl sepharose CL-4B beads (Amersham Pharmacia) for 1 h shaking and finally processed according the TAP protocol. Nuclear lysis protocol: WO 03/072602 PCT/EPO2/50003 364 SThe medium was removed from the culture dish and the cells were scraped directly from the plate with help of a rubber policeman. The cells were collected on ice washed 3 times with PBS and resuspended in buffer A (10 mM Tris-CI, pH 7.5; 1, 5 mM MgCl2; 10 mM KCl; 1 mM DTT, 50 mM NaF; 1 mM Na3VO4). To isolate the nuclei the lysate was dounced with a tight fitted pestle in a dounce homogenizer for 15 strokes. The nuclei were harvested by centrifugation (10 min. at 2000 g and 20 min. at 16,000 g) and lysed in buffer B (50 mM Tris-CI, pH: 7.5; 1.5 mM MgCI; 20 % glycerol; 420 mM NaCI; 1mM DTT; 50 mM NaF; 1 mM Na3VO4) for 30 min. on ice with frequent shaking. The protein lysate was cleared by centrifugation (30 min at 100,000 g) and 1 : 4 diluted with buffer C (50 mM Tris-CI, pH: 7.5; 1 mM DTT; 0.26 % NP40; 1.5 mM MgCI; 50 mM NaF; 1 mM Na3VO4). After 30 min incubation on ice the lysate was re-spun for 30 min at 100,000 g, quickly frozen in liquid nitrogen and stored at -80 oC. For pre-clearing the thawed lysate was incubated with 500 pl sepharose CL-4B beads (Amersham Pharmacia) for 1 h shaking and finally processed according the TAP protocol. MASS SPECTROMETRIC ANALYSIS Protein digestion prior to mass spectrometric analysis: Gel-separated proteins were reduced, alkylated and digested in gel essentially following the procedure described by Shevchenko et al. (Shevchenko, A., Wilm, M., Vorm, O., Mann, M. Anal Chem 1996, 68, 850-858). Briefly, gel-separated proteins were excised from the gel using a clean scalpel, reduced using 10 mM DTT (in 5mM ammonium bicarbonate, 54 'C, 45 min) and subsequently alkylated with 55 mM iodoacetamid (in 5 mM ammonium bicarbonate) at room temperature in the dark (30 min). Reduced and alkylated proteins were digested in gel with porcine trypsin (Promega) at a protease concentration of 12.5 ng/pl in 5mM ammonium bicarbonate. Digestion was allowed to proceed for 4 hours at 37 °C and the reaction was subsequently stopped using 2 pl 25% TFA. Desalting and concentration of peptides produced by in-gel digestion of gel-separated proteins: WO 03/072602 PCT/EPO2/50003 365 Peptides were desalted and concentrated using a prefabricated uZipTip (Millipore) reversed phase column. Peptides were eluted directly onto stainless steel MS sample holders using 2Ipl eluent (70% acetonitrile in 5% TFA containing 2mg/ml alpha-Cyano-4 hydroxy-cinnamic acid and two standard peptides for internal calibration of mass spectra). Mass spectrometric data acquisition: Matrix-assisted laser desorptionlionisation (MALDI) time-of-flight (TOF) mass spectra were acquired in delayed extraction mode on a Voyager DE-STR PRO MALDI mass spectrometer (Applied Biosystems) equipped with a 337 nm nitrogen laser. 500 laser shots were averaged in order to produce final spectra. Spectra were automatically internally calibrated using two standard peptides. The monoisotopic masses for all peptide ion signals detected in the acquired spectra were determined and used for database searching. Protein sequence database searching using peptide mass fingerprinting (PMF) data: The list of monoisotopic peptide masses obtained from the MALDI mass spectrum was used to query a fasta formatted protein sequence database that contained all protein sequences from S. cerevesia. Proteins were identified by peptide mass fingerprinting (Mann, M., Hojrup, P., Roep-storff, P. Biol Mass Spectrom 1993, 22, 338-345; Pappin, D., Hojrup, P, Bleasby, AJ Curr. Biol. 1993, 3, 327-33; Henzel, W. J., Billeci, T. M., Stults, J. T., Wong, S. C., Grimley, C., Watanabe, C. Proc Natl Acad Sci U S A 1993, 90, 5011-5015; Yates, J. R., Speicher, S., Griffin, P. R., Hunkapiller, T. Anal Biochem 1993, 214, 397-408; James, P., Quadroni, M., Carafoli, E., Gonnet, G. Biochem Biophys Res Commun 1993, 195, 58-64) using the software tool Profound (Proteometrics). In PMF, a protein is identified by correlating the measured peptide masses with theoretical digests of all proteins present in the database. Search criteria included: tryptic protein cleavage, monoisotopic masses, 30 ppm mass accuracy. No restrictions on protein size or isoelectric point were imposed.

BIOINFORMATICS

WO 03/072602 PCT/EPO2/50003 366 Functional and localization information about yeast proteins was retrieved from the Yeast Protein Database (YPD (Constanzo, M.C. et al., 2001, Nucl. Acid Res, 29: 75-9; Hodges, P.E. et al., 1999, Nucl. Acids Res 27: 69-73)) released in August 2001. In order to get a more concise classification for localization and function, YPD classes were merged. Protein domain analysis was performed using SMART (Schultz, J., Copley, R. R., Doerks, T., Ponting, C. P. & Bork, P. Schultz, J., Copley, R. R., Doerks, T., Ponting, C. P. & Bork, P. SMART, Nucleic Acids Res 28, 231-4. (2000)). PsiBlast (Altschul, S. F. et al. Gapped BLAST and PSI-BLAST: Nucleic Acids Res 25, 3389-402. (1997)) was used for homology analysis. All additional analysis software has been developed in house, using Perl and Python. ASSAYS FOR ASSAYING THE ACTIVITIES OF THE COMPLEXES PRESENTED IN THE INVENTION An exemplary ATPase-assay can be carried out by contacting a complex having ATPase activity (such as f.e. complex 141, 44,120,27,97,110, 115, 208, 257,309, 337, 347,349,386 ) with an ATP substrate under appropriate conditions and detecting the release of free phosphate. The detection of free phosphate can be carried out, e. g., using a coupled spectrophotometric assay by measuring the phosphorolysis of 7 methylinosine catalysed by purine nucleotide phosphorylase. (see e.g. Rieger CE et al, 1997, Anal Biochem, 246: 86-95) An exemplary chromatin remodeling assay can be carried out by contacting a complex having chromatin remodeling activity (such as f.e. complex 60, 72, 86, 95,116, 154, 193, 207 ) with an array of nucleosomes assembled on radioactive (32P phosphate) end labeled DNA under appropriate conditions and detecting the changed nucleosomal structure. The detection of the changed nucleosomal structure can be carried out, e.g., using electrophoretic mobility shift analysis through electrophoresis through agarose gels and measuring the radioactivity of the bands (see e.g. Steger, DJ et al, 1997, Methods 12: 276-85) An exemplary DNase assay can be carried out by contacting a complex having DNase activity (such as f.e. complex 56 ) with double stranded DNA and ethidium bromide under WO 03/072602 PCT/EPO2/50003 367 appropriate conditions and detecting the amount of fluorescence produced by ethidium bromide intercalated in double stranded DNA. This assay is based on the decrease of fluorescence after cleavage of the double stranded DNA substrate. (see e.g. Friedhoff, P. et al, 1996, Methods 240: 283-8) An exemplary DNA binding assay carn be carried out by contacting a complex having DNA binding activity (such as f.e. complex 11, 74, 108, 125, 190, 277, 407 ) with a radioactive [32P] end-labeled DNA substrate under appropriate conditions and detecting bound protein. The detection of DNA bound protein can be carried out, e.g., by filtrating the solution through a nitrocellulose filter and determining the radioactivity bound to the filter (This assay is based on the retention of nucleic acid-protein complexes on Nitrocellulose whereas free nucleic acid can pass through the filter. (see e.g. Nowock, J. et all., 1982, Methods 30: 607-15) An exemplary DNA endonuclease assay can be carried out by contacting a complex having DNA endonuclease activity (such as f.e. complex 149, 367, 369 ) with a radioactivity [Tritium 3H] labeled DNA substrate under appropriate conditions and detecting the release of radioactive DNA fragments. The detection of free radioactive DNA fragments can be carried out, e.g., separating DNA substrate and cleavage products through agarose gel electrophoresis and quantifying the radioactivity of the bands (see e.g. Goldstein, JN. and Weller, SK, 1998, Methods 244: 442-57) An exemplary DNA exonuclease assay can be carried out by contacting a complex having DNA exonuclease activity (such as f.e. complex 152 ) with a radioactivity [Tritium 3H] labeled DNA substrate under appropriate conditions and detecting the release of free radioactive nucleotides. The detection of free radioactive nucleotides can be carried out, e.g., measuring the release of acid-soluble radioactivity by adding 5% trichloroacetic acid, centrifuging and measuring the radioactivity of the soluble fraction (see e.g. Goldstein , JN and Weller, SK, 1998, Methods 244: 422-57) An exemplary DNA helicase assay can be carried out by contacting a complex having DNA helicase activity (such as f.e. complex 41, 50, 139, 229, 230 ) with a radiolabeled DNA/DNA double stranded substrate and ATP under appropriate conditions and WO 03/072602 PCT/EPO2/50003 368 detecting the the release of free DNA single strands. The DNA/DNA double stranded substrate is prepared by annealing a radioactivity [32 phospate] end-labeled DNA oligonucleotide with an DNA oligonucleotide of complementary sequence. The detection of free DNA single strands can be carried out, e.g., using gel electrophoresis and measuring the radioactivity of the bands. (see e.g. Kyono, K. et al, 1998, Methods 257: 120-6) An exemplary DNA polymerase assay can be carried out by contacting a complex having DNA polymerase activity (such as f.e. complex 53, 150, 189, 219 ) with single standed DNA template, a nucleotide mixture (NTPs and dNTPs), primase and single stranded DNA-binding protein under appropriate conditions (in an appropriate buffer) and detecting the release of single stranded DNA-binding protein. This assay is based on the recovery of the intrinsic fluorescence of single-stranded DNA binding protein (SSB) as it is displaced from the DNA template during DNA synthesis (see e.g. Griep, MA, 1995, Methods 232: 180-9) An exemplary DNA topoisomerase I assay can be carried out by contacting a complex having DNA topoisomerase I activity (such as f.e. complex 137 ) with a supercoiled plasmid DNA substrate under appropriate conditions and detecting the relaxed plasmid DNA product. The detection of relaxed plasmid DNA can be carried out, e.g., using agarose gel electrophoresis to separate relaxed plasmid DNA from supercoiled substrate DNA and staining DNA bands with ethidium bromide. (see e.g. Onishi , Y. Et all, 1993, Methods 210:63-8) An exemplary DNA topoisomerase 11 assay can be carried out by contacting a complex having DNA topoisomerase II activity (such as f.e. complex 130 ) with a supercoiled plasmid DNA substrate and ATP under appropriate conditions and detecting the relaxed plasmid DNA product. The detection of relaxed plasmid DNA can be carried out, e.g., using agarose gel electrophoresis to separate relaxed plasmid DNA from supercoiled substrate DNA and staining DNA bands with ethidium bromide. (see e.g. Onishi , Y. et al, 1993, Methods 210:63-8) An exemplary RNA binding assay can be carried out by contacting a complex having RNA binding activity (such as f.e. complex 13, 162, 205, 209, 238, 351, 363, 366 ) with a WO 03/072602 PCT/EPO2/50003 369 radioactive [32P] end-labeled RNA substrate, e.g. a poly (A) RNA, under appropriate conditions and detecting bound protein. The detection of bound protein can be carried out, e.g., by filtrating the solution through a nitrocellulose filter and determining the radioactivity bound to the filter. This assay is based on the retention of nucleic acid protein complexes on Nitrocellulose whereas free nucleic acid can pass through the filter (see e.g. Wahle, E., 1991, Methods 66: 759-68) An exemplary Cap binding assay can be carried out by contacting a complex having Cap binding activity (such as f.e. complex 143) with a radioactively labeled capped RNA substrate under appropriate conditions and detection of the formed protein-RNA complex. The detection of the protein-RNA complex can be carried out, e.g., using a gel shift assay to measure the altered electrophoretic mobility of the complex bound to the radiolabeled RNA substrate. (see e.g. Schwemmle, M. et al, 1991, Methods 201: 139-45) An exemplary RNA decay assay can be carried out by contacting a complex having RNA stabilizing or degrading activity (such as f.e. complex 132, 167, 187,226 ) with a RNA substrate under appropriate conditions and detecting the occurance of RNA fragments. The detection of RNA fragments can be carried out, e.g., by separating the fragments through agarose gel electrophoresis and hybridization with radioactively labeled RNA probes of complementary sequence. (see e.g. Peltz, SW et all, 1993, Methods 7:1737-54) An exemplary RNA exonuclease assay can be carried out by contacting a complex having RNA exonuclease activity (such as f.e. complex 77, 142, 231 ) with a radioactivity [32 phosphate] end-labeled RNA substrate under appropriate conditions and detecting the release of free radioactive nucleotides. The detection of free radioactive nucleotides can be carried out, e.g., by adding 20% trichloroacetic acid, filtrating the solution through a filter and measuring the amount of acid-soluble radioactivity (see e.g. Ross, J., 1999, Methods 17: 52-9) An exemplary RNA helicase assay can be carried out by contacting a complex having RNA helicase activity (such as f.e. complex 43, 128, 129 ) with a radiolabeled [32P]RNA/DNA heteroduplex substrate and ATP under appropriate conditions and WO 03/072602 PCT/EPO2/50003 370 detecting the the release of free DNA single strands. The RNA/DNA heteroduplex substrate is prepared by annealing a radioactivity [32 phospate] end-labeled DNA oligonucleotide with an RNA oligonucleotide of complementary sequence. The detection of free DNA single strands can be carried out, e.g., using gel electrophoresis and measuring the radioactivity of the bands. (see e.g. Kyono, K. et al, 1998, Methods 257: 120-6) An exemplary mRNA splicing assay can be carried out by contacting a complex having mRNA splicing activity (such as f.e. complex 155, 158, 160, 161 ) with a radioactively labeled RNA substrate under appropriate conditions and detecting the release of spliced RNA species. The detection of spliced RNA species can be carried out, e.g., by fractionation of processed RNAs in a glycerol gradient and subsequent analysis by denaturing polyacrylamide gel elecrophoresis and visualization by autoradiography. (see e.g. Schwer, B. and Gross, CH., 1998, Methodsl7: 2086-94) An exemplary rRNA processing assay can be carried out by contacting a complex having rRNA processing activity (such as f.e. complex 3, 54, 146, 156, 163, 176, 281 ) with an pre-rRNA substrate under appropriate conditions and detecting the release of free processed rRNA species. The detection of processed rRNA species can be carried out, e.g., using a primer extension or northern blotting assay by measuring the size of the rRNA species. (see e.g. Kressler, D. et al, 1997, Methods 17: 7283-94) An exemplary GTPase assay can be carried out by loading a complex having GTPase activity (such as f.e. complex 58, 79, 175, 183) with a radioactivity [gamma32P]-labelled GTP substrate under appropriate conditions and detecting the amount of radioactivity bound to the GTPase protein and the release of free radioactive phosphate. The detection of the remaining GTP substrate bound to the GTPase protein can be carried out, e.g., by filtrating the solution through a nitrocellulose filter and determining the radioactivity bound to the G-protein. (see e.g. Ridley, AJ et al, 1993, Methods 12: 5151-60) An exemplary GTPase activating protein (GAP) assay can be carried out by contacting a complex having GAP activity (such as f.e. complex 315 ) with a substrate GTPase- WO 03/072602 PCT/EPO2/50003 371 protein loaded with radioactivity [gamma32P]-labelled GTP under appropriate conditions and detecting the amount of radioactivity bound to the GTPase protein and the release of free radioactive phosphate. The detection of the remaining GTP substrate bound to the GTPase protein can be carried out, e.g., by filtrating the solution through a nitrocellulose filter and determining the radioactivity bound to the G-protein. (see e.g. Ridley, AJ et al, 1993, Methods 12: 5151-60) An exemplary guanine nucleotide exchange factor (GEF) assay can be carried out by contacting a complex having GEF activity (such as f.e. complex 6, 15, 46, 82, 96, 101, 122, 127, 198 ) with a substrate G-protein loaded with radioactivity [Tritium 3H]-labelled GDP under appropriate conditions and detecting the amount of radioactivity bound to the G-protein and the release of free radioactive GDP. The detection of the remaining GDP substrate bound to the G-protein can be carried out, e.g., by filtrating the solution through a nitrocellulose filter and determining the radioactivity bound to the G-protein. (see e.g. Sasaki, T. et al, 1990, Methods 265: 2333-7) An exemplary histone acetylase assay can be carried out by contacting a complex having histone acetylase activity (such as f.e. complex 126, 136 ) with a histone protein substrate and radioactive [Tritium 3H]acetyl-CoA under appropriate conditions and detecting the acetylated histone. The detection of acetylated histone can be carried out, e.g., by filtrating the solution through a nitrocellulose filter and determining the radioactivity bound to histone. (see e.g. Tanner, KG et al, 1999, Methods 274: 18157-60) An exemplary histone deacetylase assay can be carried out by contacting a complex having histone deacetylase activity (such as f.e. complex 80, 88, 137, 185, 188 ) with an acetate-[Tritium 3H]radiolabeled histone substrate under appropriate conditions and detecting the release of free radioactive acetate. The detection of free radioactive acetate can be carried out, e.g., by extracting the solution with ethyl acetate and determining the extracted radioactivity. (see e.g. Nare, B. et al, 1999, Methods 267: 390-6) WO 03/072602 PCT/EPO2/50003 372 An exemplary protease assay can be carried out by contacting a complex having protease activity (such as f.e. complex 42, 210 ) with a double labeled peptide substrate with fluor (e.g. EDANS) and quencher chromophores (e.g. DABCYL) under appropriate conditions and detecting the increase of the fluorescence after cleavage. The substrate contains a fluorescent donor near one end of the peptide and an acceptor group near the other end. The fluorescence of this type of substrate is initially quenched through intramolecular fluorescence resonance energy transfer (FRET) between the donor and acceptor. When the protease cleaves the substrates the products are released from quenching and the fluorescence of the donor becomes apparent. The increase of the fluorescence signal is directly proportional to the amount of substrate hydrolysed.(see e.g. Taliani, M. et al, 1996, Methods 240: 60-7) An exemplary proteasome assay can be carried out by contacting a complex having proteasome activity (such as f.e. complex 63, 106, 148, 157) with a double labeled peptide substrate with fluor (e.g. Abz, 2-aminobenzoyl) and quencher chromophores (e.g. Nba, 4-nitrobenzylamide) under appropriate conditions and detecting the increase of fluorescence intensity after cleavage. The substrate contains a fluorescent donor near one end of the peptide and an acceptor group near the other end. The fluorescence of this type of substrate is initially quenched through intramolecular fluorescence resonance energy transfer (FRET) between the donor and acceptor. When the protease cleaves the substrates the products are released from quenching and the fluorescence of the donor becomes apparent. The increase of the fluorescence signal is directly proportional to the amount of substrate hydrolysed. (see e.g. McCormack, TA et al, 1998, Methods 37: 7792-800) An exemplary protein acetylase assay can be carried out by contacting a complex having protein acetylase activity (such as f.e. complex 19, 87) with a protein substrate and radioactive [Tritium 3H]acetyl-CoA under appropriate conditions and detecting the acetylated protein. The detection of acetylated protein can be carried out, e.g., by filtrating the solution through a nitrocellulose filter and determining the radioactivity bound to the protein (see e.g. Tanner, KG et al, 1999, Methods 274: 18157-60) WO 03/072602 PCT/EPO2/50003 373 An exemplary protein kinase assay can be carried out by contacting a complex having protein kinase activity (such as f.e. complex 20, 30, 36, 38, 70, 75, 78, 83, 103, 113, 124, 159, 164, 212, 215, 218, 222, 232, 274, 376 ) with a suitable protein or peptide substrate and radioactivity [gamma 32P]-labelled ATP under appropriate conditions and detecting the amount of the phosphorylated protein substrate. The detection of the phosphorylated protein substrate can be carried out, e.g., by filtrating the solution through a nitrocellulose filter and determining the radioactivity bound to the nitrocellulose filter. (see e.g. Volonte, C. Et al, 1992, Methods 854-8, 860-3) An exemplary protein phosphatase assay can be carried out by contacting a complex having protein phosphatase activity (such as f.e. complex 16, 25, 135, 151, 221, 223, 224, 225, 286, 406 ) with a suitable radioactivity [32 phosphate] labeled protein substrate under appropriate conditions and detecting the amount of radioactivity bound to the protein substrate and the release of free radioactive phosphate. The detection of the phosphorylated protein substrate and the released free radioactive phosphate can be carried out, e.g., by filtrating the solution through a nitrocellulose filter and determining the radioactivity bound to the nitrocellulose filter and the filtrate. The phosphate radiolabeled substrate is prepared by incubating a protein or peptide substrate with a protein kinase and radioactivity (gamma32P)-labelled ATP. After completion of the reaction the kinase is inactivated by heat denaturation. (see e.g. Volonte, C. et al, 1992, Methods 854-8, 860-3) An exemplary transcription factor assay can be carried out by contacting a complex having transcription factor activity (such as f.e. complex 1, 12, 24, 45, 105, 117, 131, 145, 170 ) with a plasmid DNA template with a G-free cassette containing a promoter sequence, ribonucleotide mix (ATP, CTP, GTP), radioactive [alpha-32phosphate]UTP and nuclear extract from HeLa cells in an appropriate buffer and detecting the synthesis of RNA molecules. The detection of RNA molecules can be carried out, e.g., separating the reaction products through polyacrylamide gel electrophoresis and measuring the radioactivity of the bands.(see e.g. Hipskind, RA and Nordheim, A, 1991, Methods 266: 19572-82) An exemplary mitochondrial translocation assay can be carried out by contacting a complex having mitochondrial translocation activity (such as f.e. complex 201, 204 ) with WO 03/072602 PCT/EPO2/50003 374 radiolabeled ribosome-bound Mhp as a substrate under appropriate conditions and detecting the translocation of nascent Mhp polypeptide into mitochondria. The detection of radiolabeled Mhp can be carried out, e.g., using SDS polyacrylamide gel electrophoresis and autoradiography. (see e.g. Gautschi, M. et al, 2001, Methods 98: 3762-7) An exemplary nuclear import assay can be carried out by contacting a complex having nuclear import activity (such as f.e. complex 26, 40, 85, 111, 168 ) with a nuclear protein substrate under appropriate conditions and detecting the localization of the protein substrate in the nucleus. This assay is based on the increase of fluorescence after import of the labeled substrate into the nucleus, alternatively an unlabeled substrate can be detected by immuno-fluorescence microscopy. (see e.g. Jakel, S. And Gorlich, D., 1998, Methods 17: 4491-502) An exemplary RNA nuclear export assay can be carried out by contacting a complex having RNA export activity (such as f.e. complex 93, 119, ) with a nuclear RNA substrate under appropriate conditions and detecting the cytoplasmic localization of RNA molecules. The detection of RNA species can be carried out, e.g., using a fluorescence in situ hybridization assay. This assay is based on microscopic detection of appropriate fluorescence labeled probes directed against the RNA substrate. (see e.g. Stauber, RH, 2001, Methods 259: 119-28) An exemplary ER-to Golgi transport assay can be carried out by contacting a complex having ER-to Golgi transport activity (such as f.e. complex 73, 98, 102, 147, 174 ) with a VSV-G cargo substrate under appropriate conditions and detecting the cargo protein in vesicles from ER microsomes and delivery of cargo-containing vesicles to the Golgi. The detection of VSV-G cargo protein can be carried out, e.g., by isolating ER membranes/vesicles and detection of the cargo protein by immunoblotting (see e.g. Allan, BB et al, 2000, Methods 20: 411-6) An exemplary ER protein import assay can be carried out by contacting a complex having ER import activity (such as f.e. complex 23 ) with a fluorescently labeled protein substrate under appropriate conditions and detecting the localization of the protein WO 03/072602 PCT/EPO2/50003 375 substrate in the ER. This assay is based on the increase of fluorescence after import of the labeled substrate into the ER. (see e.g. Jakel, S. and Gorlich, D., 1998, Methods 17: 4491-502) An exemplary cystathionine beta-synthase assay can be carried out by contacting a complex having cystathionine beta-synthase activity (such as f.e. complex 165) with serine and homocysteine substrates in an appropriate buffer and detecting cystathionine formation with a spectrophotometric assay. (see e.g. Kabil, O. et al, 2001, Methods 276: 19350-5) An exemplary adenylosuccinate lyase assay can be carried out by contacting a complex having adenylosuccinate lyase activity (such as f.e. complex 166 ) with a phosphoribosylaminoimidazole succinocarboxamide (SAICAR) substrate under appropriate conditions and detecting phosphoribosylaminoimidazole carboxamide (AICAR) formation with a spectrophotometric assay. (see e.g. Schild, D. et al, 1990, Methods 87, 2916-20) An exemplary iron transport assay can be carried out by contacting a complex (such as f.e. complex 178) having iron transport activity using ferrous ions as substrates under appropriate conditions and detecting the transport of the ferrous iron across membranes. This assay is based on the quenching of the Phen Green SK (PGSK) fluorescence entrapped within the organel/vesicle upon binding to ferrous iron (see e.g. Shingles, R. et al, 2001, Methods 296: 106-13) An exemplary glycosylphosphatidylinositol (GPI) anchor synthesis assay can be carried out by contacting a complex having glycosylphosphatidylinositol (GPI) anchor synthesis activity (such as f.e. complex 181, ) with radioactive [14C]Mannose substrate under appropriate conditions and detecting the incorporation of [14C]Mannose into glycosylphosphatidylinositol (GPI) anchor by autoradiography after separation on thin layer chromatography (TLC) plates. (see e.g. Sutterlin, C. et al, 1998, Methods 332: 153-9) An exemplary aminoacylation assay can be carried out by contacting a complex having aminoacylation activity (such as f.e. complex 51, 106) using a radiolabelled amino acid WO 03/072602 PCT/EPO2/50003 376 and the respective tRNA as substrates under appropriate conditions and detecting the formation of aminoacylated tRNA.The detection of aminoacylated tRNA can be carried out, e. g., after spotting the reaction mixture onto TCA soaked filter pad and measuring the trapped radioactivity in a scintillation counter. (see e.g. Shiba, K. et al, 1997, Methods 272: 22809-16) An exemplary SUMO conjugation assay can be carried out by contacting a complex having SUMO conjugation activity (such as f.e. complex 182) using purified or recombinant SUMO-1, radiolabelled El and Ubc9 proteins as substrates under appropriate conditions and detecting the formation of Sumoylated forms of El The detection of Sumoylated forms of El can be carried out, e. g., by gel electrophoresis followed by phosphorimaging (see e.g. Rangasamy, D. and Wilson VG, 2000, Methods 275: 30487-95) An exemplary actin polymerization assay can be carried out by contacting a complex having actin polymerization activity (such as f.e. complex 81, 153 ) with G-actin labelled with pyrenyl iodoacetamide as substrate under appropriate conditions and detecting polymerized actin.The detection of polymerized actin can be carried out, e.g.,by measuring the increase of fluorescence using a fluorimeter. (see e.g. Jahraus, A. et al, 2001, Methods 12: 155-70) An exemplary sterol lipid homeostasis assay can be carried out by contacting a complex having sterol lipid homeostasis activity (complex such as f.e. 211) by extracting lipids from cells under appropriate conditions. . The detection and identification of cellular lipids can be carried out, e. g., using a tandem gas chromatography-mass spectroscopy. (see e.g. Beh, CT et al, 2001, Methods 157: 1117-40) An exemplary vacuole fusion assay can be carried out by mixixing two types of vacuoles (vacuole 1 and vacuole 2) both containing the complex with vacuole fusion activity (such as f.e. complex 109) under appropriate conditions and detecting vacuole fusion. Vacuole fusion can be detected, e.g., by using vacuole 1 lacking Pep4 protease and vacuole 2 lacking alkaline phosphatase such that alkaline phosphatase can only be actived in fused vacuoles. The detection of alkaline phosphatase activity can be carried out, e.g., by a colourimetric assay measuring the hydrolysis of para-nitrophenol.

WO 03/072602 PCT/EPO2/50003 377 (see e.g. Haas, A. Et al, 1994, Methods 126:87-97) An exemplary acetyl CoA carboxylase assay can be carried out by contacting a complex having acetyl CoA carboxylase activity (such as f.e. complex 90) using a (14C) NaHCO3 substrate in an appropriate buffer and detecting the incorporation of 14C into malonyl CoA by using standard liquid scintillation counting procedures. (see e.g. Witters, LA et al, 1988, Methods 85: 5473-7) An exemplary actin filament motility assay can be carried out by contacting a complex having actin filament motility activity (such as f.e. complex 107 ) with rhodamine-labeled actin in an appropriate buffer and detecting actin filament movement. The detection of actin filament movement can be carried out, e.g., by viewing rhodamine-actin using a fluorescence microscope. (see e.g. Evans, LL et al, 1998, Methods 111: 2055-66) An exemplary translation factor assay can be carried out by contacting a complex having translation factor activity (such as f.e. complex 4, 48, 123, 134, 138, 140, 195 ) with tRNAs ,mRNA, the appropriate ribosomal subunit and radiolabelled amino acids as substrates under appropriate conditions and detecting the release of the synthesized protein after precipitation. The detection of the synthesized protein can be carried out, e.g., using a scintillation counter by measuring radioactivity. (see e.g. Briones, E. et al, 1998, Methods 273: 31956-61) An exemplary ubiquitin conjugation assay can be carried out by contacting a complex having ubiquitin conjugation activity (such as f.e. complex 34, 69 ) with El or E2 enzymes and radiolabelled ubiquitin as substrates under appropriate conditions (in an appropriate buffer) and detecting the release of thiol ester after SDS-polyacrylamide gel electrophoresis. The detection of the radioactive thiol ester bands can be carried out, e.g., by autoradiography or by using a scintillation counter. (see e.g. Lin, H and Wing SS, 1999, Methods 274: 14685-91) An exemplary protein binding assay can be carried out by contacting a complex having protein binding activity (such as f.e. complex 55, 112, 121,180, 186, 250 ) with the appropriate protein substrate as recombinant GST-fusion under appropriate conditions WO 03/072602 PCT/EPO2/50003 378 (in an appropriate buffer) and detecting the binding of the complex to the GST-fusion protein. The detection of the complex bound to the GST-fusion protein can be carried out, e.g., by using Glutathione Sepharose to retrieve the GST-fusion protein, elution of the bound proteins and SDS-polyacrylamide gel electrophoresis followed by Coomassie staining. (see e.g. Kardassis, D. Et al, 2000, Methods 275: 41405-14) An exemplary vesicle fusion assay can be carried out by contacting a complex having vesicle fusion activity (such as f.e. complex 71, 118, 169) with early endosomes loaded with anti-DNP antibodies and early endosomes loaded with DNP-beta- glucuronidase as substrate under appropriate conditions and detecting beta-glucuronidase activity after immunoprecipitation of the anti- DNP antibodies. The detection of beta- glucuronidase activity can be carried out, e.g., using 4-methylumbelliferyl beta-D-glucuronide as substrate and measuring fluorescence production in a fluorometer. (see e.g. Colombo, ML et al, 1997, Methods 272: 7707-12) An exemplary oxidative protein folding assay can be carried out by contacting a complex having oxidative protein folding activity (such as f.e. complex 172 ) with a reduced and denatured RNAse A substrate under appropriate conditions and detecting RNAse activity.The detection of RNAse activity can be carried out, e.g., following the hydrolysis of cyclic CMP by measuring the increase of absorption at 296 nm with a spectrophotometer. (see e.g. de Crouy-Chanel, a. Et al, 1995, Methods 270: 22669-72 An exemplary multidrug ABC transporter assay can be carried out by contacting a complex having multidrug ABC transporter activity (such as f.e. complex 39 ) with a fluorescent dye substrate under appropriate conditions and detecting the transport of the fluorescent dye across cell membranes. The detection of the fluorescent dye can be carried out, e.g., using a spectrofluorimeter assay by measuring fluorescence intensities. (see e.g. Kolaczkowski, M. Et al, 1996, Methods 271: 31543-8) An exemplary pirophosphatase assay can be carried out by contacting a complex having pirophosphatase activity (such as f.e. complex 191) using inorganic pirophosphate and luciferase substrates under appropriate conditions and detecting luciferase activity. The WO 03/072602 PCT/EPO2/50003 379 detection of can be carried out, e. g., using a luciferase assay and measuring the luminescence output. (see e.g. Eriksson J. Et al, 2001, Methods 293: 67-70) An exemplary N-acetylglucosamine-phosphate mutase assay can be carried out by contacting a complex having N-acetylglucosamine-phosphate mutase activity (such as f.e. complex 214 ) with a N-acetyl-D-glucosamine 1-phosphate substrate in an appropriate buffer and detecting N-acetyl-D-glucosamine 6-phosphate formation with a spectrophotometric assay. (see e.g. Mio, T. Et al, 1998, Methods 273: 14392-7) An exemplary adenylate cyclase assay can be carried out by contacting a complex having adenylate cyclase activity (such as f.e. complex 78 ) with an ATP substrate under appropriate conditions and detecting the release of cyclic AMP . The detection of cyclic AMP can be carried out, e.g., using a specific anti c-AMP antibody. (see e.g. Chen, CC et al, 1999, Methods 274:31559-64) An exemplary alcohol dehydrogenase assay can be carried out by contacting a complex having alcohol dehydrogenase activity (such as f.e. complex 197 ) with an ethanol substrate and NAD+ in an appropriate buffer and detecting NADH formation with a spectrophotometric assay. (see e.g. Bergmeyer, H.U., Editor, Methoden Der Enzymatischen Analyse, 3. Edition, 1974, Verlag Chemie, Weinheim, Germany) An exemplary aldolase assay can be carried out by contacting a complex having aldolase activity (such as f.e. complex 62 ) with a fructose-1,6-bis-phosphate substrate in an appropriate buffer and detecting dihydroxyacetone phosphate formation. The detection of dihydroxyacetone phosphate can be carried out, e.g., using a coupled spectrophotometric assay by measuring the formation of NAD+ catalysed by glycerol phosphate dehydrogenase (see e.g. Bergmeyer, H.U., Editor, Methoden Der Enzymatischen Analyse, 3. Edition, 1974, Verlag Chemie, Weinheim, Germany) WO 03/072602 PCT/EPO2/50003 380 An exemplary arginase assay can be carried out by contacting a complex having arginase activity (such as f.e. complex 47 ) with a radiolabelled L-arginine as substrate under appropriate conditions (in an appropriate buffer) and detecting the formation of radiolabelled urea after separation with Dowex resin. The detection of radiolabelled urea can be carried out, e.g., using a a scintillation counter.(see e.g. Durante, W. Et al, 1997, Methods 272: 30154-9) An exemplary enolase assay can be carried out by contacting a complex having enolase activity (such as f.e. complex 171 ) with a 2-phosphoglycerate substrate in an appropriate buffer and detecting phosphoenolpyruvate formation with a spectrophotometric assay. (see e.g. Bergmeyer, H.U., Editor, Methoden Der Enzymatischen Analyse, 3. Edition, 1974, Verlag Chemie, Weinheim, Germany) An exemplary carbamylphosphate synthetase assay can be carried out by contacting a complex having carbamylphosphate synthetase activity (such as f.e. complex 99 ) with a glutamine substrate, HCO3- and radioactive gamma [32P) ATP under appropriate conditions and detecting the release of free carbamoylphosphate. The detection of carbamoylphosphate can be carried out, e.g., separating the reaction components chromatographically and measuring radioactivity incorporated into carbamoylphosphate. (see e.g. Pierson, DL and Brien JM, 1980, Methods 255:7891-5) An exemplary flavoprotein:ubiquinone oxidoreductase assay can be carried out by contacting a complex having flavoprotein:ubiquinone oxidoreductase activity (such as f.e. complex 67 ) with an ubiquinone substrate under appropriate conditions and detecting the formation of reduced ubiquinone. The detection of reduced ubiquinone can be carried out, e.g., using a spectrophotometric assay. (see e.g. Goodman, SI. Et al, 1994, Methods 219: 277-86) An exemplary L-glutamine D-fructose 6-phosphate amidotransferase assay can be carried out by contacting a complex having L-glutamine D-fructose 6-phosphate amidotransferase activity (such as f.e. complex 63, 3, 48 ) with a fructose-6-phosphate substrate, glutamine, 3-acetylpyridine adenine dinucleotide and glutamate dehydrogenase in an appropriate buffer and detecting the formation of glucosamine-6- WO 03/072602 PCT/EPO2/50003 381 phosphate by measuring the change in absorbance caused by reduction of 3 acetylpyridine adenine dinucleotide in a spectrophotometric assay. (see e.g. Huynh, QK et al, 2000, Methods 379: 307-13) An exemplary homoisocitric dehydrogenase assay can be carried out by contacting a complex having homoisocitric dehydrogenase activity (such as f.e. complex 173) with a homoisocitrate substrate and NAD+ in an appropriate buffer and detecting NADH formation with a spectrophotometric assay. (see e.g. Bergmeyer, H.U., Editor, Methoden Der Enzymatischen Analyse, 3. Edition, 1974, Verlag Chemie, Weinheim, Germany) alpha-Ketoglutarate dehydrogenase An exemplary alpha-ketoglutarate dehydrogenase assay can be carried out by contacting a complex having alpha-ketoglutarate dehydrogenase activity (such as f.e. complex 68 ) with an alpha-ketoglutarate substrate, coenzyme A and NAD+ in an appropriate buffer and detecting NADH formation with a spectrophotometric assay. (see e.g. Bergmeyer, H.U., Editor, Methoden Der Enzymatischen Analyse, 3. Edition, 1974, Verlag Chemie, Weinheim, Germany) An exemplary leucine aminotransferase assay can be carried out by contacting a complex having leucine aminotransferase activity (such as f.e. complex 2 ) with a alpha ketoisocaproic acid substrate and glutamate in an appropriate buffer and detecting leucine formation with a spectrophotometric assay. (see e.g. Taylor, RT and Jenkins, WT., 1966, Methods 241: 4391-5) An exemplary methionine adenosyltransferase assay can be carried out by contacting a complex having methionine adenosyltransferase activity (such as f.e. complex 33 ) with a methionine substrate and ATP under appropriate conditions and detecting the formation of S-adenosylmethionine with a spectrophotometric assay. (see e.g. Cabrero, C. Et al, 1987, Methods 170: 299-304) An exemplary mRNA guanylyltransferase assay can be carried out by contacting a complex having mRNA guanylyltransferase activity (such as f.e. complex 91 ) with a (5') PP-pur-mRNA substrate and radioactive (32P phosphate) labeled GTP in an appropriate WO 03/072602 PCT/EPO2/50003 382 buffer and detecting the enzyme-guanylate intermediate in which GMP is linked covalently to the enzyme. The detection of the enzyme-guanylate intermediate can be carried out, e.g., by measuring label transfer to the protein after electrophoretic separation and autoradiographic exposure of the dried gel. The-extent of covalent complex formation can be quantified by liquid scintillation counting of an excised gel slice. (see e.g. Itoh, N. Et al, 1984, Methods 259: 13930-6) An exemplary isocitrate dehydrogenase assay can be carried out by contacting a complex having isocitrate dehydrogenase activity (such as f.e. complex 217 ) with an alpha-ketoglutarate substrate, CO2 and NADPH in an appropriate buffer and detecting NAD+ formation with a spectrophotometric assay.(see e.g. Bergmeyer, H.U., Editor, Methoden Der Enzymatischen Analyse, 3. Edition, 1974, Verlag Chemie, Weinheim, Germany An exemplary oligosaccharyltransferase assay can be carried out by contacting a complex having oligosaccharyltransferase activity (such as f.e. complex 114 ) with a carbohydrate donor substrate, e.g. GIcNAc-[3H]GIcNAc-PP-Dolichol, and a acceptor substrate, e.g. benzoyl-Asn-Leu-Thr-amide, under appropriate conditions and detecting the formation of the glycosylated acceptor peptide. The detection of the glycosylated acceptor peptide can be carried out, e.g., by separating the reaction components by partitioning in detergent solution followed by ultrafiltration and measuring the radioactivity in the intermicellar aqueous compartment. (see e.g. Petrovskij, BV et al, 1978, Methods 103: 761-8) An exemplary tetrahydropholate synthase assay can be carried out by contacting a complex having tetrahydropholate synthase activity (such as f.e. complex 203) using 5,10 methylene tetrahydrofolate substrate under appropriate conditions and detecting the release of free formate. The detection of formate can be carried out, e. g., using a spectrophotometric assay (see e.g. Tonkinson, JL. et al, 1998, Methods 287:315-21) An exemplary phosphatidylinositol 4 kinase assay can be carried out by contacting a complex having phosphatidylinositol 4-kinase activity (such as f.e. complex 7) with WO 03/072602 PCT/EPO2/50003 383 sonicated lipids and radiolabelled gamma [32P] ATP as substrate under appropriate conditions and detecting the release of radiolabelled lipids. The detection of radiolabelled lipids can be carried out, e.g., using thin layer chromatography or HPLC. (see e.g. Wong, K. Et al, 1997, Methods 272: 13236-41) An exemplary phosphofructokinase assay can be carried out by contacting a complex having phosphofructokinase activity (such as f.e. complex 32 ) with a fructose-6 phosphate substrate and ATP in an appropriate buffer and detecting fructose-1,6 bisphosphate formation with a spectrophotometric assay. (see e.g. Klinder, A. Et al, 1998, Methods 14: 323-34) An exemplary 3-phospoglycerate dehydrogenase assay can be carried out by contacting a complex having 3-phospoglycerate dehydrogenase activity (such as f.e. complex 10) with a 3-phospoglycerate substrate and NAD+ in an appropriate buffer and detecting NADH formation with a spectrophotometric assay. (see e.g. Bergmeyer, H.U., Editor, Methoden Der Enzymatischen Analyse, 3. Edition, 1974, Verlag Chemie, Weinheim, Germany) An exemplary disulfide reductase assay can be carried out by contacting a complex having disulfide reductase activity (such as f.e. complex 18) with a protein substrate, e.g. plasmin, under appropriate conditions and detecting the resulting protein fragments, e.g. angiostatin fragments. The detection of angiostatin fragments can be carried out, e.g., by labeling the fragments with the thio-specific biotin-linked maleimide, 3-(N maleimidylpropionyl)biocytin (MPB). The MPB-labeled angiostatin fragments are bound to an anti-angiostatin monoclonal antibody coated on microtitre plate wells, and the incorporated MPB is measured using streptavidin-peroxidase. (see e.g. Lay, AJ et al, 2000, Methods 408: 869-73) An exemplary phospholipase assay can be carried out by contacting a complex having phospholipase activity (such as f.e. complex 206 ) with lipid vesicles containing 2 decanoyl-1l-(O-[11-{4,4-difluoro-5,7-dimethyl-4-bora-3a,4a-diaza-s-indacene-3 propionyl}amino]undecyl)-sn-glycero-3-phosphocholine (BODIPY-PC) as substrate under appropriate conditions and detecting the release of BODIPY-phosphatidate (BODIPY- WO 03/072602 PCT/EPO2/50003 384 PA). The detection of BODIPY-PA can be carried out, e.g., by extracting the BODIPY-PA and measuring the fluorescence emission with a fluorometer. (see e.g. Rudge, SA et al, 1998, Methods 140: 81-90) An exemplary pyruvate dehydrogenase assay can be carried out by contacting a complex having pyruvate dehydrogenase activity (such as f.e. complex 100 ) with a pyruvate substrate, coenzyme A and NAD+ in an appropriate buffer and detecting NADH formation with a spectrophotometric assay. (see e.g. Chretien, D. Et al, 1995, Methods 240: 129-36) An exemplary saccharopine dehydrogenase assay can be carried out by contacting a complex having saccharopine dehydrogenase activity (such as f.e. complex 65, 66 ) with a alpha-aminoadipate substrate and NADPH in an appropriate buffer and detecting NADP+ formation with a spectrophotometric assay. (see e.g. Jones, EE and Broquist, HP, 1966, Methods 241: 3430-4) An exemplary serine hydroxymethyltransferase assay can be carried out by contacting a complex having serine hydroxymethyltransferase activity (such as f.e. complex 14) with a serine substrate and tetrahydrofolate in an appropriate buffer and detecting formation of glycine and methylen tetrahydrofolate with a spectrophotometric assay. (see e.g. Liu, X. et al, 2001, Methods 40: 4932-9) An exemplary serine palmitoyltransferase assay can be carried out by contacting a complex having serine palmitoyltransferase activity (such as f.e. complex 92 ) with palmitoyl CoA and radioactively labeled (3H) serine substrate and detecting the formation of (3H) 3-ketodihydrosphingosine. The detection of newly formed (3H) 3 ketodihydrosphingosine can be carried out, e.g., by extraction of lipids followed by quantitation of the radioactivity by liquid scintillation counting. (see e.g. Perry DK et al, 2000, J Biol Chem 275: 9078-84) An exemplary tRNA nucleotidyltransferase assay can be carried out by contacting a complex having tRNA nucleotidyltransferase activity (such as f.e. complex 64 ) with a tRNA substrate and radioactive [alpha 32P] ATP and CTP in an appropriate buffer and detecting the modified tRNA molecule. The detection of The modified tRNA molecule can WO 03/072602 PCT/EPO2/50003 385 be carried out, e.g., separating the reaction products through polyacrylamide gel electrophoresis and measuring the radioactivity of the bands. (see e.g. Deutscher, MP, 1974, Methods 29: 706-16) An exemplary glucose-6-phosphate isomerase assay can be carried out by contacting a complex having glucose-6-phosphate isomerase activity (such as f.e. complex 9 ) with a glucose-6-phosphate substrate under appropriate conditions and detecting the formation of fructose-6-phosphate with resorcin in a spectrophotometric assay (see e.g. Bergmeyer, H.U., Editor, Methoden Der Enzymatischen Analyse, 3. Edition, 1974, Verlag Chemie, Weinheim, Germany) An exemplary 1,3-beta-D-glucan synthase assay can be carried out by contacting a complex having 1,3-beta-D-glucan synthase activity (such as f.e. complex 76, 94) using GTP(gammaS) and UDP(3H)glucose substrate under appropriate conditions and detecting the accumulation of labeled glucose into the acid precipitate using standard liquid scintillation counting procedures. (see e.g. Cabib, e. And Kang, MS, 1987, Methods 138: 637-42) An exemplary esterase assay can be carried out by contacting a complex having esterase activity (such as f.e. complex 59) using phenyl valerate substrate under appropriate conditions and detecting the release of free phenol. The detection of free phenol can be carried out, e. g., using a tyrosinase carbon-paste electrode. (see e.g. Sigolaeva, LV. Et al, 2001, Methods 290:1-9) An exemplary glutamine synthase assay can be carried out by contacting a complex having glutamine synthase activity (such as f.e. complex 31) using L-glutamine and hydroxylamine substrates under appropriate conditions and detecting the release of gamma-glutamylhydroxamate. The detection of gamma-glutamylhydroxamate can be carried out, e. g., using a spectrophotometric assay. (see e.g. Lie-Venema, H. Et al, 1995, Methods 270:28251-6) An exemplary spermidine synthase assay can be carried out by contacting a complex having spermidine synthase activity (such as f.e. complex 17) with a putrescine substrate and radioactive [14C] S-adenosylmethionine under appropriate conditions and WO 03/072602 PCT/EPO2/50003 386 detecting the formation of spermidine. The detection of spermidine can be carried out, e.g., separating the reaction products chromatograhically and measuring radioactivity incorporated into spermidine. (see e.g. Wiest, L. And Pegg, AE, 1998, Methods 79:51-7) An exemplary transketolase assay can be carried out by contacting a complex having transketolase activity (such as f.e. complex 28) using xylulose-5-phosphate and ribose-5 phosphate as substrates under appropriate conditions and detecting sedoheptulose-7 phosphate formation by spectrophotometric assay. Alternatively, transketolase assay can be carried out by contacting a complex having transketolase activity using xylulose-5 phosphate and erythose-4-phosphate as substrates under appropriate conditions and detecting fructose-6-phosphate formation by spectrophotometric assay. (see e.g. Ali, M. Et al, 1987, Methods 87:833-5) An exemplary farnesyltransferase assay can be carried out by contacting a complex having farnesyltransferase activity (such as f.e. complex 84 ) with a protein substrate, e.g. a p21 ras protein, and radioactive [3H] farnesylpyrophosphate under appropriate conditions and detecting the farnesylated protein. The detection of the farnesylated protein can be carried out, e.g., by filtrating the reaction products through phosphocellulose paper and measuring the filter-bound radioactivity using a scintillation counter. This assay is based on the retention of the farnesylated protein on phosphocellulose paper whereas the radioactive [3H] farnesylpyrophosphate substrate can pass through the filter (see e.g. Khan, SG et al, 1995, Methods 30:133-44) An exemplary ubiquitin isopeptidase assay can be carried out by contacting a complex having ubiquitin isopeptidase activity (such as f.e. complex 35) using Ub-Ub polyubiquitine substrate under appropriate conditions and detecting the the disapearence of polyubiquitin and the release of ubiquitin. The detection of polyubiquitin and ubiquitin can be carried out, e. g., by western immunoblotting using an anti-ubiquitin antibody. (see e.g. Wilkinson KD et al., 1995, Biochemistry, 34:14535-46.) An exemplary trehalose synthase assay can be carried out by contacting a complex having trehalose synthase activity (such as f.e. complex 31) using UDP-glucose and D- WO 03/072602 PCT/EPO2/50003 387 glucose 6-phosphate substrates under appropriate conditions and detecting the release of free alpha,alpha-trehalose 6-phosphate. The detection of alpha,alpha-trehalose 6 phosphate can be carried out, e. g., with a spectrophotometric assay. (see e.g. Seo HS et al., 2000, Appl Environ Microbiol, 66:2484-90.) An exemplary deneddylation assay can be carried out by contacting a complex having deneddylation activity (such as f.e. complex 5) using a protein substrate, e.g. a Rub 1/Nedd8-Cdc53 conjugate or an epitope-tagged variant of the same under appropriate conditions and detecting the deneddylated protein. The detection of the deneddylated protein can be carried out, e. g., in a Western blot using an antibody against the protein substrate (e.g. Cdc53) itself or an antibody against the epitope tag. (see e.g.Lyapina Set al., 2001, Science, 292:1382-5.) An exemplary Endosome to Golgi transport assay can be carried out by contacting a complex having Endosome to Golgi transport activity (such as f.e. complex 129, 363) with a cargo substrate under appropriate conditions and detecting the cargo protein in vesicles from the endosome and delivery of cargo-containing vesicles to the Golgi. The detection of the cargo protein can be carried out, e.g., by isolating endosome membranes/vesicles and detection of the cargo protein by immunoblotting. (see e.g. Edgar AJ and Polak JM., 2000, Biochem Biophys Res Commun, 277:622-30) An exemplary Golgi-endosome fusion assay can be carried out by contacting a complex having Golgi-endosome fusion activity (such as f.e. complex 89) with a cargo substrate under appropriate conditions and detecting the cargo protein in vesicles from the golgi and delivery of cargo-containing vesicles to the endosome. The detection of the cargo protein can be carried out, e.g., by isolating endosome or golgi membranes/vesicles and detection of the cargo protein by immunoblotting. (see e.g. Brickner JH et al., 2001, J Cell Biol, 155:969-78) An exemplary CTP Synthetase assay can be carried out by contacting a complex having CTP Synthetase activity (such as f.e. complex 373 ) with UTP and glutamine as substrates in an appropriate buffer and detecting the formation of CTP by measuring the change in absorbance in a spectrophotometric assay. (see e.g. Hashimoto H et al., 1997, J Biol Chem, 272:16308-14) WO 03/072602 PCT/EPO2/50003 388 An exemplary acylglyceride fatty acyltransferase assay can be carried out by contacting a complex having acyltransferase (such as f.e. complex 364) using lysophosphadic acid and oleyol-CoA as substrates under appropriate conditions and detecting the release of free phosphadic acid. The detection of phosphadic acid can be carried out, e. g., with thin layer chromatography and detection of radioactivity. (see e.g. Athenstaedt K and Daum G., 1997, J Bacteriol, 179:7611-6.) An exemplary transcription inhibition/repression assay can be carried out by e.g. deleting a gene coding a component of the transcription regulator complex (such as f.e. complex 365). The transcription inhibition/repression activity can then be detected by meassuring the mRNA levels of the target gene. Expression level of RNA can be detected by Northern blot. (see e.g. Oberholzer U and Collart MA., 1998, Gene, 207:61-9.) An exemplary NO dioxygenation assay can be carried out by contacting a complex having NO dioxygenation activity (such as f.e. complex 262) using NO, 02 (as saturated solutions, respectively) and NADPH as substrates under appropriate conditions and detecting the decrease of free NO. The detection of free NO can be carried out, e. g., using a NO electrode. (see e.g. Gardner PR et al., 2000, J Biol Chem, 275:31581-7.) WO 03/072602 PCT/EPO2/50003 389 4 0 D CO CC e a 0 0 .0 M 0 C0 N .~ n c .2 ( C o0 C V0 Cl) (Ih4 4- C:U CD 0x cM a E u .2 ~ ~ ~ ~ L EE 2o. " oE 2 EUE CEU 0 z >t - al :- Et= O0 0 0 05 E 0 C6 O CO O~ >U a) a) C L -J _j.CU ( 4-O o 0 0 z~ O = 0 2 E 4-E0 OOO -i 0 0 0 LL L 0 L L O COHH 0 m z: Q 0 LL = 0 0 < 0 9~ E ~ e CU Cd) x (LL LL LL L C LL L F- C6Cc r (J~ n CI C000 H - C O It E Q 0- C) O LL w o -1 z a H 0 C ('4 (N 0 0W Cl L In4 C) H 0 CU Zolce 0 WO 03/072602 PCT/EP02/50003 0)390 a) cf) C) C) (: -) C'4i, : a) cu) 0c CL)

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WO 03/072602 PCT/EP02/50003 412 W af W 0D a LL (IZ 0a) 0 > CL) a) cu (1) * 0 0,- 0 mO ow 0-"a) U) E0) 0 ~ 0 > ~ 0 00 o. t C 0 2) 0 C: = ~ 0, =. 0)0) 1- 0 - Cl) CO E- C ~~- W).0 0, cw0E~~ -- CO.

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- CL C a D LO) C) N CLco 0) C)cM N a F- 0q M 0 0 F- 0 0> ~ C 0 E 0 U) L _ > >> > 0-0 cm0a a 0 0 0. U') cc , w o o - ) 0V >.. 0.00 O 0-~ 04 < ) CL N E-0 0-U N )a C o~JI0 00 cc cc N ' 00-00- C/)C 0 0 C 0D 0) 0> LL IL 0 0 WO 03/072602 PCT/EPO2/50003 429 C: 00 C~C0 E a (n 2DO Co a) Ot C.- 5: (N a)) .> C (N> E Cc N - cu (D "a m D C F L" CoC CO~- C oq M C40 CO C4 mo 0 C:) >.f 0 C\O E 0 00 (.) 00 c~0 0 () (.) 00 u) ~ > Cox o Clco -x Q 0)W ) C)C)0 D () 0E Q CL 0 - 0 0 :- 0 ) (N 0 )C o ) o 3U 002 0 30 LL 3(z L) E C C"J -))-C .C C)o .0 0 0) 0 C\ ( WO 03/072602 PCT/EP02/50003 430 C) CD C> O n - ry 0 0 C00: 0 .0 U) w N N a) >, t 5_ 0 -5 C 0. 0L '0 CU u 0. ca ca CL cu 0) U- m D > C) CCl) 0) -c1 _ l ) 0C C) ~ C: C) J ~ r U)LL a U) O. CD l. C)C 00 00 (T- zien CL a-a.. n 0--0- 0) a. C.) :3 C.) < = .E CL0 CU 000 a- a- = >,a qOO < 2)< 2 (NU cLL) c ', 'j. CO4 mr. C 0 C) 00 0- 00 U o- 0 0- (N< coC L L) m CLCL C C14 0Cq .0 U .0 ( 0) (N) 0jNr- -: a D C C :) Co co V WO 03/072602 PCT/EP02/50003 431 00 CU C = (D U 0 cc.) ~a a ) ) 0. U)) U- 0 0LD0 0 cmo - ~ ~ C\J C4 N C))

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0 00 0O M C) QJ ~ 2 0 "0 0 LM -rr 0 wi -r 0 W 0*9-0> w -IF 00 in 64 M~ No .E 04 [a 0 a. ~ n. o C) 00 L) 0_ 0 C U() w 0 C/) 0 00 U COL0 c6 C14 ~ 0 ~0 0 SwO Q 0M COO -0 MU C\J M) -- 4 co CC) WO 03/072602 PCT/EP02/50003 432 a, a) 0 > 0) >. a), U)~0 0 C a w~ . " CU (0l w U) U)( . D -i ~ ~ ~ ~ a -jw o < - m nlC~ 0~ z 0C)0 L -D c) y- - 4-i - C) C) C) C\J U) C ) a 'c- C0' 0o Cl) 00ii 00 ~ CL o i -j D ~ C cu 0. IL 0 j- n~ Q 0o0b 0 i0 obQ o0 0 c2 0 .2- CL C 0) 0 0l -- .5 Yl) -j .- 0 (n~ coc ~~ U) COcl w .I-MZa S L) 0- 1 -1 E O CL - CD 'a C6_0 CC co - a)co COZ- -J 000(la- <00 00LD- COM) 0 w 0- 0 0 w CO ~0 U WO 03/072602 PCT/EPO2/50003 433 C -j 0) 0 ' L. C COC w co 0)-0 (n 0) a) 0 O 0 -5: Co 0 U) 0l-o 0) o cCo c E) Z3 E co v c ci c i 0 ) cco zO Co D c- N i C f i (6 -) 0- It) 0) E- 6 : 0_ N = C S Z 0DOT 0 < > LM -IF) >~ o COsL 2 co w ;Cl S x E0) )m (004) _-- I- 0 0) _- _ C E z~ z N CO ~CO C) CC) ) 0 WO 03/072602 PCT/EP02/50003 434 o, o '- -1 0 2V 04 Eg C-,1 U) uj U r- 0UqU LO C6 M CD 0' ND CD vm LL- -jL - o - 0r c C) Q C~) :2~ co> z wa o C iCi LOc C) a- ( CL DL -- iQ oL ct nD Ofw a_ 0 w L U) co <Dl<< m >DZOU U)z o It0 .4 CO o 0L CL LLWCL U) C/) ' iM re C - 1 - 04 U)U)CI)~c) coo !L--~OI ~ 0 (6 C) .,co < C14 < 00 M wL WO 03/072602 PCT/EPO2/50003 435 CO CDO C O H H _j ( D lc- :3 (D o CD N C oO ~ .00 0. CA C NN CD C D U- >, 'MC 10 ".f 00 LU U) U)CO <C) C)< >CFaQ I ~2 ~ - cr, a' L H . * Ci) (Dd < C 0)H 4- LL ' -Ja) 3 0 U E L oJ N < o - H .c 0 CU 0 l -C) Cl l 111 o< r,, T-: <O f C6~~/)D Fo D ~ H Q 0 0 n a)C))a C C) E 0 < C) U) y )U o F a)0 d (nCL) EL)z T-- 3: ry <. W y U i C/) Q 0q 0 LL U WO 03/072602 PCT/EP02/50003 436 <K <) < -F . U) 0 0 - LL M0)z c Ej CD a) c , o mC D U O> WO 03/072602 PCT/EPO2/50003 437 0 0) 0 oL 0oc 4) (J, 1.: C) z, D 0 0 30 -j U- I Z -z 3 D w L uj CD m.> w -) -0D (9 co-CDM ca0L >(9 C O( U)2 C C < Ze z~ 00z 0 o E E o~~- 9n< oZ 0 i~o ZI Z < U- I4 -4-C L~~ E5. L. -%]) > 4 i d) 0 0 z m Z F LL L .2E:P2 kuZW>tsD O0)W W 0 F- 6 -5 c ,-r a)? " - c 4 )7 0))N = a) 00 LLU : ) ao Co 0 . a) 2 S CD oo a) WO 03/072602 PCT/EPO2/50003 438 LL (D Cl U) E CD-Z o.9Co 0 a) co (0 CL a. C: 0) Eu E CU 2o i LL U) >-

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N ( ZCq ) Co7or->: 0- 0) 0 co Co e WO 03/072602 PCT/EP02/50003 439 (o dY) E (D~ E N N o x 0 o0 0 co 0 0 C.0) 0>- C6.) a_ C) w NJ C.) C) O->- C9 CO C.)C) > >4 OH O D cc Hj CO = . 0 't CD -rU L6C Qr-(OH -s> 0L W I ,17 cq .0 0' LO -j >t CD0 0 W F 0) >) (f WO 03/072602 PCT/EPO2/50003 440 a) (1) a) (I) o CD a ~ to -a ) CU M c_ co a CU U0.L> 0z .5 CO> co 0w M z ~~- - C, ' 00 CF 0 U) - C) LH z ) >, 00 C) w I~ r co -- - El 2 L n D j0 : W 0 - U)IJ 0 ox I (u w UW0 o) * L) z wU a C)0 z LU 0 <0) EZ CE C- -E(9(9 ( EC 0D H Ws (O) aj U a 0 D 0(9 C) U CL C.-0 T - o m- o 00DEE O Z 0)z 0) T WO 03/072602 PCT/EP02/50003 441 _ _ _ _ _ _ _ _ _ _ _ 0 CJ m r) 0- 0 L ~~C)) CY) ~~~ ~ ~ i Cci (60 - NI7C ~ 't~~ - D" " I )U) T : -;T 0 L of 0- < 1- co L D 7- _ LL 0 - 2 _- of C)2 U) U). U - C) > ~ im m -O LC) LL (D*J~c C 0)i SC' '- ! J l) 0 N *0 F-n 0 0~~ a -~ w 6 p E CL 0 < %q- CL0 a)CI EO z E 0 W~' Z LN z < < U) 0-2 L) L z aLx ) U)0 co(D0( WO 03/072602 PCT/EP02/50003 442 0 a 00 EU) (D 0 0C4. (I)Cl U) >z C:) C6 U) c ) C4 C.)C\ U C\F N 0C~ - -I c\ CL 0I~ < LC O ED < M ) C) C6 2 N N (J~! E 0 C) 0 D L) C4 rnC4 l C) C'4 -- - 1 Loq- 00 ww 2 0- -L, -< T co ED ) w w (D Sj x U ) c (No Co C 0) U WO 03/072602 PCT/EPO2/50003 443 LO C C) 0 a 2 CC 0 0 2 0 LO7 0 ~ - (N 0 a) 0o .5; * - (N C 0 CL 75 CL :B a) ED D EWUW OZu cZ CC~CC)O O IL 0 C / ) Co~o~~~CoC n o - Q ( CO 0 OW CL 00 ) CU0 LU E W 0 C6 L i (). Ii CLl) o C~ C J~jL 9 - (L~- F- 0N Lu x 0 X C/) 0 i t L L 0 T- CO CO (D w- co (N CO. UZZZZOZC)C) Cl cOC/) <000))W z c / N- N (N ( U) C 01) C5 L6 U)0 ) C) L WO 03/072602 PCT/EP02/50003 444 2 c~ 0 co D O C~ c i CO l N (N C) LL f- ) CL e n 0 Y :2 c - I C2) ct)' y). o o ; m 0 m ~cNJ z m 0 -m- 0 0ciP D~U> Dw Dw wwW z~~ w 0 (0) I~' c I = I IV, MO *- F =- tO) CO I - O 04 C) oN 0- - mO 0- L) 0 (N " CN )' 0 ~(J~ ~5 - D co U i~ LL 0 ) Cl Lu . CI) w~ W U C 2 oOZ U) U) CNZ =/ nUo) Cl (NO NI CO T ' m M N ' 00

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LL U) a)- Cl) i E0 L .> C6 D0 - D. W-( N N It O ce) (6 C c C -c t U O C)T- N 0 ~ 4 C) - C WO 03/072602 PCT/EPO2/50003 445 0 o o u W en U) o (. ( I S0 C: - 0 CLc. C 0 0 . 0Mc C) C C: 0 N C0 ..- o C) w w) (U C)) 0 (n 0< 0 0) COIIj~)C) co en) co Cl ) . x 00 C: Ep 2 (D E~ FD CO C- CD N - C D C D D C 0. l) 0 o ~ E .Q0 L wu w w w 0i wnj w w U) U)U) ) l -) U)U)U E uco u Cl) LO) C0 1 - q C5 ( clof o zoo 0 0 OcJZ wQ w w CD C UJ W

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WO 03/072602 PCT/EP02/50003 446 0 C.0 D c c o o> C.0~0 Cf COC D0 U)ZZ) 0 C/W CcO N a) C6) Cl)l) co r LI, E o t- 3 c (0 w ( < w w (L) z z o, >0 U) Z i R ZZ " Z z a a ) E ca co c 0,)a ) (0 c :- E- C)- n E E *(0(0 (0N cq CO C6 )C) to 0(0c N w w w WO 03/072602 PCT/EP02/50003 447 C\I -1 X0 0 0 0 0 c < a) 10 0 - > a) ) a) < N- 40 - 0 U m - w CA -C NL 4 'I cc) (4 Ci) _0 = -C U') C'O CO C"o ( l)o < 0 LL a- 0- a-0 a 0)~~c r) 0co O CM 0 WO 03/072602 PCT/EPO2/50003 448 W " 0 0 0 0 .0C/ U- LU: o : C : o ~~~~~cm ~ C c CO D~CO0~l<Co CoyC L6 LO 'tC) C a-a- V- .0 Z -OU- 00 U E - u- a-HF-Lo << CLa H i O Hr Cl) Lr co) a- Cc (.o C) Cl t H- cL - a LL LLCL IL L LL a_ a_ 0 - iL a-a LL 4? U)-o0 cn X< 0)-< a~ CO a LO 0 o U' H-Co - HM H < 0 m CC C>c0 0) C) 0C o L L U 0 0 > 0 ' n~D o < <o < C a Z~ C)tO H--z- ~ ~ u LL/ I- 0- C toa LO IL 00 If 0O()C WO 03/072602 PCT/EP02/50003 449 .)0 0) LL vL ~-CL 0

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~ r 0 0~- " M0) a 9O 0) O). 4 0 w -0a) ~ 2 75 ~ . 0) E ) a l 0) * ) . . W 9 4= 0 o C oD N C) co co <- 0- Z) a U) > co > 0) C) 0o mC Lo u-) I _o 0 L > > CL > > 0 Co o C o > >1 >1 0) C/) DO U (n C) -J ELj =) _ LL -:t C N oc"I CO) L- -a C~ a N o~ ~ ~ 11 CL~~~~/ M 2>> ) o N- - C) c- 0 N - 10- C L o C)CF C oLr 0 ) C. U) >co c 0) >0 ) > WO 03/072602 PCT/EP02/50003 452 LIo c C00 (000 a) CD U) a , 0 ) CU C: C a). (Di cc 0 c Cu/. C: LoI) HCOD co woc . ~.5 CNr- cc0 C: Q) (Dc L) C 0 0 (D 0.. D 00 Ic E mIo ( o 0 a ( a 0 0 > < ccl -\ co - mF 14c) C o c Z) -L mc C) 0~ cl C i ccc-j CC C~ a_ LU 2E - Z) 0 < C Y-0 -_ 0- af w- C ) U) >" -N I-- z- z -J z \ O LO~ ~ cc) CL I 0) z )z 0a WO 03/072602 PCT/EPO2/50003 453 0 . .) o3 a 0 0 a co r ) r) (D a C C: o a 0) 0) 0)0 0.. "O n 0 ". n 1. 3 . -. Cw v -6.. C 2 O al z 2 C0 d- O 20 98408 000040 a a c . z ) .5 o z .o m ." , "- .- CO- c - ._o o So v.go o '-- o oa- . < O G. 001 o a .

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Q CL -J 13 H U~) U) 8 3 ) Z a- a q C) 0 i CZ 1o (D c' Co iN - C'4~lo~ LZ0- w o Co ) COj WO 03/072602 PCT/EPO2/50003 455 0 C) CO _ 00 CD 0) a) CI ) m cn 0 ) c3)a) a- ~ co .~- - U > CO -C 2 co L O < > >. (0) 0 C) C4 0- C) OD C)C N I 0.-- C _z _j z 0 _ w w 00w Lo - Co 0 00 C .3 0 I0 00 (a0 -aI .- ' ( C)- c C. Z C) cUJ Z C C.00 0 z 0 Z) ,- _ o Za CLO L6~. 4- L6 L 0Y) "It 0D Z D -~ -c ~Cl) Cl WO 03/072602 PCT/EPO2/50003 456 0) 2l) w~~ co =w C~C) (1 Z ~ W C / C / O C C-4 Cl 0 M WC/) * F F-~ 0 T- - M o - -0 ir) Co) 0 - U6 0 4 l l ~ Q J - i .2-H H 1 -~~ w ) U) U o , Ceo LUO 6 ED ) -w wk XCL). L -G D- Cl C C) o) C E u (1) ui CoO co cp Fo~ - 0 U-) Co( OcO') UJ) -U 0.0 m 0 -c (9 _ C0 o C: - - 0 OC) - 7 r,, - C~ CO CG Co T- CO GD C o Cor T- 04 . C C%4 Co) Co) F- CO w w co C0 1 WO 03/072602 PCT/EP02/50003 457 0 1 0 o a) 0 4w - > ci z 6 C5 f- o_ w \ ~ 0 0 0O LI) U) UJ N-CJ C'

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0 J O Coo o) w 00 F7 H H H H H 0- ~ ~ C CO - LO c CO CCJ CO W w co ~ ~C a) - CO4C) C y Y o C p U) ~~CO CO -.r o P Dto ' u on w flD fl) C/ E~ I - f 0 W W 0 CO W(9D H 01- W00 w W- c w -y Q 0 WO 03/072602 PCT/EP02/50003 458 LL (Dz 0 = 0 0 -0 1 0 00ju 0) m * NT I Q 0LL L z U), D. CO c6 CO x i-D~ C E 0 CL CL 0 Nl (D CO CD 0- NCD~ ,~i ZZD D ~ CI CI) Cy o ) 1 Ch U) oa. (D U ) oc I 0) 00 0 0 0 j 00 a _ 0 - M W L C) LL LL <~z z 0 a 00 WO 03/072602 PCT/EP02/50003 459 co U.) 0 0 ) LO 0 0 00 (D a)D Co, a C0 C L 0-0 -r c'C t CDo F~ C)WC 9 OO Il~O>I0HW 00 a C) (if w 0 O* L 0 C0 L < < < w~ w x 0 <Y N ~C)0 C)I ~ Wcl S) R- LL L C 75~ W 0 < mCU LL aD Ci) < <- <D u <D p Iw X. CU o)Cl)C# <OC - E~ ~ 0 0_ LL < E) C) -0 E0 u) 2- C CO U0 co LO <l <O CO C4 m LO U-) 'It - t C C) N't 0 C) E Cj 0 0- UU_ U_ U) _jN m WO 03/072602 PCT/EP02/50003 460 O o C C"J j - J 0~1 CT~ I( 0 ;i 0, T- c0 U.) ccCNJ \,m ( C\J C C) - 0 (0 - 13f 0 . *0; i' <I G M Z L- WI < Cf) 0 Ca W~1 a- -rL 1~ 0r < e1 L.. (I C)i ~ -L m I ) - f- Ii ,0 U 0 m- o -I' - LL-rinU CDC/ C0 CCC-c E c: < C < 0 - c0 - "i - - 0~0 x W0 U) z\ M 0 < \ 0 )L 00 -0 -aZM M C: 0 )C CO O O i COH H> > 0 _0 WO 03/072602 PCT/EP02/50003 461 00 z

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T 0) U) U)C U) &F- U)0 o CL) op (~ Q ~ EQ UF 0 <FD -C ( ? CU -O(JL 0U < 0c 02 Y UDm E c m a TU WO 03/072602 PCT/EP02/50003 462 C- C) cj (D a) n LL (DF CL LL . LL LL 0 x. Xo CO h-L O f uC) U CD -z 0 Dc= E CO(O1 H mC~ ozo M~ L6> 0 ( 1 o-o 0U -i < 0 C0 0 cr) C-~~ N CO 'tLO O~ 00 (M Mo Co CO ) M W WJU W WW W W W ILF- 01. 000 2 0 m a-. a-~ af f C.- C -4 CY. CO) 0)CDCLW L C: CD CO _j =-Uj :C0 IL F Q, 0 - c a- [i nof oa c) (If "F L o 1- U0 - C i a ) W 'o 0 t co .. C ) o LLo - O w UJ a)W . . O W W - Fcu :r fL 0 12) m ~ w- n k ~O 08 1- a) CL. oo 0C cj CL C D L..~ H- 0 0 C X l o) cl 0UH C6 ol v5) Cl6 C6 Cl) C) EmbC < oo O/wUWJUo- Hww o: = cU - CU ) U L~( < CLCL0 - 0- IL 0- IL a-LC a-Ql -a <0) < w wwwof 0) CDa 0 C6 - "C WO 03/072602 PCT/EP02/50003 464 LLS 0 Cd) ca )) U 7 c V 0 U)>-c D a-0 0C0-L ( - - - CTj - -( J It) >- CL a - a a- a 0 0 a_ - a- a_ 0 a) N NC~~ LOo -t-( 0) LULa o). <m u u mwuj a- ww U) L f) y 0- of .- 0 w -a IL G a -0 U LL CE CDc)I co a - o ~() C 0 =.CY 0) a-_ )4 0. - a- 0 a f DE r 0) a) 0 ) CU 0) mm 2w W 0uOfW D Z)c,0 w w (N co 0) Cci c C)a .0 - 0 ~CCO N _a - 0 . a N - ~ o - ~ 0 c L- ) N C6 7 -N 0 C) N 6 - 0) N - N t mwww > iZa~aoaoaMaLa. CA m CD I-- co co C> (0 WO 03/072602 PCT/EP02/50003 465 ZZZ -Z Z Z wwa- [z 0a-T N D ) - a D- V D - la- a_ ) a_ 0 D- - IL ) u - w N 0- a C CO~L DD ofI fQ f fo fw co) ) zW J z L ZZHZ -f - O 0-Mwa)f CL U)Z Z ~ a) U) WW CLQZZ H[- <I):F z z Of 0 C m a 0- a- ( CL ) 2: 1+ WO 03/072602 PCT/EPO2/50003 466 o 0 c 0 ,n ca a) '4-- C) c = c) Ec u i)) c C6) C) - CN c CO _ a-E L) 0 i L0 ()N : 04 't -It<Q CD 4 -D 0 0N FN >- co 0 -0 - (D w ~ o c0_NC C O~ w >--I 0- U _ N Q- o > &i 0) & E o CL C a) 0 CL LL o'~ t- o C/u C 0 0 , I C) a) C) 0E 0 E)N co cn cl 1: C1 C4 W U) n W 0 ~ D / 0 0 < -6 z I -)oJ 2 C z o - 0 LL -~ C CO o w --O ) < ~~Cl6 Cc) -M >'- >- - - > - 3 : :

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WO 03/072602 PCT/EP02/50003 467 C: C:U) 2- 0 0) O z + 9 o a w~ 0 X:w d0). Oocoo 0~lc CDO~ < 0Cj 0 f I0 CL ~ >> ILI 00 C>- cDOco/)I ci ci WO 03/072602 PCT/EPO2/50003 468 -5: 0 0 ~z :3 M E t cu C,) I ~ C M OC 0 O 0- U) (0 O (Y)~ CCO Co a_ )W>na < >0 0- =- n-I 0- > (0W o0> o> o > >L m.> 0 > Icc>. LO -) w _I (o 0-d- C/ a ( : 'c2a - i-o c >c < c 2 aW - 0 IL LZ n- <ma oCL 0> o ca >>0>0a >cc( U0->> N r~a)f (D U)c -~ co 0 CaOC CL0- a- w >O >t CO C 0-COO2 0 O 1)C COD 0 o)U coc WO 03/072602 PCT/EPO2/50003 469 aI 0) ci) cuE m~ t C 0.. Cl) C) nl l -J LL..00 Cl) > (0 X0 Co :2 TCO I- wo I I Y CO T U) to) C: CO Lo l) E U)U) E ) 3) d CO) C CCw S X-2 n - IL w > (L 0- >t >o o > 0 > C > Clo cc Cl) 0 o a .. > CC L >o00 . > cn e Cl) U) E (D 0- 0 C- 2 F C 0 -n-w I > a -- J > > 0 ca > 0 - _>> i co - y x-- c o ~ 0) 0- w- co N-)), LOC ~ 2 ~ ~ ~ .C > CoD-iC a) ) C6 0I (o m o E ~ ~ ~ ~ l 11) Cl) . C'F=C ) )a > 0 w CL LU 0 00. w L C - z 0 LL I ->>wo0 t0M>> 0) y c 0 -U)

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WO 03/072602 PCT/EPO2/50003 470 o > C 0 (n m 0- c LLC _I LL , l 0 ) U M U-) z w - f F -~l >(Di c. Clt Ni c 006 -i~j x C.) 0. 0a (. ) 0 LL o '4C JI 3:(, Q- L L 0 -)) U o L CL Ho C CL a.~c c) a* Lo u) C/) U) C) ' J a- = U) c w~ wDl 00I z E00 0) E =~~'J 0 3 0u COC ) O 0 L C C6C -0 c >C w~7 U) E Co \j W C O- U) -al COOco H w m 0 75 U) ( WO 03/072602 PCT/EP02/50003 471 LO LO -O L l CD O C R C l) a) 2 C) C ) coI co~ a)N " L- I *o -- N -~ - T- U' CO O NH L6C6 0) CV - CO o LL w -j o 0 () 0- ( wm -a ca H Ho w I 0 ) 3:LUor 0 w E C l - COj T- M~o 0 N 04 C,0 LLm 7 L L nC LL L ~ LO LOO I co -~ - C1 LC)m D I\ 6 LO I- D COC z af Io w 2 o _0 2. z 0 U) I- Z O Ili c C6 L d 0 0 0 Io r-0 0) (D)~ v~-~ o C CDCOCOM <<LI co > C) .9 L0 -C 0- -a fl 0 z CO~o = w c 0) 0o 0)- D)) CO QU) ((10 < 0L >0 Q Li- 0 M. M a)0 -1. 0 Co ) o cO <~ ~ m0 CL 50 <W O DWU oL -) U) ) L (if. W.-~~f ~ C -t x Irfl 0~~ 0o XL CO C) U -o Co- _c_ (D Co 0co t 0-i o H0H0<00O~ 00 m N C CO 't L co (Y WO 03/072602 PCT/EP02/50003 473 - 0 -0. Lr >< 60 0) E - ' O c u) ) -_ LD (D CL a- a - cN D - .)o~ o E 0 - ~ ~ o-.3~U mo n cw~c, ~LL Ir- U) 07) U) U) LO 0' C6 C) ce) L LO I WO 03/072602 PCT/EP02/50003 474 , ~LO 0) 0 C.N Co It M) m c ?)C) t CD 0 CD) 0 U) c r oE 0 (n Z C.U in - 0 - C C4 C4I WU coOLL 0 4 -LU E- o) E c LL U- . w 0 0 L o m < o -0 4-1- < oo w - o cL o) 2 - - 0 SL L > -\ Co j C~ <- Ct' C 0

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WO 03/072602 PCT/EPO2/50003 510 4 ~ C'4 N *- C') (0 CO) CO) N" N - C'i CD CD CD CJ D CO 0)COH>- >- > 0 00 Cq C~J NI- ' ) ~~~~~. co 0 L I (' c 0 U) - r CD C) (. ) CD-I- C >I W U) U) or- 0 Z J >~ < 0 Z Z E Z) Of 0 2 D JUEU W.1JU) < = 0~U U x i -1 0 Dx jj CLO a- (DC Z (0 0 Z Cf' O < \ cz- (6 0-Z 7 o L z :E z C: :Cn D '0 c d0 U)U )( 5- c O U) U) U) D En~ 0- w 5 -1 -1 E -j D~. 0 a- D - co co -CO CO) N\ N N N - N CD0 a D (o (o C) cq ZZZD D cl Z z z zw e WO 03/072602 PCT/EP02/50003 511 Ceo coI N CO C'.4 cO ) CO c 0 C\D U-0 -O~~ N z~ N ~ C6O ci6 o~-~~OC)I OC cjCO WO 03/072602 PCT/EP02/50003 512 CL x \CjqD It (0 0'NC U) U o U w ) U)UL - E ,xJ - .' - i - 0 Cl) COQ) Z Z Z (n 0 Of (0 ClO U) < O~~ Z ca LL L CA In WO 03/072602 PCT/EP02/50003 513 a) - -S a) --- , > ) a o 0 C 0 CD cc- z~ "coo> 2 -~~~C mLC a ) ~ 0 C~iC] ) N 'C ~ c C t- " C)~ 0 -~ C z w . 0 0 z * O ~ a * ~ ~ ~ 0 0 C.) (DI0 I c) ~ ~ 0) 0N En" >)C) (L ry'C" I C") (9 -6LU) (a CO D1 =3 U) C) o ~ z cl CCCL] l m l (.0 C) .) o ~cy (0 T CD D I) "E - ) O . >" 0 0 Co CL 'h-. - C - C)) C6 M WO 03/072602 PCT/EPO2/50003 514 Lo~ I- co ~ C14 0 w -~>1 cI -QQ ) 7 o aZ 01F LO _t "t 0 0 (0 (N0 0.. < 0 m co 0 (D coCqH LO z.W D LL.00 z of a- WO 03/072602 PCT/EPO2/50003 515 (D -j a) 0) (D .E " 2 0c0 OOZ LL W -j C\F~ C\) rni M- C m t t o I I mO - -T- I 1O 1 "1" 04 N' M ~ CD C) CD-CJ o~ .~ C\I C\J Co C 0 ~ l 0 >0 D 0. C. Co C. N ~ c'J I 0. co I LO C~O I I 1 0 c l) Z o C) (N (m l D Cl l co 4 C;) C/0 cq ml Cl) 0 J > 0 0 CD <0 a - ~ Z ) C) w~l 0) CL CO CwLO a-) L -0 0- E 0 - N rOOD MO 0LL-Jac Z Z Z C0 U) Cl) Z z W COD 0 U WO 03/072602 PCT/EP02/50003 516 Lo) N 00 U) o > :p U0 U o0

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6 LL .. ~ Cli N a_ C) m WO 03/072602 PCT/EPO2/50003 520 (D.0 3 x C ) Cl c a ) ( ca coo 0) -U - . C 0 LL U-L 0 U) 0 E ~) L C/) U- .2-J cy U- uO - Cl OF- -c 0D 1-- 12 x~U U-J~ 2 a Eo l) I- Co C-u EO - ~ C F t o w .0.cn " 0 ( ... 0 EC L (D~ ) cl) z oC'J m < Cl) Cl E In E 2t C uZ, IL o U- U- LLoa 0 LL U 0 o C F-F- coN e U-- U- CCO a co C Co, WO 03/072602 PCT/EPO2/50003 521 00 0 00 3-'-(0 c) tO 6 C6~' ' ' ( ( Q D D D 0'- fDD 0 Q coo lU 0 0t D0 V~0 WLL M v e z( Z zl' m' (00 C) c'! 't(t0 O . .0~r 0-.0-0 mm m- 0(00 LL C/) LL1 0 0 (.0 (NJ C M~O 00- L =LL-CFLm IOp w o = C Z mZz a) _( x It M L Lo o a E U) C m C w 2 mZ M ) WO 03/072602 PCT/EP02/50003 522 i C ) C: C:) C) _o 0' 0- W QQ - CD N~ C) co) (0 (0 C) D- IC c D -r 0- Lo (I o' ( (0 0. ' 0 8EAM) MD E~ O:DD) E Cf) C) _ 0 LM 4 C 0 2i z E z z ()0 : Z. NJ(I ,t.. C)( o CD O0 J N O (Y M - )C ( D (NI ~ ~ ~ c e. (0 C: C':) . . CO - C) C)~ ( ) I) 0 (=) ( C: C) ' C O LL D-C DD 0 Itt - 0 W0 0O00 Z)of :2z z0 LL co o wT L Z z a- f 0 u) t) u c/ > > >- - I WO 03/072602 PCT/EP02/50003 523 coPc C14 C) (0o 0 0 O 0 o CY _: 0' ) no0 ()0 ' 0 (D Z < )c LU X<Cf) 0u. l 01 -0 -o -N C (0 ED) co cc m m (00 iDt) N~N 't 0C. (0 (000 C 0 of M iL "t "t W (0 N (0 E 00 rv co Z 0 0 00jQ Dz0 C) coD an D ~ D 2 0a a. 0~C C) m m~ co~D0 L N E i0o CL' m- No.I -- a- -0 ZOD m >-M oo 'c DU) I WO 03/072602 PCT/EP02/50003 524 (NM 01 U' : : 00 - 0 z 0 ooo E ol0-) -a .~- 00 (D 'a C'1 coJ -a~i C1 ; 0~ COO F= W~ o- 0) 0 E f ) - 0 0 0 zz 00 w z (D0 w z WO 03/072602 PCT/EPO2/50003 525 0)0 0 -- 0 = CD a -0 o co > a) -c: -Cc - c 0 ) v ci C\ cn 1 Cl CD <l < < .q7 co m d. Y) - 0 y C) c C6 co C14 C- -o ~ C o C (o CD fy ( cocomw 00co0 CLlC CL Co .2-- _ ' CL Co o 0N 0-D0 ID I 4 0-x IL '0 00:p E0E0 E (D M 0 Co co ElCl z 0. 2 00 IL CY MO) 80 0 Col E f0 - E 0 0~ l)~ - U) 0 Z C C) 0- c CO - Hm~C) 0 LO o C) (n () vi Coi C) o D - I'- *- ' ) C - Q <mo ~0- C) U) HN< cOO 0) 0 e L -- CL -i ~ ~ ~ vi;i(6co 0) 0r 0 Z:)CO D D C/) 0a-DZ C) 0eN InC) 0- O N cc -0 moC - C4 WO 03/072602 PCT/EP02/50003 526 d - < < ca -<m <m< <Lo- CO ca (o M < :: C) CO) qr t I- r- TI - - Nl '~- C\ (N l N ~ N co co co V - C%4 N N ELD CL f 0- -C 0 L0- m m 00 m a- m m m N ~ V C) 0 mc 2 C 5, a-~ 0 O a-0 a-- CL m0 m~Q m0 - m0-a- 0 0 0 0 0 00 00 00 0 0 0 00 00 0 WO 03/072602 PCT/EP02/50003 527 C N C)0 ca C 0 0 OL CL cu CO Loc 2j < .t0. CD C\1 m cD CLf C) :E C~ > cl ~ ~ C N ITi Cq >-O C) C ce) kn WO 03/072602 PCT/EPO2/50003 528 I- C) T- T- (0 C c~i o C ^ mZ <00 - m zCi) Q SM , 0 ON 0 0 0 a ma o 0c 0 o we s L. C 0 A G O. 0 s.. - 0 (V L. C) C a c a amVa a ci l c (V <L :o o a) ae) M > uioo 22 3 2u0 a) 2 t ao) O Ew 0-~ Z- 0 CL 1 (u a- C. 0 (n 0 <o IL CO -O - c Z o , - co o) o Z2 .< E Z2 o a_ > - 0- ,> . L P > - L > a C'tC CO ) tc Y enE < C:)~ C1 <4 LLz N 04 C E. OD , < 0 0 I < r m z 0- a - a OfCOsoL00 CO < 0 -Z H C_ E m Z O n j C0 1 . . o < .0 ) 'J '- --- LL COL L .2- Z\ 'j AMO > > < 0 a- L 0C_0 t - ) Lo I- ( D ( C - q 2- ' 0 0 0L 0 CC CO1 0 0 J0 1 1 1CLC .0)- -C) 5,i -1 -1L -< L C) Z. < < < F- ( IIf - F -< w CON 0 CO 00 < F= x z ) x L WO 03/072602 PCT/EPO2/50003 529 UL LL LL L U- LL ]I (~ C0 _ ~ 04 CD LO ' N- LL LL ~< -F LL L -L < 0 LL - 0) N-~ I LO CD 0-.. iU - LO C) C 0 &0 a 1- 4 ' Pr ( 0 m- 0) C!= 0 D LL N LL cD LL m0) - I- - - LL coU - ".. N co (D F< U- < H < LLS L- ( "U<-_ < F LL <~. <: -U H~- < F- *H- (DCO--LI o I C~lC)F U - - 0 -f - < -00 0a U)U) C\j -t (0 0) LOt a -)x L UIL L U-L L a) 4N N1 - LLr0)0)L < < ~ .0ZVF-W LL 0 0 "a H H H F- IL r_ a'- ~< CD0 0D<c a) L 0 z L6- 0 L CD0 < o - - E - 0 -) 0 NC E (L (LL L D co> 0 N -q M N (0 _- LL F- U-2: 0 C- U - LL< < < < << cc a) U- < 0 -a-O HF- -F- F-C) co a o c' a< T U)C/) HF- < o a' < Z o Cf) N ~ ~ ~ ~ C co~(((0)~0*0 IL L U-LIL IL I- L IL O -1 - -J F-F- F---- >>> - WO 03/072602 PCT/EPO2/50003 530 T- - (0 0 CU C) -~C4 .- co (i) Z: 0j Lo-I LC) w. U-) 0 'o I I C N 0') i LI C ( 0 ) N Nqc 04CN LLLL U- C14 LL. Z 90 z U cu Cfl9 - :t N No -: CO) * x . LLLL IL U-L L o D~ (D H- I- Co - HH <E l a) )C) 76 zr - - 0) C5 [ C 0 CD No E -a iro c E "m LO (oj ON m LL U.. > EO 0 Z E H : U- LL wLL LL - < H < 0 0 0 0 wC < < < < -e ( H -o 0 U HO 00 cm 42 F/) F-O OUH CO < ) -0 C4 CO PO 0 WO 03/072602 PCT/EPO2/50003 531 U) > co W002-0m0<<01j Co~~L CCi L6 CTi t_:c'I c co CJ~-~ (6 C\F ' I CJ D ' C 6 C, 1t I- N _ 'D I- y o 0 1- F-- M C G LL LL LL C Co 0L CD Z) 0 D D- 0- - H- C L b-I CL b- Cr H 0 z rL CL ry of W L W O U) UL (j LL < u)~ H C D- 0 a' 0 Cq ) < M 0 _ D F- a Mx ( _ --- < a1- a- co _ z 0- 2 ; X Z , X cal x( H"~ o f ~ o x. E-0 >Z C) a) 0o E a f -6 N l~ -a L z -7 -a E- 'a 0 a- <l EL cEL CD j oO EI 0 0- E - z->, EN CL ED =) E -0 N->10 CO(N DO CD a- L~j F- F 2!0 WH 00 ': - 0 00 0- 0 ILI U 1: o10 04 CO CD N-D m CD CD C6CD CD WH NL (.. CD mO CI CD Cl)-H F- L L-L>- WO 03/072602 PCT/EP02/50003 532 C C.0 (o to 0) ( C ) * C) (0 m Lo coc CNJ 0 ~ LL- LL Z LL. L CD I 0) IN N LL (D Or 1- 1 z - C a (No t- 1-r C > m) - O - C D ( <i U.. LL Li- T- 0LL U)- -- CO LL (0 0( 0 U- L C: C) 6 U..~~~~L x. U- LiU -00 C -i o i IL4 WO 03/072602 PCT/EP02/50003 533 0 C)C r)1 -U) < z U) . _ LO L ) V ZO Lo (D LL F- U- < ~( - CO z LL<a L L 9CD 0 = U) ~ <n < C a (n CL (1 cu~ ~ EcDI - UC) xZU L-00 (D 0+1 () -: A - U) a WO 03/072602 PCT/EP02/50003 534 a-j ~ a> 0, 0> 0 >, a, o- "n .' u v a 0 a 0 a) m~ Eo co E ~ >,0f >, 0 EL LL~ COC 0 n U -~ ~~ (0 )F > L 0 r 00 LC) D caf N0 0c 0~< 2 2 0 a-<- Z 00 C) ~ Q Z Cl) C) U D C3)C c 0- (o o0 IF 0 SC6 CL Wflj - 6

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WO 03/072602 PCT/EP02/50003 535 Cu C: CO CD 0 -ju m0 w (D ;E Cu 0 0 w 0-, n -u 0O CO LC Lr - ) > co LO co n~ LL > u 0 2 a: U o i wu I w0 0 5 8If - ZILQ -- D 0- m- CuL Z c LL m Cl U)0 Cu -2 _-E 11. u 0- 0. in co CI.CE L u 0 < ~ - < 0 [if U)0< 1--1 < 0 cU)w< WC=/) Z~ Wu Cu WC/N -o W o C" ) (a 0- . L OW Oco o C) IL>--> n mC:a Co 5 a 5 o - WO 03/072602 PCT/EP02/50003 536 0') 0 0: C M) C: 00L C6 CD o am- Um S6_ <~ oz CL . 0 M" * r) COf CO CDI ) > < a C X -cLL T (D 0 ' 0 X LLQ0~.L (D Z Tc <l § . I CX)~~ 0~~ ~ 0 Z o C) a) C/)) a) - >Lyc0 (DG -o m E- 7 CCTo CO F-> Lo M < WO 03/072602 PCT/EP02/50003 537 CD C~C Z) C5U) -CO U) m < 0 0O H ZC UI ~- ~ - -~ LO I- - 0~- '1 CY) m LO) DUO CO0 COH F m CLj ~ LO 'U O U-) -co >H u=OH LL l HI 0 U) > _) a _ tJ) ~~O-f LL aI Co co ml LO IE U) ~ L H ZQHH ~ U

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WO 03/072602 PCT/EP02/50003 540 m 00 CO c CO MCO Co a I~c 00 L Co Co Co C C - C CO CO Lo co M- Mi ZoC C C U) C) UJ 2 UJ Of If -5 1- w5 Z mmC m z LLL 0 m m (L:5 f) Co 0 C~ C.) O C4 oE 0) 0 L- X x P D KH"t m ommz >0 CD 0 o~Z O o =- 0 ~ CC C o- CoI Co6 r, cr 66 cu C: c4 omm E Zw oxm m Co~~o~~o0 C Co6 o~C4 CH >-> M M MW Z L (6 C6 v5 I WO 03/072602 PCT/EPO2/50003 541 T- CD N co, ca E 0-, co 0 < < - : c o) CD r 0 D 0.- nj -J u- al w- 0 -o o o = 00 Cc 0< c)-c)< E -w w w z O CD C~ LU C' co- o C\J o * . - - 0 0 N 0U C~O OO->>-> 0 i LU 0 ml C w l) cDc)iH - Lo IC) 1-0 c9 co x C/ OIK LL oc~ LoDo Eu C) Q-LL C) 0 J W DCL 0 Cl) 0 co E ) < c .. e D(D 0) (DW WmDDU)U) 0- 0 (Dm -Q 0 . <WU <~ ~ - < -E -oC h-~~ ot CO b -- o- D < 0 < < zC~ o O C CUW WUJ 2E- - - < U w J 0O < < 1Z0 0 0 0 CL 0Q~nZcL0 flCOCOCOWWWl)C C\ .0't LO ( 0) 0 z0 0 C co

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WO 03/072602 PCT/EPO2/50003 542 0 - - co m LU D L) (D (D ( - Z 0 - 0- Of Of 0 o W O 0. c _ .0 _ 0t N -< .~ CL Ufl < m OU w c OH D C z < ct) u l L (f ~ ) <lCl ClC )H Z3 U 1 ) C) < p- LOp q 0 0 wz W L0 U) 0 (D 0 EZ Co CO CO DC 9 ~ ~ : Cl) Of) U)U) ) l U U U <~~ Q - - ~ K ~ c 0 - O 0) c: 2Lna fl U) xw F-, :t)U)- U ) E a (D > W - LO ,1*CL 0 E C N C) IL C.) L WO 03/072602 PCT/EP02/50003 543 U) co F- > C)C ZCO 0D LO K ~ ~ C a Y -CO( cof z UC)C) Cl) Cl5 <l w 0 o l cc~ WO 03/072602 PCT/EP02/50003 544 ________ Q0 L C -~l .4- (V Q C) L (9 a - ) _) L oC\ iCj U Owwz Qc) .a ca. x' Zu XECCL Z 0 < . Z ~~~F 0) -c~E o ~ C) ~ ) (/V E(I (D) MV m) o- (D U)) 0JI <(x) 0()0 0 a) CN -C E < cq cD ) (0 1- U ca 'a m cl CL N LL L ::: 0 C I (VD :E0 L6n WO 03/072602 PCT/EP02/50003 545 0D N 0 C -J J _j d0 ~ ~ N~ (N (N (N 04J 0N CO) CO) CO) M It It (D tl- CNJ tI P- - -j - 1-j-i -i -j -J -i .J .. J -j -.J -1 -.J -J . . Cl) .0 Cf Th xc 00 OOC 0 4c i K ~ ~ ~ c ) -(. 01 WO 03/072602 PCT/EP02/50003 546 ___ 0 C) 0 Ct) wn (j) LU CO o N () C"J 0 o X a) 0 > C0 z 0 &5W C6 M (6i -e -(.0 1,- C) CD ) N Y 0 < n - ) 0" -0 LL W - i 0 0 C4 w~ F -2 CD' 0k WO 03/072602 PCT/EP02/50003 547 LO Qo co 0 co 0 0r~ cC) C) C DN - -J - j J0-i C) m -~-~ - N N N1 N~ N~ N1 m~ C~~l N n - j - - j - i - - 1 - 1 it LL Y "t ~~~C -, -1. 0 - L a L C L IL 0 - 0 - a >- :E N N J OflcW X a f f O f O 2 : 2 .wwz1 z CO) N . 0- 000 D N L p U RE 0Or- .. z .20 o _-o r- 0 CO0 0 > 00 00 wO0 J w o0 LO) -: - 0) ~-~ -~ -N N N N N N1 CIO N 0 N It -j-i .. J .J -J 1 1 J 1 (6 _ 6 LO * N ~CN WO 03/072602 PCT/EP02/50003 548 C o CY) ce C 't C - - CD No 00 WO 03/072602 PCT/EP02/50003 549 C-) a) a- C) D 0 ) z r) w n- W~ Wco .

C6 U) 0) t - -Coo)T 0 0 I a_ - uL 4 C; 0 0 Z 0 0 -Q .2 . oLL *50 -IL < a) (D z ) - 0 (D ~ s co L- QO Ox ( E ~~ E& & -0- - < C m) (0(0 0- 0) CLC CL 0 C) LO el- t LO- C" - co C) nOC o <O -i al WO 03/072602 PCT/EPO2/50003 550 0 C) co 0D CD C) C) C)C) V: f Ci ) o -C 0 3: - C Cu~~Y o~ L) 0 0)u 0u0 0. 0 c : < I- CD a > o z~ 0) LO 0) Qf lyi) 0

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V z < x C c 0O Lc0 C/)NI >0 z~ U LD-C0 0 IL oo ) L- ) 0 -0 Cu C-- 0 2 0Z Z) Q 0 ! CN ) 0 CU) 0 x08 0- 0 (1 C ) 0 () / Co U) r) MLC) CO 0O <06U 0 U-) C:) U a N0 Cu ) < z 0 0 :2 :2 S2 0 0 uix 72 U) U) C/) a WO 03/072602 PCT/EP02/50003 551 0) c O0) M CDo o COC Co ) < c: < Q6 CT co o) 0 Z~~C to m_ r too C3) It~ It tL' &I C; C O LD~~~~ o t 0 _W2 0j 2 U 2 0) (N C CfO " & C C -l -J C6 Q - Co c6~~U C/) Ei x) c o- ( 0C No ~ o 0 V) 0 0 cCAio)6 ( x 0 C~C6 -i CYI ) WO 03/072602 PCT/EP02/50003 552 ~J ~J j r n 2E 2 Co) CO~~ 00~ c Cco. C) EL C* U) ) C.) ~ - ce) 'f CO C C6CO co CO Of~ - L- LLC I I 040 a_-C0 Er U) U)). 0 -- C.. >CO &v N-C mCO CO C ry U- m F CCO EC 0__ _ __ _ I WO 03/072602 PCT/EP02/50003 553 0 0O E a) LL z C,) co ' 0 C)C CO Nq . ' N N 0~C -j - I L 0 C) coco CL- 0 Omcoco :!: CO0 Cc5 > 0 0 0_0 D) cr) 0 U) . U 0 1 =1 '.-.-*- C(Y) Ox- -5 N N) 04 N 6 - c ) N L) 0 - C~ Cf)cr) co c O 0)c M M C CO (D QO C~ ceO E ro CO co CO CD C CO O( CO (D It CO0 CO co -t :5 E L L u -. C w. F- c 0 cu- 0 CO) -a) o j ca 0 L) 0 0 X mL L CO IL 5 0 )0) aD E 0) CO c C -C CO 0q NLLN . C p-- (0 Nt (N Cf) ~~~~< <u-I IVLf f c)C l

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WO 03/072602 PCT/EP02/50003 554 (I) /) ~ ~ '~i C- C) m CDO m M~ 0) 0 : CO 04. C'- (Y) co co LL LL U. - 0 >% Co (H .2- 0 Cl) N >C L L L CD) Co) Co < CoW C o- CD) C 0 m CO CD) CD) Co 0) C c Co cD ' "D D C O C Cl) CD (o Q 0 cy)Zo (0 -Y D E Y o C0 ()C r r * Yq H :' H - -t 0 -t H;' "= 0 E ~ 8 - 0 0 HL ,d- * c- 0~ LLE a) 0 co CD ~- w Co t 0T .0 0 t U- mL U- L LL ~-iQC C)/ N _ - . - Co Co mC oO Co (oi (o C C ) C Q (D Co) (NI (N m caf It) WO 03/072602 PCT/EP02/50003 555 C) -j I C) U)-i 0 0I. m- m m m U U) ca i 0 0 - - 0 ouN aor corn mor coO o~- a - CL E a- M o C L a_ 0 l a- CO co- cor (a~H~ i oCD~DcrnOCD - CO C O N- C N ~ N NO M - N MO 'E 0 mo m moc 0 0 1- (D m mac 0 Q 0 0 H C EZD O 0 ZD a_ a-D~ CLz ( -m 0 M u a 0Z 0 0 ILM L m< 01- U 0 QLC 0 0 ' a Ofo u 0) _ \ - <E0~~0C n coLO $-aa. xo CL a oaEz 5 0 CD.f~ ~ 0 CD ~ a)C/ e) cC) CH (Do (D com 0 5, U) U) 4 NU - - C a- a- 0- LL NC C) 0) m m co mca0 F-- o u m 0 i a- 0-I - MINL L mO 0- M) LO k irn WO 03/072602 PCT/EPO2/50003 556 ~-0 CO N NOD CD 0 CD) E ) U) 4u LL - Co U) 0 ) < -j0 -0 z xa C\T C, q7 -X- I': C6f C6Kc ;t co N N I~C N I ~ ~ o OD _ ~ N, -,t t,- (L m m~a o LO 0 MCM M X 0-CO 0 .c00 0 0 Ix l~~0 0 U)CN .0 0 0 0~0 0 0 I ~ ~2- .0 K ,- ~t r- N -- ~- M LOCM N 1 o o 10 0 0 0 10 C4 m <m 15 -m 0- m- z -m z n l -h Lr ZU LO co 00) C)LOx a) ( 0 ~ m < CD~E EL <) 11- 0 z Co J~ co U) - M- E IL U)N r Eo Eo N Eu5M CL 0 U_ 0o~ - LL C O o0 a) a)0~ 0-~00 a)to C; C ITD l -a 00 & , C6 -a cc) c Co N LL EO< coomEm 0L E LmInm c mC 00t C) a- a - - a- a-L cv L6 C 6 C- c'0 cC~a L N 0 C cq coi V0H(6 c C4V \ I 0 6 -j 0 C 10 ) MM M M O _____ ____ ____ ____ ____ ____ ____ _ If WO 03/072602 PCT/EP02/50003 557 ~cia LL LL I I a) I Z D Co ca Loco ~Wa- OLL CO C4 (N7 N1- m a- E- CcD 11 aN~ (N- f CL- a-N oozO CDD\D wED 0 o m Nm I- m 0 < U) U) LLc w x/ c U us. m OaO .- DC Oc Ol ' m L c IIDl(u ' L WO 03/072602 PCT/EP02/50003 558 0O) "t r, (D~c LO C t LO) 00 M 0 CDO " m0 C ( D 0O 0 (D C-) 0 0. >, LL > U-) C- N CN C) CY) CD -j C) LOO;t N LO M <c)o 0 z~ z ~E ECO O ~ l o ~ c 0 L L)~ UJ J CDN o - a- L 0 000 co Z ) Z 0 ;-5;04 U WO 03/072602 PCT/EPO2/50003 559 0)'T CD 0 CD 0 cu. C) CD -DO 00 0 C:> O -T CC)0 L6 0oO 0)0 ~ o 0 ICom a c ED~ZOD C/2DmPOZOIQ w d - toj L T- Ceo 0- IL -i U-LL E 0 0 Cf) C: m ) .- 0 0, IL -r 5, (5 0 a) 0- 0- 0 .0 c~ cZo 0 0M )f_ C ci IL 0 z £2 - 0 zL (D FnO 0, - ~L60 Z C) )0 c 0 C Z 0 4.1 m 0 U Co) z - Ca - t z a_ 0)~~~t ;;1 C)toto)LL LO CC (3) CD C) LO 'IT .0 L CD C) C cli ) C)C~l C,4 L6 N 04 C5 c WO 03/072602 PCT/EP02/50003 560 C5 CO LO c<r< ~ 0 0z C:) Mzl T r- , 0 -J z -0O < 0 <c U)U)U)U)U)U)U)U)U)U of 0 ~ m m~ a_ a-mm- - _0 z O mrr'a/ of) 00- 0 0 0-0o-() 00 0-00 of O0- 0 U)r WO 03/072602 PCT/EP02/50003 561 Ld CY LL o Df-f<ZOcl 0 U )C WO 03/072602 PCT/EP02/50003 562 -~ 0 a) on~o.~0a) 2: 0. t: 0 co0 0o~ Co ~ 0 N ~ Ma. C~ N l l C/) [i UW) ) f U () o ci) N N W)- 0.W U) W~ 0 5 QN C6~ N * iC C) 0 w C200LCu Ocu CC/C LO~~a Q00 E 0) 0 . OL 0 ~ O "Cj :2 U > W CY) C LO D (j U') D 0' C3) 0) L IZ WO 03/072602 PCT/EPO2/50003 563 tC < C >C > -0 _) L0L L C, 2i L6 - M~C 1: -yi C\4 m C CT C CF w o z F- LL ~ (6<UX-2 0oCO l C) OLmUm > <w 0 0 (C C1 - O c- -_ 00 cq ~ C6 0 C .4 cr Cq C Lr N N C\j C\I a.FH 0O0OF-IZZ -0000 0w LL wI D D wl Cl mO m/ mCOww a/ 0 M0 a l .- OLUC CO 0 M 0- w - - 0 '2 C U C) " 0 CNJ Of w 0 w C~l :, o c 2 CN 6 c; N~ cN CO 'E 0 > :tl=! U .~I 0 C) C) C.' -~ xo C - 0 1 ~0 0 yOC)C U) (a 0CI EM Z cog N-c C Y * o CO) >) c, CO , EO IL E~D w 0 0 E O C C a . r- ) a co 1Z. CO E 0- (o I' -C, 2 H N NNm C6O0-NN u CLu Jq L U Lo <<<CO W. -01 - ~ ~ U U) 0- . " CJ - - - C6 Cq C4OR 0 ce) 00 00C o coyiL MWW <0W0DoZZ/)CO6O 0 - WO 03/072602 PCT/EPO2/50003 564 0 cu CY C-'O > - o 0) . s.. O) C. (1 0 m n a Z r'70 u_ >>->- Owcn 01 W W Joo C S .. o iJ - - Z LU a 0 0< c o - C 0. - ~ ~~~~ w- co w o c o 4 - 0u cctt CC) fl J -OmO 2nZH 0 Ll. 000 0) 0011->>> >> O_ OZ 0 . C- o Co co =. 0 0 . C D o ___________N_________________T-_ iO WO 03/072602 PCT/EP02/50003 565 (Y, C Y) Z (0 0).C).5 M. Z Z F- co- : co W - r C Z F- to CL- (N r 0 o~0.0- H HEW -w Z cW WU w 0- D-C~~ W W W *~~i Z WD -0 0 o I-- u 0 OC) -a z Z Z m v Lo) m "t - N (0 tI Z co U-'vL) Qy W~ IL I0 0 m if o- " O < (X - w - Q .2)X f a 0 f 0 Of "5 C- 0 cjn 0-L z C- of m Et) m N -0 ILZ~O C\ Q fL www LU) ww afW 0 ~lcj 00- 0- CL L LN 0 f--0- f a.-m - 0- 0- m -- "0 =02O0 0y 0f f 0c)W i 20 00 w [If 000 W ry [i oWa a m m a- o- ma a. a- a 0 0x0w w D nm0_ 0_ ELrm (L IL IL- 0)ccr)(( - Cv, m ~-(0 H010 0-rn WO 03/072602 PCT/EP02/50003 566 0 -J 0 0 0 C 2i 0) 0 cf) n z la - m - m-mo = 0- E0 Z-c Zo Wo m D z z N 't co LL, . z L C -- I - () WW mLL m J m U P ryza- 0 CO) 0 IL I IL Z - z (L N-C) a cd .0 E 0 a. a. - aa w. w0-- Gfl m Z O0 0 . w -i-- CD N M tm o C ) _q L6 1.- d' coF q') C6 L0 * C0'C' I i C'6 (6 M- Lo I-(J - M Of 0 - w * [If COf D ( o~C~' to N-C)z zz I- w~wwu .0 0 Zo ~ WO 03/072602 PCT/EP02/50003 567 j - - - Co' . r- 0 N m ,4 - o -,t D 0 of 0 fl 0 0 of0 of [i0foD l fr D O wI I I co 1 0 00 1 CO CO M w w I Z [LI- _I W- Co LO W~ Z Z D-m w La- (0 WZ O COW WUJ EL m 00 Z 0 D ~ CL ) 0 m < CL wIy)2 m I i I - I I Co - - I I I I 4 N r- 0D E~~ co w ,S m - -( N CO c o '- Z ZZ w -Cn O-W WZ 0 WW LUG.M Z0 M 0.. NC14' O 00co (D C O C 0Co Z LO I- U) LUWLUO LU0 U)U LU LU0ZZ U)- E f l 0 - a fLo C 0 c ~ 0 . 0. mC 0 0 m a- a-I -0 a -a -I 0 (D ) - (n CD 01 CN CO S2 It w~0 Z Q - a- ~o o a.t a- a- a 0-a~~o D IL maaa m . m ~ l m O CO f Lo m C Z z z z z z - - -C1- WO 03/072602 PCT/EP02/50003 568 U) 0 < 0 0 < z ~z tz c'i <Q < < >Lj 0CO F- 1- 0-= C' U < 00 a. 0 00 Ew (00 Z Z a- m I_ E' _j CL w L 0 0 cie 0.tQ 0 0 0 l 0Dw Z~~~' F-(LU L 0 00 C C o .2 o L. o 0 ZCo 0c C Z- <0 f LELILa Co -00 m 0 0 -N 0 0c 0 ll IY el 00Ccol000 00 0 < L z 0C CCo C4 17 00 CO <E C00<z0 C) C0) Z a ce) C to ( c00 WO 03/072602 PCT/EP02/50003 569 CO c 0i 0 D( 0 5: 2:- < z (0 (Nz ~~t( CC c) 0 0 0 0 0 0 0 0 CL 1 0 - a 0- 0 0 - Ctl) L CU CLC o0 cc0i a_ CLDD a)uCLC 0 ~ oEa.

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2 e. 0I 0)0 WO 03/072602 PCT/EP02/50003 570 0 CJ 0 (D 2 0) > w C~CD CL a Cl) 0 0 0 0 0~ 0-o-00 m a)c CLc'0 0 c a ) 0 2 )(D a Eo 0 E - 0)0 ) 0 0 00 o-2 0o C)z 0 L0 LC c La 0D z < L WO 03/072602 PCT/EP02/50003 571 C-, c a- )Z Of J-0iafll w Co af O - a 000 Of E I C9OOOOP D co N 4 c6 ) I 0D0 0 Z> 0 0 Cw 0 0 00 0q Cl) 65 (16~ 0 W - j- ox 0: 0 ) 2x o ~0 o M . (a a co _a ) C C - I, - - C\, Co0 I, o C l Q C"4 D2 Itj &F CJ -- "t Ltc) LO ~ =CE 0 2"1E 0 0 0 0 0 0 0 0 ~E F- 0z < 0 CL z 000 T-Jcl)> 0O 0 0 0 0 D 00 C-4 't L0 0co-0C6 0 00 202i00 WO 03/072602 PCT/EP02/50003 572 CO LO - 0) co "t CO N N 0 a)~ m0O((n 0 N u > _ 0 0 0 0 0) >- C N C6C U) U- -Lc C~f N , 4o L6 cc LO 0) N N C14 000000 0 00 2 La 00 , 0 _n bo C ) C) M~ U o o oLC) 0 n m F d ~f c) 0Q0 L)0 C)0 C C)E w LLo w o0=~0 .2 L) 00 oo0 200 0 m m m Cm 6 0 0~ r r 0000- ol 00f2 oOO "0.00CCLCL0O CO CL 0 a N - -C-5 -Lii U -No) Co L) - Nj i T-00000 TZ N\ Lo- CO LOCJ N. Co C- N 0 0 00 000F-N N o -o LO LO WO 03/072602 PCT/EP02/50003 573 a3y C: c 5 (D 0 wwww w w IL m m L3O CwLO W D - J t Q 0 wH~ I Q H N; 0- CL CL U) P Lo~~o~ C~ O: O ) 0N m 0 N N0. Lo m 0 N L O cD 2 Ci)-0 4 fDO C6 U. a.. a)C < a. Cf) 0 a. O D/) N0 aH c'i . w- w w ww I m LL o NL m 0 CL m mO m m NNa L6~~~ N4 C: 0 co ,tC0 ) OIjN C L6P-7w w ai q V.: i oZU-CDiO6 n 0 u L ' fL WO 03/072602 PCT/EPO2/50003 574 -C 1 ,t C-0 C C-) -J t) d, a) .l) 2 0-. S -~ C: ~ U) 3 (m 0 cu m CL U)) U. C3) LC z - 0 L Zl ci, C-4~ C D N 0 ) U- -j >< o3 L 0 LL ~-- -o 0 9a L6 c N ~E~ Cl. U C) T- w zU) ) ol - dW w n-I-0 o C0) C) ry U) U) F 0- C 00 " _0 7 C5-L6 &Cl 0- U) cm C) U)0N L -: C:c WO 03/072602 PCT/EP02/50003 575 LO cc N N~ LO N 00c ~0I U) _x z ~~ a- . 0 >. Lr c X\ 0 C~l C6 V G) U) 3: 0 -~ M. m.CJ U) -J U) )2 COCO . TI~ O=0 (0) (L 7: I co U) W- C. ) 7 ) (pi~ CD (D CD a) (D< 5C < LLei 0 L 0E L ~~E E(n 2C 6 E 0 -< a) C

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WO 03/072602 PCT/EP02/50003 576 ) co 0 ) (1 3 ~ < .0 c z 0. co 0 ) 1 0 < - : -~ N M M C- 0 -) c. C~l c) C6-l (6 C\ N C~CR U)j a) -Q 2 = 0 a -L -- 2 1 02 OE U) F- CL '- f (D CL ~ n c~~ -5LO 0-~) 6 : 0J < x.--.:: CO Z N a) CO a) C U) E U) 0 Ci c E~ = 0 2D -~ 0- -a ( u \ N~ CF 00N wuzOQ 0XU) < 0 < 0 L _j D L U) CL C - 0 Ld l) U 1/ WO 03/072602 PCT/EPO2/50003 578 0 co) z co, N 0i >. C) 0 LicyZ IL COLI c~c5 C) ;- o co 00 = 1 0 M0 oi cl- x5 -j cl 0r E 02 co (D. o.0 L6 0~ L6 06 d 04 0 0- E m' CL > 0 0) E < 0 E C) C) C) < O)FE0 0 01 Ea. i 0 cc) 0Z 0J E _C) 0 < < 00 -i0 ><J 0. X Eco< 3 )L U a- W 0.0 .. C) J 0 l)E 0 0 ~ < 8< < < < C'I C6 U5) 0000000 0 0 0 0 0 WO 03/072602 PCT/EPO2/50003 579 C-) -J (D o C: a) 0 a,0o o : C: o -0 a u, o '0 C C 0 CL E~ E ao 0 ~ E < uCI U~ ~ - a) C co 0) co 0) C0 d L6 4 t-: 0-c-N D "" - L6) os 64 N o CO co CO LO CC) N~ U- << <CC (nC ca MC CLC CC CLC CC 0 0 w N f fW 0 0 [fw w G I f NO It CO - C ) C) I Ny Zr coo LO M CO C14 r- MCL 0) N a, LD 0 .< L . 2 (i .- a-, 0- ~ re Of~~ ' C co I C) c - 65 N wl LO (-' N CO) C Lo) 0 CO 0 N CO cr CO 20-~ 0 5 cNiL C LOC to MO nL M Cn-4<= an H of < a) z a) a, 0 C <, (nC 0 CL W Cly U5 a ... x x Sco C) c) (:6 .. D co a) I 0 - a, a, CD -; S CO ) >, E E- co Mi E~ co C t O-co N m m M0- C m 0a- a z 0m m [if 00 0 0 O 0 0 0.8 00 o W Of 0 C6 0 (I) c w a < uZor L CT T ~ - M N6 CO7 CO7 CO C6 CIF L6 N- CO ;I CO <<0 0 LO ON WO 03/072602 PCT/EPO2/50003 580 CD (9 a)) C.) a) co ) ccu( C)) Cl <0 (0010< Co No Co LO C) zr CO IL 0- t o 0 L W CL J 00 n (0 5 O CO- W -;i~~~~~ 6 - 4 0 . 0 0 - ILIL a CO IL (0 C) 0) o C m) ~ CoO Cola & t-: If C6 0 0)L <00u~< LU) CD) 0 < 00 WO 03/072602 PCT/EP02/50003 581 a ) a) m~ .0 2 ~~ .2 0 c o z '-O 0 0 j a- w w ~oo o 00C CDC 00 000 0 CLD~D <O~- 000 CL (L C I 0 0 O EfC C~L OL m 0 CY Lf) T O~r M 0 C') . 0 0 Co2 I 0 0 N 0 0- U- 0N CoO) o- -- ~ ~ o~ n c < f-H Mo < Mc~ a_ 0 z a) W O_0 a 0 a-o ZD- x y -r C6 C o (D 0: - L6) 1- M-j C ,4-N CO- (DClD) U) 'TnDO N E 'a00004 ' 0O Ec4 c E 0l Q~ 0 5, O F= ca 0 ~ 0 c o () 0.L)0 ~O E m m C6 (= L 0 co (M o)0) C )loP C 1 I'l'OL Y CCoO CO ) C0)L O"tN- C O C O M C ) C - w - ~-. m - m 0- (J Co Co Io a- - CoO0) ( CIL Co C m N m It L 000 < 0 0 0 0 0 WO 03/072602 PCT/EPO2/50003 582 CD NI' Z E8 CL* 0 m w co N t, m 0 w C CL > - C>) _'> LO )~ O - L0O (0 * -:-~ N N~ It "I C N ILL M -<IL CL CL D- - IL0- w 0 0 7: U-)_3 0- - a- 0- Cl) E LL~ -~ LL W0 L 0 U&OMoc1 2V00 c _0 ~ - I- 0- LI- LL IL>* 0- D > 0 -J >- .2) =C c 0- Cl) o 0 U).~' = N - N (1 u x- 14 0 - ) ; x) L6 6 (00? - x~ N' a--0O 06 N 0 z 0 ci 0 0-Z T- -o tW .a E2 E - Z~ N N N U) Z 0 ~ ~ ~~ 0 0ULCJc L I I -I 0-0 C6 10 10 - L WO 03/072602 PCT/EP02/50003 583 N * N z E ca 0- w# Co C- z N , LC Z Z )C>- -iU 0 U- o ~ 0- 0- CL U') I ~ N>. ~E LL w' o a. ,N CL. Cf. -c.n W >- Q ~ ~ LL IL o S0) l-C IL c:, au) ) C '0) o j TL 1 N CO ~ CO -- ' N co N -. N co ~ u < M - LLLH 0-- - f L C- -LL WJ ~ O J.c Wal. azom CU.(~ -JZW [fZ W - i -U LL. 0) -co xw N6 Z z .- a ) 0- Lo -aC D XD ' z~~~ ~ " C WEO (D~C/ C: C%4 I'-~ L CO -C N -~ CON d-. N~ *~ -C - 0) CLwo ja Z (.) NLN 2 <w 0I' CCa- a O40) LO (0T C: -N t I'l N4 N N LLiL ( 0 . L -j W D uj- n_, [if w >- 0 0 Ow 0- IL ( 0>->- > - 00 It) WO 03/072602 PCT/EPO2/50003 584 0 z C) 0 C6 G C'iOM Cj C0 CL a-W 0 - D U =) 0 0 () 0 - C I R'~ - 0. oLc~z> co , I C) Cq N 0) a y o- o- a- ) o C4 C6 04 ~L (D L >OIC6CLD I- I 6 Lo 0) ILU ) EL Ci ( . (3 0_ 0DL T ) L a ( Z' Zx z 00 0- (N m 0 o)1 C:z _C t C - U) 0~ ly zU, U) )z w wO UE wL WCO U) :D (nM UcI M U CL y 2 -~ 6 C) : Cfl - Cl a.~i U)CO U)~ MtfCC)) oic\j CO N -Q C" q EL a- a- ac - CO 0 -1 w z Lu to ~ ~-00 WO 03/072602 PCT/EP02/50003 585 CY) co ( Co (NI to 0) ) D (0 C (NC 0 CD 10 00 V 03 C \ Co o co 03 C3 0 > w X ~.&~(~3L (6 6 - co~ (~ It: -~ - I H 0- - - 00 IL : C 0 a- Z w 010 2: 00 o a~-0 0 - c) 2 z C)O 0- o,- > < 0 EO co C) 0(9wwwU D e 2 .a (NJ ci, (NJ c~ L O 6 L <~ CL 0L a 0- 0 - IL W W -j LL -1 C) 3: T- 2- :-E - -2 Z) Z. IL 0)O Z C () U LL 0 'IT0 H 0 ~ 0 Eom Cl QO 0 (N - O c 0~0 0 c CL c 0- Zb C) - !E ItC) L- m I 0 Y 03 CDL ( 00(0 I) Tr (L vu 0 o 0- LL IL Cc - n 0 00L(D 2 53:z o M: Z 0 cli a) \F 000 < 6i ) a L CY WO 03/072602 PCT/EP02/50003 586 (D LL- - - m ql, D C T-C:)~ C\J C) N It CO n (0) 0) * z wL < OlQ- L) 0Ci < ~ (*t 1- - 61It - l 04 c) m0 m\ 0 C n w a_(L - 0 C - C.j C) L (YI ~- - Of x~ 00 I1n WO 03/072602 PCT/EP02/50003 587 o ) C\I o y m 0 "t CD C) - -; - I < ca N cj o or- COi C" ULL L U- E O 0 FL -~0 on OCDO0I~ JJ~ZO ODCD 0 00 WO 03/072602 PCT/EP02/50003 58 Lo~ 0) 't T- 0 00~ U') 0) (0 m co () o CY LfD CDO ND V-- NOD 0) CD- CO C= C\ C f) L 0- <U. _D ( D ( D 3 : . Ca- o It) < - -~ ~C)0 O00Z z 0 < L N CO 'i 0LL 0 0 - 0 0LLg-10 0 2 L IL CD - I I C I. C *U N- EE * Q I L) 0 L) L flD Ci mI 5 2! Z 0- a. L 0 C: N 0 oi Z-j> W < ~ 0 U <F.2 LL 0OL~ I CL~ 00C 0 L L , 0.0 aZ C0c a- i, CO m 0-LO N N It) - 5\ N E N N~ U- m 0 0 00 0- UW W QJ LI E W 3 Cua L - LL(9 1 1 CL c, LL 7-O C I-- CO U- U) 5 :2 0 o M m - 0->- 0 L C.)D S m f 0 ) T WO 03/072602 PCT/EP02/50003 589 0)LOI LO~ 00 - - cO l C - O U') C0 co 1- 0) cli CO a- a e a L- j - j - i - j Oo LO N0- ( LL~L z L C:) o CO I - 0 EL (D CL w E N=>C m z- 0 i -L ~~-~ CD~ CD- -o - o N~\ C CO VO- - (j - C W oj 0 I ~ W 0 QO D C0 C) W < L 00 WO 03/072602 PCT/EP02/50003 590 m io co t, C6 Cl oo <- C) c t "t CO I- - C'J (N (N (N (N (Nj co C D co co - ' . -j -i-j -i i -i -i - -j - i ~-J a-l U)U)U UC ) (0() U)0(o( ) Ui) w0 D wQ 00 wOO D Can0 0)cl 0 Q (D~ w D a) 0)C zO z

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WO 03/072602 PCT/EPO2/50003 650 0 C0 S~ El .- n~~H 40- 0- mCD o C ,:3 t (N (N (l (N (N Co ,- m Lo (6 co 0-L>> -oooo 000000 OWWO~o~oCOC WUCOCOCO)U 4 c6 (0 U) N w WC) ><L w o e)OW 0 C-) QHO 0 0 C0i C> 0 L)0 UJ~~ULU w w wW Wu X)W~> 10) oW(NO O = oCCC~ NC( w 0N Cow U 0 - i wU)U) o ox E 0 - - - x.- - UCO 0 - ( - 0 _-t CD N 0. ( N ( ' -*(N (N N v>iC Lo Oo 0 C) C) )' 00 COCc), (ONW/ Cd inl L6 C6 00 Cl) w - 0 Cl) C/) ~ (0 - Co ~- CO N- 00IF z - - N . (N (N (N N C o 0 - ceo CO M SO 0 ZWw w wwww x w w w m LL0 WD W W 0 0 0 w 0 w WC/c> 0 > 0 Lo) N- N- o WO 03/072602 PCT/EPO2/50003 651 ____________ o I-) 0) 0) C.) 0) o a a) 2 L2 CL 0 0)6> C) zC Se CO) C'4 N -J -J -J -J -J -j Lf 0 EL. r- 0 w 0)0 (0 WW 0 0 c) C) C/) ) (-)(. CO oC CDO - CL c~) C.0 - o)0 c x oX >< W WW W 1 WO W WC) CI)C)lc) NCW) Cow L C Cl) 00 >o - I- - .L6 )l 00 x 0 x~ 0 LO w .. N, I. WoN o W WO N iO - C o LoC CO4 LL 0 0 0 0 0 0 I- OD-J,, C 6 : o 0 6 L 0C 00 Z cCc)C C)U ~ NT N- L6 WO 03/072602 PCT/EPO2/50003 652 0 0 0-0- m U) Cd) . U C:D 2 90 0 >c <<oi mc. o M I< mZ < 0 wa w I~ <D CD~ I I-I=ZH WU wcO 11 a LL LL LL l LG ( C.) L- ) f LL LC .. C 7 H 0 0l H C)U 0 on 0 lLw 0 0 DC ,. o o - (D~2~ C E mO .. . z LLLL ZCE' ) 0o - L 7- M lc 0 =3 .~- Cl a) Z~ L CL .. CO COE - H<H 2- a-U> C'fl 3I I LL U_. CD) L y CO C UN T- CO< Z -o z < WO 03/072602 PCT/EPO2/50003 653 Q 20 a) 0 .0 - C: ~ ~ l .. C) 5 C) - w.

0~ CU CD > a) C: 0 IL~~ ~ ~ ow D0- E E a ww N N o CO CO f C\1 CD 1-O7 0) 0) CN (Nj .0 o > o <. < cy- Co <~u iO CO O o 5 0 0 w CD (D .0 0 .0 00co Go c Co WO 03/072602 PCT/EPO2/50003 654 co LO) Co) 0 T-0 a) a) 0 (j) 0 0)0 a a) (H COC Ha a) c0 C:, - a ) a ) r= 5) - ) 0 C) >' Ho 2t Coc 0- 01 mH x co C) 0 co - -C6 0 .~ ~ 0 (N F- a- 0~ M-0 (N Cl D0 C) co >a- -J I 0Ww>> 0)> l ZH F <00 a a- 0 -1 - CO) Of 1 0 aCI3 0 ca0 .9 Q z N 0) o (D C) F-OO 0 0 CL 0_ C4 - 0 0 0 UQ~') m (DWOl2Z ')>-CO O IO H \ C 0 / z0 .0 Ca . Co Lf LO) (o 00 CC) co co It kn 4

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0 O 00 U- 75 -)XC U~LCfl Cl) a) - 2- 0cn f WO 03/072602 PCT/EP02/50003 670 ______ 0) 00 2 a" =0Cl) o I -= a, i a, Cl a CL Ej > a- (D C ~ Cl 00)I- 0 0 0. IL 0 0 0,~ 9 a, o U) U 00 0 00~ 0- u Ir- LO LL,0 'E 4 - 0 0 l y LO : -E LL x a q:E ca c-~ 0~ 0 co co NO c UIC) W 0Q 0 N NN N r WO 03/072602 PCT/EP02/50003 671 00 C?) 0 , m0ucuc E E N La) C E 0 0) tO ~ 0 IL 0 (D Mi CL m C CL 0CDm 0 C) (I) 0) 0 C :) LO 0.. .. 0O CI 0 0 ~ N &LC) - - C14 N Of0 )W 0 0 Z W u co I 0 I L 0 2 cr C~j - 04 w f- f a-0.. m.L 0l - - LC) F- Q-L - N~ C 0 H HO WO 03/072602 PCT/EPO2/50003 ________672 hC) N-o i-3 (0 (.0 1- 00 00 > -- C.)> =_ _ __V_ _ _ 0 0 ci) U) =~ "0 0 ' .cu .0_ C: =- w >,cci >, 0i a CL - M 0 CO T co =~ C: CO0 L 0 ~t Zt Z -Nu 0- C-m C - u I- am O i~~iz (D :2 <Z~

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0 0 0 C - a Z) C ( a.. C0 0 CDU .. -0 c) CU o U) o C ) o z U) 0 0 in - C Ua) U'- e'- U)0 0. 0 C-" CU "' F- -J I F-' 0 D D 0 a0 M D Co _r __ C CD ) a) 0 C 0 ,- .2c E 0 E . . o 0 CUo 57. oCU C- (" U)-C T- 0 0 0L 0 ") CU C 0"" (D . 0 c) C co . co < - C U = CUa) -aE r- . UCo o U a ) U D C) CL. CC 4 c - CU "6 0 0E • ~ r c <" "0. - z o a) CU 0 L :L_ •0 ,,z' o.- -o .. .. 0. ..c E .

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4 . - 00 4e 0 0 - ~ 2C C 0 C - a E 0 _a U)c U a( ~.0 m) E 0U)U 0 9 U) E = ." .) ca a "U C 4 - CU . n n5 CU (D C U) I_ o Cc C - < E x cu U) CD < 0 a) wZw 0 I7 n =7 t7n d(n C w < CU CU < 0 :E E) CU (D -D 0 2 -og CD CO o 0u 2) a ) a ) C -- co CU 0 0- 0 CD-~ 0 3 V 0- 3 o =. cm a)V 0 ~ a) a)U o 0 c 0 0 0 0 0 >.--r .> ( 0 -) a 0 *C0 C) a) a EC(Ua CD 0 -0 0 0 J 0 0 0C 0U 0 -J c/ <* 0 - 0 - 0 L 0 CD ) 0 -o 0 0 ~ 0 CU C 0< V 0 -< < <. 0 00 WO 03/072602 PCT/EPO2/50003 802 E M) 00 0 - 0 -- O Om a 2 .o a o C V 0 n 0E 0 0 0 In -0 :P E < < I 1-- < 0 Co o00 ( CU C Co C_ 0 C 0 = 0 E E - Co 0 Co . o .0 L. 0 0 E1 co 0 a.)au. 0. 0 a 0- 0) C . Co 2 - 0 2 *ao 2 o~ .0 D 0 a0 C) E E Co 0 0 0 C 0 E Coo 0 e E FD cu m .o 5 Co (a Co2 C 0) m) .o E 0 < . g 75 4 ' 0 0 0 C fc

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S- - z C .o .o o.s" £, E -o-ea E 41 0 "" o 0- O 0 C a -~ ~ C :a) OtC) _ 't-" C r-' ",'- CIF- O 03 C C: < < o > • a- 0 ) 0 c 0 .... . . "o 0a) W m 0 0 - 0 C2a) Cr ) 4-- "- 0 a)> S0 0 E 0 0,q 0 C 0 > C- 0 .0 0 = o ? >C C: m= 0 0 ' 3 n,- 4- 0 ,' Ca O C/< CL 0 (a 0a 0 0 4- E 0 0. u~ c U 0 ) 'o co 0 C t~ 0) N ~~'3 m 0 , cC 2~C4= * 00 0. C O cm~ a E a) a)t 2 0 L. 0" z' 0) a)~ C) m _ _ __ _ _ CD 0 CL0 WO 03/072602 PCT/EPO2/50003 806 EE _ E E c/D U) U.0M.0 0 0 E .2 0 a a) co ca 02 2 < m coi a) 0> a) a a ) C.) .0) (D ILE E C) c: Z ) a) EcuL0 . E 0) (D 0 a) to U) U a) CO Co C. E o .

ca0) 0~~~~( a)~C -a -C CU W~aw o~~ - .~ d a ) a:5 0, 4. a a) 0 >, (CD >) 0 = aCDC U) U E tp)a ~0 d U ) m C cc a)( u nc ~ )a) U)C: E FD C cu E 0 C 4') a) cu 2 ~ a C: Fn r 0 u( a) 00 0. Y~ (D E5 a) a) a 0. :3 a) E:(C 0u .C 0 -C: 0 0.o 4-o 0) r- E ) LO a):a C)C 4- 0. U) .0 Yd) >0.:C) C 0au (a. C: ( 0- 00 a:) 0 _0 0. 0 co -EC IL) CD 2 01 3 co C: - fn0 C ) IC ) 00 N N LL CL F1. Hv C/) H- H ( <C0 00 < < <_ in m m ___ m0 WO 03/072602 PCT/EPO2/50003 807 E E C C 0 0C E*n CD 0 c 0 0 c .cn cc ~ 0 0 m Ci) EO -5 E2 a)CD 2 o 0 w 0DC =44 c~ C .22 E CD 0 D =C D 0 E0L a wl 0 0 75-I' _) C) U ) C) >L oc C cu C: C 2 C 0 o 0 0 0 E- CL 0 -0 -= C co : H) 0 C a) Cu 0 C n~ 0 0n C: M 0 .20 - -a ED C) ca .2 a o ' No .

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o0 _ Co_ <) U" 0) m0- 0E . z O .o O S D |(n I o ca UL U) U) -0) 0. o o ~ 1- "- .co . = - -. , C . ._o C , z 0- Fu. E CU a) 0n o. _ F 0 C o a 2 n (D _0 ,o a) cu E- 0 0 O _ 0 "O ,. 0 O r 0 e 0) c. E) a) 4 E -0 0 o U) 0 U) a) 0 Q •)- ~ ~ - = .,._, "- "-" 0 c : 0 "0- r > U 4- C.) Z C) 00 U) 0) 0 U ) C *). . E L. )- . "- a) u0 "-0 c .> > E E _ CC 2 > > =3 E E c ~ a) 00 V co U) CU E ) U) C:) c C: c c . .. _.- _,- -- C O O - - 0 0 " 0 0 ' > > O 0 > u .a .TI- ._ _ 0. o C o - - 0 0 - C_ - C - - C -0 C 23 13 c- I 4- m 1_ "o 1- 1. _ CL 1- 04 CO 04 - 0 * 0 0 C) a) *1 -E E . CDU) 0 a)- c0 0.0 .o00 F) 0. 0r N n a)( 0 a) I I C C' N w r 0 -J0 .0 0 Eo C o C CL Co -0 0o o0 0~~ ~ miu m Q ) C WO 03/072602 PCT/EPO2/50003 809 0) -4- E 4 EC 0) < E~ ) -, ~ .' ) = z -0 U) z c 0 C. 0 Y) 0 W C: C C l) FD 0 0 i) a a a) 0 C I )Z 0 -:D 1-) 0-) 1~ Q IC C) 0 ) ZR on 0 0 0 0 -) _~~ 4- C ) .0) C -se .X C: Z)) Z U) D*"U)xR o~ ~ 0 ou U) U) -~ - -~ 4 .

- .~ . -~C 0) -0m C C (a C C D D D 0 ~ D D- D l)I au U(n 0) C1 CU 0)U -~0 0 . a) La m c En 0 -4 0 E 2 ) E a) (n =3 .~ 0 U) aau .> C) 'E i 0 E w E0 0 0 o) 20 L Z CD a ~ a "0C a) ) U>)0 . - o ( t0 U) , " 0) a)0 )-, LC - 0 C 2 ~ Ca 0 4- - M - 0 co 4-- 4- 4- 0 0 0 0)i gL. ~~0 C 0 0. > ~co CM 0 0 0 4--22 ~ - U E U -a 0 ) 0 O0 C & -o .n- a) a CL cu CD C 0 N E *C0 ) aa 7 0) ) Q E ru = C C 0 a a >0 U) M C: Ei 0 4 2 CLC U) U) _2 0 a Co c- U) I U) C -- > a) 0 -~CO - C C C . 2 . 0 > - 2 2 0"4 L- 0 m =0 E a.U 0- -a Q 0 a_ 0C) 00- a- <<Um U/) oc C-4 ) io Q aD w N UU- -0 0) Z)D D N < < <<< Lo _ m c m __ 00 00 0)C )0 WO 03/072602 PCT/EPO2/50003 810 C<C 0 z2 E. 0)(1 Q)' 4 0 C .0 - 00 4- ze &- 2 I 0~ ~ U) -oo . o (D)0 0. -4 - = E ~E E o SD 0 0C0 0) " n 00 . 0) 0)) - 0. 0. (D 0 - 0 > 00 .- =E L C C Z 0. 0 0 ECU 0 0 0 t 1 0) c 0n 0n n)0 .0.0. a) a m4- a)) L- - c r 0a0 0 U) a - M c c m. 0 .0 ca 0 0 m) 0 U) ~ Cl c1H0 u) H0 0 *L 0 CL 2:~C 4-1 0 0- )0 co0 :E E 0 C: C a 0 " 0 0 0 ) =.-0 0) U) 0 0 0C 0)~- p)1 U 0 L, I 0 w0- 0a) CHH 0 .= - Xx U) o O a) 0) C] ca0. U)O CLc E E E 00 0 et -o ) - 0 a) E U) 'o FL FL .c a0) C2 C U) cm _0 -' r 0 0)Ccoj C J <) E 2CH H 0 - .- 00 0 -0 0 0C) 0 c C 0 (n) c 0 0 0 (D -. C 0.C a) 0 U) U wU w z 2 <l' C . 0 0 0) 0) z o~ E 0 ) o c'~ 0'C E.2 C4- C 0= 0I 0 0 0 0 ~ 0 ~ 4- U 4-0 a)-0 0L C 00 E CL 00) 0 0 A C]0 0 0 ) . o o 0) 0 ) C - E~ C. E 0 0 4.- 0 - 0 0 -C o o >L L 0 E~ 0 -cu -0 0 -0) 46Ho'S E OH O 0D 0E 0 0 >_ 0 00 0 00 WO 03/072602 PCT/EPO2/50003 811 U) U U) U) U)L) 0~ ~ 0 Ut C. ca. (n. a) Ln0 m 0) 0) 0. - - L. 75 4 - o a..- 0) c) 0 ) > U cn' w) w4- 0) - 0)a)) U) ) a ) (D U) 0 2~ 2 0. 2 co a) -1 -- 2 CL CL CL 0 (a -0 -00 U) < U) U) C) 2D CL1..0U)CO 0)o 0.0. a) C)c) ) ~ j x CD a) a)a E _ _ 0 0D 4IO:Cl 0 L C) U) . C) 0 0 -0 *c3 C) 2:, 0-U U E- E ca00 4 0 o 0 U C:) (3 ) .i L .~2 C0 0 0 0) 0. U) 0~ QU:0 0 -0 -4 4 bo b 0 FL0 00 U -' >< 4- U) i) U) U) U 0) 0) -0 CD E E cu 00- 4 4 H 0 0 0 L) C. EE( 0 0)0 [ C: C 0 C U) E o 0 ~~o 2 2 ~ U) C ~ 0. 0 4- '4--a 0U) a M 0 0 4- E 4- 0 0 0 0 0 75 0 C 0 0 0- CL 0 - 0 - m .. 0 5 aD 0 M a >-a a) 0 0 0 -7 .0 0-0 0 C i CU) U 0 0 0 0 C > 4-0 0-0C 0 a-0 -v- ) a a 00. Il D: C) 0 U) 0 ~ U) U) ca 0 0.-' 0C- . C U C.0 CCE)000U U 0) Q 0 cl 00 0 ) 00 0 0) 0 1 C)l 0 0 '- WO 03/072602 PCT/EPO2/50003 812 U) cl) ) (D 2 0 z a) P L 0: 0) ) . 0 C o 0 mn E* C.c)o 0 L _0 _-2 0 0 < ~-- 0 0 0 U 0 a V -)0 0 0 0 0 w =2 cD C.) CD a)0 cu0~ o _ 00 = ) 0 M o ) o 0 0 :3 0: 0 a)0 050 0) -0 .0 0 (Z 0o cs- 0~ a) co o 0 Ca ) a) 0) o0" 0 E )0CD 4- U o o 0 0 FD C3 0 0 (D 0 U D0 0 c 0 00 NC NU .0C ca 00 co= 0 06 = 0 0 2 mC 5&- 5.. U) x CL 0D a) 0 0- U) 0 00(Dc 0 0 2 2E CN - C 0 .i (D 0n 0 a 0 0. 00 2. Vo 0 (D 0E 0 LP cm - cU)- U) D.C C: ) U) 0) 0) .V !=0 = -<-0 0a 0- -<V ~ 0 o 00 >< U) X w)~ 0 x N 0 0 00C0L 0.0 Co > E 0E 0- E 0z 0 u 0 0u 0 04- 0 z 0 a ) V 0 0 0: 0 _0 -0 0 E 0. 0 0 0) 0 00 F= a) 0) E U) 00 1p - Co . 00 E. 0 0. (D~ 0 U) 0 C/) 0 0 ) 0 a- z CL 0 CL C - ci C-=4 o 0 V u 0. C 0 00 E dC E ~ 0 0 o 0 n a) C 0 0u 0nt5 a C) (D0) U 0. 02 0.0 0. ) 40 a) 0.Cc V 2C- 0-02 c- .E Oo 0 cu H. (o 0 C)- - 0~: 4- Co 4- c C C 0 o0 o 0 0 0a0 0 :L X cn in in CoC Q 0 - 0 0 0 0 r 0 0 a) 0uC WO 03/072602 PCT/EPO2/50003 813 0 E Q)0 o E U>c)' o1 0 < r. C: . - 0~-Q~.i j -2 0 cc 9o<~ 0 0 0 0 L). 0. 0c z-D 0 .CL a" V5-Cl Iz C) "Ic-n ) .0 U E 0 .2 E E E . - x 0C2 c a) cc 000 ox 0 0 CLCoC U) co - oU) 0 cio mV 0 o E- A E E 0 CDi 0 0) E~ E CL~ 2 2 0~ E 0) 0) 0 n 5.- 0 C) 0 0 -n a) D E ai) _ 7**ml

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WO 03/072602 PCT/EPO2/50003 814 T z Z~ z 0 2) ci) 0 (1c c) 0 4-0 L- - Cl)0 0 0 -4' -cC) E c) E 0l C-)l C) 0 C.) Cc )0U 3 c) . 00 4-'4-1 a)~ (D 22 2 C" z L)) Ln (Lic c oi cci 2 l C C) 0 E3 c20 Ec 4- Cl) < ) L c 0 0 E ) to) cc 0cc 0

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l -~~ = 0 i i -.. 0). C L) a)CD 4-.-)l <C a) c ~H i l U) Co <c j w cc 0 (L. 0. o CI) 0 a)ZL 4- a c cu, 0 0. 0E 0 Z: CL 10 0: a)1 (D 0 C 0 Q 0 0 0 0000 0 E o WO 03/072602 PCT/EPO2/50003 815 .2 -2 .2 o0 o0 'a 0 0 0 0 cQ E E E E0C 0 w) 0. w) C:l) U) En U) U) U) a) T a) a) (D C 0 " 0 0 < <0 <0) <0 F r z 0Z Z9 z2 0 (1) a) ( 3 o0 U)W (a ) U)a5 C 0 0 0W'4 2 4- 4- D0 o ~ >~ 0 0) Z i.. 0) .

.0 E cn U) a .. 0 1 0 ~ T 0~Q o) .co 0 -0 X 0C .La =) C) 0 ) U . 0 . C) 0 t= 0- E a) 0 0 U) U) * 0 0 _ E~ CL C) Fu E 0 N I- 00E < Lo (a 0 U z *5 U 0: c- 0* C <) 0) 0 ) .0 0)4 - U C 4) q1 ) 1 ) rl) cr L (1 C=3 = 30 5~E U) > ~ > cu 0 a) 0 .0 < c ( az z 0 4 (D<E E (a~ U)zE E 0) <2 E 2 a) _~~ 0)) 0- > D ) ~ 4 C . . 4- (13 0+ CL 0 00 Zo E E :E 9 E 2 0 0 0 0 0 0 0 0 (C () 0 00 WO 03/072602 PCT/EPO2/50003 816 C x 00 0~0 Q- 2 ; E . .a c o 0 C C c C 0 0 C 0 0 -c 0 0 O 0 m wL wc w o o o2 o2 0. c" E e c ._ 00= = =- ".' - 0 < S0 - '5 0 e 0 0 o z o 0 0 0_ O O > o . 0 0 -- n (- 0 co > 20 o E . 0 x>2 . - C - ( < = CD S0=0 .0 a a) a) 0a U) 7-- 0 " c -c a." 2o 2n . c . C 0 " - .. . , C a_ C C E CU C a ~C r_ 0 .. 9 E c e 0 0 0 coo a e- o - .2 -- < = - - - o . E E I a 0 a CD >CC 0 C 0C C ."a C < 0 00_ 0 C 0 a)C 4? -M cu 0 0 0 0 E 20 Es 05 - - - :3 o. 0 5- - CD C CD 0CD _ 0 =. ., " .- , Cl) . ._C rU Do E 0- 0 0 5- :3 .0 0 Q0C 0 CD 0 E 0 " ~U -0 a) 0 >i o" E (D CD_ o =3 E~o 0 0 c co - CD - -' 0..0 oC 9P w o -< c u 0 CL CD -n -n CD E ._ a CD _ -.. C -Y .-- 0. I c 0u 0 w 0- 0 - C ,.a) C. ,_ ,_ ,_ ,._ .20 (0 CDC C E CD (D a)0 0 0) 0N 04 C ~ E LC 0 a a)) 0-5 CD Q2 .2 0 Cu~C E ( D U) CD 0. 0 cc CD CD CD m Cn 0 S0 Cu 0 a).9 C 0 C. C C 0L 0 .r- 0 0. D O 2 00 _0 = = = CL0. . E .~0 a ) C wD .C C C) C L)(0 Id co (nJ 0 c c c m 0 I 0) 0D 0 00 0 0 (D c _ _ _ _ e y _ _ _ _ _ 0 j WO 03/072602 PCT/EPO2/50003 817 oD EE o 02 cc, c, 0 0 E_ Ci) C : 75CC U5 Co Mc ci) 0i L) cn Cc zo 0 a " U) U0 a) 2 .- = . 0 C El E, 0 00 d_ 0~ U) 4 0 a) ze i) 0 0) C 0 C 0 0Co E Ca 0n0 7 a ) ( Cc Cn C CL C) - C C: C0 0 CCU m E :3 x " -cC ci 0) C 0 wl C.) n Z a) ~ H C >O 0)0 0 0o Cl) C , C 0- En 0 U)C co 0 a. C) 0_ 0 o~( 0 0oCC) o i 0) m~ 4lC0- a)i (n cn El i 0 a 0o 5 a co a Co >. CL 0 0C 0Z C x ca 0- a) 0 - (D -0 Coo -E ci Em CL 3 a Ca Co > 0 0 0 C 0 oi 0 Ca) a) co M C- CL C! C Co(n~C CU c i) a)' a 2I) a) 0)-' " 0 - - ~ .- C -0 a~ 0 ) a2 0 C So~- m C C l) 0 0 0 a) m 0 H 0H~ d. C ) Eo E 1- 0 CO *~CO.2~ C N) CCL4 CL M 4-'0 C 0 a 0 0 0) Ca) - < . 45 -0 =c C

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WO 03/072602 PCT/EPO2/50003 833 .2 E a)- a) .0 aD-j 0 cc 0. 0 0 ft- CL a)2 al) 0 ) ZD C= U ) E E E EE C) z c)EmE )E C.)a 0~0 .0~c = 0. z-~ 0 . ) a)~~C 0 a)ry~~ c ~ ~ 0) C) D( C U) X cn *. CL0 a) 0 :E " 4 L C) 20 C cc co 0--T 0.F 73 0 A (D~~ c4a ca 0. (D 0 2~U 0 C0 o ~ 0 C: 0 0 ca 0 c l 0 ..M > 0-- 0 4 ~ 0)C 0 >4. CC) 0 . o <~~0 . ~L -3) CD c a) _ cc( n 0 0 0 0 - ~ a) E c: o-M (DC~ . ~ a) a) C. a ) cu E - > U) 0 C .) 0 0 C.) c ( 2 5,E c a) 0) 5 E Cln 0 0 w _r L c m CI) (D 0.0. E a- 3 -a-r U) U) (D CU C.) am a. H _ _ _ CDCD D D 00c WO 03/072602 PCT/EPO2/50003 834 (D a) CD E E .0E 0 0 0 0 0 0 Ei E Ea E E) oL a) 0 a) (a 0 a) 0. ' C ) ra :5 C ) a 02 02 0) 0 ) C.) cu < o~ E:~ 0 a <) 0 U) c LO g) ..- c- o 0 0a 0 0c C) 0 U) ) ~ .2 0 U cu j~ E co 0a)C Q- I- a) ~ 44 - 0n com U) D 4- CU U)U - .0 r-00 co E~ci a1) 0 24- (D 0: -- - 0 = a) 0cc ~ - U)~~c .. U). . 0: 0 =i U0) >4(aD caa 75- -FD .C-0 .2 0 U) 4- cn a) a) U) U) =0 C: ) (a 0 0:= 0C 4-. co -~ C: CD = ~> 0 )e0 o~ ~ 0 f 0u. :.0 0 C: 0 . . 0 0.u C m: C/)~ a> w 0 m__ (D: 0 CL cn. 0 0 w _ _ _ _ _ _ _ c_ _ a) WO 03/072602 PCT/EPO2/50003 835 aD ) Q) ED E 0E E U) 00 0 a Ci) cD CD u5 0 0 0 .0 U) .0 ~-~-D0 0 2 0~ 75 CD i3 0a-D~ 0 0 C = tp a) (D O E = m c< 5- CD 0 / = cn- m a )C b CD < 0 a) a) a5 0 ) 0 0_ Z CY 0 -~ -o CLC U) co COcna E C) C Of Z) 0 Q 00 Ca) El) E~ a) = 5-C, ~a) CD (n ~ ~ C (D( (D c U) c E a5 a 0 0 a) 0 c C CU C C C C: >5 0u C) mD CD~ C) x CCD 0.( -~3 CD 0 0 .

0: w) CL 0 ~ .C 0L >- T ~ Iz I ) E C - 4- -- 0- 0. CD O cD CD 5 0 0 a) CD cu co _L E ~' C D 0 CD 0- 0 5 ., C0 "D0 x - D~0) CD Zn -_ 0. D 0 C: a) C: 0 0) c N 0-CD0 0 (nc>1 E 0 0~ 0 C= 00 a: IL 0~Ht M LL U-. .l .. n T YI TI 7 13 I 00 WO 03/072602 PCT/EPO2/50003 836 E C: i6 .DE .0C/ 00 0 3 E2 0) 24-*. 00 E -E 0 . CP Cl) co 2 .) E~ Dz 2 z ~ a a)) a)0 0) < 4M E- 6 0 ~ M U a)a) C r:-; 0 c~ w ** o a) UC) -- C mI C: - C U) U) 0 -. 0 c0 2- C U ) CD 2 cm r0c - 4) (n) CU C 22 0 a L:3 a-r)0 a) a) C)) a) CD C.) 0± 0 zU) mU .0 U) C E ou (n E a) C U) (D V0 0 a.c C * :CL LMU 0. S-r- CL 2C a) a)V0)' (n _ C C30 C 0 .I CL 0 -0) m 0 0 CD 00 = CU w ~A' )a 0L T0 -D Co c 0 >1 0 0 00 LL Q. U ) Cl) C. E >, CO E: , ~ * U) 4- (D a m a) o ~ 0 0) (n 2: E ) .

CL a) c5 C] 0 0..~~ ~ C3- 0 - ~ o ~ C In CL 0 =_ CO. U). C1 0 CO H OL H CO~~ 00 0 >1 I: I I a) I WO 03/072602 PCT/EPO2/50003 837 .0 0D E U) U) 2 0_ &- 0 000 00 E mE o) o- ~ - 00 0)C 0 ~ ; a a) Ca) Co a U) on ( W CD 2 ' a) ) -1 l z 0~ Z~ 2 z ,0Zz a)' CA) ca a) a'-DD : C CO ) Da o) -0 C: ) - CL ~~0 0 (n a)C 0 C a C: C.) Z3 a) C M 0 z o 0 0'~-o C Z 2 CLg 2 *C- =12 ~ a'o a 0 0-CU o of 0-C U) 7)C .C) cn H ) (n J: a E 0' 0~ 0 0~ E 2 C:: 0-0 E 0 (N E U) ca U) U) 0 C:. C):_ U> - CL oU) 0w (9 C LO 0. a' u -2 -o 0 CD a IU) 0 r-) C: z 0 (n a' a C D 0 co. O) - mI 0 > co c E: U U) 0) ) Z = < (n (n zz a)- ff 4- C:a) QL E CL 0 Of co E'~ 00 0~ o

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cm E U)-c 7 0 () 0 E -o; cm: E CD E ) - 0toc O~~C 0 A) 0 C:0' >1 r-C 0 C: C: 0 0 0o 0 -=L 0 'a 5-.r <~C\ CL 4- a..C C o. .2 Co .0 a) a' ) t: 0 =5U 0) 2: * -0 >' C ' C D ca a) TO) .e 0 C L. C: a'e a' C: CD~ 0U C DCL C: 2 o l ml n NC < a)N-( D a IfO 0)l cc 2 fl- 0- H u) Co o Co) Co) Co Cfo TI IT I2 11 I- 1= I 00 WO 03/072602 PCT/EPO2/50003 838 E a) a) (1) .(nU E E E E 0 0 0 0 0~C U) (1) U) L C : CD -0>1 o 0 0 0.9 0 E E E E a 0-~c w -0 EC L. 0 0~ E 0 9 1. - - -~ - ) 4 .0 0) a) Wl o 0 C oo 0 C EVC. ) E: -) C: (D 0 C a) C 0 E 0. E 0 U)U U ) o a) 0 a CC C 0 CD -U) m _EC a) _)a a ) 20 20 00 2 ~ 0 LO - 4-> C O 0 U) L- _ C .C) 4 .0 >- 0 4 0) a) a) CU a) 0) V VC~) C: va 0 ca) 0 . Ci) c.) U) a) S0 0) f& C C 0 C. CL C 0. 0. a) It! 0 (E -0 >~ 00 0L M. CO . m- 0. Z a.) a) - U) c 0) C0 CF a) ) a): (D C Ca) ) C: 2:1 2 ) 0 cu co) v c C) CD a)-a) > Ca) U a) fn 0 Nf a) >n *D rD- ) I~~~ c Ccc. a -0) a) ) U) C) 0)- C4:C2 0: 0- ( 0 0 a) 0 0 U) - o >~ a) a) C~ . I- m 0)m C N: NL . a L a5 = 8 I I I I00 WO 03/072602 PCT/EPO2/50003 839 EC C: E) 0 .0 0 ca CD ca E mf EC 0 0 o U U 0 .(n 0 4 0o FD (n '~0 -0 U) m 0D 0) 00-* - E 0) U, E)C C: a) OU) a)' a) a) r_ c 0~o En 0) -6~> > , C =.55 'a 0 -a FD -~0 C1 C: >1 =< 0 a) >i CLL a) 6 a) Z Z DO.~~ C4U) Fa UJ-FD .00 C CC( O C C) 0 2a2 C0 U) 0 0. 2 ca U) C < >1 y) 0 0) 0 ~ *C o C C c 0 EC 0 C - 0 0 0 0 . on 0 .0 C: C u .0 0 Z 2 -0: C C C Z Ua) Ef C- c 0) cm 210U) w, Ua ) a) <UM 0 0 Za Cl L 0. C U) 0a) _ 0 L- L (n 0) C C ccU U .0 C0 a). ~ U )) aC). L. (D _ o 0 - U) U U,) CD CD_ 0. EC:'C 0 CD 0f C0 0. 0D E ~ C if~~c 00U W C) U 0 L- 0 - C: 00 Vp C: -0 00 C 5 0) 0 *C .c 0 .C a. a r_ a) C ,. . 0 :L Z a) C U) E4- E 00 c0 0 0 0c U) 0 >1 CD := if =: U) 4 o c C - V0 E . C (DU .~~~ U) 0(D E C ~~ 4- 4--C V U, 0 0 f "0' 0. = ) 1 0 2L a) a p " 5 TCZ C C U) CD -~ C U) EEC - f C ) C L > C .C U) >, 0 0 C C C 0 .2 03 C 2 0 0 C) - a- U) Ua0- D 0. U)) > 2 m- L - L WO 03/072602 PCT/EPO2/50003 840 2u 0 aE E coa-E (n1-U 0 U) 0 0 0 w) 0i 0 Cu ) 0 .0 -r =3 E mn Z c ) C: U) 420 -- 0 5C U) w o U) a) 0 -r D a E uS :n 0 CE o ) ~ ~ U 0 C ) o U) U m Q) C) U) C .0 0 3: . c-I C2. - (n U If oh 0)) 0- 0 0 a 0 ( U) cu C 7) C Cu c r_ c- M c * C- ~ C/ ) - U) = C u auC C 0 -~~ 0 -14 -l cu 4 0 cuu 0C0 > 0 0 0 C.) ~ 0 0 CU Cu LD Cc CUc <u i) 0n :t! _n U) (1) C .2 0 a)CO(1 0. Cu Cu 4- Cu v 0 0~ 0 ou Cu U) -cu 0 0 E0 CCuCu 0-0 0 Cu0Cc E 4- *C C 0) 0- 0 .. aC ) C 0 0 C CL cu Cu -0 r_ Cuc Cua) =3 Cu Cu 0- *_U zC S L4- Fn .2 0 7 a) C-I ) Cu U)- a) C U) S Cu 0 a) Cu 0 *~~C 4-. U O0. . 0 In 0a) ~ C 0.>2 0. 0 x.2 o < - .2 Cu 4- 0 < Cu 2 - Cu 20o 0 0 co 0t cu 0 0 F- : < _) _ __ 00 WO 03/072602 PCT/EP02/50003 841 ci, a) E 0 E 0L- 0 U 0 00 0 _0 E E ,W E w -a "a -aw E 0 0 0 0 Co~~~ (n 0- 0 0 a) 22 < or can 0 a) w a) a) 0 0 CL 0 -0 0 0 0 :5 0o x x (1) CD C 0 0 ) .If a) <~ aU) c ) ___z 0 ) cu X a 0- m4 L- -E 0 0 00 r_ L-U _n E0 E co 0 0 CL) - 0 0 a ) au LO 75 0 c 0 0) 0 aa) *Cu (I) a ~ -d 4f C SE o 0o (I) E 0E 4- > )3 00 (D 0 C: m a) 01 E E) -0 > C ) C:- 0~ 0 0 0) 0a)~a 0 E a0) a- aD L- C0 CL C ca a) a) 0 0 co 0 ~ c 42 0) m 0 -~acc a) CM cci 04 co4- c 2-a a) C *e a) ( o o C/, C -) _ _0 - C- WO 03/072602 PCT/EP02/50003 842 E 5- 0)o - •D- ..- >,S = - .i= 0 o 0) .- - - o 0)n c 0 J. . o _ .2 0 CU . o o V , nE 0 c 0 0 0.0_ 0 0. 5 - LE . 0 CU C -U .- 5- o e - S. - a) .5 5g w a)u co 02 o a) () c ,. or- 0Q - E0-D C- 0 2 0" 0-- 0 z a) a Cd) D W n a 1o 0 E - -- [ . • .0 C ) 0 0 E- C: CU -0 -- 0 O) 0 tp W--a 0. i_ 3 - ._ o V ' u U) ca. L ca. " a C 0 o . -o 0 o m) ,) 0 a C- 0 0 - 0 E- D0 V), -0 0 c a n .-. a)C ) w M 0 2 C)' E c 0 EHz. a) a))0) co U) coC -FD ca ( N CO0 CD CU C c h 2' 0 o5 ci). o~ n .... - E2 -00 -0 0.

0 c E • •0.- o ,.5- -, L) 00 . C)") -- . 0 oo 2) () IL -a oc 7- m , 0 a) _ . 0- E E -) C CO 0 x (D -- 0 Cio C CD 5 E. F) a) 0) ") E V5 0 0 0- cuC' 0 . Cla 0l =._C) 0 0 s' -0 CE 0 c I c a). fln 0) C~

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C 0 WO 0 a C. zL 5D 0) 0 ) X0 00)0 0 E~ a) 0CjCi .L o ~ 0 r_ 0 4- -'.1: ~~~0C C: C 00 CD C0 CL 0 0 C CL (n CD(9Z CD c) m_ _ _ _ a)_ M0 WO 03/072602 PCT/EPO2/50003 843 cn (D o 0 ) a) a) o 5 0 0) co U E E 0. 0 0 0 0 0) 0 0 * 0 ) r_ C: r_ r_ M U. .0U a * a:I- -

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=- -I 4'4 E) z U ( ) U) U) 0 D 0 0~ 0 C: C_ 0)0 C CD a) 0~ U 0 S? CU) E -E < ol 0)D _ _ _ __ - F 0 0C 00 0 a) CL a) E C _ 0 0U)- ( u4 oa 5 i5 ) a L 0) a) 0C) .rE 0) 0C CL >>1 ) 0n 0 E U)~~ ~ 0- 0W ) .C0 4- o. 0 cn 0I U cu 0 b ac 2 01 0~. )U 0 0 07 0_ 0: 0~ 0 Cl)~C 4-U)U) E) UC 2 0 )C U -- 4 - - a ) z , aa a)- 0 CDc ; L- 0) ~- (D U) 0 CL 0 0 a) U) c)-~~ 2 040 0 U CCC N) U) o 4- C U0 U) U) C~~~ ~ ItE5-)5 0 , 0C ~U '-" ~ 0) WO 03/072602 PCT/EPO2/50003 844 -p -5 o 2 c Er- -0 LE "aa 0 0O CO 0 E ou m E E o E E E 8 3 . Cn 0 0 4 .- .u c c n C oCO v C- o oo o S-iE 1 i C) 2 2 aO of~ a "-.g -5 y o z £ z P c E (D cE ME 0 282 . < C . 0 z 2 z e -.

5.-u 0, ) 0 0 .. 0 .. co 0 4 . 4- 0 .0 0 ft 0 00 I-- - or t- __ I. .. __ Hh (D a) C D NCL aC - _.. - = i e a -', C 4m 0 C1 0,0 - c <- a E . • -z ' c : ) 0 .,o( E- C ) Q.::3 O 0 0 ( C C E 0 C> 0 0 0. SN --. D C 0 o0 . " o c . a > a 0 0..) ... E . (n 0 E 2 x z E ( c, Cc " o (D 0, . 0 - _o 0, 0) C - z) o , a a 0* 0) 00 0 2 CO m 4,0 - a) c 4 - . - C 0 f a" a C o .- r-n 0- -,'-0 O ) CO C n C 4 Cr 4- 0 a) U) r_ C a,)C C0 0 0, 0 0. U_ ,)i C) 00 0i - 0, 0, 0 - 1 CO C - 0) C a.- N- CL 00, C: 0, 0~~~~ 0 )i C 0 C E ) EO :FW C CO C. 0 . a) co a) E CN ) 02 <lf 0 C) C) 0 C) W W W -- ,, _ 1 3 _I -.. I J 100 WO 03/072602 PCT/EPO2/50003 845 o 0 .0 0- .0 0 0 0 0 0 - a) 0 )E o: CD (1 00 -0 C- 0.- 0)- <0< -1. a) C: 2 o 0 02 ) ~ Co C o C C) CLC <0 _0 S E0<<O . , 0 C: a) x "0 -a -0-,0 E 0 M C 0. Co2. 4- E- c) a)0) a) C~ a) C C) C 0~ C p 0 -LoU zl 0 C:~l COcaO oD Iz0 a) > CL Co > 0 _c( a) 2. 0 0) a E C 0a C 0 (D >a)) )a 0 a o a) cm z) M 03 E w CO 0- =:U C)U auma)( a) cm -0 4 a) a ) m 0 0 0O a 0)0 2< 0- 4 0 ) 0) zl 0 0)V-0 a) C 0 a d=0 2 0c 2.2 Z ) .0 - CL C S0 0 a 0 > i~E x -oC _ 0 V 4- - umc 0. 0 4.. CL 00 -0 a c Co 0 V V 0 0 co U) () w) 0 E Ja 4-) 'F o -( Co Eoa CC) =0 (D- Co CO Co 0 0 a) 0 a ~ C OC _c_- <a) 0 0 < 0 )V C 0 ~~~~a Z 2 ~ 0 0 )c C ( 01 0C -0 E 1 0 -0 L 0- E Cn D () V- V- .)4 0 0-Cf) CO) Cf) Cl)"I ______ ___ __ __ __ __ __ I__ _ I 1 00 WO 03/072602 PCT/EPO2/50003 846 .T .2 .5CLO 0. 0L< 0~ 0 0: 0 C) ) cm 0m < c . C -0 CU C L En c L (jD a)C >- . <0 < <0 C0 E co 0 E E~ E E E)C 0o - 0 Vo 0 -0 0CU 0. o 0 0 0~ :t 0 :L a C o 0 :t -0 = 2 ~23o ~ < CO ~ . aUf~0C) CUa 0C) C l 00)CD r- ) CUE M/ U CU CU 2 CU) 2 -o 2L E 4o 0 0 r_ 4-Z x o 0 CU CU) CUm CUE CU- 0 CL 0 CO E > C-CL 4 0 CU 0 C L' w C) > M CU 0 0 0 0 0 0.C1 0 0 0 (U. 0' CU0 0 0. C C. ) 0) c m 0o Q) V z z L.z 0 C C _ _ D C(C D CO U mr co Nl T" Cl) Cl) C - I -j -j 00 WO 03/072602 PCT/EPO2/50003 847 E E E LI) Mn M) 0 0 ca0 E0 .2 20E CU( CU 0UU ~ cc :-p m-a U) (D () 0 ~ C .2" .2 E E E 0 4- *9 0 E V c 0 V 0 ) 0U) U) 0 C: (D E a) .I- 2 o 0 ~ 0 ~0 0 0 L U) U E E E a)~ a)~ c < 2 C) E Z W a. W IL0. U) U) a) a) a) U)U) w0M ') 0 0 p m 0 L- 0 0 0 - CU 0 U) 0 0 0~~ U" ' V V V c CLV V : - , 0 o .0 0 mI~ Z )M: +~ >>L. E o 0 <U,4 CU CU C Z CUL0 V) 00 w ~ <" 4 wl <V 0) S CU mU C)~w _U o o t a) (D- U) cnCU Va) z 0 c o a) > CCUa 2 E >1 a) Un ) V- o- 2 o O 0 . 0 0 ) 0co -n V a 0 a) 0 a) w V 0a) 0 - a 0 zC "C 0- l-? 0 . 2:,~~3 u - 0 d 0 0O 0 0 0 C) (D _0 0a 0 0 C C 0 =) V U V C V2 :to_-0 cn r > 0 V 2 C (D- - U C V 0 4- - 0 U)~~ U) .4- 0) *- >~ 0 c C"50 0 o CO 2 ca a) - : :t! a) a0- > , - :E. 0. UD 0 a) > 00 U) U) C . 0)D U) .C~ 5 V - U) ~~~~'~- a)> ) - ~ 0 0 CU -1.. 0 42 :3 E) E~ cu) U - CU ) d) -F 05 C V 0 o 0 C " E C*:.0 ~ U) 0 . 0: .2 CU cr CL V 2 * > C )CU in)e .2CL m- 0. mL 5 0 a) rI E) CO C>C i ) CO C) < s; "a :E < -J - -j __ ____ _ ______ 0 WO 03/072602 PCT/EPO2/50003 848 Ci) a) () a) Ef E E cL o 0 0 U U) Cf, a, .0 (n Cc 0 0 0 0 ' 0 0 a~ L 0(i 2 U 2 0 0) 0,L c O ot.C < 000< C) -~ C)o~ 0o U)C )0C 0 C) ( 0 z 0 0 0- z -T- 0) 2 11 :4 ~0 0 C: 0 a,(1 a, 0 2 ai .- " CO) P -.e 0. *. 0 C0 -0 _0 e I" F- M F- C >1 0 - CL0 U) < I Do 2) TL10 1.0 0 if 5n 0 E L. U) 0 E c S u a) <a, C ~ O C:B if. .a Z -c 0 2o C -0 -- _0 0, 0)n o 0 a) .4-. ) 0)0 0~ E co 0 0 0 4-- . 0) 0 0, 0 a,0 CU 0, a, 0u 0, a) 00 0 0 0 E. 0 -5 0) 0)U * c 0 E) -+0 ' 0, 0 0 C- 0 :L- 0C 0 a) 0 E, C, .) M ( 0~~a c)~o o 0 20 .2 CL n 0~ 0u 0 rc 0 E _ l2 0 0 0 Vo 0 a, E 0.i 0. if < 0- a), s 0(Da 0 > ->' (n CD 0a a,0 > 0N 0 (D E 0 D Q)Z ) ) co 0 0 E E 0 0) a)0 2__ _ _ _ _ _ _ 0 WO 03/072602 PCT/EPO2/50003 849 2- C C C a c C E =0 IL. 0 0 0 0 0 0 lD wu = U. . 2= . . 0. o (D C 0~ o ) 0. o 0 0 c C) U) (l) to) C) Cl) 0 . S C 0 c C C: C C: C C: E0 m 3 mu om cu mu .- 2 M 0. U) E 0 -) .- 0 a Z CDa) C 75 05 0 0a 0 M C Z - -0 O - I - 10- < Z ___ _ _ D ~ D~ D ZJ: ccm 0 0) 1... C42' >1 >1 >1 4 - >1 0 4 0. L. L. L. i -F 00) C C) L < E E < 0 U zl z 0 u x x x x (D a) a) CD a) CL C - - a< E 2 E E E 0 0 0 0 0 0 cu o 0 0 U) x U) Cl) co) co -- c 0 0 0.0 0 cu E Cu Cu (n Cu0C :5 0 5 ~ a 5 cn a) 0 a) a a) CD 0Cn E E 2 E E 4 C c C C (D mCu CO) mu (a 0 a)CD a) a) m 2C SE 0 CL (D c D a) a) a) ..0 0 V0 0 0 0 E 0 0) 0 0 c 0 a) ) a a)0 x CU Cl) Cl) U) cu u Cu Cu CCu0 a) ) a) a) a) ) l)a) E E E E E E (n _1>1> >1 _1 cu a 0 0a 05 05 -a a) :f CL s.- 0CC W U. 0 W- W W a) a) a) ) 0 5>, C CU 0.L 0 0. 0- 0- 0L '5 E E E E E E2 : 0 0 0 0 0 0 L.0 C.) C 0 0 0 0.0 o Q 0 0 CO U wU Lu w w w uJ ui w _ _E 2__ _ _ _ 2_ _ _ _ _ _ 00 WO 03/072602 PCT/EPO2/50003 850 EE EE 0- ( ) C Ur D U) 00 o E E cc 2 2 ~ cu :p' <0(/. CI 0 0 WE 0 z0 )EEEEa 0- 0 Ca) =) E .. .2 CDE 4- Z. a) a) a) a) CL 0) E 2 'D) (D L) a a)) E "0 >1 CL -) 0 0 U) oI C U) 0 0 c _ C: >0 c c a zU 0 " C M C0M o)*'u 0 0 z 0 EE ___ S L- S;n- O 00 a) en oL0 0) C: C 0- 2 0 L. 0 C: 0 ED 0 0 o =" " 0 " a) . 0 c: a) (n) a) 21 EE 2ND'. a) C: r- a) a) _ 00 0 0: 0 - C )C E) 0 U 0 0o a 0 2- C 0 a a) 0.0 0 L> Of 0 4-- 4 E 0) .0~~ CL E ~ < 0.C a)Z -- z-4. 0 0 E C:- a-: 0 a) (DC0 a) C) 0 09 ca u) 'a 0 a)0 E o C!)- >9S __ __ _ __ _ __"_ =_ __ 'a _ __ _ __ _ WO 03/072602 PCT/EPO2/50003 851 ci) 0 0 r- 0u Z ) CL m 00 cci Z* 0 0 Z E p a) 0 ClU :6 a)) Cc C . -~ 0 0a D ~ ~~~ 0 0 OO.0 0-i C2 0- (n EC: c a) a) CD CoM) _0 0 (D he < < < o c 0u c ) Z Z Z0 a)~4 0 F w (D~i

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0 2 0 HZ c a)) 0~ 0 *0 E cl) (D 0 0 -a cci C (D 0 ml 0) 0~ 0 0 U) T 00 (D C L 0 - ~ 0 0 . cc C)) E >- 4- 0 0= o 0 0 0 CN 2a 00o 0. 0 0. (D C 4 0o CD ED ~ 0 0 0 0 U) 02 - 4 .- -- ll 0 0c x 0 0) CoCl a) _ , - -u r_ a 0 - 4 - a) 00 * U o. 0 c C 0 c:ca ccU CL a) 4 0 n V I ( 0i .L* ' .!::4 Q-C _0 > 0 0 H0 0 L- 0 C: -J -J - - : 7D_ m_ _ _ _ _ _ __a_ _ _ _ WO 03/072602 PCT/EPO2/50003 852 .0 .00 0U 0 C C.) C00 0 0o C0 U 00 _ 0 LP 00 w# D 0 00 0 aa C U) C~U (n 0 C)> 0) CCI a) ) Z U 0 ) CU < C) CU C.) a) 4C a) z 2 *5 2 C ." c C E CL (D 'C' cu 0E 0. 0JL 0C C x.. - -n m ) Cn m CD'4 0) ". = 00 0 - ca Z 0. 0- (n 0 CL CU in 0 . 0 C o Do) co (D U) 0E0 0.0 0fl f C 0 E L 00 .0 2 2 4 0. (DC C 0 U) 0. = > co CL 0. 0) Zn C (nU C cu 0) '0 4-~ 0 ) 0 EoC C UC 4- 4-- 4- C C 0C 0 0 SE 0 cU U 0 0 c CD (1) cu A 0 0. E o co 0L 0CL0 0.9 Z >1 c 0- 0 0 2- CUuC ) 0 C UC <U) 0 a) . = :2rc 0 .0 .0 CCI:L15U) 0e 0 0U~ 0 ~ 0~ 0 4 4 E u) -D C _Z cu ) 0 0 0 C C C 0. C C- 0 0 0 0 .§ ) 0- 00 C0 _ CLE D E 0:L r 0 0 0 c0 00 0 H I CL H 0 FD EL E o: L E E 75 0 0 ILC __ _ _ _ _ _ _ _ _ _ 00 WO 03/072602 PCT/EPO2/50003 853 .2 M .') Cn CU .0 A . )C ( 0a Co 02 (D - nCO 0 n 0a) C C C C cC ~ C ~C : C C)>u a) a). >, C (DD ) 0m w) Co * O 0 cn 0) co 0) co 0) (n uiil LU a- 0 )C W/aL 0 Li i a _ . Wa E E E E E= E E 0 0 0 0 0 0 0 CO Co Co Co (o Co cn 0) 0 0) 0 0)00 0) 0 0) 0 0) 0 Z 0 C . 0 . 0 -0 C .0 C .0 Cn CL (n 0 C - CL Cn CL CD C) U () U)I -J C0 E FD L.~ Co : a)~ 0 =Cl) Co0)f -0 co E L C E E R) (D a) a ) (D a)C ) S0 4-- 4- 4 4-- 4-- 4 0 0 -4 0 0 0 0 0 E- C 2 C E C C; C Cl) 0 a) a) ) w) 2 2 - 2 2 0 0 0. 0.>1 0. 0. 0. 0. 0L 76 cu cu E E Eo E E E E 0 04- 0 0 0 0 0 CO c Co ) oco Co Co Co 0 0 C4 00 0 0 0 .0 .j 0 .0 .0 .0 .0 _0 0 0 0 *0 _ 0 0 C 0 0 0 0 0 .rC 0) .C. C. C C. c C C0 C. C) 0. C. 00 0 0 0 0 0 0 - - - 4~LO C) a_-C _ _ _ _ ~ .0 _ _ _ _ 0_ WO 03/072602 PCT/EPO2/50003 854 .2 L 0 .- 00 M~ L 0 U) (n U) ) ) ) (DU .- 0 ~ 0~( a~00 0 ) 0 (D U) , U) > 0) cn 0) w1 0 0) U) a) a)~"~ r0 .. 0 L 0 . 0U 0 c c_-CL E E E E E E E o 0 0 0 0 0 0 U) U, (n En M, Un U, 0) 0 0) 0 0) 0 0) 0 0) 0 tm 0 0) 0 -0 w 0 0 _ Z2 2'C 2': 2Z2 E2 Z2 E 0. CZ 0U :0 , l - ~0 , ~ 0~ f~0U CD47-( z2 0- C3 n 0.w0, c -U 0- D E~ 0 -. r- 0 a) (D.0. 0 2 a) . = 0 C; 0 a) 4-' a) a) CD 0U)U ~0 0C-. 46 0 0 0 0.0 .0 00 0) 4- 2) 2) CL0 0 CL 0- 0CL - 1 - - 00- 0 2 E2 E 2 Uo 2 0 0 04 0 0 Un U) (n .0 U, U, CL 000 0 0 40 .0 .0 .0 E r-. - U 0 '0 0 -0 0 -0 _ 0 LO 0 0 0 U, 0 0 .c0 V- c.0. 0) 0. C) C) C) 0 0 00 0 0 0 002 C ) m- UD 0-: 000 . 0 .0 WO 03/072602 PCT/EPO2/50003 855 0 cci .0 cn 0 .(n 0 .0 0 cci Ow0 .(n 0 U) 0 Cl . ci > i) . c ) ci) . D> a) > 0)C (D 0) U ) cc ) U ) a ) ci0 )0 C~C: ) (n. C) U. 0) to. co 0) co 0) (n 0) V 0 LU D -FD LU) W0) zO. L W 2c c 2 c i 2) a) 2i 2 2 0) 0- )0L 00 w 00 0) a- 0 0) 0)_ C 0 0 0 0 0 0 0 'a 03 'd5 ZS Z c Z 0 Z E E U) U) U) w w) U U) i a) a) a)a a) a) (D a) 0) E) 0) 0) ) 0) ) 0) a) a) (D (D a) (D a (D 4-4-- 4- 4-- 4- 4 0 0 0 0 0 0 0 0 0)a) aI) -' - U 4-'- 76' E E E E E E E E 0 0 0 0 0 0 0 0 U) Un () U) U) (n U) U) 0 0 0 0 0 0 0 0 -0 *0 0 0 0 0 0 0 0 0 0 00 00 00 0 )LO) [I- co OD N N (IN (N co) m~* co _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ 00 WO 03/072602 PCT/EPO2/50003 856 .52 02 mo 0 .0 cn .0 U) 0 U) 0 ) 0 C (D cC) (nU ) -co a) ) ~ 13C) m C ) C (D M" (D C) . Ca) Cn ) >n C) (n C) >n C) U) C)0 ) > ) ai ) a) 0 l ) a ) a ) C 0) C) 0) C r- 2 C: " = 2 2~C L. 0-. a_ Ill w) CL~ w) 11 W E E E E 2 E E E 0 0 0 0 0 0 0 0 co cn C) U) cn (n cn cn 0 0) 0 0) 0 0) 0 0) 0 0) 0 0) 0 0D)0 00 C5 0) CD 0 E C) LO CC) E E E 2. E - ) -) U -D 0 ( 22 4-L- 4-- C C 00 0 0 0* 0c 0c - 30 Z~ 2 C L C) L 0. S.75 -Fa 2: S. SFu. 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0 . CL CL 0 - cu 0 0 ) On U) a ) C m " " m " m "cc C- o a- U)a- a 0. 0 0 0 2~ 2 . CL 0 0 U) ) . 0. ciu L-c r U)- 0C a) ) Uo Z a o co 2 Ua) _u C z 0 0 0 C .6 ai) 00 CL m) C U N 0. : L- 0 U U) CL 0 0 ) 0 u 0. c3 CD 0. 0 C V i) 0 0 70c >~~ C.) I 0 V) 'a C : a 0 Co -7. U) V > 0 > >4 fl (DU (D~U U L 0) cc a )) cu G- 0- 0 0 L C 0 2:1 m 1. Z &- 10 1 C 0 :- C C -0 CU co _ ci) W U0 U Cl-05 0 a ) 0 0 0 W C- -)Q 0- 2 _0 2Z0. Z fl 0 C'N LO) 0 0 0 > _ _ _ _ _ _ z- < < WO 03/072602 PCT/EPO2/50003 860 .0 E E E )10 0 0 cc *.. (n U U) o0 0 0 0w E E E 00 0) 00C <ED (a - 0 2 2 li 0 0 Of~ U ... E5C T 0 C 0 - 0 L Zi a 2 -a3) 0 0 C=) 0 E0 coi Um 75 ) CU U '0 0 El C: Cu ci) C) 'a5 2 '17 cC/ z 2 . z 0 z 0 0~ a 2 0 a )U [i a O Oa) 0 HD 00 0 C-) CU 0) 4--0 C 0 S<0 E .2 0) C 0m ) Ea 0 0 . -L 0U (nCLQ CD M 2n CU 4-) CD 'o co ca U)~~ m3 E wa. c ~ ~ 00 U "0 0- -) Si CL 0 4-> 2 ~ a) .0)i 0 0~C. 2 0 (n .o 0 LIT aU~2 ) CD EE C0 a) a)0 0 a) U - _0 EU -o - S;) co0 0 c-( a a a a) 0 CD CU (n o E 4- * C:~ 0 co ci) )n M Da) a 0fl Eo o ~ 1U c- C 4-1 0 :3 -0 = 2 2 2 = oo0) LO zCO Z I Z IZ I 00 WO 03/072602 PCT/EPO2/50003 861 2o E E 0 00 0 3 0 00 E E 0 0 E E U)0 0 U' 0 fl0 0 __ C) 0 3 D ~~ I- C3 C 2, a)' 0 ) C :U)-U C uV 0. C CD 4 2 2 Z -0 tm m <C. C: I- m E ~ < 0 Z.- 0 / L)) O 0< c E) C (D0 a,0 aa,.0: 0 LZ (D~ I .0 co a,) C) 05 .0 E -5c >1 2 4- a) C a, ) = C Co a) 0 0 a. 0 CO CO 5 <0 Up < C~ .C 0 (V 0 cc . V ( - E - '4a), c 0 0t 0 0~ i.L4 0 0 U' a 2 a, , D 0 U' 0 E ~ < fl 0 cu C C6 o a, c , - CM C Q -r (V- C a 0 Co 0- a 0 = 0( CL I- 0 - I-. E C Cl U) - 0D - -0 C < 0u > c C 0 -0 Sa, C5 (I) 0 .0 ~< 2' vl- cN' z z zIZ I z z 0i: WO 03/072602 PCT/EPO2/50003 862 a)< E * oz o) E o 0 C C 0 0 0 0 E cn i6 0, o a*) 0 0 . o 0 c 0 E C * .2 co 0 z E CL >O C 0 0 )) _n a- C C 2 w 0 cc < = C: 0 C:- C -~ L. o 0 Z 0 *2 C *) 0 -0 O 0 "- C) EU 49 CL t a. ) Cn cn C 0 0 C 0 ca V 0co 0. " r- a. L ) (D~ CO m ) LC) ... c 0W 0 t' -aC E 0o 3 .. C: C C: 03 0 C) D E 0 a 0 C V z 0 U) E C:L .0C C7) 0) 0 0E =3 _) U. 0 > C L .E 00 =3 2 0 -)0 0 VU C = C C) 0 u a 0)) a) E0 C /)0o C C) IL0 0) L E CC . (1) 0 0. 0 0) EE C 0 10 E C V C 0 >)~ C LL 0 ) C) >0 2D 0) a) C) =) 4-C . 0)0 -n X CcoC 0 t S 0 (D C a .0 CE) V -0 E- 0.C C C)0. <0 CC V .00 0 ) V m _ C) .0 CU 2 r. C: 0.4) : -.- 0C : 4- 73-) * 0. 0 0 4- 0 C 0 . 0 . = ' - 0 o =) "< c - L-~ C) =3C U) *-) 0- .00 .0 CO- CC 4- >4 OCL 0 ~ 0 4 a)a 0..0 c- Z 0 Z Z Z. Z ZZ co WO 03/072602 PCT/EPO2/50003 863 .o .9 . .o 0 0 0 0 . -0 0 . . 0 . C. 0 0 0 0. 0. 5 '0 C . C E - E E E c.. O9O C-" r- C, C'- C -- t o o oo < f o. D a_ fl . c cf . Z 0 .. _ C O C ." SC c o - C . E 0- .< 0 0 .: 2 - =- E 2 z . -2i= .E a. E c 0 0 0 0 t t C C- CE z O _ C - O C -C 0 0 E g -- - e o ' 5E Ze C Cz Z ZEZ 2 m *00 "- 0- 0 . -- C) Tu Cu z zz z z - m z Of oo0 0 en u r 0) a) Cu C" < 0) Cu (D Cu 0 U) % - -- E -z - cu r- 0 1 0 X 0 Clu Cu C: o..9 Cu 0 - . o C D " . , C o u 0 0 o a)u 0 o "00 0 • .. _ 0 2 C C c C - " " C ,o o co 0 - Cu 0I- -y (D 0 Cu E .2Cu C Cu 0.0 0 - 0 .

E a0 0 UE ,. u 4.- - . ) oI)t Cu 'n Cu CL z r- " (n 0u C :m Co a-) Z C iT- E 0_ 0z " - ,, 0' 0 !L 0 00 E 0 0 Z ZZ cu~~~. 2.2220a)o C5 Cu - 2 0 0- CuD 0 1 0. Cu C L L. Ct C -C Cu a ) < ~ C 4- L Cu Cu 2n 42 Cr CD :p E E z 0 C 0( 0 E C a cm 0 o 0. C C D c0 0 E c). 0: Cu- (u Ca 0. C 0Fc . - 0 *C C C vCu 0 ~ C 0 C- 0 .- u = a) C 0 i C ucu u a0) ~ CU .0 CY 0 Z 0 Cu 0L Cu L. a:z 0-oQ CD c0- E__ 40 1- " LC ) 1- 0O o 0 0 0 0 0 Z a- Z Z Z E 0 WO 03/072602 PCT/EPO2/50003 864 (n U) E ~' E E CD C mU 0 co CO _ ca) ) < 0 0 ~ 0 U, 0 Z E 0 0 E 0 0) ui0 E LE . 00 Itf 0 V C tf 2 L LL Z: 2, C CLo Z0 ~ Q 0. o a(n CL0 EOE 0 15 0 0 M co. CD -0. < 0 C3 Z 0 z 00 0. 2 Cl Z) 2 C 0-ZC CL: a) 0) 0D 0 DCU a E c0 0 DU U, 0 a) 2 24 D U C C L CU C _ C E (D <, zu C: 4 E0 E-: (nC U 0 0 a) .Cu co 0 s.o. CE Cb M ~ - 0D C.- -0 0, CLU Q) 0 0. 1) C C 0 C., ~0) C: ~ U - 0 U 2D o- 0 - U, 0- Ca m a .- m ~~~~c 0. U C 0f C s-O 2 C) Cr 0 LOCn ) R C: 4h-05- U C4 0 = - 0 r0 U 0. a) CU 0 42 .2- 2, CL C ~ E 0 0> 0 U, 0) 0 0- 0. 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V =p= U -p = c mC cn~~ 0 -Lc:- L c a) 0. CL 0- m) C)0 a ca 0 __w o 0 ~ 0 cu 0 ) E )CDa)a U) Un Cl)Cl U) CO ( a)a) (D l) a a) a) ) U) Cl ) 4- in 4 1)4 . Ca 4- CU 4-U)C ) 3 C]u a) m Ca a) co (D co < a) a E-"E~ E~ E E~ E o_ Ec 0 0 4--7 0 0 0 ;, 0 4S 0 0 0o 0 0.. 0 c 0E -E 0- r * ~ a~ F . CL~ zL zE0-c < = =3 < Z3= < = < < C) =3 a U) C4c Cl) a) ) Do a) in a) C) 0 < ~ < .0r - 0 Z LO cy) _0 0 VD 0 co 0 =3C .n a) a) Clna U) Cl ) CJ1 )Cl Ua) C). a 2] ) 0C 2E a)a ~ E a) 0E _ -r C.- l) a) < 0 < 0 . 0 .2, U)4 U)U . 0 .0 00 0 . 0C L0- a) C]). <4U) 01 U) < C ) 0) LO) co LO - co C) T- CN co Mo In m o m 0 o 0_ 0a- 0IL (L a-0 0- IL 00 C0 y- Ir 0 W 0 0 o WO 03/072602 PCT/EPO2/50003 890 cz 0 00 0 0: .0 E Z~ 0 ~ ~ (nc * 00 .2 Q- _. 0 C) U) ch c U) U) U) - :(I) c0 U) 0 -d 0) 0) m 0 0) = (n U) U) Uo U) co U) in CO ')U) cu m) U) U ) U )U E ' E E E E ~- E L ' 0 -- 0 - 0 0 - -r 0 _ 0 U) -9, E CL E. 0. E . '.E Z. o o =<=< < < < =3 C: A) 0 LO C: 0) E) 5

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00 (D) U) C:U> 76 a) 75 0l cu U) > n C.) CD a) a) E) CL U a) cn wU0) U) -D c) in 0 U) a) "ff a)C0a () U) a) 0 4 E co - c~ U) L) 0 a ) 0 a) U) 0 c (n Vh (n U) 0) a) 0~. ~ V C: E E) E 0 En m) C. -) ( 4- 0 -5 -5 0co _0 0 U) '5 C E < < E ~ E w 0- 0 z z z .C Z Z 0=) 2 U .5- - C) co J cOr CO) CO) 1) OD (Y o 0 0 C) 0 iii ( 0.. 0.. 0 0. 0C0 WO 03/072602 PCT/EPO2/50003 891 0 0 0 0 0 0 0 0 .0 Co cc cc 4-a to M4.4 a) a) 0 _0 a0 "0 "0 -0 -o "0 4-'~0 a- ) 0 0)a0) a) 0 C ) (n F)C o oC CoC 0~ - o - -0 '0 O2 0 0 0 0 0 0 0 S.. 4-2 L- S. . S. . IL ILf~ oC L IL IL 113- C CoC 'E O 00 0 10 . 0) 0 0) 0 z a) a) Co Coa)o C o o C o C -o0 . ~-E E~ E E EE 0 yCo 0. 0 0 0 0 0 0 0 0 0 0 (D ~ Co Co D C - En U) Co () 4' Co co ca Co Co C c u z~-~Z2r- L-Co~ S.-) 2 2 UCL- ~ . o~0Co in~ D-C I -0 :20E- CL D (L C L~O.k 0 cco 0* 0 E CL ECo CO 0 D a) .00 0 Co CL c Co Coa E Cu E E E 0 D0 0 0 0 0 O Co 0) E 2 0 o 0 L) (o r- 0 C- Co 0 ) Co Co C Z co3 Co Co 2 cc E E E a)ZCOC 0 0 0 C.) 0 4- 0u Co 0) CO ca C >, 0. (D Co Co Co Co CD~~( -FD - 4' Co Co ) 2 CO 2 0- 0. 0 Co COO C) W 0 ( ~~D0 E. 0--cC c cc 4.4 Co 0- CO a 0 N)C) U Co 0 ~ (D C - 4' 4D co co -- co .0 o Co a)2 cu CN Cl) N 2 _= 4- Z1 CCD oC co0 0 Co0 ) 00 C C a) 4- E- 0. 0. 0 0.= Cn 0l 0 ) . 0- E 0 z- 0.0 4-) 04-'0 - ~ CL4 0 C) C CO~ 00l oCoC o C CL 0L0 CL L C E U) E~ 0 = 0 C :3 0 - . o 00 _ _ __ _ CL 4) Z u a)l a) COaZ) NE N ) CD) LC (0 a- 0L a.CL C C WL CL L C 0 ~C 0 0. 0 0 0 WO 03/072602 PCT/EPO2/50003 892 Z C: 0 0 0- - E 0' > 0L 4- 0 ( cu mC a) *" ~ 02 co L- (n 0)5 0))0 C) 0 (C Ci) a)) () . m C >. r- =S _0 0- 0- U CD a) a) -'-S) .0 E 00 0 0.0 2 0 0 00 0 n 0n a)- -E = C) = 3 C) n ) < 0 ~ M in~LOC UQa (DO 0 .H C Q _ ( C L M-04- 0 ( -c 0) 0 E) E , "0 c U 0- 0S' 0c 0L-0 -ca 0)C)' = EE 0 0, 0 0 0 - c E " CCL -e 0 L 00 a) C)) E 2 E C= ' 0 0. 0. C: CC a) E ' E cc ( 0 0) 0 0 (D= .. -' U) a) ) 0 ) - ( CL A- CL(C>5 . <C) C) 0.) 0 0 Oz . +-(0 0 0 L H CLCa) L LC CL CL _ 0 0 o 0 o 0 0 E 0 WO 03/072602 PCT/EPO2/50003 893 L.0 ~0 2Qa5 1- 2 a

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flZw U) V5 LCu CO 0~ 0 0U 4- Q) 0 0U w 0 0 E CL 0 ) 0o 2o CL z (n 0 E ca<L 4- w) ) 0 0 0 "a 73 0) U)a- ) -0 Xu -0 ED L6x U) >1 0 E 'V (0 Vu 0r :3 .0 0 0 . r_ C4- 0 C2- U) E C:~ M0 -r D4 8< _ 0 _ -0 UL (D 0-Z UU0 E) a) 75 0) 0 0 0 En 0. ~. z 2 >1 0 < Co N: >1 C:0 0 D Z-) 0~ XZ 0 0 -0 0- -1 00 0 L- 0 0 42 0 0o 0 0 0 E WO 03/072602 PCT/EPO2/50003 895 00 0 0 0 .4-, .4 0 0 0 "00 0 0 0 if 0 Ef E EE 0) > 0 0 CCl G) ) a) C ~Cd) 0I <l 0 00 <0 0 <0 <0 <0 Z 2 Z z 2Z 2 Z 2Z z2 (n en ci; C.) 0 0 0 0 0 0 - CT f l Z - 0 L Z 40 0 0~~~Z T) -n - r- 0) :5~~~ *o 0 - 0 V C >,~ ~ ci > 0 ,> 0 i 4 0 "o0 W cox ) CD Ia) cO X C . _ D CL CI) 0D 0 0 ca < . 0 0) 0 ) 0 < 0 0) ( =CCA (n CD n . ~C) 40- w 9 ci) 0 0<0E 0f 0) -0 Z 0. 0 0) CD 0 ci, ifE -xf ~o0 0 00) I+i<f n -0 0l 0 Gl O E- 0Y) 0p 0) CD 0 xi a) =~ c a) 0) Cl) E 0) 0 En ci )C 0 L C)0 0) Co 0D 0 4-' ox C: X (D 0 0 a) CL -0 7; E - 0 0 0 D4 >0 0_ (D0 c 0D .- 0 r 0 C~ -0 w i ca 4- 0o 0 0 0 > > 0~ > o~ '3D-E L co E E > (D_ C = WO 03/072602 PCT/EPO2/50003 896 a, a) a) a , 0 E E E E E _0 (a. U) U D nC -0 0 0 0 0 0 o L. L. . L. S.. - > cU a 0)=C E 1 ~ 0 , > .0 a . a) 0 U) CL.- 0) C - na a, a, L. a - a ~ a . ~ 0 0 >1 r_ E~E~E20 o0 0 0 t < S aL a,0 V ) t 0) 0a) 0D 0)0 0 _ CL 0-_ CL w C~C 0 ,L E C Z~'r (D 2 0- ~ 0 cu< ia CL 0-a 0L Q0)c C j CM_ _0 CL 0 0 a- a) a, CO co. C) S... a) 0 0/ a)C U) 0 C , 0 a,, E 0 E za Z 0 0 X 0 CL 0 0 : U)) E E - 5 C 0 Wa, -4-0,0 _ C 0 C c - C VaIc 0 0 0C 0X 2 0 x 0 E 0 A 4 - 4- 4- 4-- M04 a, Z 0 a, 00,- ~ 0 0E 0 02 m c. a/ r_ a cZ - C: E a,0 0 0 0 Ofa 0 0 ~ ~ ~ ~ ~ . CL C - L C c>0 0 0 .0 V0 V V 0 0 0 > ~C. 2) = 0") C- .0 .0 V-) . .0 C) CU 2i CU o 4- C- 4-) 4- 4-, c U oC 0~ 0 00 0.0 WO 03/072602 PCT/EPO2/50003 897 0 .2 M 0 +1 cn - cn cn 0~a Ca a) ~0 ) O CO (D) 0 a) C i) (D a) 0l ' 0)CD 0 a)) a) 0) al ) a) m W co*~~ U)~ 0))) c = 0 ~ t i) a) ai) a) c, 0 c.. " C '. C " rZ s c, > Wua-. w 0 wf 0-. wO. Ic, 0)20 E E E E E E 0 0 C: 0 0 0 0 0 Cl) (n (D co C0 Cl Cna) 0) 20. c, )0 00 ) 0) 0 .) . C 0 zo Cm .0 00 70 0 FD 0 - a-0 C) " ~ ~ ~ ~ 4 =C-c 0 Q -w mIn C n C a) W 0-s. a) (D_- Cl CT - a)a Ua) a) 0 U)) E~ an a) c o 0l C ci) E E E E 0 n C 0a a) 0 " o 2 ~ a) ClDl C) -0 -0 0 0 C0 (n C) 0) ( Fu cu 0 0 0 0 0 0 E 0 6E 0 -2 2 2 0 E 0r C) 0 - ca 0 0~ 0 0) _r- I- rI- E. >. 00E0 0 0 0 V~ 0 ?,) Cl) C L- 0 > C > 0 a) E 2 C.0 2 0 0 _, CD s-- *0 20 2 CLA 2-0 0 0 C C - a. 2,sO CL a) 2: a)) cI ( 0 0 >I >I c u)C)C) / I fl~ f~ __ __ _ __

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cm : Vn z DC o 0 E- 0 E Cr_ m. a) U c 0 - 0 -) C - o5 Co a ED C E: c 2 oa o 0 C 0 o C ) CD U)C: a 0E2 o _ 0 =-) < C '- -c 0 0 .-- 0 <0 .0 mU) C U-- H 0 E . O t * 0 4- o a)0 00 E ).0 =3 C 0 C;) a n Cn 0 00 E- 0a 0- Cl CL 0 0 0 U) o . "- -- .. '- 0 a U) U) o - C - o C0U)U) -u 0 0.e .. . )o a >U -00 E U)0 0a) ) 0) 5...~U .0 .

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0 0 cc .0 oU 0. 0. CCr 4- E : -E c c C: ) 'EU)a) Q 0 ) U) 00 0 a 0 C: 0/ U) < 0C C) z _0 U a) Ea) 0 2 ). C C -- cm0 ) I. 0 - Z ) C : 0 2 0 = -0 Q- 0C _0 Q- F) : a) E. : C) .0 o 0 70 (n..I~U _0 l. 4- (C) 1 0 U) Z3.9 - . a a LM00 . U ?) C)0 E C 0 0 0 E _0.c a) E) C: 0 =0 >< E CZC 4-C) 5 U o0 :Z 4- .0 -0 a) 0)2 O a4 ) M- U) 0 o U ) U) o o E 0>~ E 0C 0 0n C: . c0 w0) 0 cn 05 - 0- 0- E- -J0-) a) 0 0 2 0. 2 I U) U) Cl) Cl)0) Cl) l) 0 WO 03/072602 PCT/EPO2/50003 900 OCO a) g 0 = E .2 0. .-- :3 O o o i *- O 20, ao4a D O" > - 0 0 0 -0. 0 0 0 v Ec o .- E' c r_> c: C: c 0 - . . M m c o D~~~ C :0=3 O < . o - 0 c o S o o E CD, CD CD C tw S 0 E E <0 C. C) a. ) u E Ca) a) a ) > U) > o ~ 2 .~ x, 2w - . CD CD E CD0 0 oa) x E 08 00 42 m c 04- D - > 0 0 0 - 4- -0 -u - r" .4. -' .. CE 0 C0 >D 0 0 0 o a -o - , ," c. c O E 0 U) X - ,. .- - L o " 0 C a 0 r_ t-. D 2 . f 0 0 Cl) < > 0. 0 E •. " . a - o.(.9 - " 0 ._ 8 D - 0 - 0 5 m -- E. ._ "E. C _ a> -t. .- C E 8 0. ~~~a :r- -;D . o U a) L o 2 0. 0a5 o aU) co 0 " 0 m | a. 1_ _ r- - a) a) 0, co C: a a_ 0-- 0 4s 0-- o 0- < c ) >& .0 a) 0CD Q .N CD .. " >- 0 > 0 E c o CD) 40 x &. E) 0 ) 0 a) C0 a E co -- 0 aC - - , 0 m) i-D a. E , C CD > a_ a). x "5z CU m . 0 m *C D a)) a, W C= D -) -o X 0 C 4) V £ -- . . 0Fn " o "" 0 ~ a," 2. 0 00. 03 "' 0 0 r- c: E - ffi CD C c 03 0 a : - 0 Cc 0 c o) C) > E- a) a) > m a_.- . 0 C 0 0 CU 0 0 m Ca U) CD > CD > I9 CD o CD m ~ . co4 m ' 4 - 0 5, 0073 00t U) :t- a) C a) C XE CO.~ C ~ U -0 > 0 0 cm a 0 c U) a)C 0 a) 0. 0 0 0 0 T3 >- 0 EDE cu C: oC -C 0- L- 0 0- - CJCN C/) 00 4-. o~ 0 0o 0~~ ~ 0 LULi LU L U U L C) CD) a/ /) ) -5)C) l C WO 03/072602 PCT/EPO2/50003 901 00 0 0 0 'S 0 ca 0- 0. 0. U) CL 0 Q-C CL Q) Q) C U) ) ) U) (nU .n ) U U) >) >) UC ) ) U M 0u 0 0. .

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(nC- CL a) C) 07 . ) U 0 >1 ~ ~ ) 0 a) 0 CD)a C - C: (n 4-U) 3 < < 0 2: 0 ) 0 )a Z 0 Z Z 0 Z CL o > C > Z~O 0.O- C a) 0 . U)a 0 a) CL - 0 4- 0.0 0 - 0 0~t= c 2£ 0 Z. _L 2 0O 0 0 0M a)U CL a) o) cu - 0 a) a)Z a ~ C a a 0) U)E C ) a)ccL . 0.U) E 0. 4- s. X 0 en CD a) a) a) r_ C !W a) L_00 0 CU 0 0 = 4- - a . E' E 00 0 a C: E M ) n0. tm <a 8~~" M 0 ZO) ~ ) 0.~~( CL CC .L)U .2 0 N . 0 a) a n 0 ~~C'J 0 *cu ~0 a a)~~~~C a) ) ~ 0 a) 0 a) 0 a) a Vr0 .2 Cf) 'E .2 U) CLC~ ) c C- CD z.a.(D C CU > (u m 0.) ~C0 CL z)/ m. 00 *0 00 U) a)* ~ L.a) U) CD = -0 c o~ m U 0 n( D z C Go ~ 0 2 -0 " a)E C: w CL .2 C: 0. C- W ) 0 ) CO m~ 000 0- 0 z- a) 0-a 0 c .2l 8 u U) a) aa=Ca) " co C (D C- 4.C C (0) 0 00 00. 0 0. 04 0 0. 0 C 0 0) a)C 4

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C' >.~ a) 0 a) ) 0 a) 0 ) a) 0 2 0w V OC C) CU) c C: ) C a) IQ . LL C(0 O CL C C)."4 5 a 0 (0 (0 0- 0O L- C Fn 000 0 I Z Zo w UJi W Ui Wi W W WC U) CO) co)C) U) C) (n CO 0') WO 03/072602 PCT/EPO2/50003 903 a)0) <U E E E E Z0 E 02 00 U) U) 0 0 0 -~ 0 0 C0 0E U) ) U E 0 E 0~ U) <) 0 (n -o 0. L ) < a)- CL L- E 0 ) E E~ 0 c 0t w c 0: 0y 0~~ ~ ~ 0na : C . CL P L UU Q U a (D0 c o0 C 0) C:" : <4- -4 C 0 a))0 (n ci) 4w CL U < 0) 0) U.) *.. C 0 0 U) C: Ur) 0) a) U) 0 0 . Ca0 *0- _ _ CC c 0- = 0)0 " 75 I C Z o 0 Cow~ ca D .o .T.0 U) C: .4-' 0) a) c ) L Uf) .0 .0. COC/ 0 z _U 7 ~0 < C cc )F < - CD U)U) 4 U) ) U) E - 4 C: co 04-- 0 0 4-U) 0 0 ~ a) =s m 0 5 .2 c: U)wu 0) E) CL Co U) L a) a) (n 42 C 0 C. (D a)aUX)0U C -Fu U)cuc E4- U) (n U ) ~ 0) 0) cn ( 0 a) E) U)E -0~~- 2U E cn C ) 0 U) 4-2 4-' 0) .2 0 0 U) a) U) U) U) 0 0- 0 ~0 0 0 *5CL .. = 0 0 2>2 ~0 0 a) 0.

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o> <) 0 0 L r- 00 0U) co 0) CC CC() CC) CU WO 03/072602 PCT/EPO2/50003 980 C l) - UC) ) .)Cl C)~= C) C) Ccal . m M ) C L.) Co >U) C. D .0 U) p, 0) = w 0 ) c E 0i 05 co (n a) 2 C., 0 0) m) U- =) 0) Ln (D (n C: a))C 4- w.0 " L =$ > '0 a) C C D a) a) ca m Eo V a) 0 C n a) U) E a)~o C - ) i~~ V M COV 0 0 0 -L . o C 6- 0 0 (D V 0 z) C 0. m (n M aC ) L) E C) C) _ C) C)M - W > - ' m > E 0 a)0 a)O 0)C a) C C) C C) a)o 0 C) C) t w. 0 M r. Vm Cl) U) a _0.= - w 4- .4- - O C: .0 .00 o, E V c C) C) cC) C m 0 ~ 0 0 .0 0 Ca C CL_ CL -0 C0 r_ C C )000 C)i cu C) .0 a) 0) 0- X ) a ) WO 03/072602 PCT/EPO2/50003 981 -o 00 . CD u to U) 0 ) A-- ZM)- .0 L U) ) > )4 )) c Cl) CD U)0 .V CL (D C: ) Z -0 2 -2 0 ) I-0 co " 2 o>V cu w cc 0 m 0D- ) CDU =~~~. Q)) 2 to 0 h CD CD Un C: :5 ch C: w ) .cD CD U)0 C C 0)> 0) >2 co *E cu a) V CDo C '- U n~ .2 C : CD 0 a) V v. Ca) 0 w0 V n 0 C 0 (n ~ )- 0 0) Vn U)f 00 U) .0 C > a 00 o 00 C) 0? co~ CU)a m 0 > 0 C.)~ .2cU) E c~ . 0) C 0 0 [i cc D cu -0 -0 _ 0 L)- L ( E r- O C U) m) U): in Cc C ) u U) P m~~2 0 C ( 0 a ) .- U) 00 E E u- 0 0 (n 0/) CL IL o2 Co * 0 in a) -0C 0 )0 z - a) = Z 0 w 2CCU X. 0. ~ _C ID 0) E~0U 0 C 0 U)C E ~ 0 2 E o l U) U) U) m0 E) (D4 C; O0 0u 0a cu a) ) 0 WO 03/072602 PCT/EPO2/50003 982 Ci U) uC c Ca . C(D C U)' (n U)C) 0) CC c~au C a) a) a) .o 0 E a) u) 0 an ) U) 0l ) C) t 0 o co n m( ) CU a) E: 0 *co ) -D~~U Ir- A2- - )V a) .- 0 o .'6 _o co - E - a) 0 a) _0 a) r- o U0 cc a)m a C )Cl C: n E 5 0 U) aU) (D a)m a) a E E a)a U) _-0 a "C E > ) ) a a) C- ) 0 V 2 0 c0 0.a)C l U) CU (n U) 0 0l CCC >' a) > a U) 0' > " CD (D a) z E = U) C) 0 ) a) (D S U) .0C = E E L a) ) L- a)L: C) 0 (D -C ( C) c r , CU C: 0:r co Vn U) C ) a) a ) 'o a 0 0 C 0 0 0 UC .0 - 0 E E 0 0u 0 E - 0 0 5 CL C 0 C C C C) CU - 0 00 co) .La.~ 0 0 ~ 0 C) 0 C.= a l) 0 CC 0~ if -- M 0 0 _u r_ -in 0 -C~ ~ w~C . .0 00 0> <6 w Ca 0 0 02 .0

I

0 0 U) x x c 0 0 E CD Q I L. _n CCL 0 F 0 0 0 F=~. 00D. 2 0 &- 0.0 0 z0 W U) LU 0 > 9 )0)0') __) ____ m 71 WO 03/072602 PCT/EPO2/50003 983 4-- = -V a)0 0 >1 (n a) U) E ( a) U) ) U) 4 .- 0 U) a cu ( U) "3 CU~ ( U) ( 0 0 T.0 a) - m a a) aca 10~~ U) C= a) (D ~ a~) ) ~ -~* E C 2, 0 cu (I) q)~ 0 0 0 ) (n CDC 0 U) _m (n- -V; .2 0u ) CL a) a EC E c U) U)>. ~V = a,~~~~~~~ rC 0a)a CII ~ ~ - - 0 a U) = a) - a) 0- *. .0-a)> z) A 0~) S2 2 .2 (n .2 _0 CL -0 CL o , a)5 U)~ 0 C ) ~ ~ . a) U) ca. Z. a) _ U -* 1 CLV 0 0 V 0 . 0 ~ t ) 0 >, _0 a)V ) V (0 _ ) U): D0-( :3 0 C: a) n( h ) 0a "a- z( E 0 w) on ct " ( 0 cc ( ) C E .0) C 40U> 0 ) 0 0-;_t- 0 4 12L a) a) (D 5E V (00cn a ) c m 0 L 0 - 00 m0 0- u a m < E 0 0 0- 0 00 0 0 a) a) 22 cn 0 0o 0 C. -a U a (CL .0 0 0)~c 0)0- WO 03/072602 PCT/EP02/50003 984 a) -n a, U) V) co a) a) E2 a, T) a) - a (D -0 a, 0 =, .- a)a, E X E) U) E cn a, a, a, E E S2 a , E (D a), n ( - CD - n U a-- C b, 'E (n a,) - ~ ~ a .2. a . a a, M U ) a, maa a a, a, a, a, coD_ a, a) a, a, a,. ( > 0) a,) M 40 42 , , a>, = ~ -- -0 a, C: a, a, a, a, (Da V 0) c C U o : ~a ,2 C 0 a, aa a - 0 >, a, (j =~ m C C ~2 22 0 a x a'a 00 a_ 00 01 *0 Ca 0 T- a, a, WO 03/072602 PCT/EPO2/50003 985 C. C) a~U ) U) 0d Cd) .9 . - =0 Cd) L Cd) (d) C0 = 0 M - a C.) () a)_ n 4- E OW CO U)c d U) CO ) cu ) a) : d M ) M a) ca 0) cu C.u _ a) C.) a)U)0 > .0z U) C.. C< -c U) L - ~ U (D A >1 ": .- ) C: I) E U)~U) U 0 0b C0 0 : CL Clo C V (D U) Cd : 0 ~ ~ ~ ~ r cu -0U U.9C .0 U 0 c E~ Ec U) 0. - ) C) > E a) CL > 0- 0- 0) a) a) C)C:C U) C) 0 C: S2 U); "U U ) )U *0 ccC U) 0: C: U) C_ -) CD ". El (-D >4- , = U) a) c cu 0) . (D cu a) - CoC Cd) E U ) - 0 C: a)~ ) Ca Cl) 0u a)L U ' C ) E U) l 2) CU)- 0) U)e U) > 0 a C: (D al ) U) U) CU ( C: ~ ~ ~ a U)) - : w - C: C 0 Ca o. ) U) V C C) a ca ::! =0 0 U) 0l 0 u to w 4- CU CU C: C.) 5U) ") V 0rM-0C MC 0 caZ C.) 0 ZC 0 .. ~CC 0 0 0. 0) 0 Z El CU 0 CUC (DC . o .2 00. E - ' - E - d) - :E3 U) U) tm 0 0 U) *9cuU) - 2 0.0 o 0. cu 0 W m . 0 0u ml CLE E Cz E a)C cl ) 2 <d ca c M EU 0 o 0(DD 0 0 WO 03/072602 PCT/EPO2/50003 986 a,-0~ a) .4. a : E Cl) Cl) a) 0l 0 l E E w E o wA ol a) 0- .2) a) o -co U)L L a) a, a)a)a a 0 ::: c C -) c *Ea 4- cn C Da5 C: - a) a C. E5 a a) Oa 0 ~- ~ a co a) . 0. $ 0 E LL 0 E LL_ > .2 .- L. a 0n " LC :p a) o 0 a - 0 o w 0n .0a > c a .~C - . l> > >l) Cl a A) ( 70 -- 50 C -Q ) a) C) C: Ll) C') CD 0. 0 -- U),C C) m -o 1n a, _) w~C) a) aa) ( -5 0 -0U 0 -L G O) 0a)) .) 3: co 0 a) CDa ~a) 0,,n 0E QO 0 C) a) 0 ~ a 0 = a) co0 - ) CD - D 0 D C0 a) - co . CL CL s..= oz 0 u 0 a, a, - a, , 0~~~~ *0 00 o o5 a) Q) 0 - 0 0 00 C -0 . 0 C l m o O aD m 0-0 a) Ea E E 0) 0 5w (D 4 0U w 0 CCO a) 73 a))a 0 0: 0 o) cc 0z a- 5- 750- E a) in 0u o S a, C ( a) ) a) a n Q) 8A b CC)CO C .4,a) a)a o 0 0 a, 0 U .2 0, 0 .0 o 00 0 0 0 iin~ WO 03/072602 PCT/EP02/50003 987 QC.) (D ) C:) 0 " - .

.

C C) ai) E 0 Cli 0) m:C C) U) ( C) Co o o C fn 0 -( a) CLc= w gc ) _- w 7 5 m-. .- - 0 m a) -, 0 CL- 00 o~ a) -i - -) C) a:~ ~ V C ) 4- ~ C: -0 C o ) o C: >~a V).:w ~Ci c ~ c 0 C: 4-0 0' 0. c o •) r- -)C ) r- C Z: o C)o 0..9 W =l ~ Q -i) wI 2l 4--c >) = 0 > -. > l E ci o a 0 0 mT -0) co CD 1) "- D - Ca (D CL E n > cu E 0n .. r> n ._ 0 0 0) C m M o " - m 0- O a)) 0 ( ) Z o - " - n ,0 E in. : 0. .9=03-- -j C a) ) 0 E c "0 0) nt: 0, o- -2 > o x E t o x m 'ooo E 0 ) 0 ) Z (oW U) 4 4-0=3 EC En o "3 r_ - m Z cu u > - o 0 0 .)0 2 o 0 C0 cc 0 C.) c 0 LF C : C 0- ) 0 - V 0 0-i CL 0l 0) X) C: cc CO E n 0 U) LD C:0 0 M C:( C D 5 c 0 4- o20 0 C: Ci7)-15 - - -F 0 00 :p 0) -l) (00 00d - ~ 0 C- 0 o a)a CL0 a) 0) .0 .) 0 C.) 0. t M WO 03/072602 PCT/EPO2/50003 988 0) (D E a) > ca)en C - U) C) C ) 'c l) C o 0 0 CL V co 2-~ U) 0 En 0 a) a) U) CD 0 co 0 m< u)) C C> 0C C 0D Cn rn 0 :3 "F (DS CD E C 5 =3 c (D CD- a) - r a) (D o' a) C) CC2 E E I- - > 0CO1 co 0- o) - E C U) 4- CU a) r- a .0- Q- E ~ 0 CC 0 U) _ 0.s. .~' 2 ~ C 0)~ Cn C 0 E 0 0 n a) U)cu0 0 CDc C; = : 4- E o A4-m, ( , (n > a co 0 C C E M 0 0. CC CD C ) 0 0 0 z a m EE C D C : C)- .. u 0 0 0) 0 c) c C <. 2 E C C t CC.L< x )< x CL a)X E -a E 0 E 0 0 0 0 0 0 I 0 d)d) 0 CDC * a %- (D 0 0 LL 0 a 00 X 0 CLz 0 0 E 0) 2) 0 0 ( 0o _ _ ) 2O 0 V-) 00 V- l WO 03/072602 PCT/EPO2/50003 989 on Co U (a co U 0) a)) i6 . CU ) U)M E) U) wd 0 ) w E .L E) (D .2) ) u) D 0 -'. CL .- L -0 -) V U)= T 0a)*~ E w U) U)0 E c0 0 > '., 0 ) :cl )) am E 0>) - (nQ)*D ~ ) - a) T- (D E E " * v E = -Ec I U 2: 0 cL o. E a ) U) U) U) 0 C) 0 ) t U)U) (n- U CLU) u >C < 0- C U nY --o 0L >, >, =~ a5 c

.

0 V 0 in o E 3 ) -e .0 = F i o U)~ C)U ) M M~ C M) 2 ca m* c -E 0 ) U)a D : 00 00 UU) 0 -0 0 0~:Q 23 2 U.2 - U)2 - .- ) U t E W-~:3 0. C.o C CD CO a) C 0 E C42 Z C aU ) Z C0 ) Uo a) QQ E (~D OOO0 0 C 0- = E o o E o 5 .U) o_ o UU) C: ~ ~ ~ ~ U 0 = c : ) i; C M .0C 0c ( d M 5 0 0 U) 2< 23 :3 :3 f 00 U- a- WO 03/072602 PCT/EPO2/50003 990 U) U :E acu) a) cu m) a) U) ) C: 0 a) ) C 2 cu a) (b 0) CD L (1 U) W )~U0) c t5U) .0 0m cu C D U (D ca. 0) 0)U cn r)) SE " E ~E > a 3. ) a) C a) M 0) U) o w~ t~ o (D - E ' o- 'E IL-U 0 U)a " .. E o (n o) 4 ~ - 0 o a ) -~ -- -- ) =) o~ - .- s a) .) En 0 0 -, a ) U ~ 0 . 2 c o 0 E 0 0 (D U) '0 : -0 w c ( - a ) co -b a) C 0 cn E .0 L 0 10 U) 0 ( 0 -0- U - r- 2 0 -0 U) (n U) = -- ) 0 -U D.~ ~~ ) = = . :6 0 > 0 r CO ul E w E 0 = U -a In 0D U D 2- 09U 0 V 0 =.0 V 0 E~ o~ o~ 0 a) 0 -a a) cD M~ -2" 0 L 00 U) 0) >ci U) m) m 0m0 :E.~5 w -a0 c o 5 E :6:7 2 ~ i5 .) 0 ) a) E 00 U) n 0 0) U) U U) U) C 0- -' .0) U) cc U fn.E 0. co(i a) 0 a) U) U) 0 C C 0 cu a). 0 (a C 0 0 0 ) a) 2 (D, 00C CL E a)U)n U) r- 75 00 0 U) >U) U) U) 2 x x x E E 0) 0) 0 0- D 0 ~ 0 m c 0E C E E (9 0 0 05 0 U) J-.~. :3 0 m0L.-0 0_ C) U n mc -0 Uo .0 u -0 Uo com0'> 0 0) V- 0 ("I N- C WO 03/072602 PCT/EPO2/50003 991 au ) U):U U) U E) a) (D E LU n C C) U 0 CD a) ) V) _ cn c E cu E Y *:a l) a E -.- E a ) 2 . 2C E : -0 ( C.) 0 Vu Vo V" V) 4q . 4a CVD T) 0 )-~) Ca m 0 V \ U 0 ( U) U) Ca U a) = - - C) Cu~ : c w 0 E ~ . 00 E 0 C Cu 0 a u- cc 0- V E- c c" il Vn c) E Z6. E- .- 0 U) a -V E (EL Eu E -L) - C ) a 2 -0 " wo a - :3 <0.-2 0 0LL c0Cu 0 > ( .n _e V a) ( o + E -E (U C) -o w ECza o) C.) CU :3r L 0 C C) > V CZ ( 0 0 - 0 .0 ~ EW a) (D 0) M a) 0 ~ ~ ~ ~ ~ U .0 c ) E') C 0 o) a)) ca U)C C CL C- 0 0 CL U) CiL -0 (nU) 0) C) 0) C) Cl o 04- 0 C 0 oD CD 00CL 00070 aa C fl o ao E) EX -CU -0 V 00 Cca Cu c C:- E -- E a 0 (D (D Cu Cn. CD CI) a m. xS .. E2 00 0. 00 00 C 0 cV -0 = E c\ E 0 0 04 ( N (Nl - - -V- WO 03/072602 PCT/EPO2/50003 992 04 75 a)) (D0 (D =3 a ai (D Cl)> ci -~ E d 'uCl C Uc) 2 xl a~ 2 F - ( 4 - .-E o~l 0' CO 0 t a _ 0 a) C - E (n m. 0' 0' E c:) -o 0' . c > 0 a 0 ~ ) 0 C cn ,- C) 0 0 m - C1. CD0) 0 ca 0 C o 3 -0 " CO =) C 0 D 0' CIO .

CO 0' o 0 _i0 M CO V C o Va COC o . CO .~ CO \I r C C O a ) 0 f~ . Co) ID ) m' cii 0 c m j C. m 0 0 0 0 C-) c +(50' 0) 3 =5 0'0 o Eo E E E So- 0: 0 0 0i : w' w' 0 0 0 0 0 0 0' "O C 0 0 C 0 0 C) -c co L 0 -. 0 = - C 0 M C 0 CO CO ca CO5 0 O/). C _3 ~ E EE E EE _0 0- 000 0 Cl) ClD 2 2- 2 c~i (DQ O 0 2 CL U" ) a ) CLi) A- U) 0' 0 ~ 0. ~p0 0 a) ) -1. CD c. L.) -: 0) co 0 00 _) 0 CL) En E(O ~n 0.( 0 n 0 0 E E E S C) 00 > 0 0 x 00 - (D CL a) a.).0' L . ' 0 M E = - 61 75VoE " 0 To 0 0 =co 0 CO 0 O 0 0 Z CO 0 C OO CO)c CO .0co .0 CO m0C V) LO CD CD N N N N CNI CN WO 03/072602 PCT/EPO2/50003 993 0 0 E 0 0 _n cn U) (n ., C U) U) U) ~ V . 0 ~U) cS c)u) 0) a) tp a ) Un ) a) ~ -o U) .2 >0 cc E) 0 a) cz E 2o co C, E- 5 ' ca i Z 3 E p co .n-a 0 0 a) U 0 U. a) a) cna 0 =3 0 U0 O u w 0 U=Ca ) ?U U) U 0 E ) 0 . .- I-o * m : > c 5 - U ) o ,E M WE c po w" Z 0 0U E (D E -o c c E ( U) 0. E c o 00 E -2 cLU (D .0 a ) co a)a) r- 0~ U) C 0U 0E 0 E oC :~.0 >) E. U 0. E *0 *0 U) U)= =3 0 (0 U) 5- ) U) - > 0 - 0 2 -v~~~ (D 0 . U)0aU) E =~~~ 0) U)= E0~ 0 E0 .cu~0 0)U) T U5 ) "-i 55 D 0)L-~ C- 4-- C o E - 'D (1 ) 3 E E o 2 c0) a a) a") (1 ) ) .0 E "00 0 ~ ~~~00 E~o>. - U) a>- 0 r- ca C C co " I, X- rn ~ ~ ~ ~ ~ U Ln w0=.7 5 U) U5- ) O M U) *4 ) U ) 0 r U a) .~V 0 0- 0 m) 0. U) m U) Cc 0 z z z 0 0 0 00 0 U 4- CU (n ca m 0 a) UU :E5 ) 0) D 0 0 a)) U)U) U) cn0 0 0 %- L- 0. ( < 0 2- ZC 0 C 00. U)) CO X 0- CL x E 0) 0 )cn 0 0D( co oEC E~

E

WO 03/072602 PCT/EPO2/50003 994 U) i6' C 0 E E 02C oc 0 0 C o =-Co r_ wo L- _ ". Co 0C o 't E * CD -o cu -0 Eo > > - C ' 8 C 0 -a) (n a 4? cu c ) a)5 C C 4- E c,, E u) a)o C: BE Eo Co. E 0~ a) (o< ~ S 0 -C:C 0 E - CO a) 0F a) =~0 < ~ 2C ~ ~~ ~2o~ E u -o a)o.0 Co~~~~ ~ ~ > > o - ~ '2~ C 4 o ' -~~~ Q..~ 0 C ~ E C C 0 CoU C C: c1 .0 " _0 ' Co o~ co -L a 0 co (1) E C 21 _0 C 1o Q C ca ±2 cn .9 :to (n a) C o o C 0) :3 Co o 0- . C (D .E~ ~ C o 0 o >0E C 0 0) a) CD -M, -( 0 a = 1 C 0 - C 0 0:-La :C 0 o (n c 0 0 U co Co CoL 0n= W O O C 0 0 - D O : 0 0 - D Q 0 L- ~ ~ - C. = E~Co 0) 0 C0 C Co Co o (DC .C Co 0 >,- Co -- ' C 0 in.C 0. C 0 00 0 0 c 00. -- > C: (D 0 co Co .0)C CD 0. 0 C a) Co CD x 0 CLo C 09~ 0 E00 a. 00 0 0 co Ce) WO 03/072602 PCT/EPO2/50003 995 -~cu mu U0 CD cu _u m )c E -C C Cl uM~. E C ... E Cu) C~) 0 l co a) ) a ) _ 2~ M Cu 0I WC(D -~~ Cl C) 0 ml L. C - . Wu w~ Ca) w E Cu~~ CuCu U~C ME E Cu C) (D) CuE)C) C~)- ~ E~( Wou~ Co C 0 0 ) 'w c - ' lu E 0' ECl LE >1 a) Cu 'F Cu.0 o D ou Cu 0- 0 C: 0u CE Cu Cu C E E E E CL Cl) C CE C0 CuaC u. E~ Cu C 7l u Cl) CuD . ~ 0 0 Ca) W :3CF 0. 0 Cu Cu) 0 0. E o E T_ 0 = 0 -)Wo W1 to a) o 0. u 0 0W' . CuW CE E 0 CL) o~ a5 . ~ C ) < Cl) 0C~ C 2 zl l 0 0 -0 0- co 0 C x0 C ~ Cu~ ~. ~0 E C 0 Cu 0 zl Cu 0 C.) 0 C u t. Co 0 . 0 E)QCl) 0 0 E -a < 7- < ~W 0u .0 Cuf .0 C\J C14 CO CO CYO CO 0r WO 03/072602 PCT/EPO2/50003 996 0) a) r al) > 0 a C) o)~ U E ca~ .C - n a o 0 a) m) =~ -c 0 4- =1 m) m0 2. (D 0 o) a)~ C U ) ca o 0u L *. 0 - L~ ) 70 U) ~ ) 0 0 0 - E U) (n a) X0 r C) = LL "0 - l U)0 - r- o M C-.. U) U Lo'~ 0 U) 0 U) C) c j 0 ' L = O - . E Z CP V o V C.) C o Cl U) Cl) Clf * O o q c 0 0 1) 0 a) 4- U)r WE C) o- t. ~ ~ ( -- - a) U) ID M. 1) "i C . 0 C) rV U)' : - - 0 U) U) r_0 0 ) V a) Ca 0 (D En U ~ ) V U)a V 4--- U ) 75 0 C.) C - - (n a) I 90 C. C.) V M. U) a) a) 0 3 ( 0C -0 C E- CZ 0" 0" 'i) C o 0 C 5 0 .7 a) =' 0 C 4- 0M CM) C Q )CUC a)U 0 U) 0. m 4-' 2 - -"C 0 C 0 ) U U) _2 U)CL c 0 d) C 0. C.) C C V E 0. U) 0 _ C.) 4- 73 0 U _0 0 Ca 0 A- l o CD EC 8 E oE U) Z) U Lf mce) T- Co IT-O WO 03/072602 PCT/EP02/50003 997 UV E) - )a) ) -- a) _O cu C: cn)~ U) Qm a) U) 0: 0n " (n ) )A o 0 CO - - CU c U) -'-' w> -o t 0 (3) a ) 0 0 c) v CL D- T: =) LL 0 U) CL Z o o -0 E = "a 0) C) 0 C) a)5 0 E0~ E_ 2> 0, (D 0 00 0 0 E -6 0 > C) C ) (/) 0) U ) 0_- w) 0 CC0 0 C w) w M 0 E'0 CO -0 CU C 0 00 0 0 S2 E a 0 E) '- s~ o).2E m2C)C)f=-OaEcE (D E L E 0 o E -,! > cu (1 >) 0 0 E l > .q am om c a c- 0 " '-S~Pz E c co 0.o- > c~. o 5 cn . ED 75 L 00 _0 C) 0 . 0 0) L. w ~rc c * *) 0 .Z 7 U) -0 2~ E Fn0 "x CC) E x a) 0 :r_ ) C) CD~ X >) 0( E CL d) 0t5 o E (n C0 co a) C 0 ) C cu n . ) .0 co C: 0O c 0o E~ CO co a

U)-

WO 03/072602 PCT/EPO2/50003 998 0 .2 U) C: t D l CD Cn CU L0 D 0D a) (n a)- ~ -~ CD L. 4- cC a) CL) U) C t) C> wi ~E E CD 2 WDL 0. E ,- CL >) (D m c m C C -) ;-; U) 0 0 . a) > U) CwE (nC 0 F E0 0 . mo ( n. CD 0D U) C a) U D C .C D C o .2 L u a) a0= a) 0C)- 0 Co ( ED a) (D CD C CD 0CD ~C ) LIE~~2 CD 0 a)-~U C) E >) 0 , C.) o c a) a U 0 D)) Cl) U C 2~c a)c 2 (n in (D .- Cn .2- 0 0 C E D E 'E SO- a) - / 0 0 - 00 CD C C 0 0 0* CD 'CC~~<-~*9.<0 0 ~ < 0 0 0 EC E~ 75 E. -aZ E z n 0 0. (M o0 ) w i 0) L I- " c- 0 a) C 0D C 2 C = = ." .C = 6 ) 0w 0 0 0L 0 VC CL CL r_ CDc CoC 0o CD r) a)0 0 00 CD 0 . C: E) 0 2).- C E 0 0D CD a) C 0 c d) EEE c .4-. - 0 0 IC 0 0 E 0 CD E0 0 0 0) cu)- a) 0) m E 0., :t:0 0 0 - a) 0) CD X C ) c - 0 00 aD~C) c~ E ~~~C E C . C0CD . U .2 .0 CU (a CD .cu E cu CU) 0 w 0 ) 0 ca 0) WO 03/072602 PCT/EPO2/50003 999 U)) U :E E (D . U)) >)U (D a) U ) c E 7 -! U U EI co 0 m) 0C - .- u w U)~~ c) E SC 0)7 C) 4- 'CU) (n !, E 0i oa C. d ) - ) ( a) _u n ) 0- L-) C>( C U)o> -cl U) c:- C. (D- w) m ) o.. E 'n c U) 0 ~ U)(D U E :;, C) E , ) > C E c) 0) U)0 75 (- c c- 7 o- Mn oC o- O C) C 1 ca C aC o C -c0~ .2 ~ ~ > _ _ C: >, - z ,-a "a) n > U) T .2 (D _) c: C) co 0 - - C U) U) 0 U)U) .c co 5: m a- > c: C> 00 ..- m)C) C I U) CU) > 0 0 0 a.) a) o ) .2 .2 C) <I U C C .2 0 0 0 L0 _ 'D0C U)i Z ECC 0)EE i cm 0 0E U) ". w " c U 4-U v U U

-

0I 0 41 U 0) C- CL o a U) U))) C m). C vC . a. ) Q) U) ..- ~a C 00 E -0-02 U) 8 U) 0 oU) x x E r < 0 0 0 0 E 0 E (29 00 0 )< 0 X U) W )C. mC 0 01 04 0 0 C

Claims

1. A protein complex selected from complex (I) and comprising (a) at least one first protein, which first protein is selected from the group of proteins in table 1, sixth column of a given complex, or a functionally active derivative thereof, or a functionally active fragment thereof, or a homologue thereof, or a variant of said protein, the variant being, the variant being encoded by a nucleic acid that hybridizes to the nucleic acid encoding said protein under low stringency conditions; and (b) at least one second protein, which second protein is selected from the group of proteins in table 1, seventh column of said given complex, or a functionally active derivative thereof, or a functionally active fragment thereof, or a homologue thereof, or a variant of said second protein, said variant being encoded by a nucleic acid that hybridizes to the nucleic acid encoding said protein under low stringency conditions; and a complex (11) comprising at least two of said second proteins, wherein said low stringency conditions comprise hybridization in a buffer comprising 35% formamide, 5X SSC, 50 mM Tris-HCI (pH 7.5), 5 mM EDTA, 0.02% PVP, 0.02% BSA, 100 ug/ml denatured salmon sperm DNA, and 10% (wt/vol) dextran sulfate for 18-20 hours at 400C, washing in a buffer consisting of 2X SSC, 25 mM Tris-HCI (pH 7.4), 5 mM EDTA, and 0.1% SDS for 1-5 hours at 55'C, and washing in a buffer consisting of 2X SSC, 25 mM Tris-HCI (pH 7.4) 5 mM EDTA, and 0.1% SDS for 1.5 hours at 60C.

2. A protein complex comprising a first protein selected from the proteins listed in table 1, second column of a given complex or a homologue or variant thereof, or a functionally active fragment or functionally active derivative of said first protein, the variant being encoded by a nucleic acid that hybridizes to the nucleic acid of said first protein under low stringency conditions, and at least one second protein selected from the group of proteins in table 1, seventh column of a given complex, or a variant or homologue thereof, or a functionally active fragment or a functionally active derivative of said second protein, the variant of said second protein being encoded by a nucleic acid that hybridizes to the nucleic acid of said second protein under low-stringency conditions, and wherein sad low stringency conditions comprise hybridization WO 03/072602 PCT/EPO2/50003 1062 in a buffer comprising 35% formamide, 5X SSC, 50 mM Tris-HCI (pH 7.5), 5 mM EDTA, 0.02% PVP, 0.02% BSA, 100 ug/ml denatured salmon sperm DNA, and 10% (wt/vol) dextran sulfate for 18-20 hours at 400C, washing in a buffer consisting of 2X SSC, 25 mM Tris-HCI (pH 7.4), 5 mM EDTA, and 0.1% SDS for 1-5 hours at 550C, and washing in a buffer consisting of 2X SSC, 25 mM Tris-HCI (pH 7.4) 5 mM EDTA, and 0.1% SDS for 1.5 hours at 60C.

3. A protein complex comprising all proteins selected from the proteins in table 1, third column of a given complex or at least one protein being a homologue thereof, or a variant thereof or functionally active fragment or functionally active derivative of said protein, said variant being encoded by a nucleic acid that hybridizes to the nucleic acid of said protein under low stringency conditions; wherein said low stringency conditions comprise hybridization in a buffer comprising 35% formamide, 5X SSC, 50 mM Tris-HCI (pH 7.5), 5 mM EDTA, 0.02% PVP, 0.02% Ficoll, 0.2% BSA, 100 ug/ml denatured salmon sperm DNA, and 10% (wt/vol) dextran sulfate for 18-20 hours at 400C, washing in a buffer consisting of 2X SSC, 25 mM Tris-HCI (pH 7.4), 5 mM EDTA, and 0.1% SDS for 1-5 hours at 55°C, and washing in a buffer consisting of 2X SSC, 25 mM Tris-HCI (pH 7.4), 5 mM EDTA, and 0.1% SDS for 1.5 hours at 60 0 C.

4. A protein complex that comprises all proteins as listed in table 1, third column for a given complex or at least one protein being a homologue or a variant thereof, or a functionally active fragment or a functionally active derivative thereof, the variant being encoded by a nucleic acid that hybridizes to the nucleic acid of any of said proteins under low stringency conditions, except at least one protein of the proteins listed in table 1, third column, wherein said low stringency conditions comprise hybridization in a buffer comprising 35% formamide, 5X SSC, 50 mM Tris-HCI (pH 7.5), 5 mM EDTA, 0.02% PVP, 0.02% Ficoll, 0.2% BSA, 100 ug/ml denatured salmon sperm DNA, and 10% (wt/vol) dextran sulfate for 18-20 hours at 400C, washing in a buffer consisting of 2X SSC, 25 mM Tris-HCI (pH 7.4), 5 mM EDTA, and 0.1% SDS for 1-5 hours at 550C, and washing in a buffer consisting of 2X SSC, 25 mM Tris-HCI (pH 7.4), 5 mM EDTA, and 0.1% SDS for 1.5 hours at 600C, with the provisio WO 03/072602 PCT/EPO2/50003 1063 that the complex comprises at least one protein selected from table 1, seventh column of a given complex.

5. The complex of any of claims 1 - 4 comprising at least one functionally active derivative of said first protein and/or a functionally active derivative of said second protein, wherein the functionally active derivative is a fusion protein comprising said first protein or said second protein fused to an amino acid sequence different from the first protein or second protein.

6. The complex of claim 5 wherein the functionally active derivative is a fusion protein comprising said first protein or said second protein fused to an affinity tag or label.

7. The complex of any of claims 1 - 4 comprising a fragment of said first protein and/or a fragment of said second protein, which fragment binds to another protein component of said complex.

8. The complex of any of claims 1 - 7 that is involved in at least one biochemical activity as stated in table 2, column 8 for a given complex.

9. A process for preparing a complex of any of claims 1 - 8 and optionally the components thereof comprising the following steps: expressing a protein of the complex, preferably a tagged protein, in a target cell, or a tissue or an organ, isolating the protein complex which is attached to the protein, preferably the tagged protein, and optionally disassociating the protein complex and isolating the individual complex members.

10. The process according to claim 9 wherein the tagged protein comprises two different tags which allow two separate affinity purification steps.

11. The process according to any of claims 9 - 10 wherein the two tags are separated by a cleavage site for a protease.

12. Component of a protein complex obtainable by a process according to any of claims 9- 11. WO 03/072602 PCT/EPO2/50003 1064

13. Protein selected from the group of proteins in table 1, ninth column of a given complex or a homologue or a variant of thereof, or a functionally active fragment or a functionally active derivative of said protein, the variant being encoded by a nucleic acid that hybridizes to the nucleic acid encoding said protein under low stringency conditions, wherein said low stringency conditions comprise hybridization in a buffer comprising 35% formamide, 5X SSC, 50 mM Tris-HCI (pH 7.5), 5 mM EDTA, 0.02% PVP, 0.02% Ficoll, 0.2% BSA, 100 ug/ml denatured salmon sperm DNA, and 10% (wt/vol) dextran sulfate for 18-20 hours at 40 0 C, washing in a buffer consisting of 2X SSC, 25 mM Tris-HCI (pH 7.4), 5 mM EDTA, and 0.1% SDS for 1.5 hours at 550C, and washing in a buffer consisting of 2X SSC, 25 mM Tris-HCI (pH 7.4), 5 mM EDTA, and 0.1% SDS for 1.5 hours at 600C.

14. Nucleic acid encoding a protein according to claim 13.

15. Construct, preferably a vector construct, comprising (a) a nucleic acid according to claim 14 and at least one further nucleic acid which is normally not associated with said nucleic acid, or (b) at least two separate nucleic acid sequences each encoding a different protein, or a functionally active fragment or a functionally active derivative thereof, or a homologue or a variant thereof, at least one of said proteins being selected from the first group of proteins according to claim 1 (a) and at least one of said proteins, being selected from the second group of proteins according to claim I (b) or (c) at least two separate nucleic acid sequences each encoding a different protein, or a functionally active fragment or a functionally active derivative thereof, or a homologue or a variant thereof, said proteins being selected from the proteins of complex (11) according to claim 1.

16. Host cell, containing a vector comprising at least one nucleic acid of claim 14 and /or a construct of claim 15 or containing several vectors each comprising at least one nucleic acid encoding at least one protein selected from the first group of proteins according to claim 1 (a) and at least one nucleic acid WO 03/072602 PCT/EPO2/50003 1065 encoding at least one protein selected from the second group of proteins according to claim 1 (b).

17. An antibody or a fragment of said antibody containing the binding domain thereof, selected from an antibody or fragment thereof, which binds the complex of any of claims 1 - 8 and which does not bind any of the proteins of said complex when uncomplexed and an antibody or a fragment of said antibody containing the binding domain thereof which binds to any of the proteins of the group of proteins according to claim 13.

18. A kit comprising in one or more containers: (a) the complex of any of claims 1 - 8 and/or the proteins of claim 13 and/or (b) an antibody according to claim 17 and/or (c) a nucleic acid encoding a protein of the complex of any of claims 1 - 8 and/or a protein of claim 13 and/or (d) cells expressing the complex of any of claims 1 - 8 and/or a protein of claim 13 and, optionally, (e) further components such as reagents, buffers and working instructions.

19. The kit according to claim 18 for processing a substrate of a complex of any one of claims 1 - 8.

20. The kit according to claim 18 for the diagnosis or prognosis of a disease or a disease risk, preferentially for a disease or disorder as stated in table 4, third column for a given complex..

21. Array, preferably a microarray, in which at least a complex according to any of claims 1 - 8 and/or at least one protein according to claim 13 and/or at least one antibody according to claim 17 is attached to a solid carrier.

22. A process for modifying a substrate of a complex of any one of claims 1 - 8 comprising the step of bringing into contact a complex of any of claims 1 - 8 with said substrate, such that said substrate is modified. WO 03/072602 PCT/EPO2/50003 1066

23. A pharmaceutical composition comprising the protein complex of any of claims 1 - 8 and/or a protein according to claim 13.

24. A pharmaceutical composition according to claim 23 for the treatment of diseases and disorders, preferentially for diseases or disorders as stated in table 4, third column of said complex.

25. A method for screening for a molecule that binds to a complex of any one of claims 1 - 8 and/or a protein of claim 13, comprising the following steps: (a) exposing said complex or protein, or a cell or organism containing said complex or said protein, to one or more candidate molecules; and (b) determining whether said candidate molecule is bound to the complex or protein.

26. A method for screening for a molecule that modulates directly or indirectly the function, activity, composition or formation of a complex of any one of claims 1 - 8 comprising the steps of: (a) exposing said complex, or a cell or organism containing said complex to one or more candidate molecules; and (b) determining the amount of, activity of, protein components of, and/or intracellular localization of, said complex and/or the transcription level of a gene regulated by the complex and/or the abundance and/or activity of a protein or protein complex dependent upon the function of the complex and/or product of a gene dependent on the complex in the presence of the one or more candidate molecules, wherein a change in said amount, activity, protein components or intracellular localization relative to said amount, activity, protein components and/or intracellular localization and/or a change in the transcription level of a gene regulated by the complex and/or the abundance and/or activity of a protein or protein complex dependent on the function of the complex and/or product of a gene dependent on the complex in the absence of said candidate molecules indicates that the molecule modulates function, activity, or composition of said complex.

27. The method of claim 26, wherein the amount of said complex is determined. WO 03/072602 PCT/EPO2/50003 1067

28. The method of claim 26, wherein the activity of said complex is determined.

29. The method of claim 28, wherein said determining step comprises isolating from the cell or organism said complex to produce said isolated complex and contacting said isolated complex in the presence or absence of a candidate molecule with a substrate of said complex and determining whether said substrate is processed in the absence of the candidate molecule and whether the processing of said substrate is modified in the presence of said candidate molecule.

30. The method of claim 26, wherein the amount of the individual protein components of said complex is determined.

31. The method of claim 30, wherein said determining step comprises determining whether any of the proteins listed in table 1, third column of said complex, or a functionally active fragment or a functionally active derivative thereof, or a variant or a homologue thereof, the variant being encoded by a nucleic acid that hybridizes to the nucleic acid of said protein under low stringency conditions, is present in the complex.

32. The method of any of claims 26 - 31, wherein said method is a method of screening for a drug for treatment or prevention of a disease or disorder, preferentially of a disease or disorder selected from the diseases or disorders as listed in table 4, third column.

33. Use of a molecule that modulates the amount of, activity of, or the protein components of the complex of any one of claims 1 - 8 for the manufacture of a medicament for the treatment or prevention of a disease or disorder, preferentially of a disease or disorder as listed in table 4, third column.

34. A method for the production of a pharmaceutical composition comprising carrying out the method of claims 26 - 31 to identify a molecule that modulates the function, activity, composition or formation of said complex, WO 03/072602 PCT/EPO2/50003 1068 and further comprising mixing the identified molecule with a pharmaceutically acceptable carrier.

35. A method for diagnosing or screening for the presence of a disease or disorder or a predisposition for developing a disease or disorder in a subject, which disease or disorder is characterized by an aberrant amount of, component disposition of, or intracellular localization of the complex of any one of the claims 1 - 8, comprising determining the amount of, activity of, protein components of, and/or intracellular localization of, said complex and/or the transcription level of a gene regulated by the complex and/or the abundance and/or activity of a protein or protein complex dependent on the function of the complex and/or product of a gene dependent on the complex in a comparative sample derived from a subject, wherein a difference in said amount, activity, or protein components of, said complex in a corresponding sample from a subject not having the disease or disorder or predisposition indicated the presence in the subject of the disease or disorder or predisposition in the subject.

36. The method of claim 35, wherein the amount of said complex is determined.

37. The method of claim 35, wherein the activity of said complex is determined.

38. The method of claim 37, wherein said determining step comprises isolating from the cell or organism said complex to produce said isolated complex and contacting said isolated complex in the presence or absence of a candidate molecule with a substrate of said complex and determining whether said substrate is processed in the absence of the candidate molecule and whether the processing of said substrate is modified in the presence of said candidate molecule.

39. The method of claim 35, wherein the amount of the individual protein components of said complex is determined. WO 03/072602 PCT/EPO2/50003 1069

40. The method of claim 39, wherein said determining step comprises determining whether any of the proteins according to claim 13 is present in the complex.

41. The complex of any one of claims 1 - 8, or a protein of claim 13 or an antibody or fragment thereof of claim 17, for use in a method of diagnosing a disease or disorder, preferentially of a disease or disorder as listed in table 4, third column of said complex.

42. A method for treating or preventing a disease or disorder characterized by an aberrant amount of, activity of, component composition of or intracellular localization of, the complex of any one of claims 1 - 8, comprising administering to a subject in need of such treatment or prevention a therapeutically effective amount of one or more molecules that modulate the amount of, activity of, or protein corn position of, said complex.

43. The method according to claim 42, wherein said disease or disorder involves decreased levels of the amount or activity of said complex.

44. The method according to claim 42, wherein said disease or disorder involves increased levels of the amount or activity of said complex.

45. Complex of claims 1 - 8 and/or a protein as listed in table 1, seventh column of said complex as a target for an active agent of a pharmaceutical, preferably a drug target, in the treatment or prevention of a disease or disorder, preferentially of a disease or disorder as listed in table 4, third column of said complex.