WO2002086122A2

WO2002086122A2 - Protein-protein interactions in adipocytes

Info

Publication number: WO2002086122A2
Application number: PCT/EP2002/003768
Authority: WO
Inventors: Pierre Legrain; Laurent Daviet
Original assignee: Hybrigenics
Priority date: 2001-03-14
Filing date: 2002-03-14
Publication date: 2002-10-31
Also published as: AU2002304814A1; WO2002086122A3; WO2002086122A9

Abstract

The present invention relates to protein-protein interactions in adipocytes. More specifically, the present invention relates to complexes of polypeptides or polynucleotides encoding the polypeptides, fragments of the polypeptides, antiodies to the complexes. Selected Interacting Domains (SID®) which are identified due to the protein-protein interactions, methods for screening drugs for agents which modulate the interaction of proteins and pharmaceutical compositions that are capable of modulating the protein-protein interactions.

Description

MORE AND MORE PROTEIN-PROTEIN INTERACTIONS IN ADIPOCYTE CELLS

FIELD OF THE INVENTION

10. The present invention relates to proteins that interact with adipocytes. More specifically, the present invention relates to complexes of polypeptides or polynucleotides encoding the polypeptides, fragments of the polypeptides, antibodies to the complexes, Selected Interacting Domains (SID®) which are identified due to the protein-protein interactions, methods for screening drugs for agents which modulate the

15 interaction of proteins and pharmaceutical compositions that are capable of modulating the protein-protein interactions.

In another embodiment the present invention provides a protein-protein interaction map called a PIM® which is available in a report relating to the protein-protein interactions of adipocytes. 0 In yet another embodiment the present invention relates to the identification of additional proteins in the pathway common to the proteins described therein, such as metabolic pathways.

BACKGROUND 5 Most biological processes involve specific protein-protein interactions.

Protein-protein interactions enable two or more proteins to associate. A large number of non-covalent bonds form between the proteins when two protein surfaces are precisely matched. These bonds account for the specificity of recognition. Thus, protein-protein interactions are involved, for example, in the assembly of enzyme 0 subunits, in antibody-antigen recognition, in the formation of biochemical complexes, in the correct folding of proteins, in the metabolism of proteins, in the transport of proteins, in the localization of proteins, in protein turnover, in first translation modifications, in the core structures of viruses and in signal transduction.

General methodologies to identify interacting proteins or to study these 5 interactions have been developed. Among these methods are the two-hybrid system originally developed by Fields and co-workers and described, for example, in U.S. Patent Nos. 5,283,173, 5,468,614 and 5,667,973, which are hereby incorporated by reference.

The earliest and simplest two-hybrid system, which acted as basis for development of other versions, is an in vivo assay between two specifically constructed proteins. The first protein, known in the art as the "bait protein" is a chimeric protein which binds to a site on DNA upstream of a reporter gene by means of a DNA-binding domain or BD. Commonly, the binding domain is the DNA-binding domain from either Gal4 or native E. coli LexA and the sites placed upstream of the reporter are Gal4 binding sites or LexA operators, respectively. The second protein is also a chimeric protein known as the "prey" in the art. This second chimeric protein carries an activation domain or AD. This activation domain is typically derived from Gal4, from VP16 or from B42.

Besides the two hybrid systems, other improved systems have been developed to detected protein-protein interactions. For example, a two-hybrid plus one system was developed that allows the use of two proteins as bait to screen available cDNA libraries to detect a third partner. This method permits the detection between proteins that are part of a larger protein complex such as the RNA polymerase II holoenzyme and the TFIIH or TFIID complexes. Therefore, this method, in general, permits the detection of ternary complex formation as well as inhibitors preventing the interaction between the two previously defined fused proteins.

Another advantage of the two-hybrid plus one system is that it allows or prevents the formation of the transcriptional activator since the third partner can be expressed from a conditional promoter such as the methionine-repressed Met25 promoter which is positively regulated in medium lacking methionine. The presence of the methionine-regulated promoter provides an excellent control to evaluate the activation or inhibition properties of the third partner due to its "on" and "off' switch for the formation of the transcriptional activator. The three-hybrid method is described, for example in Tirade et al., The Journal of Biological Chemistry, 272, No. 37 pp. 22995-22999 (1997) incorporated herein by reference. Besides the two and two-hybrid plus one systems, yet another variant is that described in Vidal et al, Proc. Natl. Sci. 93 pgs. 10315-10320 called the reverse two- and one-hybrid systems where a collection of molecules can be screened that inhibit a specific protein-protein or protein-DNA interactions, respectively. A summary of the available methodologies for detecting protein-protein interactions is described in Vidal and Legrain, Nucleic Acids Research Vol. 27, No. 4 pgs. 919-929 (1999) and Legrain and Selig, FEBS Letters 480 pgs. 32-36 (2000) which references are incorporated herein by reference. However, the above conventionally used approaches and especially the commonly used two-hybrid methods have their drawbacks. For example, it is known in the art that, more often than not, false positives and false negatives exist in the screening method. In fact, a doctrine has been developed in this field for interpreting the results and in common practice an additional technique such as co- immunoprecipitation or gradient sedimentation of the putative interactors from the appropriate cell or tissue type are generally performed. The methods used for interpreting the results are described by Brent and Finley, Jr. in Ann. Rev. Genet, 31 pgs. 663-704 (1997). Thus, the data interpretation is very questionable using the conventional systems. One method to overcome the difficulties encountered with the methods in the prior art is described in WO99/42612, incorporated herein by reference. This method is similar to the two-hybrid system described in the prior art in that it also uses bait and prey polypeptides. However, the difference with this method is that a step of mating at least one first haploid recombinant yeast cell containing the prey polypeptide to be assayed with a second haploid recombinant yeast cell containing the bait polynucleotide is performed. Of course the person skilled in the art would appreciate that either the first recombinant yeast cell or the second recombinant yeast cell also contains at least one detectable reporter gene that is activated by a polypeptide including a transcriptional activation domain. The method described in WO99/42612 permits the screening of ιore prey polynucleotides with a given bait polynucleotide in a single step than in the prior art systems due to the cell to cell mating strategy between haploid yeast cells. Furthermore, this method is more thorough and reproducible, as well as sensitive. Thus, the presence of false negatives and/or false positives is extremely minimal as compared to the conventional prior art methods.

The causes of non-insulin dependent diabetes mellitus (NIDDM) and obesity are often related to defects or problems with adipose tissue. Adipocytes play a critipal role in lipid storage and metabolism. Adipocytes also act as endocrine cells to influence physiological parameters such as insulin sensitivity and body weight (Flier, et al., Cell, (1995) 80: 15-18). For example, the ob gene encodes leptin, an adipocyte secreted endocrine factor (Zhang, et al., Nature (1994) 372: 425-432). Leptin has been shown to reduce body weight and blood glucose in obese, diabetic rodents (Pelleymounter, et al., Science, (1995) 269: 540-543).

NIDDM is treated predominately with insulin. However, insulin is not convenient to use in that it must be injected 2-4 times per day and must be stored properly to prevent loss of efficacy. Other drugs used to treat NIDDM include troglitazone (" Rezulin"), a PPARY agonist, Glucophage and sulfonylureas. Unfortunately, there are safety concerns related to the use of these drugs. The identification of safe, effective, orally available drugs for the treatment of NIDDM would greatly enhance the quality of life of patients who suffer from this disease.

Several adipocyte-specific enzymes and receptors have been shown to be important targets for anti-obesity and anti-diabetic drug discovery. For example, agonists of the β3 adrenergic receptor, which is found predominantly in the adipose tissue in man (Arner, et al., New England Journal of Medicine, (1995) 333: 382-383), have anti-obesity and anti-diabetic properties in rodents and are currently in phase I l/l 11 trials in man. The thiazolidinedione class of compounds (TZDs), including troglitazone and ciglitazone, has been shown to improve insulin sensitivity and thereby reduce hyperglycemia and hyperlipidemia conditions in rodents and in humans (Saltiel, et al., Diabetes, (1996) 45: 1661-1669; Sreenan, et al., American Journal Physiol, (1996) 271 : E742-E747; Nolan, etal., New England Journal of Medicine, (1994) 331 : 1 188-1 193. Troglitazone (" Rezulin") is approved for use in the U. S. and Japan. Many TZDs, including troglitazone and ciglitazone, are potent activators of Peroxisome Proliferator Activated Receptor gamma (PPARy), a member of the nuclear receptor family of transcription factors (Tontonoz, etal., Cell, (1994) 79: 1 147-1 156; Lehmann, etal., Journal of Biological Chemistry, (1995) 270: 12953- 12955). PPARB, is a key regulator of adipocyte differentiation and is most abundant in adipose tissue. This shows that it is still needed to explore all mechanisms of adipocyte differentiation and to identify drug targets for metabolism diseases.

The adipocytes (differentiated PAZ6 adipocytes) studied in the present invention are obtained by the method described in the PCT patent application WO96/34100. SUMMARY OF THE INVENTION

The present invention relates to identifying protein-protein interactions in adipocytes.

The present invention also relates to identifying protein-protein interactions in adipocytes for the development of more effective and better targeted therapeutic applications.

The present invention is also aimed at identifying complexes of polypeptides or polynucleotides encoding the polypeptides and fragments of the polypeptides of adipocytes.

The present invention also relates to identifying antibodies to these complexes of polypeptides or polynucleotides encoding the polypeptides and fragments of the polypeptides of adipocytes including polyclonal, as well as monoclonal antibodies that are used for detection.

The present invention also concerns the identification of selected interacting domains of the polypeptides, called SID® polypeptides.

Furthermore, the present invention concerns the identification of selected interacting domains of the polynucleotides, called SID® polynucleotides. Also, the present invention relates to generating protein-protein interaction maps called PIM®s.

The present invention also provides a method for screening drugs for agents which modulate the interaction of proteins and pharmaceutical compositions that are capable of modulating the protein-protein interactions in adipocytes. The present invention also relates to administering the nucleic acids of the present invention via gene therapy.

Also, the present invention provides protein chips or protein microarrays. In another embodiment, the present invention provides a report in, for example paper, electronic and/or digital forms, concerning the protein-protein interactions, the modulating compounds and the like as well as a PIM®.

BRIEF DESCRIPTION OF THE DRAWINGS Fig. 1 is a schematic representation of the pB1 plasmid. Fig. 2 is a schematic representation of the pB5 plasmid. Fig. 3 is a schematic representation of the pB6 plasmid.

Fig. 4 is a schematic representation of the pB13 plasmid.

Fig. 5 is a schematic representation of the pB14 plasmid.

Fig. 6 is a schematic representation of the pB20 plasmid. Fig. 7 is a schematic representation of the pP1 plasmid.

Fig. 8 is a schematic representation of the pP2 plasmid.

Fig. 9 is a schematic representation of the pP3 plasmid.

Fig. 10 is a schematic representation of the pP6 plasmid.

Fig. 11 is a schematic representation of the pP7 plasmid. Fig. 12 is a schematic representation of vectors expressing the T25 fragment.

Fig. 13 is a schematic representation of vectors expressing the T18 fragment.

Fig. 14 is a schematic representation of various vectors of pCmAHLI , pT25 and pT18.

Fig. 15 is a schematic representation identifying the SID®'s of adipocytes. In this figure the "Full-length prey protein" is the Open Reading Frame (ORF) or coding sequence (CDS) where the identified prey polypeptides are included. The Selected

Interaction Domain (SID®) is determined by the commonly shared polypeptide domain of every selected prey fragment.

Fig. 16 is a protein map (PIM®).

DETAILED DESCRIPTION OF THE PREFERRED EMBODIMENTS

As used herein the terms "polynucleotides", "nucleic acids" and

"oligonucleotides" are used interchangeably and include, but are not limited to RNA, DNA, RNA/DNA sequences of more than one nucleotide in either single chain or duplex form. The polynucleotide sequences of the present invention may be prepared from any known method including, but not limited to, any synthetic method, any recombinant method, any ex vivo generation method and the like, as well as combinations thereof. Polynucleotides which can hybridize to any of the polynucleotides discussed above are also covered by the present invention. Such polynucleotides are referred to herein as "hybridizing" polynucleotides. Hybridizing polynucleotides can be useful as probes or primers, for example. According to an embodiment of the present invention, such hybridizing molecules are at least 10 nucleotides in length. According to another embodiment, such hybridizing molecules are at least 25 or at least 50 nucleotides in length.

In an embodiment, the hybridizing molecules will hybridize to any of the polynucleotides of the present invention under stringent hybridization conditions. One example of stringent hybridization conditions is where attempted hybridization is carried out at a temperature of from about 35°C to about 65°C using a salt solution which is about 0.9 molar. However, the skilled person will be able to vary such conditions as appropriate in order to take into account variables such as probe length, base composition, type of ions present, etc.

The term "polypeptide" means herein a polymer of amino acids having no specific length. Thus, peptides, oligopeptides and proteins are included in the definition of "polypeptide" and these terms are used interchangeably throughout the specification, as well as in the claims. The term "polypeptide" does not exclude post- translational modifications such as polypeptides having covalent attachment of glycosyl groups, aceteyl groups, phosphate groups, lipid groups and the like. Also encompassed by this definition of "polypeptide" are homologs thereof.

By the term "homologs" is meant structurally similar genes contained within a given species, orthologs are functionally equivalent genes from a given species or strain, as determined for example, in a standard complementation assay. Thus, a polypeptide of interest can be used not only as a model for identifying similiar genes in given strains, but also to identify homologs and orthologs of the polypeptide of interest in other species. The orthologs, for example, can also be identified in a conventional complementation assay. In addition or alternatively, such orthologs can be expected to exist in bacteria (or other kind of cells) in the same branch of the phylogenic tree, as set forth, for example, at ftp://ftp.cme.msu.edu/pub/rdp/SSU- rRNA/SSU/Prok.phylo.

As used herein the term "prey polynucleotide" means a chimeric polynucleotide encoding a polypeptide comprising (i) a specific domain; and (ii) a polypeptide that is to be tested for interaction with a bait polypeptide. The specific domain is preferably a transcriptional activating domain.

As used herein, a "bait polynucleotide" is a chimeric polynucleotide encoding a chimeric polypeptide comprising (i) a complementary domain; and (ii) a polypeptide that is to be tested for interaction with at least one prey polypeptide. The complementary domain is preferably a DNA-binding domain that recognizes a binding site that is further detected and is contained in the host organism.

As used herein "complementary domain" is meant a functional constitution of the activity when bait and prey are interacting; for example, enzymatic activity.

As used herein "specific domain" is meant a functional interacting activation domain that may work through different mechanisms by interacting directly or indirectly through intermediary proteins with RNA polymerase II or Ill-associated proteins in the vicinity of the transcription start site. As used herein the term "complementary" means that, for example, each base of a first polynucleotide is paired with the complementary base of a second polynucleotide whose orientation is reversed. The complementary bases are A and T (or A and U) or C and G.

The term "sequence identity" refers to the identity between two peptides or between two nucleic acids. Identity between sequences can be determined by comparing a position in each of the sequences which may be aligned for the purposes of comparison. When a position in the compared sequences is occupied by the same base or amino acid, then the sequences are identical at that position. A degree of sequence identity between nucleic acid sequences is a function of the number of identical nucleotides at positions shared by these sequences. A degree of identity between amino acid sequences is a function of the number of identical amino acid sequences that are shared between these sequences. Since two polypeptides may each (i) comprise a sequence (i.e., a portion of a complete polynucleotide sequence) that is similar between two polynucleotides, and (ii) may further comprise a sequence that is divergent between two polynucleotides, sequence identity comparisons between two or more polynucleotides over a "comparison window" refers to the conceptual segment of at least 20 contiguous nucleotide positions wherein a polynucleotide sequence may be compared to a reference nucleotide sequence of at least 20 contiguous nucleotides and wherein the portion of the polynucleotide sequence in the comparison window may comprise additions or deletions (i.e., gaps) of 20 percent or less compared to the reference sequence (which does not comprise additions or deletions) for optimal alignment of the two sequences. To determine the percent identity of two amino acids sequences or two nucleic acid sequences, the sequences are aligned for optimal comparison. For example, gaps can be introduced in the sequence of a first amino acid sequence or a first nucleic acid sequence for optimal alignment with the second amino acid sequence or second nucleic acid sequence. The amino acid residues or nucleotides at corresponding amino acid positions or nucleotide positions are then compared. When a position in the first sequence is occupied by the same amino acid residue or nucleotide as the corresponding position in the second sequence, the molecules are identical at that position. The percent identity between the two sequences is a function of the number of identical positions shared by the sequences. Hence % identity = number of identical positions / total number of overlapping positions X 100.

In this comparison the sequences can be the same length or can be different in length. Optimal alignment of sequences for determining a comparison window may be conducted by the local homology algorithm of Smith and Waterman (J. Theor.

Biol., 91 (2) pgs. 370-380 (1981 ), by the homology alignment algorithm of Needleman and Wunsch, J. Miol. Biol., 48(3) pgs. 443-453 (1972), by the search for similarity via the method of Pearson and Lipman, PNAS, USA, 85(5) pgs. 2444-2448 (1988), by computerized implementations of these algorithms (GAP, BESTFIT, FASTA and TFASTA in the Wisconsin Genetics Software Package Release 7.0,

Genetic Computer Group, 575, Science Drive, Madison, Wisconsin) or by inspection. The best alignment (i.e., resulting in the highest percentage of identity over the comparison window) generated by the various methods is selected.

The term "sequence identity" means that two polynucleotide or polypeptide sequences are identical (i.e., on a nucleotide by nucleotide or an amino acid by amino acid basis) over the window of comparison. The term "percentage of sequence identity" is calculated by comparing two optimally aligned sequences over the window of comparison, determining the number of positions at which the identical nucleic acid base (e.g., A, T, C, G, U, or I) occurs in both sequences to yield the number of matched positions, dividing the number of matched positions by the total number of positions in the window of comparison (i.e., the window size) and multiplying the result by 100 to yield the percentage of sequence identity. The same process can be applied to polypeptide sequences. The percentage of sequence identity of a nucleic acid sequence or an amino acid sequence can also be calculated using BLAST software (Version 2.06 of September 1998) with the default or user defined parameter.

The term "sequence similarity" means that amino acids can be modified while retaining the same function. It is known that amino acids are classified according to the nature of their side groups and some amino acids such as the basic amino acids can be interchanged for one another while their basic function is maintained.

The term "isolated" as used herein means that a biological material such as a nucleic acid or protein has been removed from its original environment in which it is naturally present. For example, a polynucleotide present in a plant, mammal or animal is present in its natural state and is not considered to be isolated. The same polynucleotide separated from the adjacent nucleic acid sequences in which it is naturally inserted in the genome of the plant or animal is considered as being "isolated." The term "isolated" is not meant to exclude artificial or synthetic mixtures with other compounds, or the presence of impurities which do not interfere with the biological activity and which may be present, for example, due to incomplete purification, addition of stabilizers or mixtures with pharmaceutically acceptable excipients and the like. "Isolated polypeptide" or "isolated protein" as used herein means a polypeptide or protein which is substantially free of those compounds that are normally associated with the polypeptide or protein in a naturally state such as other proteins or polypeptides, nucleic acids, carbohydrates, lipids and the like.

The term "purified" as used herein means at least one order of magnitude of purification is achieved, preferably two or three orders of magnitude, most preferably four or five orders of magnitude of purification of the starting material or of the natural material. Thus, the term "purified" as utilized herein does not mean that the material is 100% purified and thus excludes any other material.

The term "variants" when referring to, for example, polynucleotides encoding a polypeptide variant of a given reference polypeptide are polynucleotides that differ from the reference polypeptide but generally maintain their functional characteristics of the reference polypeptide. A variant of a polynucleotide may be a naturally occurring allelic variant or it may be a variant that is known naturally not to occur. Such non-naturally occurring variants of the reference polynucleotide can be made by, for example, mutagenesis techniques, including those mutagenesis techniques that are applied to polynucleotides, cells or organisms.

Generally, differences are limited so that the nucleotide sequences of the reference and variant are closely similar overall and, in many regions identical.

Variants of polynucleotides according to the present invention include, but are not limited to, nucleotide sequences which are at least 95% identical after alignment to the reference polynucleotide encoding the reference polypeptide. These variants can also have 96%, 97% 98% and 99.999% sequence identity to the reference polynucleotide.

Nucleotide changes present in a variant polynucleotide may be silent, which means that these changes do not alter the amino acid sequences encoded by the reference polynucleotide.

Substitutions, additions and/or deletions can involve one or more nucleic acids. Alterations can produce conservative or non-conservative amino acid substitutions, deletions and/or additions.

Variants of a prey or a SID® polypeptide encoded by a variant polynucleotide can possess a higher affinity of binding and/or a higher specificity of binding to its protein or polypeptide counterpart, against which it has been initially selected. In another context, variants can also loose their ability to bind to their protein or polypeptide counterpart.

By "fragment of a polynucleotide" or "fragment of a SID® polynucleotide" is meant that fragments of these sequences have at least 12 consecutive nucleotides, or between 12 and 5,000 consecutive nucleotides, or between 12 and 10,000 consecutive nucleotides, or between 12 and 20,000 consecutive nucleotides.

By "fragment of a polypeptide" or "fragment of a SID® polypeptide" is meant that fragments of these sequences have at least 4 consecutive amino acids, or between 4 and1 ,700 consecutive amino acids, or between 4 and 3,300 consecutive amino acids, or between 4 and 6,600 consecutive amino acids. By "anabolic pathway" is meant a reaction or series of reactions in a metabolic pathway that synthesize complex molecules from simpler ones, usually requiring the input of energy. An anabolic pathway is the opposite of a catabolic pathway. As used herein, a "catabolic pathway" is a series of reactions in a metabolic pathway that break down complex compounds into simpler ones, usually releasing energy in the process. A catabolic pathway is the opposite of an anabolic pathway.

As used herein, "drug metabolism" is meant the study of how drugs are processed and broken down by the body. Drug metabolism can involve the study of enzymes that break down drugs, the study of how different drugs interact within the body and how diet and other ingested compounds affect the way the body processes drugs.

As used herein, "metabolism" means the sum of all of the enzyme-catalyzed reactions in living cells that transform organic molecules.

By "secondary metabolism" is meant pathways producing specialized metabolic products that are not found in every cell.

As used herein, "SID®" means a Selected Interacting Domain and is identified as follows: for each bait polypeptide screened, selected prey polypeptides are compared. Overlapping fragments in the same ORF or CDS define the selected interacting domain.

As used herein the term "PIM®" means a protein-protein interaction map. This map is obtained from data acquired from a number of separate screens using different bait polypeptides and is designed to map out all of the interactions between the polypeptides.

The term "affinity of binding", as used herein, can be defined as the affinity constant Ka when a given SID® polypeptide of the present invention which binds to a polypeptide and is the following mathematical relationship:

[SID®/polypeptide complex] Ka =

[free SID®] [free polypeptide] herein [free SID®], [free polypeptide] and [SID®/polypeptide complex] consist of the concentrations at equilibrium respectively of the free SID® polypeptide, of the free polypeptide onto which the SID® polypeptide binds and of the complex formed between SID® polypeptide and the polypeptide onto which said SID® polypeptide specifically binds.

The affinity of a SID® polypeptide of the present invention or a variant thereof for its polypeptide counterpart can be assessed, for example, on a Biacore™ apparatus marketed by Amersham Pharmacia Biotech Company such as described by Szabo et al. (Curr Opin Struct Bio\ 5 pgs. 699-705 (1995)) and by Edwards and Leartherbarrow (Anal. Biochem 246 pgs. 1 -6 (1997)).

As used herein the phrase "at least the same affinity" with respect to the binding affinity between a SID® polypeptide of the present invention to another polypeptide means that the Ka is identical or can be at least two-fold, at least three-fold or at least five fold greater than the Ka value of reference.

As used herein, the term "modulating compound" means a compound that inhibits or stimulates or csn act on another protein which can inhibit or stimulate the protein-protein interaction of a complex of at least two polypeptides or the protein- protein interaction of at least two polypeptides.

More specifically, the present invention comprises complexes of polypeptides or polynucleotides encoding the polypeptides composed of a bait polypeptide, or a bait polynucleotide encoding a bait polypeptide and a prey polypeptide or a prey polynucleotide encoding a prey polypeptide. The prey polypeptide or prey polynucleotide encoding the prey polypeptide is capable of interacting with a bait polypeptide of interest in various hybrid systems.

As described in the Background of the present invention, there are various methods known in the art to identify prey polypeptides that interact with bait polypeptides of interest. These methods include, but are not limited to, generic two- hybrid systems as described by Fields et al. (Nature, 340:245-246 (1989)) and more specifically in U.S. Patent Nos. 5,283,173, 5,468,614 and 5,667,973, which are hereby incorporated by reference; the reverse two-hybrid system described by Vidal et al. (supra); the two plus one hybrid method described, for example, in Tirade et al. (supra); the yeast forward and reverse 'n'-hybrid systems as described in Vidal and

Legrain (supra); the method described in WO 99/42612; those methods described in Legrain et al. (FEBS Letters 480 pgs. 32-36 (2000)) and the like.

The present invention is not limited to the type of method utilized to detect protein-protein interactions and therefore any method known in the art and variants thereof can be used. It is however better to use the method described in

WO99/42612 or WO00/66722, both references incorporated herein by reference due to the methods' sensitivity, reproducibility and reliability. Protein-protein interactions can also be detected using complementation assays such as those described by Pelletier et al. at http://www.abrf.org/JBT/Articles/JBT0012/ibt0012.html. WO 00/07038 and WO98/34120. Although the above methods are described for applications in the yeast system, the present invention is not limited to detecting protein-protein interactions using yeast, but also includes similar methods that can be used in detecting protein-protein interactions in, for example, mammalian systems as described, for example in Takacs et al. (Proc. Natl. Acad. Sci., USA, 90 (21 ): 10375-79 (1993)) and Vasavada et al. (Proc. Natl. Acad. Sci., USA, 88 (23): 10686-90 (1991 )), as well as a bacterial two-hybrid system as described in Karimova et al. (1998), WO99/28746, WO

00/66722 and Legrain et al. (FEBS Letters, 480 pgs. 32-36 (2000)).

The above-described methods are limited to the use of yeast, mammalian cells and Escherichia coli cells, the present invention is not limited in this manner. Consequently, mammalian and typically human cells, as well as bacterial, yeast, fungus, insect, nematode and plant cells are encompassed by the present invention and may be transfected by the nucleic acid or recombinant vector as defined herein. Examples of suitable cells include, but are not limited to, VERO cells, HELA cells such as ATCC No. CCL2, CHO cell lines such as ATCC No. CCL61 , COS cells such as COS-7 cells and ATCC No. CRL 1650 cells, W138, BHK, HepG2, 3T3 such as ATCC No. CRL6361 , A549, PC12, K562 cells, 293 cells, Sf9 cells such as ATCC No.

CRL171 1 and Cv1 cells such as ATCC No. CCL70.

Other suitable cells that can be used in the present invention include, but are not limited to, prokaryotic host cells strains such as Escherichia coli, (e.g., strain DH5-α), Bacillus subtilis, Salmonella typhimurium, or strains of the genera of Pseudomonas, Streptomyces and Staphylococcus.

Further suitable cells that can be used in the present invention include yeast cells such as those of Saccharomyces such as Saccharomyces cerevisiae.

The bait polynucleotide, as well as the prey polynucleotide can be prepared according to the methods known in the art such as those described above in the publications and patents reciting the known method per se.

The bait and the prey polynucleotide of the present invention is obtained from adipocyte's cDNA (human differentiated PAZ6 adipocytes), or variants of cDNA fragment from a library of human differentiated PAZ6 adipocytes, and fragments from the genome or transcriptome of human differentiated PAZ6 adipocytes ranging from about 12 to about 5,000, or about 12 to about 10,000 or from about 12 to about 20,000. The prey polynucleotide is then selected, sequenced and identified.

A human differentiated PAZ6 adipocytes prey library is prepared from the human differentiated PAZ6 adipocytes and constructed in the specially designed prey vector pP6 as shown in Figure 10 after ligation of suitable linkers such that every cDNA insert is fused to a nucleotide sequence in the vector that encodes the transcription activation domain of a reporter gene. Any transcription activation domain can be used in the present invention. Examples include, but are not limited to, Gal4,YP16, B42, His and the like. Toxic reporter genes, such as CAT^R, CYH2, CYH1 , URA3, bacterial and fungi toxins and the like can be used in reverse two-hybrid systems.

The polypeptides encoded by the nucleotide inserts of the human differentiated PAZ6 adipocytes prey library thus prepared are termed "prey polypeptides" in the context of the presently described selection method of the prey polynucleotides. The bait polynucleotides can be inserted in bait plasmid pB6 or pB5 as illustrated in Figures 3 and 2, respectively.. The bait polynucleotide insert is fused to a polynucleotide encoding the binding domain of, for example, the Gal4 DNA binding domain and the shuttle expression vector is used to transform cells.

The bait polynucleotides used in the present invention are described in Table 1. As stated above, any cells can be utilized in transforming the bait and prey polynucleotides of the present invention including mammalian cells, bacterial cells, yeast cells, insect cells and the like.

In an embodiment, the present invention identifies protein-protein interactions in yeast. In using known methods a prey positive clone is identified containing a vector which comprises a nucleic acid insert encoding a prey polypeptide which binds to a bait polypeptide of interest. The method in which protein-protein interactions are identified comprises the following steps: mating at least one first haploid recombinant yeast cell clone from a recombinant yeast cell clone library that has been transformed with a plasmid containing the prey polynucleotide to be assayed with a second haploid recombinant yeast cell clone transformed with a plasmid containing a bait polynucleotide encoding for the bait polypeptide; cultivating diploid cell clones obtained in step i) on a selective medium; and selecting recombinant cell clones which grow on the selective medium. This method may further comprise the step of: characterizing the prey polynucleotide contained in each recombinant cell clone which is selected in step iii). In yet another embodiment of the present invention, in lieu of yeast, Escherichia coli is used in a bacterial two-hybrid system, which encompasses a similar principle to that described above for yeast, but does not involve mating for characterizing the prey polynucleotide.

In yet another embodiment of the present invention, mammalian cells and a method similar to that described above for yeast for characterizing the prey polynucleotide are used.

By performing the yeast, bacterial or mammalian two-hybrid system, it is possible to identify for one particular bait an interacting prey polypeptide. The prey polynucleotide that has been selected by testing the library of preys in a screen using the two-hybrid, two plus one hybrid methods and the like, encodes the polypeptide interacting with the protein of interest.

The present invention is also directed, in a general aspect, to a complex of polypeptides, polynucleotides encoding the polypeptides composed of a bait polypeptide or bait polynucleotide encoding the bait polypeptide and a prey polypeptide or prey polynucleotide encoding the prey polypeptide capable of interacting with the bait polypeptide of interest. These complexes are identified in Table 2.

In another aspect, the present invention relates to a complex of polynucleotides consisting of a first polynucleotide, or a fragment thereof, encoding a prey polypeptide that interacts with a bait polypeptide and a second polynucleotide or a fragment thereof. This fragment has at least 12 consecutive nucleotides, but can have between 12 and 5,000 consecutive nucleotides, or between 12 and 10,000 consecutive nucleotides or between 12 and 20,000 consecutive nucleotides.

The complexes of the two interacting polypeptides listed in Table 2 and the sets of two polynucleotides encoding these polypeptides also form part of the present invention.

In yet another embodiment, the present invention relates to an isolated complex of at least two polypeptides encoded by two polynucleotides wherein said two polypeptides are associated in the complex by affinity binding and are depicted in columns 1 and 4 of Table 2.

In yet another embodiment, the present invention relates to an isolated complex comprising at least a polypeptide as described in column 1 of Table 2 and a polypeptide as described in column 4 of Table 2. The present invention is not limited to these polypeptide complexes alone but also includes the isolated complex of the two polypeptides in which fragments and/or homologous polypeptides exhibit at least 95% sequence identity, as well as from 96% sequence identity to 99.999% sequence identity. Also encompassed in another embodiment of the present invention is an isolated complex in which the SID® of the prey polypeptides encoded by SEQ ID Nos. 34 to 771 in Table 3 form the isolated complex.

Besides the isolated complexes described above, nucleic acids coding for a Selected Interacting Domain (SID®) polypeptide or a variant thereof or any of the nucleic acids set forth in Table 3 can be inserted into an expression vector which contains the necessary elements for the transcription and translation of the inserted protein-coding sequence. Such transcription elements include a regulatory region and a promoter. Thus, the nucleic acid which may encode a marker compound of the present invention is operably linked to a promoter in the expression vector. The expression vector may also include a replication origin.

A wide variety of host/expression vector combinations are employed in expressing the nucleic acids of the present invention. Useful expression vectors that can be used include, for example, segments of chromosomal, non-chromosomal and synthetic DNA sequences. Suitable vectors include, but are not limited to, derivatives of SV40 and pcDNA and known bacterial plasmids such as col El, pCR1 , pBR322, pMal-C2, pET, pGEX as described by Smith et al [need cite 1988], pMB9 and derivatives thereof, plasmids such as RP4, phage DNAs such as the numerous derivatives of phage I such as NM989, as well as other phage DNA such as M13 and filamentous single stranded phage DNA; yeast plasmids such as the 2 micron plasmid or derivatives of the 2m plasmid, as well as centomeric and integrative yeast shuttle vectors; vectors useful in eukaryotic cells such as vectors useful in insect or mammalian cells; vectors derived from combinations of plasmids and phage DNAs, such as plasmids that have been modified to employ phage DNA or the expression control sequences; and the like.

For example in a baculovirus expression system, both non-fusion transfer vectors, such as, but not limited to pVL941 (SamHI cloning site Summers, pVL1393 (SamHI, Smal, Xbal, EcoRI, Notl, Xmalll, βgrlll and Pst\ cloning sites; Invitrogen) pVL1392 (Sgflll, Psfl, Notl, Xmalll, EcoRI, Xbal\, Sma\ and SamHI cloning site; Summers and Invitrogen) and pBlueSaclll (SamHI, BglW, Pst\, Λ/col and Hindltt cloning site, with blue/white recombinant screening, Invitrogen), and fusion transfer vectors such as, but not limited to, pAc700(SamHI and Kpn\ cloning sites, in which the SamHI recognition site begins with the initiation codon; Summers), pAc701 and pAc70-2 (same as pAc700, with different reading frames), pAc360 (SamHI cloning site 36 base pairs downstream of a polyhedrin initiation codon; Invitrogen (195)) and pBlueBacHisA, B, C ( three different reading frames with SamHI, BglW, Pst\, A/col and Hindlll cloning site, an N-terminal peptide for ProBond purification and blue/white recombinant screening of plaques; Invitrogen (220) can be used.

Mammalian expression vectors contemplated for use in the invention include vectors with inducible promoters, such as the dihydrofolate reductase promoters, any expression vector with a DHFR expression cassette or a DHFR/methotrexate co- amplification vector such as pED (Pst\, Sal\, Sbal, Smal and EcoRI cloning sites, with the vector expressing both the cloned gene and DHFR; Kaufman, 1991 ).

Alternatively a glutamine synthetase/methionine sulfoximine co-amplification vector, such as pEE14 (HindWl, Xbal\, Smal, Sbal, EcoRI and Sc/I cloning sites in which the vector expresses glutamine synthetase and the cloned gene; Celltech). A vector that directs episomal expression under the control of the Epstein Barr Virus (EBV) or nuclear antigen (EBNA) can be used such as pREP4 (SamHI, S 7I, Xnol, Notl, Nhel,

HindWl, Nhel, Pvull and Kpnl cloning sites, constitutive RSV-LTR promoter, hygromycin selectable marker; Invitrogen) pCEP4 (SamHI, Sfil, Xhol, Noil, Nhel, Hindlll, Nhel, Pvull and Kpnl cloning sites, constitutive hCMV immediate early gene promoter, hygromycin selectable marker; Invitrogen), pMEP4 (Kpnl, Pvul, Nhel, Hindlll, Notl, Xhol, Sfil, SamHI cloning sites, inducible methallothionein Ila gene promoter, hygromycin selectable marker, Invitrogen), pREP8 (SamHI, Xhol, Notl, Hindlll, Nhel and Kpnl cloning sites, RSV-LTR promoter, histidinol selectable marker; Invitrogen), pREP9 (Kpnl, Nhel, Hindlll, Notl, Xhol, Sfil, SamHI cloning sites, RSV- LTR promoter, G418 selectable marker; Invitrogen), and pEBVHis (RSV-LTR promoter, hygromycin selectable marker, N-terminal peptide purifiable via ProBond resin and cleaved by enterokinase; Invitrogen).

Selectable mammalian expression vectors for use in the invention include, but are not limited to, pRc/CMV (HindWl, BstXl, Notl, Sbal and Apal cloning sites, G418 selection, Invitrogen), pRc/RSV (Hindll, Spel, BstXl, Notl, Xbal cloning sites, G418 selection, Invitrogen) and the like. Vaccinia virus mammalian expression vectors (see, for example Kaufman 1991 that can be used in the present invention include, but are not limited to, pSC1 1 (Smal cloning site, TK- and β-gal selection), pMJ601 (Sail, Smal, Afll, Naή, BspMII, SamHI, Apal, Nhel, Sacll, Kpnl and Hindlll cloning sites; TK- and β-gal selection), pTKgptFI S (EcoRI, Pstl, Salll, Accl, Hindll, Sbal, SamHI and Hpa cloning sites, TK or XPRT selection) and the like.

Yeast expression systems that can also be used in the present include, but are not limited to, the non-fusion pYES2 vector (Xbal, Sphl, Shol, Notl, GstXl, EcoRI, BstXl, SamHI, Sacl, Kpnl and Hindlll cloning sites, Invitrogen), the fusion pYESHisA,

B, C (Xball, Sphl, Shol, Notl, BstXl, EcoRI, SamHI, Sacl, Kpnl and Hindlll cloning sites, N-terminal peptide purified with ProBond resin and cleaved with enterokinase; Invitrogen), pRS vectors and the like.

Consequently, mammalian and typically human cells, as well as bacterial, yeast, fungi, insect, nematode and plant cells an used in the present invention and may be transfected by the nucleic acid or recombinant vector as defined herein.

Examples of suitable cells include, but are not limited to, VERO cells, HELA cells such as ATCC No. CCL2, CHO cell lines such as ATCC No. CCL61 , COS cells such as COS-7 cells and ATCC No. CRL 1650 cells, W138, BHK, HepG2, 3T3 such as ATCC No. CRL6361 , A549, PC12, K562 cells, 293 cells, Sf9 cells such as ATCC No.

CRL171 1 and Cv1 cells such as ATCC No. CCL70.

Further suitable cells that can be used in the present invention include yeast cells such as those of Saccharomyces such as Saccharomyces cerevisiae. Besides the specific isolated complexes, as described above, the present invention relates to and also encompasses SID® polynucleotides. As explained above, for each bait polypeptide, several prey polypeptides may be identified by comparing and selecting the intersection of every isolated fragment that are included in the same polypeptide. Thus the SID® polynucleotides of the present invention are represented by the shared nucleic acid sequences of SEQ ID Nos. 34 to 771 encoding the SID® polypeptides of SEQ ID Nos. 772 to 1509 in columns 5 and 7 of Table 3, respectively.

The present invention is not limited to the SID® sequences as described in the above paragraph, but also includes fragments of these sequences having at least 12 consecutive nucleic acids, between 12 and 5,000 consecutive nucleic acids and between 12 and 10,000 consecutive nucleic acids and between 12 and 20,000 consecutive nucleic acids, as well as variants thereof. The fragments or variants of the SID® sequences possess at least the same affinity of binding to its protein or polypeptide counterpart, against which it has been initially selected. Moreover this variant and/or fragments of the SID® sequences alternatively can have between 95% and 99.999% sequence identity to its protein or polypeptide counterpart.

According to the present invention variants of polynucleotide or polypeptides can be created by known mutagenesis techniques either in vitro or in vivo. Such a variant can be created such that it has altered binding characteristics with respect to the target protein and more specifically that the variant binds the target sequence with either higher or lower affinity.

Polynucleotides that are complementary to the above sequences which include the polynucleotides of the SID®'s, their fragments, variants and those that have specific sequence identity are also included in the present invention.

The polynucleotide encoding the SID® polypeptide, fragment or variant thereof can also be inserted into recombinant vectors which are described in detail above.

The present invention also relates to a composition comprising the above- mentioned recombinant vectors containing the SID® polynucleotides in Table 3, fragments or variants thereof, as well as recombinant host cells transformed by the vectors. The recombinant host cells that can be used in the present invention were discussed in greater detail above. The compositions comprising the recombinant vectors can contain physiological acceptable carriers such as diluents, adjuvants, excipients and any vehicle in which this composition can be delivered therapeutically and can include, but is are not limited to sterile liquids such as water and oils. In yet another embodiment, the present invention relates to a method of selecting modulating compounds, as well as the modulating molecules or compounds themselves which may be used in a pharmaceutical composition. These modulating compounds may act as a cofactor, as an inhibitor, as antibodies, as tags, as a competitive inhibitor, a? an activator or alternatively have agonistic or antagonistic activity on the protein-protein interactions.

The activity of the modulating compound does not necessarily, for example, have to be 100% activation or inhibition. Indeed, even partial activation or inhibition can be achieved that is of pharmaceutical interest.

The modulating compound can be selected according to a method which comprises: cultivating a recombinant host cell with a modulating compound on a selective medium and a reporter gene the expression of which is toxic for said recombinant host cell wherein said recombinant host cell is transformed with two vectors: wherein said first vector comprises a polynucleotide encoding a first hybrid polypeptide having a DNA binding domain; wherein said second vector comprises a polynucleotide encoding a second hybrid polypeptide having a transcriptional activating domain that activates said toxic reporter gene when the first and second hybrid polypeptides interact; selecting said modulating compound which inhibits or permits the growth of said recombinant host cell.

Thus, the present invention relates to a modulating compound that inhibits the protein-protein interactions of a complex of two polypeptides of columns 1 and 4 of Table 2.

The present invention also relates to a modulating compound that activates the protein-protein interactions of a complex of two polypeptides of columns 1 and 4 of,

Table 2. In yet another embodiment, the present invention relates to a method of selecting a modulating compound, which modulating compound inhibits the interactions of two polypeptides of columns 1 and 4 of Table 2. This method comprises: cultivating a recombinant host cell with a modulating compound on a selective medium and a reporter gene the expression of which is toxic for said recombinant host cell wherein said recombinant host cell is transformed with two vectors: wherein said first vector comprises a polynucleotide encoding a first hybrid polypeptide having a first domain of an enzyme; wherein said second vector comprises a polynucleotide encoding a second hybrid polypeptide having an enzymatic transcriptional activating domain that activates said toxic reporter gene when the first and second hybrid polypeptides interact; selecting said modulating compound which inhibits or permits the growth of said recombinant host cell. In the two methods described above any toxic reporter gene can be utilized including those reporter genes that can be used for negative selection including the URA3 gene, the CYH1 gene, the CYH2 gene and the like.

In yet another embodiment, the present invention provides a kit for screening a modulating compound. This kit comprises a recombinant host cell which comprises a reporter gene the expression of which is toxic for the recombinant host cell. The host cell is transformed with two vectors. The first vector comprises a polynucleotide encoding a first hybrid polypeptide having a DNA binding domain; and the second vector comprises a polynucleotide encoding a second hybrid polypeptide having a transcriptional activating domain that activates said toxic reporter gene when the first and second hybrid polypeptides interact.

In yet another embodiment, a kit is provided for screening a modulating compound by providing a recombinant host cell, as described in the paragraph above, but instead of a DNA binding domain, the first vector encodes a first hybrid polypeptide containing a first domain of a protein. The second vector encodes a second polypeptide containing a second part of a complementary domain of a protein that activates the toxic reporter gene when the first and second hybrid polypeptides interact. In the selection methods described above, the activating domain can be p42 Gal 4, YP16 (HSV) and the DNA-binding domain can be derived from Gal4 or Lex A. The protein or enzyme can be adenylate cyclase, guanylate cyclase, DHFR and the like. Examples of modulating compounds are set forth in Table 3. In yet another embodiment, the present invention relates to a pharmaceutical composition comprising the modulating compounds for preventing or treating obesity or metabolic diseases in a human or animal, most preferably in a mammal.

This pharmaceutical composition comprises a pharmaceutically acceptable amount of the modulating compound. The pharmaceutically acceptable amount can be estimated from cell culture assays. For example, a dose can be formulated in animal models to achieve a circulating concentration range that includes or encompasses a concentration point or range having the desired effect in an in vitro system. This information can thus be used to accurately determine the doses in other mammals, including humans and animals. The therapeutically effective dose refers to that amount of the compound that results in amelioration of symptoms in a patient. Toxicity and therapeutic efficacy of such compounds can be determined by standard pharmaceutical procedures in cell cultures or in experimental animals. For example, the LD50 (the dose lethal to 50% of the population) as well as the ED50 (the dose therapeutically effective in 50% of the population) can be determined using methods known in the art. The dose ratio between toxic and therapeutic effects is the therapeutic index which can be expressed as the ratio between LD 50 and ED50 compounds that exhibit high therapeutic indexes.

The data obtained from the cell culture and animal studies can be used in formulating a range of dosage of such compounds which lies preferably within a range of circulating concentrations that include the ED50 with little or no toxicity.

The pharmaceutical composition can be administered via any route such as locally, orally, systemically, intravenously, intramuscularly, mucosally, using a patch and can be encapsulated in liposomes, microparticles, microcapsules, and the like. The pharmaceutical composition can be embedded in liposomes or even encapsulated.

Any pharmaceutically acceptable carrier or adjuvant can be used in the pharmaceutical composition. The modulating compound will be preferably in a soluble form combined with a pharmaceutically acceptable carrier. The techniques for formulating and administering these compounds can be found in " Remington's Pharmaceutical Sciences" Mack Publication Co., Easton, PA, latest edition.

The mode of administration optimum dosages and galenic forms can be determined by the criteria known in the art taken into account the seriousness of the general condition of the mammal, the tolerance of the treatment and the side effects.

The present invention also relates to a method of treating or preventing obesity or metabolic diseases in a human or mammal in need of such treatment. This method comprises administering to a mammal in need of such treatment a pharmaceutically effective amount of a modulating compound which binds to a targeted mammalian or human or adipocyte protein. In a preferred embodiment, the modulating compound is a polynucleotide which may be placed under the control of a regulatory sequence which is functional in the mammal or human.

In yet another embodiment, the present invention relates to a pharmaceutical composition comprising a SID® polypeptide, a fragment or variant thereof. The SID® polypeptide, fragment or variant thereof can be used in a pharmaceutical composition provided that it is endowed with highly specific binding properties to a bait polypeptide of interest.

The original properties of the SID® polypeptide or variants or fragments thereof interfere with the naturally occurring interaction between a first protein and a second protein within the cells of the organism. Thus, the SID® polypeptide binds specifically to either the first polypeptide or the second polypeptide.

Therefore, the SID® polypeptides of the present invention or variants or fragments thereof interfere with protein-protein interactions between mammalian or human adipocyte proteins.

Thus, the present invention relates to a pharmaceutical composition comprising a pharmaceutically acceptable amount of a SID® polypeptide or variant or fragment thereof, provided that the variant has the above-mentioned two characteristics; i.e., that it is endowed with highly specific binding properties to a bait polypeptide of interest and is devoid of biological activity of the naturally occurring protein.

In yet another embodiment, the present invention relates to a pharmaceutical composition comprising a pharmaceutically effective amount of a polynucleotide encoding a SID® polypeptide or a variant thereof wherein the polynucleotide is placed under the control of an appropriate regulatory sequence. Appropriate regulatory sequences that are used are polynucleotide sequences derived from promoter elements and the like.

Polynucleotides that car, be used in the pharmaceutical composition of the present invention include the nucleotide sequences of SEQ ID Nos.34 to 771 .

Besides the SID® polypeptides and polynucleotides, the pharmaceutical composition of the present invention can also include a recombinant expression vector comprising the polynucleotide encoding the SID® polypeptide, fragment or variant thereof. The above described pharmaceutical compositions can be administered by any route such as orally, systemically, intravenously, intramuscularly, intradermally, mucosally, encapsulated, using a patch and the like. Any pharmaceutically acceptable carrier or adjuvant can be used in this pharmaceutical composition.

The SID® polypeptides as active ingredients will be preferably in a soluble form combined with a pharmaceutically acceptable carrier. The techniques for formulating and administering these compounds can be found in " Remington's Pharmaceutical Sciences" supra.

The amount of pharmaceutically acceptable SID® polypeptides can be determined as described above for the modulating compounds using cell culture and animal models.

Such compounds can be used in a pharmaceutical composition to treat or prevent obesity or any metabolic diseases.

Thus, the present invention also relates to a method of preventing or treating obesity or any metabolic diseases in a mammal said method comprising the steps of administering to a mammal in need of such treatment a pharmaceutically effective amount of:

(1 ) a SID® polypeptide of SEQ ID Nos. 772 to 1509 or a variant or a fragment thereof which binds to a targeted mammalian or human adipocyte protein; or

(2) SID® polynucleotide encoding a SID® polypeptide of SEQ ID Nos. 772 to 1509 or a variant or a fragment thereof wherein said polynucleotide is placed under the control of a regulatory sequence which is functional in said mammal or human; or

(3) a recombinant expression vector comprising a polynucleotide encoding a SID® polypeptide which binds to a mammalian, human adipocyte protein. In another embodiment the present invention nucleic acids comprising a sequence of SEQ ID Nos. 34 to 77 1 which encodes the protein of sequence SEQ ID Nos. 772 to 1509 and/or functional derivatives thereof are administered to modulate complex (from Table 2) function by way of gene therapy. Any of the methodologies relating to gene therapy available within the art may be used in the practice of the present invention such as those described by Goldspiel et al Clin. Pharm. 12 pgs. 488-505 (1993).

Delivery of the therapeutic nucleic acid into a patient may be direct in vivo gene therapy (i.e., the patient is directly exposed to the nucleic acid or nucleic acid- containing vector) or indirect ex vivo gene therapy (i.e., cells are first transformed with the nucleic acid in vitro and then transplanted into the patient).

For example for in vivo gene therapy, an expression vector containing the nucleic acid is administered in such a manner that it becomes intracellular; i.e., by infection using a defective or attenuated retroviral or other viral vectors as described, for example in U.S. Patent 4,980,286 or by Robbins et al, Pharmacol. Ther. , 80 No. 1 pgs. 35-47 (1998).

The various retroviral vectors that are known in the art are such as those described in Miller et al. (Meth. Enzymol. 217 pgs. 581-599 (1993)) which have been modified to delete those retroviral sequences which are not required for packaging of the viral genome and subsequent integration into host cell DNA. Also adenoviral vectors can be used which are advantageous due to their ability to infect non-dividing cells and such high-capacity adenoviral vectors are described in Kochanek (Human Gene Therapy, 10, pgs. 2451-2459 (1999)). Chimeric viral vectors that can be used are those described by Reynolds et al. (Molecular Medecine Today, pgs. 25 -31 (1999)). Hybrid vectors can also be used and are described by Jacoby et al. (Gene

Therapy, 4, pgs. 1282-1283 (1997)).

Direct injection of naked DNA or through the use of microparticle bombardment (e.g., Gene Gun®; Biolistic, Dupont) or by coating it with lipids can also be used in gene therapy. Cell-surface receptors/transfecting agents or through encapsulation in liposomes, microparticles or microcapsules or by administering the nucleic acid in linkage to a peptide which is known to enter the nucleus or by administering it in linkage to a ligand predisposed to receptor-mediated endocytosis (See Wu & Wu, J. Biol. Chem., 262 pgs. 4429-4432 (1987)) can be used to target cell types which specifically express the receptors of interest.

In another embodiment a nucleic acid ligand compound may be produced in which the ligand comprises a fusogenic viral peptide designed so as to disrupt endosomes, thus allowing the nucleic acid to avoid subsequent lysosomal degradation. The nucleic acid may be targeted in vivo for cell specific endocytosis and expression by targeting a specific receptor such as that described in WO92/06180, WO93/14188 and WO 93/20221. Alternatively the nucleic acid may be introduced intracellulariy and incorporated within the host cell genome for expression by homologous recombination (See Zijlstra et al, Nature, 342, pgs. 435-428 (1989)).

In ex vivo gene therapy, a gene is transferred into cells in vitro using tissue culture and the cells are delivered to the patient by various methods such as injecting subcutaneously, application of the cells into a skin graft and the intravenous injection of recombinant blood cells such as hematopoietic stem or progenitor cells. Cells into which a nucleic acid can be introduced for the purposes of gene therapy include, for example, epithelial cells, endothelial cells, keratinocytes, fibroblasts, muscle cells, hepatocytes and blood cells. The blood cells that can be used include, for example, T-lymphocytes, B-lymphocytes, monocytes, macrophages, neutrophils, eosinophils, megakaryotcytes, granulocytes, hematopoietic cells or progenitor cells and the like.

In yet another embodiment the present invention relates to protein chips or protein microarrays. It is well known in the art that microarrays can contain more than 10,000 spots of a protein that can be robotically deposited on a surface of a glass slide or nylon filter. The proteins attach covalently to the slide surface, yet retain their ability to interact with other proteins or small molecules in solution. In some instances the protein samples can be made to adhere to glass slides by coating the slides with an aldehyde-containing reagent that attaches to primary amines. A process for creating microarrays is described, for example by MacBeath and Schreiber (Science, Volume 289, Number 5485, pgs, 1760-1763 (2000)) or (Service, Science, Vol, 289, Number 5485 pg. 1673 (2000)). An apparatus for controlling, dispensing and measuring small quantities of fluid is described, for example, in U.S. Patent No. 6,1 12,605. The present invention also provides a record of protein-protein interactions, PIM®'s and any data encompassed in the following Tables. It will be appreciated that this record can be provided in paper or electronic or digital form.

In order to fully illustrate the present invention and advantages thereof, the following specific examples are given, it being understood that the same are intended only as illustrative and in nowise limitative.

EXAMPLES

EXAMPLE 1 : Preparation of a collection of random-primed cDNA fragments

1.A. Collection preparation and transformation in Escherichia coli 1 .A.1 . Random-primed cDNA fragment preparation

For mRNA sample from differentiated PAZ6 adipocytes, random-primed cDNA was prepared from 5 μg of polyA+ mRNA using a TimeSaver cDNA Synthesis Kit (Amersham Pharmacia Biotech) and with 5 μg of random N9-mers according to the manufacturer's instructions. Following phenolic extraction, the cDNA was precipitated and resuspended in water. The resuspended cDNA was phosphorylated by incubating in the presence of T4 DNA Kinase (Biolabs) and ATP for 30 minutes at 37°C. The resulting phosphorylated cDNA was then purified over a separation column (Chromaspin TE 400, Clontech), according to the manufacturer's protocol. 1 .A.2. Ligation of linkers to blunt-ended cDNA Oligonucleotides HGX931 (5' end phosphorylated) 1 μg/μl and HGX932 1 μg/μl were used.

Sequence of the oligo HGX931 : 5'-GGGCCACGAA-3' (SEQ ID NO. 1510) Sequence of the oligo HGX932: 5'-TTCGTGGCCCCTG-3 '(SEQ ID NO. 151 1 ) Linkers were preincubated (5 minutes at 95°C, 10 minutes at 68°C, 15 minutes at 42°C) then cooled down at room temperature and ligated with cDNA fragments at

16°C overnight.

Linkers were removed on a separation column (Chromaspin TE 400, Clontech), according to the manufacturer's protocol. 1 A3. Vector preparation Plasmid pP6 (see Figure 10) was prepared by replacing the Spel/Xhol fragment of pGAD3S2X with the double-stranded oligonucleotide: 5'- CTAGCCATGGCCGCAGGGGCCGCGGCCGCACTAGTGGGGATCCTTAATTAAAG GGCCACTGGGGCCCCCGGTACCGGCGTCCCCGGCGCCGGCGTGATCACCCCT AGGAATTAATTTCCCGGTGACCCCGGGGGAGCT-3" (SEQ ID NO.1512)

The pP6 vector was successively digested with S//1 and SamHI restriction enzymes (Biolabs) for 1 hour at 37°C, extracted, precipitated and resuspended in water. Digested plasmid vector backbones were purified on a separation column

(Chromaspin TE 400, Clontech), according to the manufacturer's protocol.

1 .A.4. Ligation between vector and insert of cDNA

The prepared vector was ligated overnight at 15°C with the blunt-ended cDNA described in section 2 using T4 DNA ligase (Biolabs). The DNA was then precipitated and resuspended in water.

1 .A.5. Library transformation in Escherichia coli

The DNA from section 1.A.4 was transformed into Electromax DH10B electrocompetent cells (Gibco BRL) with a Cell Porator apparatus (Gibco BRL). 1 ml SOC medium was added and the transformed cells were incubated at 37°C for 1 hour. 9 mis of SOC medium per tube was added and the cells were plated on

LB+ampicillin medium. The colonies were scraped with liquid LB medium, aliquoted and frozen at -80°C.

The obtained collection of recombinant cell clones was named HGXBPZDRP1.

1.B. Collection transformation in Saccharomyces cerevisiae The Saccharomyces cerevisiae strain (Y187 (MATα Gal4Δ GalδOΔ ade2-101 , his3, leu2-3, -1 12, trp1-901 , ura3-52 URA3::UASGAL1-LacZ Met)) was transformed with the cDNA library.

The plasmid DNA contained in E. coli were extracted (Qiagen) from aliquoted E. coli frozen cells (1.A.5.). Saccharomyces cerevisiae yeast Y187 in YPGIu were grown.

Yeast transformation was performed according to standard protocol (Giest et al.

Yeast, 1 1 , 355-360, 1995) using yeast carrier DNA (Clontech). This experiment lead to 10⁴ to 5 x 10⁴ cells/μg DNA. 2 x 10⁴ cells were spread on DO-Leu medium per plate. The cells were aliquoted into vials containing 1 ml of cells and frozen at -80°C. The obtained collection of recombinant cell clones was named HGXYPZDRP1.

1.C. Construction of bait plasmids

For fusions of the bait protein to the DNA-binding domain of the GAL4 protein of S. cerevisiae, bait fragments were cloned into plasmid pB6. For fusions of the bait protein to the DNA-binding domain of the LexA protein of E. coli, bait fragments were cloned into plasmid pB20.

Plasmid pB6 (see Figure 3) was prepared by replacing the NcoMSa polylinker fragment of pB1 (see Figure 1 ) with the double-stranded DNA fragment: 5' CATGGCCGGACGGGCCGCGGCCGCACTAGTGGGGATCCTTA

ATTAAGGGCCACTGGGGCCCC 3' (SEQ ID No. 1513)

5' TCGAGGGGCCCCAGTGGCCCTTAATTAAGGATCCCCACTAGTG CGGCCGCGGCCCGTCCGGC 3' (SEQ ID No. 1514) Plasmid pB5 (see Figure 2) was prepared by replacing the Ncol/Sall polylinker fragment of pB1 with the double-stranded DNA fragment :

5' CATGGCCGCAGGGGCCGCGGCCGCACTAGTGGGGATCCTTA ATTAAGGGCCACTGGGGCCCC 3' (SEQ IS No. 1515) 5' TCGAGGGGCCCCAGTGGCCCTTAATTAAGGATCCCCACTAGTG CGGCCGCGGCCCCTGCGGC 3' (SEQ ID No. 1516)

The amplification of the bait ORF was obtained by PCR using the Pfu proofreading Taq polymerase (Stratagene), 10 pmol of each specific amplification primer and 200 ng of plasmid DNA as template.

The PCR program was set up as follows : 94° 45"

30 cycles

72° 10' 15° ∞

The amplification was checked by agarose gel electrophoresis. The PCR fragments were purified with Qiaquick column (Qiagen) according to the manufacturer's protocol.

Purified PCR fragments were digested with adequate restriction enzymes. The PCR fragments were purified with Qiaquick column (Qiagen) according to the manufacturer's protocol.

The digested PCR fragments were ligated into an adequately digested and dephosphorylated bait vector (pB6 or pB5) according to standard protocol (Sambrook et al.) and were transformed into competent bacterial cells. The cells were grown, the DNA extracted and the plasmid was sequenced.

Example 2 : Screening the collection with the two-hybrid in yeast system 2. A. The mating protocol

The mating two-hybrid in yeast system (as described by Legrain et al., Nature

Genetics, vol. 16, 277-282 (1997), Toward a functional analysis of the yeast genome through exhaustive two-hybrid screens) was used for its advantages but one could also screen the cDNA collection in classical two-hybrid system as described in Fields et al. or in a yeast reverse two-hybrid system.

The mating procedure allows a direct selection on selective plates because the two fusion proteins are already produced in the parental cells. No replica plating is required. This protocol was written for the use of the library transformed into the Y187 strain.

For bait proteins fused to the DNA-binding domain of GAL4, bait-encoding plasmids were first transformed into S. cerevisiae (CG1945 strain (MATa Gal4-542

GaM 80-538 ade2-101 his3Δ200, Ieu2-3,1 12, trp1-901 , ura3-52, Iys2-801 , URA3::GAL4 17mers (X3)-CyC1TATA-LacZ, LYS2::GAL1 UAS-GAL1TATA-HIS3

CYH^R)) according to step 1 .B. and spread on DO-Trp medium.

For bait proteins fused to the DNA-binding domain of LexA, bait-encoding plasmids were first transformed into S. cerevisiae (L40Δgal4 strain (MATa ade2, trpl-

901 , Ieu2 3,1 12, Iys2-801 , his3Δ200, LYS2::(lexAop)₄-HIS3, ura3-52::URA3 (lexAop)₈-LacZ, GAL4::Kan^R)) according to step 1.B. and spread on DO-Trp medium.

Day 1 , morning : preculture

The cells carrying the bait plasmid obtained at step 1.C. were precultured in 20 ml DO-Trp medium and grown at 30°C with vigorous agitation. Day 1 , late afternoon : culture The OD_600nm of the DO-Trp pre-culture of cells carrying the bait plasmid was measured. The ODβoonm must lie between 0.1 and 0.5 in order to correspond to a linear measurement.

50 ml DO-Trp at ODδOOnm 0.006/ml was inoculated and grown overnight at 30°C with vigorous agitation. Day 2 : mating medium and plates

1 YPGIu 15cm plate

50 ml tube with 13 ml DO-Leu-Trp-His 100 ml flask with 5 ml of YPGIu 8 DO-Leu-Trp-His plates 2 DO-Leu plates 2 DO-Trp plates 2 DO-Leu-Trp plates

The OD600nm of the DO-Trp culture was measured. It should be around 1. For the mating, twice as many bait cells as library cells were used. To get a good mating efficiency, one must collect the cells at 10⁸ cells per cm².

The amount of bait culture (in ml) that makes up 50 ODβOOnm units for the mating with the prey library was estimated.

A vial containing the HGXYPZDRP1 library was thawed slowly on ice. 1.0ml of the vial was added to 5 ml YPGIu. Those cells were recovered at 30°C, under gentle agitation for 10 minutes. Mating The 50 OD600nm units of bait culture was placed into a 50 ml falcon tube.

The HGXYCDNA1 library culture was added to the bait culture, then centrifuged, the supernatant discarded and resuspended in 1.6ml YPGIu medium.

The cells were distributed onto two 15cm YPGIu plates with glass beads. The cells were spread by shaking the plates. The plate cells-up at 30°C for 4h30min were incubated.

Collection of mated cells

The plates were washed and rinsed with 6ml and 7ml respectively of DO-Leu- Trp-His. Two parallel serial ten-fold dilutions were performed in 500μl DO-Leu-Trp- His up to 1/10,000. 50μl of each 1/10000 dilution was spread onto DO-Leu and DO- trp plates and 50μl of each 1/1000 dilution onto DO-Leu-Trp plates. 22.4ml of collected cells were spread in 400μl aliquots on DO-Leu-Trp-His+Tet plates. Day 4

Clones that were able to grow on DO-Leu-Trp-His+Tetracyclin were then selected. This medium allows one to isolate diploid clones presenting an interaction. The His+ colonies were counted on control plates.

The number of His+ cell clones will define which protocol is to be processed : Upon 60 x 10⁶ Trp+Leu+ colonies : if the number His+ cell clones <285 : then use the process luminometry protocol on all colonies if the number of His+ cell clones >285 and <5000: then process via overlay and then luminometry protocols on blue colonies (2.B and 2.C). if number of His+ cell clones >5000 : repeat screen using DO-Leu-Trp-

His+Tetracyclin plates containing 3-aminotriazol. 2.S. The X-Gal overlay assay

The X-Gal overlay assay was performed directly on the selective medium plates after scoring the number of His⁺ colonies. Materials

A waterbath was set up. The water temperature should be 50°C.

0.5 M Na₂HPO₄ pH 7.5.

1.2% Bacto-agar.

2% X-Gal in DMF. Overlay mixture : 0.25 M Na₂HPO₄ pH7.5, 0.5% agar, 0.1 % SDS, 7% DMF

(LABOSI), 0.04% X-Gal (ICN). For each plate, 10 ml overlay mixture are needed.

DO-Leu-Trp-His plates.

Sterile toothpicks.

Experiment The temperature of the overlay mix should be between 45°C and 50°C. The overlay-mix was poured over the plates in portions of 10 ml. When the top layer was settled, they were collected. The plates were incubated overlay-up at 30°C and the time was noted. Blue colonies were checked for regularly. If no blue colony appeared, overnight incubation was performed. Using a pen the number of positives was marked. The positives colonies were streaked on fresh DO-Leu-Trp-His plates with a sterile toothpick.

2.C. The luminometry assay

His+ colonies were grown overnight at 30°C in microtiter plates containing DO-

Leu-Trp-His+Tetracyclin medium with shaking. The day after, the overnight culture was diluted 15 times into a new microtiter plate containing the same medium and was incubated for 5 hours at 30°C with shaking. The samples were diluted 5 times and read OD₆oonm- The samples were diluted again to obtain between 10,000 and

75,000 yeast cells/well in 100 μl final volume. Per well, 76 μl of One Step Yeast Lysis Buffer (Tropix) was added, 20 μl

Sapphirell Enhancer (Tropix), 4 μl Galacton Star (Tropix) and incubated 40 minutes at 30°C. The β-Gal read-out (L) was measured using a Luminometer (Trilux,

Wallach). The value of (OD₆oonm x L) was calculated and interacting preys having the highest values were selected.

At this step of the protocol, diploid cell clones presenting interaction were isolated. The next step was now to identify polypeptides involved in the selected interactions.

Example 3 : Identification of positive clones 3.A. PCR on yeast colonies

Introduction

PCR amplification of fragments of plasmid DNA directly on yeast colonies is a quick and efficient procedure to identify sequences cloned into this plasmid. It is directly derived from a published protocol (Wang H. et al., Analytical Biochemistry, 237, 145-146, (1996)). However, it is not a standardized protocol and it varies from strain to strain and it is dependent of experimental conditions (number of cells, Taq polymerase source, etc). This protocol should be optimized to specific local conditions.

Materials For 1 well, PCR mix composition was :

32.5 μl water,

5 μl 10X PCR buffer (Pharmacia),

1 μl dNTP IO mM,

0.5 μl Taq polymerase (5u/μl) (Pharmacia), 0.5 μl oligonucleotide ABS1 10 pmole/μl: 5'-GCGTTTGGAATCACTACAGG-3' ,(SEQ

ID No.1517)

0.5 μl oligonucleotide ABS2 10 pmole/μl: 5'-CACGATGCACGTTGAAGTG-3'.(SEQ

ID No. 1518)

1 N NaOH. Experiment

The positive colonies were grown overnight at 30°C on a 96 well cell culture cluster (Costar), containing 150 μl DO-Leu-Trp-His+Tetracyclin with shaking. The culture was resuspended and 100 μl was transferred immediately on a Thermowell 96 (Costar) and centrifuged for 5 minutes at 4,000 rpm at room temperature. The supernatant was removed. 5 μl NaOH was added to each well and shaken for 1 minute.

The Thermowell was placed in the thermocycler (GeneAmp 9700, Perkin Elmer) for 5 minutes at 99.9°C and then 10 minutes at 4°C. In each well, the PCR mix was added and shaken well.

The PCR program was set up as followed :

94°C 3 minutes

94°C 30 seconds

5 533°°CC 1 1 mmiinnuuttee 3300 sseeccoonnddss x 35 cycles

72°C 3 minutes ,

72°C 5 minutes

15°C OO

The quality, the quantity and the length of the PCR fragment was checked on an agarose gel. The length of the cloned fragment was the estimated length of the PCR fragment minus 300 base pairs that corresponded to the amplified flanking plasmid sequences.

3.B. Plasmids rescue from yeast by electroporation

Introduction The previous protocol of PCR on yeast cell may not be successful, in such a case, plasmids from yeast by electroporation can be rescued. This experiment allows the recovery of prey plasmids from yeast cells by transformation of E. coli with a yeast cellular extract. The prey plasmid can then be amplified and the cloned fragment can be sequenced. Materials

Plasmid rescue

Glass beads 425-600 μm (Sigma)

Phenol/chloroform (1/1 ) premixed with isoamyl alcohol (Amresco)

Extraction buffer : 2% Triton X100, 1 % SDS, 100 mM NaCl, 10 mM TrisHCI pH 8.0, 1 mM EDTA pH 8.0.

Mix ethanol/NH₄Ac : 6 volumes ethanol with 7.5 M NH Acetate, 70% Ethanol and yeast cells in patches on plates. Electroporation SOC medium M9 medium

Selective plates : M9-Leu+Ampicillin 2 mm electroporation cuvettes (Eurogentech)

Experiment

Plasmid rescue The cell patch on DO-Leu-Trp-His was prepared with the cell culture of section 2.C. The cell of each patch was scraped into an Eppendorf tube, 300 μl of glass beads was added in each tube, then, 200 μl extraction buffer and 200 μl phenol:chloroform:isoamyl alcohol (25:24:1 ) was added. The tubes were centrifuged for 10 minutes at 15,000 rpm. 180 μl supernatant was transferred to a sterile Eppendorf tube and 500 μl each of ethanol/NH Ac was added and the tubes were vortexed. The tubes were centrifuged for 15 minutes at 15,000 rpm at 4°C. The pellet was washed with

200 μl 70% ethanol and the ethanol was removed and the pellet was dried. The pellet was resuspended in 10 μl water. Extracts were stored at -20°C. Electroporation Materials : Electrocompetent MC1066 cells prepared according to standard protocols (Sambrook et al. supra).

1 μl of yeast plasmid DNA-extract was added to a pre-chilled Eppendorf tube, and kept on ice.

1 μl plasmid yeast DNA-extract sample was mixed and 20 μl electrocompetent cells was added and transferred in a cold electroporation cuvette. The Biorad electroporator was set on 200 ohms resistance, 25 μF capacity; 2.5 kV.

The cuvette was placed in the cuvette holder and electroporation was performed. 1 ml of SOC was added into the cuvette and the cell-mix was transferred into a sterile Eppendorf tube. The cells were recovered for 30 minutes at 37°C, then spun down for 1 minute at 4,000 x g and the supernatant was poured off. About 100 μl medium was kept and used to resuspend the cells and spread them on selective plates (e.g.,

M9-Leu plates). The plates were then incubated for 36 hours at 37°C. One colony was grown and the plasmids were extracted. The presence and the size of the insert were checked for through enzymatic digestion and agarose gel electrophoresis. The insert was then sequenced. Example 4 : Protein-protein interaction For each bait, the previous protocol lead to the identification of prey polynucleotide sequences. Using a suitable software program (e.g., Blastwun, available on the Internet site of the University of Washington http://bioweb.pasteur.fr/seganal/interfaces/blastwu.html) one can determine the identity of the mRNA transcript that is encoded by the prey fragment and whether the fusion protein encoded is in the same open reading frame of translation as the predicted protein or not.

Alternatively, prey nucleotide sequences can be compared with one another and those which share identity over a significant region (60nt) can be grouped together to form a contiguous sequence (Contig) whose identity can be ascertained in the same manner as for individual prey fragments described above.

Example 5: Identification of SID®

By comparing and selecting the intersection of all isolated fragments that are included in the same polypeptide, one can define the Selected Interacting Domain (SID®) is determined as illustrated in Figure 15. The SID® is illustrated in Table 3. Example 6: Making of polyclonal and monoclonal antibodies

The protein-protein complex of columns 1 and 4 of Table 2 is injected into mice and polyclonal and monoclonal antibodies are made following the procedure set forth in Sambrook et al supra.

More specifically, mice are immunized with an immunogen comprising the above mentionned complexes conjugated to keyhole limpet hemocyanin using glutaraldehyde or EDC as is well known in the art. The complexes can also be stabilized by crosslinking as described in WO 00/37483. The immunogen is then mixed with an adjuvant. Each mouse receives four injections of 10 μg to 100 μg of immunogen, and after the fourth injection, blood samples are taken from the mice to determine if the serum contains antibodies to the immunogen. Serum titer is determined by ELISA or RIA. Mice with sera indicating the presence of antibody to the immunogen are selected for hybridoma production.

Spleens are removed from immune mice and single-cell suspension is prepared (Hariow et al 1988). Cell fusions are performed essentially as described by Kohler et al.. Briefly, P365.3 myeloma cells (ATTC Rockville, Md) or NS-1 myeloma cells are fused with spleen cells using polyethylene glycol as described by Hariow et al (1989). Cells are plated at a density of 2 x 10⁵ cells/well in 96-well tissue culture plates. Individual wells are examined for growth and the supernatants of wells with growth are tested for the presence of complex-specific antibodies by ELISA or RIA using the protein-protein complex of columns 1 and 4 of Table 2 as a target protein. Cells in positive wells are expanded and subcloned to establish and confirm monoclonality.

Clones with the desired specificities are expanded and grown as ascites in mice or in a hollow fiber system to produce sufficient quantities of antibodies for characterization and assay development. Antibodies are tested for binding to bait polypeptide of column 1 of Table 2 alone or to prey polypeptide of column 4 of Table

2 alone, to determine which are specific for the protein-protein complex of columns 1 and 4 of Table 2 as opposed to those that bind to the individual proteins.

Monoclonal antibodies against each of the complexes set forth in columns 1 and 4 of Table 2 are prepared in a similar manner by mixing specified proteins together, immunizing an animal, fusing spleen cells with myeloma cells and isolating clones which produce antibodies specific for the protein complex, but not for individual proteins. Example 6: Modulating compounds identification

Each specific protein-protein complex of columns 1 and 4 of Table 2 is used to screen for modulating compounds.

One appropriate construction for this modulating compound screening is: bait polynucleotide inserted in pB6 or pB5; prey polynucleotide inserted in pP6; transformation of these two vectors in a permeable yeast cell; growth of the transformed yeast cell on a medium containing compound to be tested, and observation of the growth of the yeast cells. The following results obtained from these Examples, as well as the teachings in the specification are set forth in the Tables below.

All non-patented websites cited in the present specification are incorporated herein by reference.

While the invention has been described in terms of the various preferred embodiments, the skilled artisan will appreciate that various modifications, substitutions, omissions and changes may be made without departing from the scope thereof. Accordingly, it is intended that the present invention be limited by the scope of the following claims, including equivalents thereof.

Table 1 : bait name and sequence

4-

O

46 Table 2: bait-prey interactions

4- -4

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ON

-4

-4

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Human ADRB3 AA227-292 12 pB6 emb| AJ250915.1 |HSA250915 Homo sapiens plO gene for Differentiated PAZ6 RP 1 chaperonin 10 (HsplO protein) and p60 gene for chaperonin 60 (Hsp60 protein)

Human ADRB3 AA227 - 292 12 pB6 emb| AL031281.6 |HS224A6 Human DNA sequence from clone Differentiated PAZ6 RP 1 224A6 on chromosome lp35.1-36.23 Contains part of a gene similar to Mouse Wnt-4 protein, the gene for CDC42 (cell division cycle 42 (GTP-binding protein, 25kD) ) , ESTs, STSs, GSSs and a CpG Island, complete sequence [Homo s

Human ADRB3 AA227-292 12 pB6 emb| AL031781.1 |HS51J12 Human DNA sequence from clone Differentiated PAZ6 RP 1 51J12 on chromosome 6q26-27. Contains the 3' part of the alternatively spliced gene for the human orthologs of mouse QKI-7 and QKI-7B (KH Domain RNA Binding proteins) and zebrafish ZKQ-1 (Quaking protein homolog) . Contains

Human ADRB3 AA227-292 12 pB6 emb| AL049563.4 |HS68D15 Human DNA sequence from clone Differentiated PAZ6 RP 1 68D15 on chromosome Xq22.3-q23, complete sequence [Homo sapiens]

Human ADRB3 AA227-292 12 pB6 emb| AL049610.9|HS1055C14 Human DNA sequence from clone Differentiated PAZ6 RP 1

-4 Ul 1055C14 on chromosome Xq22.1-22.3 Contains genes for TCEALl (transcription elongation factor A (SII) -like 1) and KIAA0026 (transcription factor-like protein MRGX), a pseudogene similar to GLYCINE RECEPTOR ALPHA-2 CHAIN, EST

Human ADRB3 AA227-292 12 pB6 emb|AL112552.l|CNS01A6O Botrytis cinerea strain T4 cDNA Differentiated PAZ6 RP 1 library under conditions of nitrogen deprivation

Human ADRB3 AA227-292 12 pB6 emb| AL121754.18 |HSDJ629F1 Human DNA sequence from clone Differentiated PAZ6 RP 1 RP4-629F1 on chromosome 20 Contains parts of 3 novel genes, ESTs, STSs, GSSs and a CpG Island, complete sequence [Homo sapiens]

Human ADRB3 AA227-292 12 pB6 emb|AL137127.7 |AL137127 Human DNA sequence from clone Differentiated PAZ6 RP 1 RP5-1126H10 on chromosome lp34.3-35.3, complete sequence [Homo sapiens]

Human ADRB3 AA227 - 292 12 pB6 emb| AL139384.16 |AL139384 Human DNA sequence from clone Differentiated PAZ6 RP 1 RP11-88E10 on chromosome 13q33.1-34, complete sequence [Homo sapiens]

Human ADRB3 AA227-292 12 pB6 emb| AL353732.14 |AL353732 Human DNA sequence from clone Differentiated PAZ6 RP 1 RP11-354P17 on chromosome 9, complete sequence [Homo

-4 -4

-4 oe

Human ADRB3 AA227- 14 pB6 dbj I AB007864.1 |AB007864 Homo sapiens KIAA0404 mRNA, Differentiated PAZ6 RP 1 292 AA348-409 partial cds

Human ADRB3 AA227- 14 pB6 dbj |AB007931.11 AB007931 Homo sapiens mRNA for KIAA0462 Differentiated PAZ6 RP 1 292 AA348-409 protein, partial cds

Human ADRB3 AA227- 14 pB6 dbj |AB046798.l|AB046798 Homo sapiens mRNA for KIAA1578 Differentiated PAZ6 RP 1 292 AA348-409 protein, partial cds

Human ADRB3 AA227- 14 pB6 dbj |AK000331.l|AK000331 Homo sapiens cDNA FLJ20324 fis, Differentiated PAZ6 RP 1 292 AA348-409 clone HEP09841, highly similar to AB007931 Homo sapiens mRNA for KIAA0462 protein

Human ADRB3 AA227- 14 pB6 dbj |AK000867.l|AK000867 Homo sapiens cDNA FLJ10005 fis, Differentiated PAZ6 RP 1 292 AA348-409 clone HEMBA1000156

Human ADRB3 AA227- 14 pB6 dbj |AK001912.l|AK001912 Homo sapiens cDNA FLJ11050 fis, Differentiated PAZ6 RP 1 292 AA348-409 clone PLACE1004564, highly similar to CLEAVAGE AND POLYADENYLATION SPECIFICITY FACTOR, 100 KD SUBUNIT

Human ADRB AA227- 14 pB6 dbj |AK022041.1|AK022041 Homo sapiens cDNA FLJ11979 fis, Dⁱfferentiated PAZ6 RP 1 292 AA348-409 clone HEMBB1001282, weakly similar to ANKYRIN R

Human ADRB3 AA227- 14 pB6 dbj |AK023972.l|AK023972 Homo sapiens cDNA FLJ13910 fis, Differentiated PAZ6 RP 1 292 AA348-409 clone Y79AA1000131

-4 Human A RB3 AA227- 14 pB6 dbj |D86979.2 |D86979 Homo sapiens mRNA for KIAA0226 Differentiated PAZ6 RP 1 O 292 AA348-409 protein, partial cds

Human ADRB3 AA227- 14 pB6 emb| AJ250915.1 |HSA250915 Homo sapiens plO gene for Differentiated PAZ6 RP 1 292 AA348-409 chaperonin 10 (HsplO protein) and p60 gene for chaperonin 60 (Hsp60 protein)

Human ADRB3 AA227- 14 pB6 emb| AL031281.6 |HS224A6 Human DNA sequence from clone Differentiated PAZ6 RP 1 292 AA348-409 224A6 on chromosome lp35.1-36.23 Contains part of a gene similar to Mouse Wnt-4 protein, the gene for CDC42 (cell division cycle 42 (GTP-binding protein, 25kD) ) , ESTs, STSs, GSSs and a CpG Island, complete sequence [Homo s

Human ADRB3 AA227- 14 pB6 emb|AL031781.1 |HS51J12 Human DNA sequence from clone Differentiated PAZ6 RP 1 292 AA348-409 51J12 on chromosome 6q26-27. Contains the 3' part of the alternatively spliced gene for the human orthologs of mouse QKI-7 and QKI-7B (KH Domain RNA Binding proteins) and zebrafish ZKQ-1 (Quaking protein homolog) . Contains

Human ADRB3 AA227- 14 pB6 emb| AL035453.4 |HSCB42E1 Human DNA sequence from clone Differentiated PAZ6 RP 292 AA348-409 SC22CB-42E1 on chromosome 22ql2.1-12.3 Contains part of a novel gene and GSSs, complete sequence [Homo

oe ©

oe

-4

oe oe

Human OBR-GRP AA51-132 17 pB6 emb I AL031277.1 |HS1177E19 Human DNA sequence from clone Differentiated PAZ6 RP 1

1177E19 on chromosome lp36.12 -36.31. Contains the 3' part of the DNA-binding Zinc finger protein RIZ gene,

ESTs, an STS, GSSs and a CpG island, complete sequence [Homo sapiens]

Human OBR-GRP AA51-132 17 pB6 emb| AL031781.1 |HS51J12 Human DNA sequence from clone Differentiated PAZ6 RP 1 51J12 on chromosome 6q26-27. Contains the 3' part of the alternatively spliced gene for the human orthologs of mouse QKI-7 and QKI-7B (KH Domain RNA Binding proteins) and zebrafish ZKQ-1 (Quaking protein homolog) . Contains

Human OBR-GRP AA51-132 17 pB6 emb I AL132875.22 |HSDJ92C4 Human DNA sequence from clone Differentiated PAZ6 RP 1 RP1-92C4 on chromosome 6ql4.1-15, complete sequence [Homo sapiens]

Human OBR-GRP AA51-132 17 pB6 emb I AL133480.9 I AL133480 Human DNA sequence from clone Differentiated PAZ6 RP 1 RP11-307L3 on chromosome 9p23-24.3, complete sequence [Homo sapiens]

Human OBR-GRP AA51 - 132 17 pB6 emb I AL137012.6 | AL137012 Human DNA sequence from clone Differentiated PAZ6 RP 1 RP1-80G16 on chromosome 6. Contains a 60S ribosomal oe vo protein L21 (RPL21) pseudogene, ESTs, STSs, GSSs and a CpG island, complete sequence [Homo sapiens]

Human OBR-GRP AA51-132 17 pB6 emb|AL137012.6 |AL137012 Human DNA sequence from clone Differentiated PAZ6 RP RP1-80G16 on chromosome 6. Contains a 60S ribosomal protein L21 (RPL21) pseudogene, ESTs, STSs, GSSs and a CpG island, complete sequence [Homo sapiens]

Human OBR-GRP AA51-132 17 pB6 emb|Z83822.1 |HS306D1 Human DNA sequence from PAC 306D1 Differentiated PAZ6 RP on chromosome X contains ESTs

Human OBR-GRP AA51-132 17 pB6 gb|AC004554.l|AC004554 Homo sapiens Xp22 BAC GSHB-590J6 Differentiated PAZ6 RP (Genome Systems Human BAC library) complete sequence

Human OBR-GRP AA51-132 17 pB6 gb| AC004770.1 |AC004770 Homo sapiens chromosome 11, BAC Differentiated PAZ6 RP CIT-HSP-311e8 (BC269730) containing the hFENl gene, complete sequence

Human OBR-GRP AA51 - 132 17 pB6 gb| AC006450.13 I AC006450 Homo sapiens chromosome 9, clone Differentiated PAZ6 RP RP11-85021, complete sequence

Human OBR-GRP AA51-132 17 pB6 gb|AC007999.1l|AC007999 Homo sapiens 3q25-26 BAC CTB- Differentiated PAZ6 RP 177N7 (California Institute of Technology BAC Library) complete sequence

Human OBR-GRP AA51-132 17 pB6 gb|AC009312.4 |AC009312 Homo sapiens BAC clone RP11-425F6 Differentiated PAZ6 RP

Human S0CS3 AAl-226 20 pB6 ref |NM_000445.11 Homo sapiens plectin 1, intermediate Differentiated PAZ6 RP 1 filament binding protein, 500kD (PLEC1) , mRNA

Human S0CS3 AAl-226 20 pB6 ref |NM_000919.11 Homo sapiens peptidylglycine alpha- Differentiated PAZ6 RP 1 amidating monooxygenase (PAM) , mRNA

Human SOCS3 AAl-226 20 pB6 ref |NM_000963.11 Homo sapiens prostaglandin-endoperoxide Differentiated PAZ6 RP 1 synthase 2 (prostaglandin G/H synthase and cyclooxygenase) (PTGS2) , mRNA

Human SOCS3 AAl-226 20 pB6 ref |NM_001033.11 Homo sapiens ribonucleotide reductase Differentiated PAZ6 RP 1 Ml polypeptide (RRM1) , mRNA

Human S0CS3 AAl-226 20 pB6 ref |NM_001101.2 I Homo sapiens actin, beta (ACTB), mRNA Differentiated PAZ6 RP 1

Human SOCS3 AAl-226 20 pB6 ref |NM_001257.11 Homo sapiens cadherin 13, H-cadherin Differentiated PAZ6 RP 1 (heart) (CDH13), mRNA

Human SOCS3 AAl-226 20 pB6 ref |NM_001282.11 Homo sapiens adaptor-related protein Differentiated PAZ6 RP 1 complex 2, beta 1 subunit (AP2B1) , mRNA

Human SOCS3 AAl-226 20 pB6 ref |NM_001456.11 Homo sapiens filamin A, alpha (actin- Differentiated PAZ6 RP 1 binding protein-280) (FLNA) , mRNA

Human SOCS3 AAl-226 20 pB6 ref |NM_001457.11 Homo sapiens filamin B, beta (actin- Differentiated PAZ6 RP 1 binding protein-278) (FLNB) , mRNA

Human SOCS3 AAl-226 20 pB6 ref |NM_001613.11 Homo sapiens actin, alpha 2, smooth Differentiated PAZ6 RP 1 muscle, aorta (ACTA2) , mRNA

Human SOCS3 AAl-226 20 pB6 ref |NM_001897.11 Homo sapiens chondroitin sulfate Differentiated PAZ6 RP 1 proteoglycan 4 (melanoma-associated) (CSPG4), mRNA

Human SOCS3 AAl-226 20 pB6 ref |NM_001933.11 Homo sapiens dihydrolipoamide S- Differentiated PAZ6 RP 1 succinyltransferase (E2 component of 2-oxo-glutarate complex) (DLST) , mRNA

Human SOCS3 AAl-226 20 pB6 ref |NM_002636.1 I Homo sapiens PHD finger protein 1 Differentiated PAZ6 RP 1 (PHF1) , mRNA

Human SOCS3 AAl-226 20 pB6 ref |NM_002660.11 Homo sapiens phospholipase C, gamma 1 Differentiated PAZ6 RP 1 (formerly subtype 148) (PLCG1) , mRNA

Human S0CS3 AAl-226 20 pB6 ref |NM_002778.11 Homo sapiens prosaposin (variant Differentiated PAZ6 RP 1 Gaucher disease and variant metachromatic leukodystrophy) (PSAP) , mRNA

Human S0CS3 AAl - 226 20 pB6 ref |NM_003074.11 Homo sapiens SWI/SNF related, matrix Differentiated PAZ6 RP 1 associated, actin dependent regulator of chromatin, subfamily c, member 1 (SMARCC1) mRNA

Human SOCS3 AAl-226 20 pB6 ref |NM_003906.11 Homo sapiens minichromosome maintenance Differentiated PAZ6 RP 1 deficient (S. cerevisiae) 3-associated protein

© ©

Human GITl AA371-761 22 pB6 gb| AF164622.1 I AF164622 Homo sapiens golgin-67 (GOLGA5) Differentiated PAZ6 RP 1 mRNA, complete cds

Human GITl AA371-761 22 pB6 gb| AF172080.1 I AF172080 Homo sapiens HPC1 locus clone Differentiated PAZ6 RP 1 173P17 genomic sequence

Human GITl AA371-761 22 pB6 gb I AF196779.11 AF196779 Homo sapiens transcription factor Differentiated PAZ6 RP 1 IGHM enhancer 3, JM11 protein, JM4 protein, JM5 protein, T54 protein, JM10 protein, A4 differentiation-dependent protein, triple LIM domain protein 6, and synaptophysin genes, complete cds; and L-type calcium channel a

Human GITl AA371-761 22 pB6 gb|AF230877.1 I AF230877 Homo sapiens MIP-T3 mRNA, Differentiated PAZ6 RP 1 complete cds

Human GITl AA371-761 22 pB6 gb|AF273048. l|AF273048 Homo sapiens CTCL tumor antigen Differentiated PAZ6 RP 1 se20-9 mRNA, complete cds

Human GITl AA371-761 22 pB6 gb| AF306508.11 AF306508 Homo sapiens SUMO-1 specific Differentiated PAZ6 RP 1 protease FKSG6 mRNA, complete cds

Human GITl AA371-761 22 pB6 gb| J01415.11 HUMMTCG Human mitochondrion, complete genome Differentiated PAZ6 RP 1

Human GITl AA371-761 22 pB6 gb|M29580.l|HUMZNF7 Human zinc-finger protein 7 (ZFP7) Differentiated PAZ6 RP 1 mRNA, complete cds

Human GITl AA371-761 22 pB6 gb |M31013.1 |HUMMYONM Human nonmuscle myosin heavy chain Differentiated PAZ6 RP 1 (NMHC) mRNA, 3 ' end

Human GITl AA371-761 22 pB6 gb|M63256.1 |HUMCDR2AA Human major Yo paraneoplastic Differentiated PAZ6 RP 1 antigen (CDR2) mRNA, 3' end

Human GITl AA371-761 22 pB6 gb|S78388.1 |S78388 28S RNA, autoantigen recognized by an Differentiated PAZ6 RP 1 anti-neuronal cell antibody [human, mRNA, 2192 nt]

Human GITl AA371-761 22 pB6 gb|U81002.1 |HSU81002 Homo sapiens TRAF4 associated Differentiated PAZ6 RP 1 factor 1 mRNA, partial cds

Human GITl AA371-761 22 pB6 gb|U93181.1 |HSU93181 Homo sapiens nuclear dual- Differentiated PAZ6 RP 1 specificity phosphatase (SBF1) mRNA, partial cds

Human GITl AA371-761 22 pB6 ref |NM_001551.11 Homo sapiens immunoglobulin (CD79A) Differentiated PAZ6 RP 1 binding protein 1 (IGBP1) , mRNA

Human GITl AA371 - 761 22 pB6 ref |NM_001619.2 I Homo sapiens adrenergic, beta, receptor Differentiated PAZ6 RP 1 kinase 1 (ADRBK1) , mRNA

Human GITl AA371-761 22 pB6 ref |NM_002224.1 I Homo sapiens inositol 1,4,5- Differentiated PAZ6 RP 1 triphosphate receptor, type 3 (ITPR3) , mRNA

Human GITl AA371-761 22 pB6 ref |NM_002417.11 Homo sapiens antigen identified by Differentiated PAZ6 RP 1

monoclonal antibody Ki-67 (MKI67) , mRNA

CGGGAACAAATTGACAACCTAGCCACAGAACTGTGCCGCATAAATGAGGATCAG EDQKVALDLDPYVKKLLNARRR AAGGTGGCCCTGGATCTTGACCCCTATGTTAAGAAGCTACTTAATGCCCGGCGA VLVNNILQNAQERLRRLNHSVA CGCGTTGTCTTGGTTAACAACATTCTACAGAATGCTCAGGAACGACTGAGACGG ETARRRAMLDSGIYPPGSPGK* CTAAACCACAGTGTTGCCAAGGAAACAGCCCGCAGGAGAGCAATGCTGGATTCG GGAATTTACCCCCCTGGCTCCCCAGGCAAATAA

Human prey3488 69 CAAGGCTCTGGAAGAAGACATAGAAAACCATGCAACAGATGTGCACCAGGCAGT 807 KALEEDIENHATDVHQAVKIGQ ADRB3 v4 CAAAATTGGGCAGTCCCTCTCCTCCCTGACATCTCCTGCAGAACAGGGTGTGCT LSSLTSPAEQGVLSEKIDSLQA GTCAGAAAAGATAGACTCATTGCAGGCCCGATACAGTGAAATTCAAGACCGCTG YSEIQDRCCRKAALLDQALSNA TTGTCGGAAGGCAGCCCTACTTGACCAAGCTCTGTCTAATGCTAGGCTGTTTGG LFGEDEVEVLNWLAEVEDKLSS GGAGGATGAGGTGGAGGTGCTCAACTGGCTGGCTGAGGTTGAGGACAAGCTCAG FVKDFKQDVLHRQHADHLALNE TTCAGTGTTCGTAAAGGATTTCAAACAGGATGTCCTGCACAGGCAGCATGCTGA IVNRKKNVDQAIKNGQALLKQT CCACCTGGCTTTAAATGAAGAAATTGTTAATAGAAAGAAGAATGTAGATCAAGC CEEVLLIQEKLDGIKTRYADIT TATTAAAAATGGTCAGGCTCTTCTAAAACAAACCACAGGTGAGGAGGTGTTACT TSSKALRTLEQARQLATKFQST TATCCAGGAAAAACTAGATGGTATAAAGACTCGTTACGCAGACATCACAGTTAC EELTGWLREVEEELATSGGQSP TAGCTCCAAGGCCCTCAGAACTTTAGAGCAAGCCCGGCAGCTGGCCACCAAGTT GEQIPQFQQRQKELKKEVMEHR CCAGTCTACTTATGAGGAACTGACCGGGTGGCTGAGGGAGGTGGAGGAGGAGCT VLDTVNEVSRALLELVPWRARE GGCAACCAGTGGAGGACAGTCTCCCACAGGGGAACAGATACCCCAGTTTCAGCA LDKLVSDANEQYKLVSDTIGQR GAGACAGAAGGAATTAAAGAAGGAGGTCATGGAGCACAGGCTGGTGTTGGACAC DEIDAAIQRSQQYEQAADAELA AGTGAATGAGGTGAGCCGTGCTCTCTTAGAGCTGGTGCCCTGGAGAGCCAGAGA VAETKRKLMALGPIRLEQDQTT AGGGCTGGATAAACTTGTGTCCGATGCTAACGAGCAGTACAAACTAGTCAGTGA QLQVQKAFSIDIIRHKDSMDEL CACTATTGGACAAAGGGTGGATGAAATTGATGCTGCTATTCAGAGATCACAACA SHRSEIFGTCGEEQKTVLQEKT GTATGAGCAAGCTGCCGATGCAGAACTAGCTTGGGTTGCTGAAACAAAACGGAA SLIQQYEAISLLNSERYARLER ACTGATGGCTCTGGGTCCAATTCGCCTGGAACAGGACCAGACCACAGCTCAGCT QVLVNQFWETYEELSPWIEETR TCAGGTACAGAAGGCTTTCTCCATTGACATTATTCGACACAAAGATTCAATGGA LIAQLPSPAIDHEQLRQQQEEM TGAACTCTTCAGTCACCGTAGTGAAATCTTTGGCACATGTGGGGAGGAGCAAAA QLRESIAEHKPHIDKLLKIGPQ AACTGTATTACAGGAAAAGACAGAGTCTCTAATACAGCAATATGAAGCCATTAG KELNPEEGEMVEEKYQKAENMY CCTACTCAATTCAGAGCGTTATGCCCGCCTAGAGCGGGCCCAGGTCTTAGTAAA QIKEEVRQRALALDEAVSQSTQ CCAGTTTTGGGAAACTTATGAAGAGCTCAGCCCCTGGATTGAGGAAACTCGGGC TEFHDKIEPMLETLENLSSRLR ACTAATAGCACAGTTACCCTCTCCAGCCATTGATCATGAGCAGCTCAGGCAGCA PPLIPAEVDKIRECISDNKSAT ACAAGAGGAAATGAGGCAATTAAGGGAATCTATTGCTGAACACAAACCTCATAT ELEKLQPSFEALKRRGEELIGR TGACAAACTACTAAAGATAGGCCCACAACTAAAGGAATTAAACCCTGAGGAAGG QGADKDLAAKEIQDKLDQMVFF GGAAATGGTGGAAGAAAAATACCAGAAAGCAGAAAACATGTATGCCCAAATAAA EDIKARAEEREIKFLDVLELAE GGAGGAGGTGCGCCAGCGAGCCCTGGCTCTGGATGAAGCCGTGTCCCAGTCCAC FWYDMAALLTTIKDTQDIVHDL ACAGATTACAGAGTTTCATGATAAAATTGAGCCTATGTTGGAGACACTGGAGAA SPGIDPSIIKQQVEAAETIKEE TCTTTCCTCTCGCCTGCGTATGCCACCACTGATCCCTGCTGAAGTAGACAAGAT DGLHEELEFIRILGADLIFACG CAGAGAGTGCATCAGTGACAATAAGAGTGCCACCGTGGAGCTAGAAAAACTGCA TEKPEVRKSIDEMNNAWENLNK GCCATCCTTTGAGGCCTTGAAGCGCCGTGGAGAGGAGCTTATTGGACGATCTCA WKERLEKLEDAMQAAVQYQDTL GGGAGCAGACAAGGATCTGGCTGCAAAAGAAATCCAGGATAAATTGGATCAAAT AMFDWLDNTVIKLCTMPPVGTD GGTATTCTTCTGGGAGGACATCAAAGCTCGGGCTGAAGAACGAGAAATCAAATT NTVKDQLNEMKEFKVEVYQQQI

TCTTGATGTCCTTGAATTAGCAGAGAAGTTCTGGTATGACATGGCAGCTCTCCT MEKLNHQGELMLKKATDETDRD GACCACCATCAAAGACACCCAGGATATTGTCCATGACTTGGAAAGCCCAGGCAT IREPLTELKHLWENLGEKIAHR TGATCCTTCCATCATCAAACAACAGGTTGAAGCTGCTGAGACTATTAAGGAAGA HKLEGALLALGQFQHALEELMS GACAGATGGTCTGCATGAAGAGCTGGAGTTTATTCGGATCCTTGGAGCAGATTT LTHTEELLDAQRPISGDPKVIE GATTTTTGCCTGTGGAGAAACTGAGAAGCCTGAAGTGAGGAAGAGCATTGATGA ELAKHHVLKNDVLAHQATVETV GATGAATAATGCTTGGGAGAACTTAAACAAAACATGGAAAGAGAGGCTAGAAAA KAGNELLESSAGDDASSLRSRL ACTTGAGGATGCTATGCAAGCTGCTGTGCAGTATCAGGACACTCTTCAGGCTAT AMNQCWESVLQKTEEREQQLQS GTTTGACTGGCTAGATAACACTGTGATTAAACTCTGCACCATGCCCCCTGTTGG LQQAQGFHSEIEDFLLELTRME CACTGACCTCAATACTGTTAAAGATCAGTTAAATGAAATGAAGGAGTTCAAAGT QLSASKPTGGLPETAREQLDTH AGAAGTTTACCAACAGCAAATTGAGATGGAGAAGCTTAATCACCAGGGTGAACT ELYSQLKAKEETYNQLLDKGRL GATGTTAAAGAAAGCTACTGATGAGACGGACAGAGACATTATACGAGAACCACT LLSRDDSGSGSKTEQSVALLEQ GACAGAACTCAAACACCTCTGGGAGAACCTGGGTGAGAAAATTGCCCACCGACA WHWSSKMEERKSKLEEALNLA GCACAAACTAGAAGGGGCTCTGTTGGCCCTTGGTCAGTTCCA CATGCCTTAGA EFQNSLQEFINWLTLAEQSLNI GGAACTAATGAGTTGGCTGACTCATACCGAAGAGTTGTTAGATGCTCAGAGACC SPPSLILNTVLSQIEEHKVFAN AATAAGTGGAGACCCAAAAGTCATTGAAGTTGAGCTCGCAAAGCACCATGTCCT VNAHRDQIIELDQTGNQLKFLS AAAAAATGATGTTTTGGCTCATCAAGCCACAGTGGAAACAGTCAACAAAGCTGG KQDWLIKNLLVSVQSRWEKW CAATGAGCTTCTTGAATCCAGTGCTGGAGATGATGCCAGCAGCTTAAGGAGCCG RSIERGRSLDDARKRAKQFHEA TTTGGAAGCCATGAACCAATGCTGGGAGTCAGTGTTACAGAAAACAGAGGAGAG KKLIDWLEDAESHLDSELEISN GGAGCAGCAGCTTCAGTCAACTCTGCAGCAGGCCCAGGGCTTCCACAGTGAAAT PDKIKLQLSKHKEFQKTLGGKQ TGAAGATTTCCTCTTGGAACTTACTAGAATGGAGAGCCAGCTTTCTGCATCTAA VYDTTIRTGRALFEKTLLPEDT GCCCACAGGAGGACTTCCTGAAACTGCTAGGGAACAGCTTGATACACATATGGA KLDNFLGEVRDKWDTVCGKSVE ACTCTATTCCCAGCTGAAAGCCAAGGAAGAGACTTATAATCAACTACTTGACAA QHKLEEALLFSGQFMDALQALV GGGCAGACTCATGCTTCTAAGCCGTGACGACTCTGGGTCTGGCTCCAAGACAGA WLYKVEPQLAEDQPVHGDLDLV ACAGAGTGTAGCACTTTTGGAGCAGAAGTGGCATGTGGTCAGCAGTAAGATGGA NLMDAHKVFQKELGKRTGTVQV AGAAAGAAAGTCAAAGCTGGAAGAGGCCCTCAACTTGGCAACAGAATTCCAGAA KRSGRELIENSRDDTTWVKGQL TTCCCTACAAGAATTTATCAACTGGCTCACTCTAGCAGAGCAGAGTTTAAACAT ELSTRWDTVCKLSVSKQSRLEQ CGCTTCTCCACCAAGCCTGATTCTAAATACTGTCCTTTCCCAGATAGAAGAGCA LKQAEVFRDTVHMLLEWLSEAE CAAGGTTTTTGCTAATGAAGTAAATGCTCATCGAGACCAGATCATTGAGCTGGA TLRFRGALPDDTEALQSLIDTH TCAAACTGGGAATCAATTAAAGTTCCTTAGCCAAAAGCAGGATGTTGTTCTGAT EFMKKVEEKRVDVNSAVAMGEV CAAGAATTTGTTGGTGAGCGTGCAGTCTCGATGGGAGAAGGTTGTCCAGCGATC LAVCHPDCITTIKHWITIIRAR TATTGAAAGAGGGCGATCACTAGATGATGCCAGGAAGCGGGCAAAACAATTCCA EEVLTWAKQHQQRLETALSELV TGAAGCTTGGAAAAAACTGATTGACTGGCTAGAAGATGCAGAGAGTCACCTGGA NAELLEELLAWIQWAETTLIQR CTCAGAACTAGAGATATCCAATGACCCAGACAAAATTAAACTTCAGCTTTCTAA QEPIPQNIDRVKALIAEHQTFM GCATAAGGAGTTTCAGAAGACTCTTGGTGGCAAGCAGCCTGTGTATGATACCAC EMTRKQPDVDRVTKTYKRKNIE AATTAGAACTGGCAGAGCACTGAAAGAAAAGACTTTGCTTCCCGAAGATACTCA THAPFIEKSRSGGRKSLSQPTP GAAACTTGACAATTTCCTAGGAGAAGTCAGAGACAAATGGGATACTGTTTGTGG PMPILSQSEAKNPRINQLSARW CAAGTCTGTGGAGCGGCAGCACAAGTTGGAGGAAGCCCTGCTCTTTTCGGGTCA QVWLLALERQRKLNDALDRLEE

GTTCATGGATGCTTTGCAGGCATTGGTTGACTGGTTATACAAGGTGGAGCCACA KEFANFDFDVWRKKYMRWMNHK GCTGGCTGAGGACCAGCCCGTGCACGGGGACCTTGACCTCGTCATGAACCTCAT SRVMDFFRRIDKDQDGKITRQE

GGATGCACACAAGGTTTTCCAGAAGGAACTGGGAAAGCGAACAGGAACCGTTCA IDGILASKFPTTKLEMTAVADI GGTCCTGAAGCGGTCAGGCCGAGAGCTGATTGAGAATAGTCGAGATGACACCAC DRDGDGYIDYYEFVAALHPNKD TTGGGTAAAAGGACAGCTCCAGGAACTGAGCACTCGCTGGGACACTGTCTGTAA YRPTTDADKIEDEVTRQVAQCK ACTCTCTGTTTCCAAACAAAGCCGGCTTGAGCAGGCCTTAAAACAAGCGGAAGT AKRFQVEQIGENKYRFGDSQQL GTTTCGAGACACAGTCCACATGCTGTTGGAGTGGCTTTCTGAAGCAGAGCAAAC LVRILRSTVMVRVGGGWMALDE GCTTCGCTTTCGGGGAGCACTTCCTGATGACACAGAGGCCCTGCAGTCTCTCAT LVKNDPCRARGRTNIELREKFI TGACACCCATAAGGAATTCATGAAGAAAGTAGAAGAAAAGCGAGTGGACGTTAA PEGASQGMTPFRSRGRRSKPSS CTCAGCAGTAGCCATGGGAGAAGTCATCCTGGCTGTCTGCCACCCCGATTGCAT AASPTRSSSSASQSNHSCTSMP CACAACCATCAAACACTGGATCACCATCATCCGAGCTCGCTTCGAGGAGGTCCT SPATPASGTKVIPSSGSKLKRP GACATGGGCTAAGCAGCACCAGCAGCGTCTTGAAACGGCCTTGTCAGAACTGGT PTFHSSRTSLAGDTSNSSSPAS GGCTAATGCTGAGCTCCTGGAAGAACTTCTGGCATGGATCCAGTGGGCTGAGAC GAKTNRADPKKSASRPGSRAGS CACCCTCATTCAGCGGGATCAGGAGCCAATCCCGCAGAACATTGACCGAGTTAA AGSRASSRRGSDASDFDLLETQ AGCCCTTATCCCTGAGCATCAGACATTTATGGAGGAGATGACTCGCAAACAGCC ACSDTSESSAAGGQGNSRRGLN TGACGTGGACCGGGTCACCAAGACATACAAAAGGAAAAACATAGAGCCTACTCA PSKIPTMSKKTTTASPRTPGPK CGCGCCTTTCATAGAGAAATCCCGCAGCGGAGGCAGGAAATCCCTAAGTCAGCC AACCCCTCCTCCCATGCCAATCCTTTCACAGTCTGAAGCAAAAAACCCACGGAT CAACCAGCTTTCTGCCCGCTGGCAGCAGGTGTGGCTGTTAGCACTGGAGCGGCA AAGGAAACTGAATGATGCCTTGGATCGGCTGGAGGAGTTGAAAGAATTTGCCAA CTTTGACTTTGATGTCTGGAGGAAAAAGTATATGCGTTGGATGAATCACAAAAA GTCTCGAGTGATGGATTTCTTCCGGCGCATTGATAAGGACCAGGATGGGAAGAT AACACGTCAGGAGTTTATCGATGGCATTTTAGCATCCAAGTTCCCCACCACCAA GTTAGAGATGACTGCTGTGGCTGACATTTTCGACCGAGATGGGGATGGTTACAT TGATTATTATGAATTTGTGGCTGCTCTTCATCCCAACAAGGATGCGTATCGACC AACAACCGATGCAGATAAAATCGAAGATGAGGTTACAAGACAAGTGGCTCAGTG CAAATGTGCAAAAAGGTTTCAGGTGGAGCAGATCGGAGAGAATAAATACCGGTT TGGGGATTCTCAGCAGTTGCGGCTGGTCCGTATTCTGCGCAGCACCGTGATGGT TCGCGTTGGTGGAGGATGGATGGCCTTGGATGAATTTTTAGTGAAAAATGATCC CTGCCGAGCACGAGGTAGAACTAACATTGAACTTAGAGAGAAATTCATCCTACC AGAGGGAGCATCCCAGGGAATGACCCCCTTCCGCTCACGGGGTCGAAGGTCCAA ACCATCTTCCCGGGCAGCTTCCCCTACTCGTTCCAGCTCCAGTGCTAGTCAGAG TAACCACAGCTGTACATCCATGCCATCTTCTCCAGCCACCCCAGCCAGTGGAAC CAAGGTTATCCCATCATCAGGTAGCAAGTTGAAACGACCAACACCAACTTTTCA TTCTAGTCGGACATCCCTTGCTGGTGATACCAGCAATAGTTCTTCCCCGGCCTC CACAGGTGCCAAAACTAATCGGGCAGACCCTAAAAAGTCTGCCAGTCGCCCTGG GAGTCGGGCTGGGAGTCGAGCCGGGAGTCGAGCCAGCAGCCGGCGAGGAAGTGA CGCTTCTGACTTTGACCTCTTAGAGACGCAGTCTGCTTGTTCCGACACTTCAGA AAGCAGCGCTGCAGGGGGCCAAGGCAACTCCAGGAGAGGGCTAAACAAACCTTC

CAAAATCCCAACCATGTCTAAGAAGACCACCACTGCCTCCCCCAGGACTCCAGG TCCCAAGCGATAA

Human prey95234 70 GGCTGACTCAGACGGTTCTGAGAATGTGCTCTGTGGAAATAATCAAATATCTGA 808 ADSDGSENVLCGNNQISDLGIL ADRB3 v4 CTTAGGCATACTGCTTCCAGAGGTGTGTATGGCCCCAGAGGAAAAGGGAGATAA PEVCMAPEEKGDKDDQLNKETE AGACGACCAACTCAACAAAGAAACAGAAGACTATTTGAACAGCCTTTTAGAAGG YLNSLLEGCLKDTEDSLSYEDN ATGTTTAAAAGATACTGAAGATTCCCTTTCCTATGAAGATAACCAAGACGACGA DDDSDLLQDLSPEEASYSLQEN CTCCGATCTCCTTCAAGATCTCTCTCCTGAAGAAGCATCCTATAGTCTCCAGGA PSDESCLSLDDLAKRIEIAEDK GAATCTGCCTTCTGATGAGAGCTGTCTTTCTCTTGATGATCTTGCCAAAAGGAT CTTRHSGLLSSGPLCLPNVIFC AGAGATTGCAGAGGATAAAGGCTGTACTACTCGACATTCAGGACTCCTGTCATC GVSDYTWRLAPSPPPRYTLH TGGCCCACTCTGTCTCCCCAACGTCATCTTCTGTCCTGGGGTCTCAGACTATAC TFALFPLCCRIRRQLQQKDLEK CGTAGTCAGACTGGCCCCCTCGCCACCTCCCAGATACACCTTGCATGTCGTCAC TEQELKGNDGKEQTPSLQTLGQ GTTTGCTCTTTTCCCTCTGTGCTGTAGAATCAGAAGACAGTTACAACAGAAAGA LLKQKGFGGRKKRRESLAIYSP CCTAGAGAAGATCACTGAGCAAGAACTGAAAGGAAATGATGGAAAAGAGCAGAC SKKSRYENAERCFDPGSTQANQ TCCTTCACTTCAGACACTGGGGCAGGCCCTGCTGAAACAAAAGGGTTTTGGTGG TPPSGKRSRRAPSSDPTSSLPE CAGAAAAAAAAGGCGTGAGTCACTGGCTATTTATAGCCCAAACAGTAAGAAGAG SIQSGETKTHLTARTRETPCPT TCGTTATGAAAATGCCGAGAGGTGCTTTGATCCGGGAAGTACACAAGCCAATCA HPRASEHPAFDFVKKSSCLLAP AAATACGCCGCCTTCGGGCAAGAGGAGCCGGAGAGCGCCATCTAGTGACCCCAC ENEFLGNPLDEELLQEGLDLGL AAGTTCCCTTCCTGAAGGAAGTATTCAGTCCGGAGAAACCAAGACCCACCTCAC YTKANCSKIPVPRPFHLWFGA AGCGAGGACCAGAGAGACACCTTGTCCTACCCTTCACCCTCGAGCTTCAGAACA GFTGQFVTEEVAREQVDPERSS CCCAGCTTTTGACTTTGTGAAGAAATCAAGCTGTCTGCTGGCCCCTGGAGAGAA LPWAVAGRSREKLQRVLEKAAL TGAATTCCTTGGAAATCCTTTAGATGAAGAATTGCTTCAAGAAGGGCTAGACCT LGRPTLSSEVGIIICDIANPAS GGGACTGCTCTACACAAAAGCAAATTGTTCCAAGATTCCTGTCCCAAGGCCTTT DEMAKQATWLNCVGPYRFYGE CCACCTGGTGGTGTTCGGCGCGTCTGGCTTCACCGGCCAGTTCGTGACCGAGGA VIKACIENGASCIDISGEPQFL GGTGGCCCGGGAGCAGGTGGACCCGGAGCGGAGCTCCCGCCTGCCCTGGGCCGT LMQLKYHEKAADKGVYIIGSSG GGCGGGCCGCTCCCGGGAGAAGCTGCAGCGGGTGCTGGAGAAGGCGGCCCTGAA DSIPADLGVIYTRNKMNGNY* GCTGGGAAGACCAACACTGTCATCTGAAGTTGGAATCATCATCTGTGATATTGC TAATCCAGCCTCGCTTGATGAAATGGCTAAACAGGCAACAGTTGTCCTCAATTG CGTAGGACCATATCGGTTTTATGGAGAACCTGTAATAAAAGCATGTATTGAAAA TGGAGCCAGTTGTATCGACATCAGTGGAGAACCTCAGTTTCTGGAACTAATGCA ACTGAAGTATCATGAGAAAGCTGCAGACAAAGGGGTTTATATCATTGGAAGCAG CGGCTTTGACTCCATTCCAGCAGATCTGGGAGTAATATATACCAGAAATAAAAT GAATGGTAATTATTGA

Human prey95239 71 GAAAAAAGGGAGGAAAAGTAATGAAAATTCTGAGGTTATTACACCAGGTTTTCC 809 KKGRKSNENSEVITPGFPPNHD ADRB3 v4 CCCTAACCATGATCAGGGTGAACAGTATGAGCATAATCGGGTCCACAAACCTGA GEQYEHNRVHKPDRVHNPGHSH TCGTGTACATAACCCAGGTCATTCTCATGTACATCTTCCAGAACGTAATGGTCA HLPERNGHDPGRGHQDLDPDNE TGATCCTGGTCGTGGACACCAAGATCTTGATCCTGATAATGAAGGTGAACTTCG ELRHTRKREAPHVKNNAIISLR ACATACTAGAAAGAGAGAAGCACCACATGTTAAAAATAATGCAATAATTTCTTT DLNEDDHHHECLNVTQLLKYYG GAGAAAAGATCTAAATGAAGATGACCATCATCATGAATGTTTGAACGTCACTCA GANSPISTDLFTYLCPALLYQI GTTATTAAAATACTATGGTCATGGTGCCAACTCTCCCATCTCAACTGATTTATT SRLCIEHFDKLLVEDINKDKNL

TACATACCTTTGCCCTGCATTGTTATATCAAATCGACAGCAGACTTTGTATTGA PEDEANIGASAWICGIISITVI GCATTTTGACAAACTTTTAGTTGAAGATATAAATAAGGATAAAAACCTGGTTCC LLSLLGVILVPIINQGCFKFLL

'Jl

ACTTAATGTGCAGGTTCCTGAAGAACCCACCCACTTGGACCAACGTGTGATTGG FYLTKSLVATLPDDVQPGPDFY GGACACTCATGCCTCAGAAGTGTCACAGAAGCCAAATACTGAGAAAGACCTGGA LPWKPVFITAFLGIASFAIFLW CCCAGGGCCAGTTACAACAGAAGACACTCCTATGGATGCTATTGATGCAAACAA TVLWKDRVYQVTEQQISEKLK GCAACCAGAGACAGCCGCCGAAGAGCCGGCAAGTGTCACACCTTTGGAAAACGC IMKENTELVQKLSNYEQKIKES AATCCTTCTAATATATTCATTCATGTTTTATTTAACTAAGTCGCTAGTTGCTAC KHVQETRKQNMILSDEAIKYKD ATTGCCTGATGATGTTCAGCCTGGGCCTGATTTTTATGGACTGCCATGGAAACC IKTLEKNQEILDDTAKNLRVML TGTATTTATCACTGCCTTCTTGGGAATTGCTTCGTTTGCCATTTTCTTATGGAG SEREQNVKNQDLISENKKSIEK AACTGTCCTTGTTGTGAAGGATAGAGTATATCAAGTCACGGAACAGCAAATTTC KDVISMNASEFSEVQIALNEAK TGAGAAGTTGAAGACTATCATGAAAGAAAATACAGAACTTGTACAAAAATTGTC SEEKVKSECHRVQEENARLKKK AAATTATGAACAGAAGATCAAGGAATCAAAGAAACATGTTCAGGAAACCAGGAA EQLQQEIEDWSKLHAELSEQIK ACAAAATATGATTCTCTCTGATGAAGCAATTAAATATAAGGATAAAATCAAGAC FEKSQKDLEVALTHKDDNINAL ACTTGAAAAAAATCAGGAAATTCTGGATGACACAGCTAAAAATCTTCGTGTTAT NCITQLNLLECESESEGQNKGG GCTAGAATCTGAGAGAGAACAGAATGTCAAGAATCAGGACTTGATATCAGAAAA DSDELANGEVGGDRNEKMKNQI CAAGAAATCTATAGAGAAGTTAAAGGATGTTATTTCAATGAATGCCTCAGAATT QMMDVSRTQTA1SWEEDLKLL TTCAGAGGTTCAGATTGCACTTAATGAAGCTAAGCTTAGTGAAGAGAAGGTGAA LKLRASVSTKCNLEDQVKKLED GTCTGAATGCCATCGGGTTCAAGAAGAAAATGCTAGGCTTAAGAAGAAAAAAGA RNSLQAAKAGLEDECKTLRQKV GCAGTTGCAGCAGGAAATCGAAGACTGGAGTAAATTACATGCTGAGCTCAGTGA ILNELYQQKEMALQKKLSQEEY GCAAATCAAATCATTTGAGAAGTCTCAGAAAGATTTGGAAGTAGCTCTTACTCA RQEREHRLSAADEKAVSAAEEV CAAGGATGATAATATTAATGCTTTGACTAACTGCATTACACAGTTGAATCTGTT TYKRRIEEMEDELQKTERSFKN AGAGTGTGAATCTGAATCTGAGGGTCAAAATAAAGGTGGAAATGATTCAGATGA IATHEKKAHENWLKARAAERAI oe ATTAGCAAATGGAGAAGTGGGAGGTGACCGGAATGAGAAGATGAAAAATCAAAT EEKREAANLRHKLLELTQKMAM TAAGCAGATGATGGATGTCTCTCGGACACAGACTGCAATATCGGTAGTTGAAGA QEEPVIVKPMPGKPNTQNPPRR GGATCTAAAGCTTTTACAGCTTAAGCTAAGAGCCTCCGTGTCCACTAAATGTAA PLSQNGSFGPSPVSGGECSPPL CCTGGAAGACCAGGTAAAGAAATTGGAAGATGACCGCAACTCACTACAAGCTGC VEPPVRPLSATLNRRDMPRSEF CAAAGCTGGACTGGAAGATGAATGCAAAACCTTGAGGCAGAAAGTGGAGATTCT SVDGPLPHPRWSAEASGKPSPS GAATGAGCTCTATCAGCAGAAGGAGATGGCTTTGCAAAAGAAACTGAGTCAAGA PGSGTATMMNSSSRGSSPTRVL AGAGTATGAACGGCAAGAAAGAGAGCACAGGCTGTCAGCTGCAGATGAAAAGGC EGKVNMAPKGPPPFPGVPLMST AGTTTCGGCTGCAGAGGAAGTAAAAACTTACAAGCGGAGAATTGAAGAAATGGA MGGPVPPPIRYGPPPQLCGPFG GGATGAATTACAGAAGACAGAGCGGTCATTTAAAAACCAGATCGCTACCCATGA RPLPPPFGPGMRPPLGLREFAP GAAGAAAGCTCATGAAAACTGGCTCAAAGCTCGTGCTGCAGAAAGAGCTATAGC VPPGRRDLPLHPRGFLPGHAPF TGAAGAGAAAAGGGAAGCTGCCAATTTGAGACACAAATTATTAGAATTAACACA PLGSLGPREYFIPGTRLPPPTH AAAGATGGCAATGCTGCAAGAAGAACCTGTGATTGTAAAACCAATGCCAGGAAA PQEYPPPPAVRDLLPSGSRDEP ACCAAATACACAAAACCCTCCACGGAGAGGTCCTCTGAGCCAGAATGGCTCTTT PASQSTSQDCSQALKQSP* TGGCCCATCCCCTGTGAGTGGTGGAGAATGCTCCCCTCCATTGACAGTGGAGCC ACCTGTGAGACCTCTCTCTGCTACTCTCAATCGAAGAGATATGCCTAGAAGTGA ATTTGGATCAGTGGACGGGCCTCTACCTCATCCTCGATGGTCAGCTGAGGCATC TGGGAAACCCTCTCCTTCTGATCCAGGATCTGGTACAGCTACCATGATGAACAG CAGCTCAAGAGGCTCTTCCCCTACCAGGGTACTCGATGAAGGCAAGGTTAATAT GGCTCCAAAAGGGCCCCCTCCTTTCCCAGGAGTCCCTCTCATGAGCACCCCCAT

GTCCCGCACCAAATCTGGATCCAAGTCTTCCATATGTGAGTCATCTTCCCTCAT YVKGHAADVFEAYTQLLTEMVL CTCCAGTGCCACAGCAGCAGCTCTACTGAGCTCTGGGGCTGTGGACTACTGCCT LPYQIKKITDTNSRIPPPVFDH GCACGTGCTCAAATCACTGCTGGAATATTGGAAGAGCCAACAGAATGACGAGGA WFYFLSEYLMIQQTPFVRRQVR GCCTGTGGCTACCAGCCAGTTGCTGAAACCACATACTACCTCCTCCCCACCTGA LLLFICGSKEKYRQLRDLHTLD CATGAGCCCATTCTTTCTCCGCCAGTATGTGAAGGGTCATGCTGCTGATGTGTT HVRGIKKLLEEQGIFLRASWT TGAGGCCTATACTCAGCTTCTAACAGAAATGGTACTGAGGCTTCCTTACCAAAT SSGSALQYDTLISLMEHLKACA CAAAAAGATTACTGACACCAATTCTCGAATCCCACCTCCTGTCTTTGACCACTC IAAQRTINWQKFCIKDDSVLYF GTGGTTTTACTTTCTCTCCGAGTACCTCATGATCCAGCAGACTCCATTTGTGCG LQVSFLVDEGVSPVLLQLLSCA CCGTCAAGTCCGCAAACTTCTGCTCTTCATCTGTGGATCCAAAGAGAAGTACCG CGSKVLAALAASSGSSSASSSS CCAGCTCCGGGATTTGCACACCCTGGACTCTCACGTGCGTGGGATCAAGAAGCT PVAASSGQATTQSKSSTKKSKK GCTAGAAGAGCAGGGGATATTCCTCCGGGCAAGTGTGGTTACAGCCAGCTCAGG EKEKEKDGETSGSQEDQLCTAL CTCCGCCTTGCAATATGACACACTCATCAGCCTGATGGAGCACCTGAAAGCCTG NQLNKFADKETLIQFLRCFLLE TGCAGAGATTGCCGCCCAGCGAACCATCAACTGGCAGAAATTCTGCATCAAAGA NSSSVRWQAHCLTLHIYRNSSK TGACTCCGTCCTGTACTTCCTCCTCCAAGTCAGTTTCCTTGTGGATGAGGGCGT QQELLLDLMWSIWPELPAYGRK GTCCCCAGTGCTGCTGCAACTGCTCTCCTGTGCTCTGTGCGGCAGCAAGGTGCT AQFVDLLGYFSLKTPQTEKKLK CGCTGCACTGGCAGCCTCTTCGGGATCCTCCAGTGCTTCTTCCTCCTCAGCCCC YSQKAVEILRTQNHILTNHPNS TGTGGCTGCCAGTTCTGGACAAGCCACAACACAGTCCAAGTCTTCCACTAAAAA IYNTLSGLVEFDGYYLESDPCL GAGCAAGAAAGAAGAAAAAGAAAAGGAGAAAGATGGTGAGACCTCTGGCAGCCA CNNPEVPFCYIKLSSIKVDTRY GGAGGACCAGCTGTGCACAGCTCTGGTGAACCAGCTGAACAAATTTGCCGATAA TTQQWKLIGSHTISKVTVKIG

UI GGAAACCCTGATCCAGTTCCTGCGTTGTTTCCTGTTAGAGTCCAATTCTTCCTC LKRTKMVRTINLYYNNRTVQAI Ul GGTGCGCTGGCAGGCCCACTGTCTGACACTGCACATCTACAGAAATTCCAGCAA ELKNKPARWHKAKKVQLTPGQT ATCTCAACAGGAGCTCCTGCTAGATCTGATGTGGTCCATCTGGCCAGAACTCCC VKIDLPLPIVASNLMIEFADFY AGCCTATGGTCGTAAGGCTGCCCAGTTTGTGGACCTACTAGGATATTTCTCCCT NYQASTETLQCPRCSASVPANP GAAAACTCCACAAACAGAGAAGAAGTTGAAGGAGTATTCACAGAAGGCTGTGGA VCGNCGENVYQCHKCRSINYDE GATTCTGCGGACTCAAAACCATATTCTTACCAACCACCCCAACTCGAACATTTA DPFLCNACGFCKYARFDFMLYA TAACACTTTGTCTGGCTTAGTGGAGTTTGATGGCTATTACCTGGAGAGCGATCC PCCAVDPIENEEDRKKAVSNIN CTGCCTGGTGTGTAATAACCCGGAAGTACCGTTCTGTTATATCAAGCTGTCTTC LLDKADRVYHQLMGHRPQLENL CATTAAAGTGGACACGCGGTACACCACCACCCAGCAGGTTGTGAAGCTCATTGG CKVNEAAPEKPQDDSGTAGGIS CAGTCACACCATCAGCAAAGTGACAGTGAAAATCGGGGATCTGAAACGGACCAA TSASVNRYILQLAQEYCGDCKN GATGGTGCGGACCATCAACCTGTATTATAACAACCGAACCGTGCAGGCCATCGT FDELSKIIQKVFASRKELLEYD GGAGTTGAAAAACAAGCCAGCTCGCTGGCACAAAGCCAAGAAGGTTCAGCTGAC QQREAATKSSRTSVQPTFTASQ CCCTGGACAGACAGAGGTGAAGATTGACCTGCCGTTGCCCATTGTGGCCTCCAA RALSVLGCGHTSSTKCYGCASA TCTGATGATTGAGTTTGCAGACTTCTATGAAAACTACCAGGCCTCCACAGAGAC TEHCITLLRALATNPALRHILV CCTGCAGTGCCCTCGCTGTAGTGCCTCGGTCCCTGCCAACCCAGGAGTCTGTGG QGLIRELFDYNLRRGAAAMREE CAACTGTGGAGAGAATGTGTACCAGTGTCACAAATGCAGATCCATCAACTACGA RQLMCLLTRDNPEATQQMNDLI TGAAAAGGATCCCTTCCTCTGCAATGCCTGTGGCTTCTGTAAATATGCCCGCTT GKVSTALKSHWANPDLASSLQY CGACTTCATGCTCTATGCCAAGCCTTGCTGTGCAGTGGATCCCATTGAGAATGA MLLLTDSISKEDSCWELRLRCA

AGAAGACCGGAAGAAGGCTGTATCCAACATCAATACACTTTTGGACAAAGCTGA SLFLMAVNIKTPVWENITLMC TCGAGTGTATCATCAGCTGATGGGACACCGGCCACAGCTGGAGAACCTGCTCTG RILQKLIKPPAPTSKKNKDVPV

CAAAGTGAATGAGGCAGCTCCAGAAAAGCCACAGGATGACTCAGGAACAGCAGG ALTTVKPYCNEIHAQAQLWLKR GGGCATCAGCTCCACTTCTGCCAGTGTGAATCGTTACATCCTGCAGTTGGCTCA PKASYDAWKKCLPIRGIDGNGK GGAGTATTGTGGAGACTGCAAGAACTCTTTTGATGAACTCTCCAAAATCATCCA PSKSELRHLYLTEKYVWRWKQF GAAAGTCTTTGCTTCGCGCAAAGAGTTGTTGGAATATGACCTACAGCAGAGGGA SRRGKRTSPLDLKLGHNNWLRQ AGCAGCCACTAAATCATCCCGGACCTCCGTGCAGCCCACATTCACTGCCAGCCA LFTPATQAARQAACTIVEALAT GTACCGTGCCTTATCCGTCCTGGGCTGTGGCCACACATCCTCCACCAAGTGCTA PSRKQQVLDLLTSYLDELSIAG TGGCTGCGCCTCGGCTGTCACAGAACATTGTATCACACTACTTCGGGCCCTGGC CAAEYLALYQKLITSAHWKVYL CACCAACCCAGCCTTGAGGCACATCCTTGTCTCCCAGGGCCTTATCCGGGAGCT ARGVLPYVGNLITKEIARLLAL CTTTGATTATAATCTTCGCCGAGGGGCTGCGGCCATGCGGGAGGAGGTCCGCCA EATLSTDLQQGYALKSLTGLLS GCTCATGTGCCTCCTAACTCGAGACAACCCAGAAGCCACCCAACAGATGAATGA FVEVESIKRHFKSRLVGTVLNG CCTGATTATTGGCAAGGTCTCCACAGCCCTGAAGAGCCACTGGGCCAACCCCGA LCLRKLWQRTKLIDETQDMLL TCTGGCAAGTAGCCTGCAGTATGAAATGCTGCTGCTGACGGATTCTATCTCCAA MLEDMTTGTESETKAFMAVCIE GGAGGACAGCTGCTGGGAGCTCCGGTTACGCTGTGCTCTCAGCCTTTTCCTCAT AKRYNLDDYRTPVFIFERI.CS1 GGCTGTGAACATTAAGACTCCTGTGGTGGTTGAAAACATTACCCTCATGTGCCT YPEENEVTEFFVTLEKDPQQED GAGGATCTTGCAGAAGCTGATAAAACCACCTGCTCCCACTAGCAAGAAGAACAA LQGRMPGNPYSSNEPGIGPLMR GGATGTCCCCGTCGAGGCCCTCACCACGGTGAAGCCATACTGCAATGAGATCCA IKNKICQDCDLVALLEDDSGME TGCCCAGGCTCAACTGTGGCTCAAGAGAGACCCCAAGGCATCCTATGATGCCTG LVNNKIISLDLPVAEVYKKVWC GAAGAAGTGTCTTCCTATCAGAGGGATAGATGGCAATGGGAAAGCCCCCAGCAA TNEGEPMRIVYRMRGLLGDATE ATCAGAGCTCCGCCATCTCTATTTGACTGAGAAGTATGTGTGGAGGTGGAAACA FIESLDSTTDEEEDEEEVYKMA

UI GTTCCTGAGTCGTCGGGGGAAGAGGACCTCCCCCTTGGATCTCAAACTGGGGCA VMAQCGGLECMLNRLAGIRDFK

ON TAACAACTGGCTGCGACAAGTGCTTTTCACTCCAGCAACGCAGGCCGCACGGCA GRHLLTVLLKLFSYCVKVKVNR GGCAGCCTGTACCATTGTGGAAGCTCTAGCCACCATTCCCAGCCGCAAGCAGCA QLVKLEMNTLNVMLGTLNLALV GGTCCTGGACCTGCTTACCAGTTACCTGGATGAGCTGAGCATAGCTGGGGAGTG EQESKDSGGAAVAEQVLSIMEI TGCAGCTGAGTACCTGGCTCTCTACCAGAAGCTCATCACTTCTGCGCACTGGAA LDESNAEPLSEDKGNLLLTGDK AGTCTACTTGGCAGCTCGGGGAGTCCTACCCTATGTGGGCAACCTCATCACCAA QLVMLLDQINSTFVRSNPSVLQ GGAAATAGCTCGTCTGCTGGCCCTGGAGGAGGCTACCCTGAGTACCGATCTGCA LLRIIPYLSFGEVEKMQILVER GCAGGGTTATGCCCTTAAAAGTCTCACAGGCCTTCTCTCCTCCTTTGTTGAGGT KPYCNFDKYDEDHSGDDKVFLD GGAATCCATCAAAAGACATTTTAAAAGTCGCTTGGTGGGTACTGTGCTGAATGG FCKIAAGIKNNSNGHQLKDLIL ATACCTGTGCTTGCGGAAGCTGGTGGTGCAGAGGACCAAGCTGATCGATGAGAC KGITQNALDYMKKHIPSAKNLD GCAGGACATGCTGCTGGAGATGCTGGAGGACATGACCACAGGTACAGAATCAGA DIWKKFLSRPALPFILRLLRGL AACCAAGGCCTTCATGGCTGTGTGCATTGAGACAGCCAAGCGCTACAATCTGGA IQHPGTQVLIGTDSIPNLHKLE TGACTACCGGACCCCGGTGTTCATCTTCGAGAGGCTCTGCAGCATCATTTATCC VSSDEGIGTLAENLLEALREHP TGAGGAGAATGAAGTCACTGAGTTCTTTGTGACCCTGGAGAAGGATCCCCAACA VNKKIDAARRETRAEKKRMAMA AGAAGACTTCTTACAGGGCAGGATGCCTGGGAACCCGTATAGCAGCAATGAGCC RQKALGTLGMTTNEKGQWTKT AGGCATCGGGCCGCTGATGAGGGATATAAAGAACAAGATTTGCCAGGACTGTGA LLKQMEELIEEPGLTCCICREG CTTAGTGGCCCTCCTGGAAGATGACAGTGGCATGGAGCTTCTAGTGAACAATAA KFQPTKVLGIYTFTKRVALEEM AATCATTAGTTTGGACCTTCCTGTGGCTGAAGTTTACAAGAAAGTCTGGTGTAC NKPRKQQGYSTVSHFNIVHYDC

CACGAATGAGGGAGAGCCCATGAGGATTGTTTATCGTATGCGGGGGCTGCTGGG LAAVRLARGREEWESAALQNAN CGATGCCACAGAGGAGTTCATTGAGTCCCTGGACTCTACTACAGATGAAGAAGA KCNGLLPVWGPHVPESAFATCL

AGATGAAGAAGAAGTGTATAAAATGGCTGGTGTGATGGCCCAGTGTGGGGGCCT RHNTYLQECTGQREPTYQLNIH GGAATGCATGCTTAACAGACTCGCAGGGATCAGAGATTTCAAGCAGGGACGCCA IKLLFLRFAMEQSFSADTGGGG CCTTCTAACAGTGCTACTGAAATTGTTCAGTTACTGCGTGAAGGTGAAAGTCAA ESNIHLIPYIIHTVLYVLNTTR CCGGCAGCAACTGGTCAAACTGGAAATGAACACCTTGAACGTCATGCTGGGGAC TSREEKNLQGFLEQPKEKWVES CCTAAACCTGGCCCTTGTAGCTGAACAAGAAAGCAAGGACAGTGGGGGTGCAGC FEVDGPYYFTVLALHILPPEQW TGTGGCTGAGCAGGTGCTTAGCATCATGGAGATCATTCTAGATGAGTCCAATGC ATRVEILRRLLVTSQARAVAPG TGAGCCCCTGAGTGAGGACAAGGGCAACCTCCTCCTGACAGGTGACAAGGATCA ATRLTDKAVKDYSAYRSSLLFW ACTGGTGATGCTCTTGGACCAGATCAACAGCACCTTTGTTCGCTCCAACCCCAG LVDLIYNMFKKVPTSNTEGGWS TGTGCTCCAGGGCCTGCTTCGCATCATCCCGTACCTTTCCTTTGGAGAGGTGGA SLAEYIRHNDMPIYEAADKALK GAAAATGCAGATCTTGGTGGAGCGATTCAAACCATACTGCAACTTTGATAAATA FQEEFMPVETFSEFLDVAGLLS TGATGAAGATCACAGTGGTGATGATAAAGTCTTCCTGGACTGCTTCTGTAAAAT ITDPESFLKDLLNSVP* AGCTGCTGGCATCAAGAACAACAGCAATGGGCACCAGCTGAAGGATCTGATTCT CCAGAΛGGGGATCACCCAGAATGCACTTGACTACATGAAΛAACCACATCCCTAG CGCCAAGAATTTGGATGCCGACATCTGGAAAAAGTTTTTGTCTCGCCCAGCCTT GCCATTTATCCTAAGGCTGCTTCGGGGCCTGGCCATCCAGCACCCTGGCACCCA GGTTCTGATTGGAACTGATTCCATCCCGAACCTGCATAAGCTGGAGCAGGTGTC CAGTGATGAGGGCATTGGGACCTTGGCAGAGAACCTGCTGGAAGCCCTGCGGGA ACACCCTGACGTAAACAAGAAGATTGACGCAGCCCGCAGGGAGACCCGGGCAGA GAAGAAACGCATGGCCATGGCAATGAGGCAGAAGGCCCTGGGCACCCTGGGCAT

UI GACGACAAATGAAAAGGGCCAGGTCGTGACCAAGACAGCACTCCTGAAGCAGAT -4 GGAAGAGCTGATCGAGGAGCCTGGCCTCACGTGCTGCATCTGCAGGGAGGGATA CAAGTTCCAGCCCACAAAGGTCCTGGGCATTTATACCTTCACGAAGCGGGTAGC CTTGGAGGAGATGGAGAATAAGCCCCGGAAACAGCAGGGCTACAGCACCGTGTC CCACTTCAACATTGTGCACTACGACTGCCATCTGGCTGCCGTCAGGTTGGCTCG AGGCCGGGAAGAGTGGGAGAGTGCCGCCCTGCAGAATGCCAACACCAAGTGCAA CGGGCTCCTTCCGGTCTGGGGACCTCATGTCCCTGAATCAGCTTTTGCCACTTG CTTGGCAAGACACAACACTTACCTCCAGGAATGTACAGGCCAGCGGGAGCCCAC GTATCAGCTCAACATCCATGACATCAAACTGCTCTTCCTGCGCTTCGCCATGGA GCAGTCGTTCAGCGCAGACACTGGCGGGGGCGGCCGGGAGAGCAACATCCACCT GATCCCGTACATCATTCACACTGTGCTTTACGTCCTGAACACAACCCGAGCAAC TTCCCGAGAAGAGAAGAACCTCCAAGGCTTTCTGGAACAGCCCAAGGAGAAGTG GGTGGAGAGTGCCTTTGAAGTGGACGGGCCCTACTATTTCACAGTCTTGGCCCT TCACATCCTGCCCCCTGAGCAGTGGAGAGCCACACGTGTGGAAATCTTGCGGAG GCTGTTGGTGACCTCGCAGGCTCGGGCAGTGGCTCCAGGTGGAGCCACCAGGCT GACAGATAAGGCAGTGAAGGACTATTCCGCTTACCGTTCTTCCCTTCTCTTTTG GGCCCTCGTCGATCTCATTTACAACATGTTTAAGAAGGTGCCTACCAGTAACAC AGAGGGAGGCTGGTCCTGCTCTCTCGCTGAGTACATCCGCCACAACGACATGCC

CATCTACGAAGCTGCCGACAAAGCCCTGAAAACCTTCCAGGAGGAGTTCATGCC AGTGGAGACCTTCTCAGAGTTCCTCGATGTGGCCGGTCTTTTATCAGAAATCAC

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rji

'Jl I

GGGACAGAGGCCAGCGCGCTGCAACACAAGATCAAGAACTCCATCTGCAAAACT CKTVQSKVDCILQEVEKFTDLEK GTACAATCTAAAGTGGACTGCATTTTGCAAGAAGTTGAGAAGTTTACAGACCTA LYLYLQLPSGLSNGEKSDQNAMS GAGAAACTCTACCTCTACCTTCAGCTGCCTTCTGGTCTCAGCAATGGAGAGAAA SSRAQQMHAFSWIRNTLEEHX AGTGATCAGAATGCCATGTCATCTAGTCGGGCACAACAAATGCATGCCTTTTCC TGGATTCGGAATACCCTAGAGGAACATNCG

Human prey94498 177 ATGACGTCTATTATCAAATTAACTACCCTTTCTGGGGTCCAAGAAGAATCTGCC 915 MTSIIKLTTLSGVQEESALCYLL ADRB3 v3 CTTTGCTATCTTCTCCAAGTTGATGAGTTTAGATTTTTATTGGACTGTGGCTGG QVDEFRFLLDCGWDEHFSMDIID GATGAGCACTTTTCTATGGATATTATTGATTCCCTGAGGAAGCATGTTCACCAG SLRKHVHQIDAVLLSHPDPLHLG ATTGATGCAGTGCTGTTGTCTCACCCTGATCCTCTCCACCTTGGTGCCCTCCCG ALPYAVGKLGLNCAIYATIPVYK TATGCTGTCGGAAAGTTGGGTCTGAACTGTGCTATCTATGCAACCATTCCTGTT MGQMFMYDLYQSRHNTEDFTLFT TATAAAATGGGACAGATGTTCATGTATGATCTTTATCAGTCTCGACACAATACA LDDVDAAFDKIQQLKFSQIVNLK GAAGATTTTACACTCTTTACATTAGATGATGTGGATGCAGCCTTTGATAAAATA GKGHGLSITPLPAGHMIGGTIWK CAGCAGCTAAAATTCTCTCAGATTGTGAATTTGAAAGGTAAAGGACATGGCCTG IVKDGEEEIVYAVDFNHKREIHL TCTATCACACCTCTGCCAGCTGGTCATATGATAGGTGGAACAATATGGAAAATA NGCSLEMLSRPSLLITDSFNATY GTCAAAGATGGAGAAGAAGAAATTGTTTATGCAGTTGACTTCAACCACAAGAGG VQPRRKQRDEQLLTNVLETLRGD GAGATCCATTTAAATGGATGTTCCCTGGAAATGCTAAGCAGGCCTTCCCTACTT GNVLIAVDTAGRVLELAQLLDQI ATCACAGATTCATTCAATGCTACATATGTACAGCCTAGAAGAAAACAGAGAGAT WRTKDAGLGVYSLALLNNVSYNV GAGCAGCTTCTGACAAATGTCCTGGAAACACTTCGAGGTGATGGAAATGTGTTA VEFSKSQVEWMSDKLMRCFEDKR

'Jι ATAGCAGTGGACACAGCAGGCAGAGTTTTGGAACTTGCTCAACTTCTTGATCAG NNPFQFRHLSLCHGLSDLARVPS

Ul ATTTGGAGGACTAAAGATGCAGGATTGGGTGTTTACTCATTGGCACTCCTAAAT PKWLASQPDLECGFSRDLFIQW AATGTCAGTTACAATGTGGTGGAGTTTTCTAAGTCCCAGGTAGAATGGATGAGT CQDPKNSIILTYRTTPGTLARFL GATAAATTGATGAGATGTTTTGAAGACAAAAGAAATAATCCGTTTCAGTTTCGC IDNPSEKITEIELRKRVKLEGKE CATCTCTCTTTATGTCATGGTCTTTCTGACTTGGCCCGTGTACCTAGCCCTAAA LEEYLEKEKLKKEAAKKLEQSKE GTTGTACTTGCCAGCCAACCTGACCTGGAATGCGGATTTTCAAGGGATCTCTTT ADIDSSDESDIEEDIDQPSAHKT ATTCAGTGGTGTCAGGACCCTAAAAACTCAATCATTCTAACCTACAGAACTACT KHDLMMKGEGSRKGSFFKQAKKS CCTGGGACTTTAGCACGTTTCCTAATTGATAATCCTTCTGAAAAAATTACAGAA YPMFPAPEERIKWDEYGEIIKPE ATAGAGTTGAGGAAACGTGTGΛAGCTTGAAGGGAAAGAACTTGAAGAATACTTG DFLVPELQATEEEKSKLESGLTN GAAAAAGAGAAACTAAAGAAAGAAGCTGCCAAAAAGCTTGAGCAGTCAAAAGAG GDEPMDQDLSDVPTKCISTTESI GCAGATATAGATTCCAGTGATGAGAGTGATATTGAGGAAGATATTGACCAGCCA EIKARVTYIDYEGRSDGDSIKKI TCAGCTCATAAGACGAAGCATGACTTGATGATGAAAGGTGAAGGCAGTCGTAAA INQMKPRQLIIVHGPPEASQDLA GGAAGTTTTTTCAAACAGGCAAAAAAGTCCTATCCTATGTTTCCTGCCCCAGAA ECCRAFGGKDIKVYMPKLHETVD GAAAGAATTAAATGGGATGAATATGGAGAGATTATCAAACCAGAGGATTTCTTA ATSETHIYQVRLKDSLVSSLQFC GTGCCAGAGCTTCAAGCTACTGAAGAAGAAAAAAGCAAATTAGAATCTGGTTTG KAKDAELAWIDGVLDMRVSKVDT ACAAATGGAGATGAACCTATGGATCAGGATTTATCTGATGTTCCTACTAAATGT GVILEEGELKDDGEDSEMQVEAP ATTTCTACAACAGAGTCTATTGAAATAAAAGCCCGGGTTACCTACATAGACTAT SDSSVIAQQKAMKSLFGDDEKET GAAGGACGCTCTGATGGGGATTCCATTAAAAAAATCATTAATCAGATGAAACCA GEESEIIPTLEPLPPHEVPGHQS CGACAGTTGATCATCGTCCATGGCCCACCAGAGGCCAGTCAAGATCTGGCAGAG VFMNEPRLSDFKQVLLREGIQAE TGCTGTCGCGCCTTTGGTGGGAAAGATATTAAAGTGTACATGCCAAAGCTACAT FVGGVLVCNNQVAVRRTETGRIG GAAACAGTTGATGCCACTAGTGAAACTCACATCTACCAGGTGAGGTTAAAAGAC LEGCLCQDFYRIRDLLYEQYAIV

Ui -4

ACAAGAACAAGAGATAGAAGATGGAAGAGCCTCTAAGACTTCTTTGGAACACCT TGTAACAAAGCTAAATGAAGACAGAGAAGTCAAAAATGCTGAAATCCTCAGAAT GAAGG

Human prey6586 205 CGTGACAGGTCGCTACACCATCCTCATCAAGTACGGTGGTGACGAGATCCCCTT 943 VTGRYTILIKYGGDEIPFSPYRV ADRB3 v3 CTCCCCGTACCGCGTGCGTGCCGTGCCCACCGGGGACGCCAGCAAGTGCACTGT RAVPTGDASKCTVTVSIGGHGLG CACAGTGTCAATCGGAGGTCACGGGCTAGGTGCTGGCATCGGCCCCACCATTCA AGIGPTIQIGEETVITVDTKAAG GATTGGGGAGGAGACGGTGATCACTGTGGACACTAAGGCGGCAGGCAAAGGCAA KGKVTCTVCTPDGSEVDVDWEN AGTGACGTGCACCGTGTGCACGCCTGATGGCTCAGAGGTGGATGTGGACGTGGT EDGTFDIFYTAPQPGKYVICVRF GGAGAATGAGGACGGCACTTTCGACATCTTCTACACGGCCCCCCAGCCGGGCAA GGEHVPNSPFQVTALAGDQPSVQ ATACGTCATCTGTGTGCGCTTTGGTGGCGAGCACGTGCCCAACAGCCCCTTCCA PPLRSQQLAPQYTYAQGGQQTWA AGTGACGGCTCTGGCTGGGGACCAGCCCTCGGTGCAGCCCCCTCTACGGTCTCA PERPLVGVNGLDVTSLRPFDLVI GCAGCTGGCCCCACAGTACACCTACGCCCAGGGCGGCCAGCAGACTTGGGCCCC PFTIKKGEITGEVRMPSGKVAQP GGAGAGGCCCCTGGTGGGTGTCAATGGGCTGGATGTGACCAGCCTGAGGCCCTT TITDNKDGTVTVRYAPSEAGLHE TGACCTTGTCATCCCCTTCACCATCAAGAAGGGCGAGATCACAGGGGAGGTTCG MDIRYDNMHIPGSPLQFYVDYVN GATGCCCTCAGGCAAGGTGGCGCAGCCCACCATCACTGACAACAAAGACGGCAC CGHVTAYGPGLTHGWNKPATFT CGTGACCGTGCGGTATGCACCCAGCGAGGCTGGCCTGCACGAGATGGACATCCG VNTKDAGEGGLSLAIEGPSKAEI CTATGACAACATGCACATCCCAGGAAGCCCCTTGCAGTTCTATGTGGATTACGT SCTDNQDGTCSVSYLPVLPGDYS CAACTGTGGCCATGTCACTGCCTATGGGCCTGGCCTCACCCATGGAGTAGTGAA ILVKYNEQHVPGSPFTARVTGDD CAAGCCTGCCACCTTCACCGTCAACACCAAGGATGCAGGAGAGGGGGGCCTGTC SMRMSHLKVGSAADIPINISETD TCTGGCCATTGAGGGCCCGTCCAAAGCAGAAATCAGCTGCACTGACAACCAGGA LSLLTATWPPSGREEPCLLKRL TGGGACATGCAGCGTGTCCTACCTGCCTGTGCTGCCGGGGGACTACAGCATTCT RNGHVGISFVPKETGEHLVHVKK AGTCAAGTACAATGAACAGCACGTCCCAGGCAGCCCCTTCACTGCTCGGGTCAC NGQHVASSPIPWISQSEIGDAS AGGTGACGACTCCATGCGTATGTCCCACCTAAAGGTCGGCTCTGCTGCCGACAT RVRVSGQGLHEGHTFEPAEFIID CCCCATCAACATCTCAGAGACGGATCTCAGCCTGCTGACGGCCACTGTGGTCCC TRDAGYGGLSLSIEGPSKVDINT GCCCTCGGGCCGGGAGGAGCCCTGTTTGCTGAAGCGGCTGCGTAATGGCCACGT EDLEDGTCRVTYCPTEPGNYIIN GGGGATTTCATTCGTGCCCAAGGAGACGGGGGAGCACCTGGTGCATGTGAAGAA IKFADQHVPGSPFSVKVTGEGRV AAATGGCCAGCACGTGGCCAGCAGCCCCATCCCGGTGGTGATCAGCCAGTCGGA KESITRRRRAPSVANVGSHCDLS AATTGGGGATGCCAGTCGTGTTCGGGTCTCTGGTCAGGGCCTTCACGAAGGCCA LKIPEISIQDMTAQVTSPSGKTH CACCTTTGAGCCTGCAGAGTTTATCATTGATACCCGCGATGCAGGCTATGGTGG EAEIVEGENHTYCIRFVPAEMGT GCTCAGCCTGTCCATTGAGGGCCCCAGCAAGGTGGACATCAACACAGAGGACCT HTVSVKYKGQHVPGSPFQFTVGP GGAGGACGGGACGTGCAGGGTCACCTACTGCCCCACAGAGCCAGGCAACTACAT LGEGGAHKVRAGGPGLERAEAGV CATCAACATCAAGTTTGCCGACCAGCACGTGCCTGGCAGCCCCTTCTCTGTGAA PAEFSIWTREAGAGGLAIAVEGP GGTGACAGGCGAGGGCCGGGTGAAAGAGAGCATCACCCGCAGGCGTCGGGCTCC SKAEISFEDRKDGSCGVAYWQE TTCAGTGGCCAACGTTGGTAGTCATTGTGACCTCAGCCTGAAAATCCCTGAAAT PGDYEVSVKFNEEHIPDSPFWP TAGCATCCAGGATATGACAGCCCAGGTGACCAGCCCATCGGGCAAGACCCATGA VASPSGDARRLTVSSLQESGLKV GGCCGAGATCGTGGAAGGGGAGAACCACACCTACTGCATCCGCTTTGTTCCCGC NQPASFAVSLNGAKGAIDAKVHS TGAGATGGGCACACACACAGTCAGCGTCAAGTACAAGGGCCAGCACGTGCCTGG PSGALEECYVTEIDQDKYAVRFI GAGCCCCTTCCAGTTCACCGTGGGGCCCCTAGGGGAAGGGGGAGCCCACAAGGT PRENGVYLIDVKFNGTHIPGSPF CCGAGCTGGGGGCCCTGGCCTGGAGAGAGCTGAAGCTGGAGTGCCAGCCGAATT KIRVGEPGHGGDPGLVSAYGAGL

-4

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GAAGAAATGCTGAAGTCTTTTCACAACGAGCTGCTTACGCAGCTGGAGCAGAAG LSAALKKYQTEQRSKGDALDKCQ GTGGAGCTGGACTCCAGGTATCTGAGTGCTGCGCTGAAGAAATACCAGACTGAG AELKKLRKKSQGSKNPQKYSDKE CAAAGGAGCAAAGGCGACGCCCTGGACAAGTGTCAGGCTGAGCTGAAGAAGCTT CGGAAGAAGAGCCAGGGCAGCAAGAATCCTCAGAAGTACTCGGACAAGGAGC

Human prey22 236 ATGGCGGCGGAGCTGGTGGAGGCCAAAAACATGGTGATGAGTTTTCGAGTCTCC 974 MAAELVEAKNMVMSFRVSDLQML

OBRGRP_ GACCTTCAGATGCTCCTGGGTTTCGTGGGCCGGAGTAAGAGTGGACTGAAGCAC LGFVGRSKSGLKHELVTRALQLV

2 GAGCTCGTCACCAGGGCCCTCCAGCTGGTGCAGTTTGACTGTAGCCCTGAGCTG QFDCSPELFKKIKELYETRYAKK TTCAAGAAGATCAAGGAGCTGTACGAGACCCGCTACGCCAAGAAGAACTCGGAG NSEPAPQPHRPLDPLTMHSTYDR CCTGCCCCACAGCCGCACCGGCCCCTGGACCCCCTGACCATGCACTCCACCTAC AGAVPRTPLAGPNIDYPVLYGKY GACCGGGCCGGCGCTGTGCCCAGGACTCCGCTGGCAGGCCCCAATATTGACTAC LNGLGRLPAKTLKPEVRLVKLPF CCCGTGCTCTACGGAAAGTACTTAAACGGACTGGGACGGTTGCCCGCCAAGACC FNMLDELLKPTELVPQNNEKLQE CTCAAGCCAGAAGTCCGCCTGGTGAAGCTGCCGTTCTTTAATATGCTGGATGAG SPCIFALTPRQVELIRKFQGMQP CTGCTGAAGCCCACCGAATTAGTCCCACAGAACAACGAGAAGCTTCAGGAGAGC GVKAVQWLRICYSDTSCPQEDQ CCGTGCATCTTCGCATTGACGCCAAGACAGGTGGAGTTGATCCGGAAATTCCAG YPPNIAVKVNHSYCSVPGYYPSN GGAATGCAGCCCGGAGTTAAAGCCGTGCAGGTCGTCCTGAGAATCTGTTACTCA KPGVEPKRPCRPINLTHLMYLSS GACACCAGCTGCCCTCAGGAGGACCAGTACCCGCCCAACATCGCTGTGAAGGTC ATNRITVTWGNYGKSYSVALYLV AACCACAGCTACTGCTCCGTCCCGGGCTACTACCCCTCCAATAAGCCCGGGGTG RQLTSSELLQRLKTIGVKHPELC GAGCCCAAGAGGCCGTGCCGCCCCATCAACCTCACTCACCTCATGTACCTGTCC KALVKEKLRLDPDSEIATTGVRV TCGGCCACCAACCGCATCACTGTCACCTGGGGGAACTACGGCAAGAGCTACTCG SLICPLVKMRLSVPCRAETCAHL GTGGCCCTGTACCTGGTGCGGCAGCTGACCTCATCGGAGCTGCTGCAGAGGCTG QCFDAVFYLQMNEKKPTWMCPVC AAGACCATTGGGGTAAAGCACCCGGAGCTGTGCAAGGCACTGGTCAAGGAGAAG DKPAPYDQLIIDGLLSKILSECE CTGCGCCTTGATCCTGACAGCGAGATCGCCACCACCGGTGTGCGGGTGTCCCTC DADEIEYLVDGSWCPIRAEKERS ATCTGTCCGCTGGTGAAGATGCGGCTCTCCGTGCCCTGCCGGGCAGAAACCTGC CSPQGAILVLGPSDANGLLPAPS GCCCACCTGCAGTGCTTCGACGCCGTCTTCTACCTGCAGATGAACGAGAAGAAG VNGSGALGSTGGGGPVGSMENGK CCCACCTGGATGTGCCCCGTGTGGGACAAGCCAGCCCCCTACGACCAGCTCATC PGADWDLTLDSSSSSEDEEEEE ATCGACGGGCTCCTCTCGAAGATCCTGAGCGAGTGTGAGGACGCCGACGAGATC EEEEDEDEEGPRPKRRCPFQKGL GAGTACCTGGTGGACGGCTCGIGGTGCCCGATCCGCGCCGAAAAGGAGCGCAGC VPAC* TGCAGCCCGCAGGGCGCCATCCTCGTGCTGGGCCCCTCGGACGCCAATGGGCTC CTGCCCGCCCCCAGCGTCAACGGGAGCGGTGCCCTGGGCAGCACGGGTGGCGGC GGCCCGGTGGGCAGCATGGAGAATGGGAAGCCGGGCGCCGATGTGGTGGACCTC ACGCTGGACAGCTCATCGTCCTCGGAGGATGAGGAGGAGGAGGAAGAGGAGGAG GAAGACGAGGACGAAGAGGGGCCCCGGCCCAAGCGCCGCTGCCCCTTCCAGAAG GGCCTGGTGCCGGCCTGCTGA

Human prey54659 237 CGACCGGGTGCTGCGGGCCATGCTGAAGGCGGAGGAGACCTGCGCGCCCTCGGT 975 DRVLRAMLKAEETCAPSVSYFKC

OBRGRP_ GTCCTACTTCAAATGTGTGCAGAAGGAGGTCCTGCCGTCCATGCGGAAGATCGT VQKEVLPSMRKIVATWMLEVCEE

2 CGCCACCTGGATGCTGGAGGTCTGCGAGGAACAGAAGTGCGAGGAGGAGGTCTT QKCEEEVFPLAMNYLDRFLSLEP CCCGCTGGCCATGAACTACCTGGACCGCTTCCTGTCGCTGGAGCCCGTGAAAAA VKKSRLQLLGATCMFVASKMKET GAGCCGCCTGCAGCTGCTGGGGGCCACTTGCATGTTCGTGGCCTCTAAGATGAA IPLTAEKLCIYTDNSIRPEELLQ GGAGACCATCCCCCTGACGGCCGAGAAGCTGTGCATCTACACCGACAACTCCAT MELLLVNKLKWNLAAMTPHDFIE

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GCTGAGGCTGCAGCCCCAGGAGGCCCCTGAGACCGAAACCAGACTGCGGGAGCT TAESEALEAGEVELSEGEDDTDG CAGTGTAGCTGAAGATGAAGATGAGGAGGAGGAGGCGGAGGAGGCGGCAGCCAC LTPQLEEDEELQGHLGRRKGSKW AGCGGAGAGCGAAGCCCTGGAGGCCGGCGAGGTGGAGCTCTCAGAGGGCGAGGA NRRNDMGETLLHRACIEGQLRRV CGACACCGATGGCCTGACCCCGCAGCTGGAGGAGGACGAGGAGCTTCAGGGCCA QDLVRQGHPLNPRDYCGWTPLHE CCTGGGCCGGCGGAAGGGGAGCAAGTGGAACCGGCGAAACGACATGGGGGAGAC ACNYGHLEIVRFLLDHGAAVDDP CCTGCTGCACCGAGCCTGCATCGAGGGCCAGCTGCGCCGCGTCCAGGACCTTGT GGQGCEGITPLHDALNCGHFEVA GAGGCAGGGCCACCCCCTTAACCCTCGGGACTACTGTGGCTGGACACCTCTGCA ELLLERGASVTLRTRKGLSPLET CGAGGCCTGCAACTACGGGCATCTAGAAATTGTCCGCTTCCTGCTGGACCACGG LQQWVKLYRRDLDLETRQKARAM GGCCGCAGTGGACGACCCAGGTGGCCAGGGCTGCGAAGGCATCACCCCCCTCCA EMLLQAAASGQDPHSSQAFHTPS CGATGCCCTCAACTGTGGCCACTTCGAGGTGGCTGAGCTGCTGCTTGAACGGGG SLLFDPETSPPLSPCPEPPSNST GGCGTCCGTCACCCTCCGCACTCGAAAGGGCCTCAGCCCGCTGGAGACGCTGCA RLPEASQVHVRVSPGQAAPAMAR GCAGTGGGTGAAGCTGTACCGCAGGGACCTGGACCTGGAGACGCGGCAGAAGGC PRRSRHGPASSSSSSEGEDSAGP CAGGGCCATGGAGATGCTGCTCCAGGCGGCTGCCTCGGGCCAAGATCCCCACAG ARPSQKRPRCSATAQRVAAWTPG CTCCCAGGCCTTCCACACCCCAAGCAGCCTTCTGTTTGACCCCGAGACCTCTCC PASNREAATASTSRAAYQAAIRG TCCTTTGAGCCCCTGCCCAGAACCCCCCTCTAATAGCACTAGACTCCCAGAGGC VGSAQSRLGPGPPRGHSKALAPQ CTCTCAGGTCCATGTCAGGGTCTCCCCAGGGCAGGCGGCACCAGCCATGGCCAG AALIPEEECLAGDWLELDMPLTR GCCTCGGAGGAGCAGGCATGGGCCAGCCAGCAGCAGCAGCAGCTCAGAAGGCGA SRRPRPRGTGDNRRPSSTSGSDS GGACAGCGCAGGCCCCGCACGGCCGTCCCAGAAGAGGCCTCGGTGCTCGGCCAC EESRPRARAKQVRLTCMQSCSAP oe AGCACAACGGGTGGCAGCCTGGACGCCTGGCCCCGCCAGCAACAGGGAAGCAGC VNAGPSSLASEPPGSPSTPRVSE CACAGCCAGCACCAGCCGGGCAGCCTACCAGGCAGCCATCCGGGGTGTGGGCAG PSGDSSAAGQPLGPAPPPPIRVR TGCTCAGAGCCGGCTGGGGCCTGGCCCACCGCGGGGCCACAGCAAAGCCCTTGC VQVQDHLFLIPVPHSSDTHSVAW CCCCCAGGCAGCGCTCATCCCGGAGGAGGAGTGCCTGGCTGGGGACTGGCTGGA LAEQAAQRYYQTCGLLPRLTLRK GCTGGACATGCCCCTGACCCGCAGCCGCCGGCCCCGCCCCCGGGGCACTGGAGA EGALLAPQDLIPDVLQSNDEVLA CAACCGCAGGCCCAGTAGTACCTCTGGGTCGGACAGTGAGGAGAGCAGGCCCCG EVTSWDLPPLTDRYRRACQSLGQ TGCCCGΛGCCAAGCAGGTCCGCCTGACCTGCATGCAGAGTTGCAGTGCGCCAGT GEHQQVLQAVELQGLGLSFSACS TAΛCGCAGGGCCCAGCAGCCTGGCTTCAGAACCTCCAGGGAGCCCCAGCACCCC LALDQAQLTPLLRALKLHTALRE CAGGGTCTCAGAGCCCAGTGGGGACAGCTCTGCGGCAGGCCAGCCCTTGGGTCC LRLAGNRLGDKCVAELVAALGTM GGCCCCGCCCCCTCCCATCCGGGTTCGAGTTCAAGTTCAGGATCATCTCTTCCT PSLALLDLSSNHLGPEGLRQLAM CATCCCTGTCCCACACAGCAGTGACACCCACTCTGTGGCCTGGCTGGCCGAGCA GLPGQATLQSLEELDLSMNPLGD GGCGGCCCAGCGCTACTACCAGACCTGCGGGCTGCTGCCCAGGCTCACCCTACG GCGQSLASLLHACPLLSTLRLQA GAAAGAGGGGGCCCTGCTGGCCCCACAGGACCTCATCCCTGATGTGCTGCAGAG CGFGPSFFLSHQTALGSAFQDAE CAATGACGAGGTGTTGGCTGAGGTGACTTCGTGGGACCTGCCCCCGTTGACTGA HLKTLSLSYNALGAPALARTLQS CCGCTACCGCAGGGCCTGCCAGAGCCTGGGGCAAGGGGAGCACCAACAGGTGCT LPAGTLLHLELSSVAAGKGDSDL GCAGGCCGTGGAGCTCCAGGGCTTGGGCCTCTCGTTCAGCGCCTGCTCCCTGGC MEPVFRYLAKEGCALAHLTLSAN CCTGGACCAGGCCCAGCTTACACCCCTGCTGCGGGCCCTCAAGCTGCACACAGC HLGDKAVRDLCRCLSLCPSLISL ACTCCGGGAGCTGCGCCTGGCAGGGAACCGGCTGGGGGACAAGTGTGTGGCTGA DLSANPEISCASLEELLSTLQKR GCTGGTGGCTGCCCTGGGCACCATGCCCAGCCTGGCCCTCCTTGACCTCTCCTC PQGLSFLGLSGCAVQGPLGLGLW CAATCACCTGGGTCCCGAAGGCCTGCGCCAGCTTGCCATGGGGCTCCCAGGCCA DKIAAQLRELQLCSRRLCAEDRD AGCCACCTTGCAGAGTTTGGAGGAGCTGGACTTAAGCATGAACCCCCTGGGGGA ALRQLQPSRPGPGECTLDHGSKL

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GGGAAATGAGGAGACACTGGGAGGGTTTCCTGTCAAGAGTGTTGTTCCAGCTTT IPVFLEKLQVIQCIDVAEQALT GATTACGTTACTTCAGATGGAGCACAATTTTGATATTATGAACCATGCTTGTCG LEMLSRRHSKAILQAGGLADCL AGCCTTAACATACATGATGGAAGCACTTCCTCGATCTTCTGCTGTTGTAGTAGA YLEFFSINAQRNALAIAANCCQ TGCTATTCCTGTCTTTTTAGAAAAGCTGCAAGTTATTCAGTGTATTGATGTGGC ITPDEFHFVADSLPLLTQRLTH AGAGCAGGCCTTGACTGCCTTGGAGATGTTGTCACGGAGACATAGTAAAGCCAT DKKSVESTCLCFARLVDNFQHE TCTACAGGCGGGTGGTTTGGCAGACTGCTTGCTGTACCTAGAATTCTTCAGCAT NLLQQVASKDLLTNVQQLLWT AAATGCCCAAAGAAATGCATTAGCAATTGCAGCTAATTGCTGCCAGAGTATCAC PILSSGMFIMWRMFSLMCSNC GCCAGATGAATTTCATTTTGTGGCAGATTCACTCCCATTGCTAACCCAAAGGCT TLAVQLMKQNIAETLHFLLCGA AACACATCAGGATAAAAAGTCAGTAGAAAGCACTTGCCTTTGTTTTGCACGCCT NGSCQEQIDLVPRSPQELYELT AGTGGACAACTTCCAGCATGAGGAGAATTTACTCCAGCAGGTTGCTTCCAAAGA LICELMPCLPKEGIFAVDTMLK TCTGCTTACAAATGTTCAACAGCTGTTGGTAGTGACTCCACCCATTTTAAGTTC GNAQNTDGAIWQWRDDRGLWHP TGGGATGTTTATAATGGTGGTTCGCATGTTTTCTCTGATGTGTTCCAACTGTCC NRIDSRIIEQINEDTGTARAIQ AACTTTAGCTGTTCAACTTATGAAACAAAACATTGCAGAAACGCTTCACTTTCT KPNPLANSNTSGYSESKKDDAR CCTGTGTGGTGCCTCCAATGGAAGTTGTCAGGAACAGATTGATCTTGTTCCACG QLMKEDPELAKSΓIKTLFGVLY AAGCCCTCAAGAGTTGTATGAACTGACATCTCTGATTTGTGAACTTATGCCATG VYSSSAGPAVRHKCLRAILRII TTTACCAAAAGAAGGCATTTTTGCAGTTGATACCATGTTGAAGAAGGGAAATGC FADAELLKDVLKNHAVSSHIAS ACAGAACACAGATGGTGCGATATGGCAGTGGCGTGATGATCGGGGCCTCTGGCA LSSQDLKIWGALQMAEILMQK TCCATATAACAGGATTGACAGCCGGATCATTGAGCAAATCAATGAGGACACGGG PDIFSVYFRREGVMHQVKHLAE AACAGCACGTGCCATTCAGAGAAAACCTAACCCGTTAGCCAATAGTAACACTAG ESLLTSPPKACTNGSGSMGSTT to

© TGGATATTCAGAGTCAAAGAAGGATGATGCTCGAGCACAGCTTATGAAAGAGGA VSSGTATAATHAAADLGSPSLQ TCCGGAACTGGCTAAGTCTTTTATTAAGACATTATTTGGTGTTCTTTATGAAGT SRDDSLDLSPQGRLSDVLKRKR GTATAGTTCCTCAGCAGGACCTGCGGTCAGACATAAGTGCCTTAGAGCAATTCT PKRGPRRPKYSPPRDDDKVDNQ TAGGATAATTTATTTTGCGGATGCTGAACTTCTGAAGGATGTTCTGAAAAATCA KSPTTTQSPKSSFLASLNPKTW TGCTGTTTCAAGTCACATTGCTTCCATGCTGTCAAGCCAAGACCTGAAGATAGT RLSTQSNSNNIEPARTAGGSGL AGTGGGAGCACTTCAGATGGCAGAAATTTTAATGCAGAAGTTACCTGATATTTT RAASKDTISNNREKIKGWIKEQ TAGTGTTTACTTCAGAAGAGAAGGTGTAATGCATCAAGTAAAACACTTAGCAGA HKFVERYFSSENMDGSNPALNV ATCAGAGTCTTTGTTGACAAGTCCACCAAAGGCATGTACGAATGGATCGGGATC QRLCAATEQLNLQVDGGAECLV CATGGGATCCACAACTTCAGTCAGCAGTGGGACAGCCACAGCTGCCACTCATGC IRSIVSESDVSSFEIQHSGFVK TGCAGCTGACTTGGGATCACCCAGCTTGCAGCACAGCAGGGATGATTCTTTAGA LLLYLTSKSEKDAVSREIRLKR TCTCAGCCCTCAAGGTCGATTAAGTGATGTTCTAAAGAGAAAACGACTGCCAAA LHVFFSSPLPGEEPIGRVEPVG ACGAGGGCCAAGAAGGCCAAAGTACTCACCTCCAAGAGATGATGACAAAGTAGA APLLALVHKMNNCLSQMEQFPV CAATCAAGCTAAAAGCCCCACCACTACTCAGTCACCTAAATCTTCTTTCCTGGC VHDFPSGNGTGGSFSLNRGSQA AAGCTTGAATCCAAAAACATGGGGAAGGTTAAGTACACAGTCCAACAGCAACAA KFFNTHQLKCQLQRHPDCANVK CATTGAGCCAGCACGGACTGCGGGAGGTAGTGGCCTTGCCAGGGCTGCCTCAAA WKGGPVKIDPLALVQAIERYL GGATACCATCTCCAATAATAGAGAAAAAATTAAAGGTTGGATTAAGGAGCAGGC RGYGRVREDDEDSDDDGSDEEI ACATAAATTTGTAGAACGTTATTTCAGTTCTGAGAATATGGATGGAAGCAACCC ESLAAQFLNSGNVRHRLQFYIG TGCATTGAATGTCCTTCAGAGACTTTGTGCTGCAACCGAACAACTCAACCTCCA HLLPYNMTVYQAVRQFSIQAED GGTGGATGGTGGAGCTGAGTGCCTTGTAGAAATCCGTAGCATAGTCTCAGAGTC RESTDDESNPLGRAGIWTKTHT AGATGTTTCATCATTTGAAATCCAACATAGTGGATTTGTGAAGCAGCTGTTGCT WYKPVREDEESNKDCVGGKRGR

TTATTTGACATCTAAAAGTGAAAAGGATGCTGTGAGCAGAGAGATCAGATTAAA QTAPTKTSPRNAKKHDELWHDG GCGATTTCTTCATGTATTTTTTTCTTCTCCACTTCCTGGAGAAGAGCCCATTGG CPSVSNPLEVYLIPTPPENITF AAGAGTGGAACCAGTGGGTAATGCACCTTTGTTGGCATTAGTTCACAAGATGAA DPSLDVILLLRVLHAISRYWYY CAACTGCCTCAGCCAGATGGAACAATTTCCAGTCAAAGTACATGATTTCCCTAG YDNAMCKEIIPTSEFINSKLTA TGGAAATGGGACAGGAGGCAGCTTTTCTCTCAACAGAGGATCACAGGCTTTAAA ANRQLQDPLVIMTGNIPTWLTE ATTTTTCAACACACATCAATTAAAATGCCAGTTACAAAGGCATCCAGACTGTGC GKTCPFFFPFDTRQMLFYVTAF AAATGTGAAGCAGTGGAAGGGTGGACCTGTCAAGATTGACCCTCTGGCTTTGGT RDRAMQRLLDTNPEINQSDSQD ACAAGCCATCGAGAGATACCTTGTAGTTAGAGGGTATGGAAGAGTAAGAGAAGA RVAPRLDRKKRTVNREELLKQA TGATGAAGACAGCGATGACGATGGATCAGATGAGGAAATAGATGAGTCTCTGGC SVMQDLGSSRAMLEIQYENEVG TGCTCAGTTCCTAAATTCAGGAAATGTAAGACACAGGCTGCAGTTTTATATTGG GLGPTLEFYALVSQELQRADLG AGAACATTTGCTGCCGTATAACATGACTGTGTATCAGGCAGTACGGCAGTTTAG WRGEEVTLSNPKGSQEGTKYIQ TATACAGGCTGAAGATGAAAGAGAATCCACAGATGATGAGAGCAATCCTCTAGG LQGLFALPFGRTAKPAHIAKVK CAGAGCTGGTATTTGGACAAAGACTCATACAATATGGTATAAACCTGTGAGAGA KFRFLGKLMAKAIMDFRLVDLP GGATGAAGAAAGTAATAAAGATTGTGTTGGTGGTAAAAGAGGAAGAGCCCAAAC GLPFYKWMLRQETSLTSHDLFD AGCTCCAACGAAAACTTCCCCTAGAAATGCAAAAAAGCATGATGAGTTΛTGGCA DPWARSVYHLEDIVRQKKRLE CGATGGAGTGTGCCCATCAGTATCAAATCCTTTAGAAGTTTACCTCATTCCCAC DKSQTKESLQYALETLTMNGCS ACCACCTGAAAATATAACATTTGAAGACCCGTCATTAGATGTGATCCTTCTTTT EDLGLDFTLPGFPNIELKKGGK AAGAGTTTTACATGCTATCAGTCGATACTGGTATTACTTGTATGATAATGCAAT IPVTIHNLEEYLRLVIFWALNE GTGCAAGGAAATTATTCCAACTAGTGAATTTATTAACAGTAAGTTAACAGCAAA VSRQFDSFRDGFESVFPLSHLQ to

Ul ATGGCTTACTGAGCTAGGAAAAACCTGCCCATTTTTCTTTCCTTTTGATACCCG MECCRPDHGYTHDSRAVKFLFE GCAAATGCTTTTTTATGTAACTGCATTTGATCGGGACCGAGCAATGCAAAGATT LSSFDNEQQRLFLQFVTGSPRL ACTTGATACCAACCCAGAAATCAACCAGTCTGATTCTCAAGATAGCAGAGTTGC VGGFRSLNPPLTIVRKTFESTE ACCTAGATTGGATAGAAAAAAACGTACTGTGAACCGAGAGGAGCTGCTGAAACA PDDFLPSVMTCVNYLKLPDYSS GGCGGAGTCTGTGATGCAGGACCTCGGCAGCTCACGGGCCATGTTAGAAATCCA EIMREKLLIAAREGQQSFHLS* GTATGAAAATGAGGTTGGTACAGGTCTTGGGCCTACACTGGAGTTTTATGCGCT TGTATCTCAGGAACTACAGAGAGCTGACTTGGGTCTTTGGAGAGGTGAAGAAGT AACTCTTAGCAATCCAAAAGGGAGCCAAGAAGGGACCAAGTATATTCAAAACCT CCAGGGCCTGTTTGCGCTTCCCTTTGGTAGGACAGCAAAGCCAGCTCATATCGC AAAGGTTAAGATGAAGTTTCGCTTCTTAGGAAAATTAATGGCCAAGGCTATCAT GGATTTCAGATTGGTGGACCTTCCCCTTGGCTTACCCTTTTATAAATGGATGCT ACGGCAAGAAACTTCACTGACATCACACGATTTGTTTGACATCGACCCAGTTGT AGCCAGATCAGTTTATCACCTAGAAGACATTGTCAGACAGAAGAAAAGACTTGA ACAAGATAAATCCCAGACCAAAGAGAGTCTACAGTATGCATTAGAAACCTTGAC TATGAATGGCTGCTCAGTTGAAGATCTAGGACTGGATTTCACTCTGCCAGGGTT TCCCAATATCGAACTGAAGAAAGGAGGGAAGGATATACCAGTCACTATCCACAA TTTAGAGGAGTATCTAAGACTGGTTATATTCTGGGCACTAAATGAAGGCGTTTC TAGGCAATTTGATTCGTTCAGAGATGGATTTGAATCAGTCTTCCCACTCAGTCA TCTTCAGTACTTCTACCCGGAGGAACTGGATCAGCTCCTTTGTGGCAGTAAAGC

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CAGCTCAAAGAGGTCTGCTGTTTCAGCTCCAAAGTCAACCAAAGGCAATGGTTC YIQEDDIYDDSQEAEVIQSLLD CTACAGTGTGGGGTCTTGCAGCCAGCCTGCCCTCACTCCTAATGATTCATTCTC VDEEAQNLLNENNAAGYSCGPG CACGGTTGCTGGGGAAGAAATAAATGAAATATCGTACCCCAAAGGAAAATGTTC LKMNGKLSEERTEDTDCDGSPL TACTTATCAGATAAAGGGATCACCAAACTTGACTCTGCCCAAAGAATCTTATAT EYFTEATKMNGCEEYCEEKVKS ACAAGAAGATGACATTTATGATGATTCCCAAGAAGCTGAAGTTATCCAGTCTCT SLIQKPQEKKTDDDEITWGNDE GCTGGATGTTGTGGATGAGGAAGCCCAGAATCTTTTAAACGAAAATAATGCAGC PIERTNHEDSDKDHSFLTNDEL AGGATACTCCTGTGGTCCAGGTACATTAAAGATGAATGGGAAGTTATCAGAAGA VLPWKVLPSGKYTGANLKSVI GAGAACAGAAGATACAGACTGCGATGGTTCACCTTTACCTGAGTATTTTACTGA VLRGLLDQGIPSKELENLQELK GGCCACCAAAATGAATGGCTGTGAAGAATATTGTGAAGAAAAAGTAAAAAGTGA LDQCLIGQTKENRRKNRYKNIL AAGCTTAATTCAGAAGCCACAAGAAAAGAAGACTGATGATGATGAAATAACATG YDATRVPLGDEGGYINASFIKI GGGAAATGATGAGTTGCCAATAGAGAGAACAAACCATGAAGATTCTGATAAAGA VGKEEFVYIACQGPLPTTVGDF TCATTCCTTTCTGACAAACGATGAGCTCGCTGTACTCCCTGTCGT AAAGTGCT QMIWEQKSTVIAMMTQEVEGEK TCCCTCTGGTAAATACACGGGTGCCAACTTAΛAA CAGTCATTCGAGTCCTGCG KCQPYWPNILGKTTMVSNRLRL GGGTTTGCTAGATCAAGGAATTCCTTCTAAGGAGCΓGGAGAATCTTCAAGAATT LVRMQQLKGFWRAMTLEDIQT AAAACCTTTGGATCAGTGTCTAATTGGGCAAACTAAGGAAAACAGAAGGAAGAA EVRHISHLNFTAWPDHDTPSQP CAGATATAAAAATATACTTCCCTATGATGCTACAAGAGTGCCTCTTGGAGATGA DLLTFISYMRHIHRSGPIITHC AGGTGGCTATATCAATGCCAGCTTCATTAAGATACCAGTTGGGAAAGAAGAGTT AGIGRSGTLICIDWLGLISQD CGTTTACATTGCCTGCCAAGGACCACTGCCTACAACTGTTGGAGACTTCTGGCA DFDISDLVRCMRLQRHGMVQTE GATGATTTGGGAGCAAAAATCCACAGTGATAGCCATGATGACTCAAGAAGTAGA QYIFCYQVILYVLTRLQAEEEQ AGGAGAAAAAATCAAATGCCAGCGCTATTGGCCCAACATCCTAGGCAAAACAAC QQPQLLK* AATGGTCAGCAACAGACTTCGACTGGCTCTTGTGAGAATGCAGCAGCTGAAGGG CTTTGTGGTGAGGGCAATGACCCTTGAAGATATTCAGACCAGAGAGGTGCGCCA TATTTCTCATCTGAATTTCACTGCCTGGCCAGACCATGATACACCTTCTCAACC AGATGATCTGCTTACTTTTATCTCCTACATGAGACACATCCACAGATCAGGCCC AATCATTACGCACTGCAGTGCTGGCATTGGACGTTCAGGGACCCTGATTTGCAT AGATGTGGTTCTGGGATTAATCAGTCAGGATCTTGATTTTGACATCTCTGATTT GGTGCGCTGCATGAGACTACAAAGACACGGAATGGTTCAGACAGAGGATCAATA TATTTTCTGCTATCAAGTCATCCTTTATGTCCTGACACGTCTTCAAGCAGAAGA AGAGCAAAAACAGCAGCCTCAGCTTCTGAAGTGA

Human prey3722 353 GGAGATGTTGGGATTCGAGGGGACCCGGGTAACCCAGGACAAGACAGCCAGGAG 1091 GDVGIRGDPGNPGQDSQERGPK Melatoni AGAGGACCCAAAGGAGAAACCGGTGACCTCGGCCCCATGGGTGTCCCAGGGAGA ETGDLGPMGVPGRDGVPGGPGE n la GATGGAGTACCTGGAGGACCTGGAGAAACTGGGAAGAATGGTGGCTTTGGCCGA GKNGGFGRRGPPGAKGNKGGPG receptor AGGGGACCCCCCGGAGCTAAGGGCAACAAGGGCGGTCCTGGCCAGCCGGGCTTT PGFEGEQGTRGAQGPAGPAGPP v4 GAGGGAGAGCAGGGGACCAGAGGTGCACAGGGCCCAGCTGGTCCTGCTGGTCCT LIGEQGISGPRGSGGARGAPGE CCAGGGCTGATAGGAGAACAAGGCATTTCTGGACCTAGGGGAAGCGGAGGTGCC GRTGPLGRKGEPGEPGPKGGIG CGTGGCGCTCCTGGAGAACGAGGCAGAACCGGTCCACTGGGAAGAAAGGGTGAG PGPRGETGDDGRDGVGSEGRRG CCCGGAGAGCCAGGACCAAAAGGAGGAATCGGGAACCCGGGCCCTCGTGGGGAG KGERGFPGYPGPKGNPGEPGLN ACGGGAGATGACGGGAGAGACGGAGTTGGCAGTGAAGGACGCAGAGGCAAAAAA TTGPKGIRGRRGNSGPPGIVGQ GGAGAAAGAGGATTTCCTGGATACCCAGGACCAAAGGGTAACCCAGGTGAACCT GRPGYPGPAGPRGNRGDSIDQC

GGGCTAAATGGAACAACAGGACCCAAAGGCATCAGAGGCCGAAGGGGAAATTCG LIQSIKDKCPCCYGPLECPVFP GGACCTCCAGGGATAGTTGGACAGAAGGGGAGACCTGGCTACCCAGGACCAGCT ELAFALDTSEGVNQDTFGRMRD GGTCCAAGGGGCAACAGGGGCGACTCCATCGATCAATGTGCCCTCATCCAAAGC VLSIVNVLTIAESNCPTGARVA ATCAAAGATAAATGCCCTTGCTGTTACGGGCCCCTGGAGTGCCCCGTCTTCCCA VTYNNEVTTEIRFADSKRKSVL ACAGAACTAGCCTTTGCTTTAGACACCTCTGAGGGAGTCAACCAAGACACTTTC DKIKNLQVALTSKQQSLETAMS GGCCGGATGCGAGATGTGGTCTTGAGTATTGTGAATGTCCTGACCATTGCTGAG VARNTFKRVRNGFLMRKVAVFF AGCAACTGCCCGACGGGGGCCCGGGTGGCTGTGGTCACCTACAACAACGAGGTG NTPTRASPQLREAVLKLSDAGI ACCACGGAGATCCGGTTTGCTGACTCCAAGAGGAAGTCGGTCCTCCTGGACAAG PLFLTRQEDRQLINALQINNTA ATTAAGAACCTTCAGGTGGCTCTGACATCCAAACAGCAGAGTCTGGAGACTGCC GHALVLPAGRDLTDFLENVLTC ATGTCGTTTGTGGCCAGGAACACATTTAAGCGTGTGAGGAACGGATTCCTAATG VCLDICNIDPSCGFGSWRPSFR AGGAAAGTGGCTGTTTTCTTCAGCAACACACCCACAAGAGCATCCCCACAGCTC RRAAGSDVDIDMAFILDSAETT AGAGAGGCTGTGCTCAAACTCTCAGATGCGGGGATCACCCCCTTGTTCCTTACA LFQFNEMKKYIAYLVRQLDMSP AGGCAGGAAGACCGCCAGCTCATCAACGCTTTGCAGATCAATAACACAGCAGTG PKASQHFARVAWQHAPSESVD GGGCATGCGCTTGTCCTGCCTGCAGGGAGAGACCTCACAGACTTCCTGGAGAAT ASMPPVKVEFSLTDYGSKEKLV GTCCTCACGTGTCATGTTTGCTTGGACATCTGCAACATCGACCCATCCTGTGGA FLSRGMTQLQGTRALGSAlEYT TTTGGCAGTTGGAGGCCTTCCTTCAGGGACAGGAGAGCGGCAGGGAGTGATGTG ENVFESAPNPRDLKIWLMLTG GACATCGACATGGCTTTCATCTTAGACAGCGCTGAGACCACCACCCTGTTCCAG VPEQQLEEAQRVILQAKCKGYF TTCAATGAGATGAAGAAGTACATAGCGTACCTGGTCAGACAACTGGACATGAGC WLGIGRKVNIKEVYTFASEPN CCAGATCCCAAGGCCTCCCAGCACTTCGCCAGAGTGGCAGTTGTGCAGCACGCG VFFKLVDKSTELNEEPLMRFGR to

I—' CCCTCTGAGTCCGTGGACAATGCCAGCATGCCACCTGTGAAGGTGGAATTCTCC LPSFVSSENAFYLSPDIRKQCD

© CTGACTGACTATGGCTCCAAGGAGAAGCTGGTGGACTTCCTCAGCAGGGGAATG FQGDQPTKNLVKFGHKQVNVPN ACACAGTTGCAGGGAACCAGGGCCTTAGGCAGTGCCATTGAATACACCATAGAG VTSSPTSNPVTTTKPVTTTKPV AATGTCTTTGAAAGTGCCCCAAACCCACGGGACCTGAAAATTGTGGTCCTGATG TTTKPVTTTTKPVTIINQPSVK CTGACGGGCGAGGTGCCGGAGCAGCAGCTGGAGGAGGCCCAGAGAGTCATCCTG AAAKPAPAKPVAAKPVATKTAT CAGGCCAAATGCAAGGGCTACTTCTTCGTGGTCCTGGGCATTGGCAGGAAGGTG RPPVAVKPATAAKPVAAKPAAV AACATCAAGGAGGTATACACCTTCGCCAGTGAGCCAAACGACGTCTTCTTCAAA PPAAAAKPVATKPEVPRPQAAK TTAGTGGACAAGTCCACCGAGCTCAACGAGGAGCCTTTGATGCGCTTCGGGAGG AATKPATTKPWKMLREVQVFE CTGTTGCCGTCCTTCGTCAGCAGTGAAAATGCTTTTTACTTGTCCCCAGATATC TENSAKLHWERPEPPGPYFYDL AGGAAACAGTGTGATTGGTTCCAAGGGGACCAACCCACAAAGAACCTTGTGAAG VTSAHDQSLVLKQNLTVTDRVI TTTGGTCACAAACAAGTAAATGTTCCGAATAACGTTACTTCAAGTCCTACATCC GLLAGQTYHVAWCYLRSQVRA AACCCAGTGACGACAACGAAGCCGGTGACTACGACGAAGCCGGTGACCACCACA YHGSFSTKKSQPPPPQPARSAS ACAAAGCCTGTAACCACCACAACAAAGCCTGTGACTATTATAAATCAGCCATCT STINLMVSTEPLALTETDICKL GTGAAGCCAGCCGCTGCAAAGCCGGCCCCTGCGAAACCTGTGGCTGCCAAGCCT KDEGTCRDFILK YYDPNTKSC GTGGCCACAAAGACGGCCACTGTTAGACCCCCAGTGGCGGTGAAGCCAGCAACA RFWYGGCGGNENKFGSQKECEK GCAGCGAAGCCTGTAGCAGCAAAGCCAGCAGCTGTAAGACCCCCCGCTGCTGCT CAPVLAKPGVISVMGT* GCAAAACCAGTGGCGACCAAGCCTGAGGTCCCTAGGCCACAGGCAGCCAAACCA GCTGCCACCAAGCCAGCCACCACTAAGCCCGTGGTTAAGATGCTCCGTGAAGTC CAGGTGTTTGAGATAACAGAGAACAGCGCCAAACTCCACTGGGAGAGGCCTGAG CCCCCCGGTCCTTATTTTTATGACCTCACCGTCACCTCAGCCCATGATCAGTCC

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ATTNNNNNTGNTNNNGTNTNNAGNNANATGNTTTTNTNCGTATTNGNCNTNGNN XXFCXXXXFXFFXXFXXFFXXF NGTCANTTTNTNNTTTNNTNNTNNGNTTTTTGTNGNNGNTNTTNTTTTNTTTTT XXX TTTTNNTNTTTTANTNNTTTTTTTTTNTTNTTTTTTNTTNTTTTNT

Human prey94650 362 CCCCTCTGCCCTGCTTTGTGTCCCACCTCTCCCCCTCCACTTCCTCTCCTCCCA 1100 PLCPALCPTSPPPLPLLPPSVS Melatoni CCCTCAGTCTCACCCCCGGGCTGTCTCACTCTCTGGAGCCTCTCCTTCCTGTTC PGCLTLWSLSFLFSVPSAPYPH n la TCTGTCCCCAGTGCTCCCTACCCTCACCTCAAGACGACCATGGCCACCATCCCA KTTMATIPDWKLQLLARRRQEE receptor GACTGGAAGCTACAGCTGCTAGCCCGGCGCCGGCAGGAGGAGGCGTCCGTTCGA SVRGREKAERERLSQMPAWKRG v4 GGCCGAGAGAAAGCAGAACGGGAGCGCCTGTCCCAGATGCCAGCCTGGAAACGA LERRRAKLGLSPGEPSPVLGTV GGGCTCCTGGAGCGCCGCCGGGCCAAGCTTGGGCTGTCCCCTGGGGAGCCTAGC AGPPDPDESAVLLEAIGPVHQN CCTGTGCTAGGGACTGTAGAGGCTGGACCTCCAGACCCGGATGAGTCTGCGGTC FIRQERQQQQQQQQRSEELLAE CTTCTGGAGGCCATCGGGCCAGTGCACCAGAACCGATTCATCCGGCAGGAGCGG KPGPLEARERRPSPGEMRDQSP CAGCAGCAGCAGCAGCAACAACAACGGAGTGAAGAGCTGCTAGCAGAGAGAAAG GRESREERLSPRETRERRLGIG CCTGGGCCTCTGGAGGCCCCGGAGCGGAGACCCAGCCCTGGGGAGATGCGGGAT AQELSLRPLEARDWRQSPGEVG CAGAGCCCCAAGGGAAGAGAGTCAAGAGAAGAGAGACTAAGTCCGAGGGAGACC RSSRLSEAWKWRLSPGETPERS AGAGAGAGGAGGCTGGGGATAGGGGGAGCCCAAGAGTTGAGCCTGAGGCCTCTG RLAESREQSPRRKEVESRLSPG GAGGCTCGGGACTGGAGGCAAAGCCCAGGAGAGGTGGGAGACAGGAGCTCCCGA SAYQKLGLTEAHKWRPDSRESQ CTGTCAGAGGCATGGAAATGGAGGCTGAGTCCTGGAGAAACTCCAGAGCGGAGT QSLVQLEATEWRLRSGEERQDY CTGAGACTAGCAGAGTCTCGAGAGCAAAGCCCCAGGAGAAAAGAGGTGGAAAGT EECGRKEEWPVPGVAPKETAEL AGACTGAGCCCAGGGGAATCTGCCTACCAGAAGTTGGGCCTGACAGAGGCCCAT ETLTREAQGNSSAGVEAAEQRP to AAATGGAGACCTGACTCCAGAGAGTCTCAGGAACAGAGTTTGGTACAACTGGAG EDGERGMKPTEGWKWTLNSGKA

I—' UI GCAACAGAGTGGAGGCTGAGGTCAGGAGAAGAAAGACAAGACTACTCGGAAGAA EWTPRDIEAQTQKPEPPESAEK TGTGGGAGAAAAGAAGAGTGGCCAGTTCCAGGGGTAGCTCCAAAAGAGACTGCA LESPGVEAGEGEAEKEEAGAQG GAGCTGTCCGAGACCCTGACAAGGGAGGCCCAAGGCAACAGTTCCGCAGGAGTG PLRALQNCCSVPSPLPPEDAGT GAGGCAGCAGAGCAGAGGCCTGTGGAAGATGGCGAGAGGGGCATGAAGCCAACA GLRQQEEEAVELQPPPPAPLSP GAAGGGTGGAAATGGACCCTGAACTCCGGGAAGGCTCGAGAATGGACACCCAGG PPAPTAPQPPGDPLMSRLFYGV GACATAGAGGCTCAAACTCAGAAACCAGAACCTCCAGAGTCAGCAGAGAAGCTT AGPGVGAPRRSGHTFTVNPRRS CTGGAATCTCCCGGTGTGGAGGCTGGAGAAGGGGAGGCTGAGAAGGAGGAGGCG PPATPATPTSPATVDAAVPGAG GGGGCTCAGGGCAGGCCTCTGAGAGCCCTGCAGAACTGCTGCTCTGTGCCCTCC KRYPTAEEILVLGGYLRLSRSC CCCCTCCCACCAGAGGACGCTGGGACTGGAGGCCTGAGACAGCAGGAAGAGGAA AKGSPERHHKQLKISFSETALE GCAGTGGAGCTCCAGCCCCCACCACCAGCCCCTCTGTCTCCCCCACCCCCAGCC TYQYPSESSVLEELGPEPEVPS CCAACTGCCCCCCAACCTCCTGGGGATCCCCTCATGAGCCGCCTGTTCTATGGG PNPPAAQPDDEEDEEELLLLQP GTGAAGGCAGGGCCAGGGGTGGGGGCCCCCCGCCGCAGTGGACACACCTTCACC LQGGLRTKALIVDESCRR* GTCAACCCCCGGCGGTCTGTGCCCCCTGCGACCCCAGCCACCCCAACCTCTCCA GCCACAGTTGATGCTGCAGTCCCGGGGGCTGGGAAGAAGCGGTACCCAACTGCC GAGGAGATCTTGGTTCTGGGGGGCTACCTCCGTCTCAGCCGCAGCTGCCTTGCC AAGGGGTCCCCCGAAAGACACCACAAACAGCTTAAGATCTCCTTCAGCGAGACA GCCCTGGAGACCACGTACCAATACCCCTCCGAGAGTTCGGTACTGGAGGAGCTG GGCCCGGAGCCTGAGGTCCCCAGTGCCCCCAACCCTCCAGCAGCCCAACCCGAC GACGAAGAGGATGAGGAAGAGCTGCTGCTGCTGCAGCCAGAGCTCCAGGGCGGG

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I—' oe

CCAGGCTTCCCAACAGCTCCAACCCGGGTGGTGATTGCCCGGCCCACTCCTCCA ASPTITVAMPGVPAFLQGMTDF CAGGCTCGGCCTTCCCATCCTGGAGGGCCCCCAGTCTCTGGGACACTGCAGGGC QATQTAPPPPPPPPPPPPAPEQ GCCGGTCTGGGTACCAATGCCTCGTTGGCCCAGATGGTGAGCGGCCTTGTGGGG TMPPPGSPSGGAGSPGGLGLES CAGCTTCTTATGCAGCCAGTCCTTGTGGCTCAGGGGACCCCAGGTATGGCTCCA SPEFFTSWQGVLSSLLGSLGA CCGCCAGCCCCTGCCACTGCTTCTGCCAGTGCTGGCACCACCAACACAGCTACC AGSSESIAAFIQRLSGSSNIFE ACAGCTGGCCCCGCTCCTGGGGGGCCTGCCCAGCCTCCACCCACCCCTCAACCC GADGALGFFGALLSLLCQNFSM TCCATGGCTGATCTTCAGTTCTCTCAGCTTCTGGGGAACCTGCTAGGGCCTGCA DWMLLHGHFQPLQRLQPQLRS GGGCCAGGGGCTGGAGGGTCTGGTGTGGCTTCTCCCACCATCACTGTGGCGATG FHQHYLGGQEPTPSNIRMATHT CCTGGTGTCCCTGCCTTTCTCCAAGGCATGACTGACTTCTTGCAGGCAACACAG ITGLEEYVRESFSLVQVQPGVD ACAGCCCCTCCACCACCCCCACCTCCTCCACCCCCACCACCTGCCCCAGAGCAG IRTNLEFLQEQFNSIAAHVLHC CAGACCATGCCCCCACCAGGCTCCCCTTCTGGTGGCGCAGGGAGTCCTGGAGGC DSGFGARLLELCNQGLFECLAL CTGGGTCTTGAGAGCCTGTCACCGGAGTTTTTTACCTCAGTGGTGCAGGGTGTG LHCLGGQQMELAAVINGRIRRM CTCAGCTCCCTGCTGGGCTCCCTGGGGGCTCGGGCTGGCAGCAGTGAAAGTATT RGVNPSLVSWLTTMMGLRLQW GCTGCCTTCATACAACGCCTCAGTGGATCCAGCAACATCTTTGAGCCTGGAGCT EHMPVGPDAILRYVRRVGDPPQ GATGGGGCCCTTGGATTCTTTGGGGCCTTGCTTTCTCTTCTGTGCCAGAACTTC LPEEPMEVQGAERASPEPQREN TCTATGGTGGACGTAGTGATGCTTCTCCATGGGCATTTCCAGCCACTACAACGG SPAPGTTAEEAMSRGPPPAPEG CTCCAGCCCCAGCTGCGATCCTTCTTCCACCAGCACTACCTGGGTGGTCAGGAG SRDEQDGASAETEPWAAAVPPE CCCACACCCAGTAACATCCGGATGGCAACCCACACATTGATCACGGGGCTAGAA VPIIQQDIQSQRKVKPQPPLSD GAGTATGTGCGGGAGAGTTTTTCCTTGGTGCAGGTTCAGCCAGGTGTGGACATC YLSGMPAKRRKTMQGEGPQLLL to

I—' ATCCGGACAAACCTGGAATTTCTCCAAGAGCAGTTTAATAGCATTGCTGCGCAT EAVSRAAKAAGARPLTSPESLS VO GTGCTGCATTGCACAGATAGTGGATTTGGGGCCCGGTTGCTGGAGTTGTGTAAC DLEAPEVQESYRQQLRSDIQKR CAAGGCCTGTTTGAATGCCTGGCCCTAAACCTGCACTGCTTGGGGGGACAGCAG QEDPNYSPQRFPNAQRAFADDP ATGGAGCTTGCTGCTGTTATCAATGGCCGAATTCGTCGTATGTCTCGTGGGGTG AATCCCTCCTTGGTGAGCTGGCTGACCACTATGATGGGACTGAGGCTTCAGGTG GTACTGGAGCACATGCCTGTAGGCCCTGATGCCATTCTCAGATACGTTCGCAGG GTTGGTGATCCCCCCCAGCCACTTCCTGAGGAGCCAATGGAAGTTCAGGGAGCA GAAAGAGCTTCCCCTGAGCCTCAGCGGGAGAATGCTTCCCCAGCCCCTGGAACA ACAGCAGAAGAGGCCATGTCCCGAGGTCCACCTCCTGCTCCTGAGGGGGGCTCC CGGGATGAACAGGATGGAGCTTCAGCTGAGACAGAACCTTGGGCAGCTGCAGTC CCCCCAGAATGGGTCCCTATTATCCAGCAGGACATTCAGAGCCAGCGGAAGGTG AAACCGCAGCCCCCTCTGAGTGATGCCTACCTCAGTGGTATGCCTGCCAAGAGA CGCAAGACGATGCAGGGTGAGGGCCCCCAGCTGCTTCTCTCAGAGGCTGTGAGC CGGGCAGCTAAGGCAGCCGGAGCTCGGCCCCTGACGAGCCCCGAGAGCCTGAGC CGGGACCTGGAGGCACCAGAGGTTCAGGAGAGCTACAGGCAGCAGCTCCGGTCT GATATACAAAAACGACTGCAGGAAGACCCCAACTACAGTCCCCAGCGCTTCCCC AATGCCCAGCGGGCCTTTGCTGATGATCCTTAG

Human prey94692 373 CCCTCCCGCCTCAGCTACCCAAGTAGTTTGCTTTGTTTTTTTTAATCTAAAAGC llll PSRLSYPSSLLCFF*SKSKGVS Melatoni AAAGGTGTGAGCTTGATAAAGAAGTCTTGTGGTGAAGCAAAATGAAAAAATCTC IKKSCGEAK*KNLNLESI*II* n la AACCTTGAAAGCATTTAAATTATCTGAAGCAATTCTATAGCAAGTCTTTATAAT NSIASLYNSSTNHVKN**DMAV

GGACTACCGGCGCCTGCACAAGCCGCCCAAGGTGCAGGAGAAGTGCCAGCTGGA YEEWLLNEIRRLERLDHLAEKF GATCAACTTCAACACGCTGCAGACCAAGCTGCGGCTCAGCAACCGGCCTGCCTT QKASIHEAWTDGKEAMLRQKDY CATGCCCTCTGAGGGCAGGATGGTCTCGGACATCAACAATGCCTGGGGCTGCCT TATLSEIKALLKKHEAFESDLA GGAGCAGGTGGAGAAGGGCTATGAGGAGTGGTTGCTGAATGAGATCCGGAGGCT HQDRVEQIAAIAQELNELDYYD GGAGCGACTGGACCACCTGGCAGAGAAGTTCCGGCAGAAGGCCTCCATCCACGA PSVNARCQKICDQWDNLGALTQ GGCCTGGACTGACGGCAAAGAGGCCATGCTGCGACAGAAGGACTATGAGACCGC RREALERTEKLLETIDQLYLEY CACCCTCTCGGAGATCAAGGCCCTGCTCAAGAAGCATGAGGCCTTCGAGAGTGA KRAAPFNNWMEGAMEDLQDTFI CCTGGCTGCCCACCAGGACCGTGTGGAGCAGATTGCCGCCATCGCACAGGAGCT HTIEEIQGLTTAHEQFKATLPD CAATGAGCTGGACTATTATGACTCACCCAGTGTCAACGCCCGTTGCCAAAAGAT DKERLAILGIHNEVSKIVQTYH CTGTGACCAGTGGGACAATCTGGGGGCCCTAACTCAGAAGCGAAGGGAAGCTCT NMAGTNPYTTITPQEINGKWDH GGAGCGGACCGAGAAACTGCTGGAGACCATTGACCAGCTGTACTTGGAGTATGC RQLVPRRDQALTEEHARQQHNE CAAGCGGGCTGCACCCTTCAACAACTGGATGGAGGGGGCCATGGAGGACCTGCA LRKQFGAQANVIGPWIQTKMEE GGACACCTTCATTGTGCACACCATTGAGGAGATCCAGGGACTGACCACAGCCCA GRISIEMHGTLEDQLSHLRQYE TGAGCAGTTCAAGGCCACCCTCCCTGATGCCGACAAGGAGCGCCTGGCCATCCT SIVNYKPKIDQLEGDHQLIQEA GGGCATCCACAATGAGGTGTCCAAGATTGTCCAGACCTACCACGTCAATATGGC IFDNKHTNYTMEHIRVGWEQLL GGGCACCAACCCCTACACAACCATCACGCCTCAGGAGATCAATGGCAAATGGGA TIARTINEVENQILTRDAKGIS CCACGTGCGGCAGCTGGTGCCTCGGAGGGACCAAGCTCTGACGGAGGAGCATGC EQMNEFRASFNHFDRDHSGTLG CCGACAGCAGCACAATGAGAGGCTACGCAAGCAGTTTGGAGCCCAGGCCAATGT EEFKACLISLGYDIGNDPQGEA CATCGGGCCCTGGATCCAGACCAAGATGGAGGAGATCGGGAGGATCTCCATTGA FARIMSIVDPNRLGWTFQAFI GATGCATGGGACCCTGGAGGACCAGCTCAGCCACCTGCGGCAGTATGAGAAGAG FMSRETADTDTADQVMASFKIL CATCGTCAACTACAAGCCAAAGATTGATCAGCTGGAGGGCGACCACCAGCTCAT GDKNYITMDELRRELPPDQAEY CCAGGAGGCGCTCATCTTCGACAACAAGCACACCAACTACACCATGGAGCACAT IARMAPYTGPDSVPGALDYMSF CCGTGTGGGCTGGGAGCAGCTGCTCACCACCATCGCCAGGACCATCAATGAGGT TALYGESDL* AGAGAACCAGATCCTGACCCGGGATGCCAAGGGCATCAGCCAGGAGCAGATGAA TGAGTTCCGGGCCTCCTTCAACCACTTTGACCGGGATCACTCCGGCACACTGGG TCCCGAGGAGTTCAAAGCCTGCCTCATCAGCTTGGGTTATGATATTGGCAACGA CCCCCAGGGAGAAGCAGAATTTGCCCGCATCATGAGCATTGTGGACCCCAACCG CCTGGGGGTAGTGACATTCCAGGCCTTCATTGACTTCATGTCCCGCGAGACAGC CGACACAGATACAGCAGACCAAGTCATGGCTTCCTTCAAGATCCTGGCTGGGGA CAAGAACTACATTACCATGGACGAGCTGCGCCGCGAGCTGCCACCCGACCAGGC TGAGTACTGCATCGCGCGGATGGCCCCCTACACCGGCCCCGACTCCGTGCCAGG TGCTCTGGACTACATGTCCTTCTCCACGGCGCTGTACGGCGAGAGTGACCTCTA A

Human prey94722 380 AGATATATTAATAAAATCTGTGGAATCTTTAATTGAGCATAATGGTGGCTGTTA 1118 RYINKICGIFN*A*WWLLF*LE Melatoni TTTTAACTTGAGGCTTTTTGTTGAGCTGGATTGGAAGTGCAACTTATTAGAAAT FC*AGLEVQLIRNYSVFIPIS n la TACAGTGTATTTATTCCTATTTCTTGTTCTTTATGTGAGAGAAGATATACTTTA LCERRYTLVD*ILQSCISFTN receptor GTAGACTGAATACTTCAGAGCTGTATCTCATTTACCAATAAAATGTGAAAACAG *KQW*IPSLGLPLYRPILMV*F v4 TGGTAAATTCCTTCACTTGGGCTACCATTGTACAGGCCTATTTTAATGGTATAG ILNVKSNIX*RGWXIXIXQYX TTTGATATCCTTAATGTTAAAAGCAATATAGNTTAAAGAGGCTGGTNAATTANA FXLXXXXGVWXLPXXXX

n la GTATGTACTTCTTTTTTTTTTTTNNAAANGGNNTTTGNTTTTTAGGGGGGCGGC XFXF*GGGXRGGGGVGGGSWGG receptor GNNAGGGGGGGNGGGGGGGTNGGTGGGGGGAGTTGGGGGGGGGCCGNGGGGNGG XGXVAXGRGGGGXXXXXVXXXX v4 GTGGCNNGGGGAAGGGGGGGGGGGGGGGNCNGGNGTGNGGNNGTNTNTNCCNGC XWXXGXGRRGXGXGSACANRXX TNNGNGNCGTGGNGGNGGGGAGNNGGGCGGCGGGGGCANGGGNGCGGATCGGCN ARXXAXXAGAXVXXXGSXXPRG TGCGCAAACCGCNGGNGGAGGGCGCGGGNGNNGGCGNGCGNGGCGGGNGCGNGG GXEXPXRXXRXGGAGXCCGQXG GTGNGCNGNNGGGGGTCGNGNNCGCCTCGAGGGNAGGGNGNNGAGNGTCCNNTG XRG CGNNNGNGACGTNGGGGGGGCGCGGGGNNGTGTTGCGGGCAGGNGGGGGGGGNG CGTGGGTG

Human prey3604 390 CGACACGAGACGCTTCTCGGCAGACGCAGCTCGATTCCAGATAGGAAAAAGGAA 1128 DTRRFSADAARFQIGKRKYDFD Melatoni ATATGACTTTGATTCTTCGGAGGTGCTTCAGGGACTGGACTTTTTTGGAAACAA SEVLQGLDFFGNKKSVPGVCGA n la GAAGTCTGTCCCAGGTGTGTGTGGAGCATCACAAACACATCAGAAGCCCCAAAA QTHQKPQNGEKKEESLTERKRE receptor TGGAGAGAAAAAAGAAGAGAGCCTAACTGAAAGGAAGAGGGAGCAGAGCAAGAA SKKKRKTMTSEIASQEEGATIQ v4 AAAAAGGAAGACGATGACTTCAGΛAATTGCTTCCCAAGAAGAAGGTGCTACT^T MSSVEAKIEDKKVQRESKLTSG ACAGTGGATGTCATCTGTAGAAGCAAAGATTGAAGACAAAAAAGTTCAGAGAGA LENLRKEKINFLRNKHKIHVQG AAGTAAACTAACTTCCGGAAAGTTGGAGAATCTCAGAAAAGAAAAGATAAACTT DLPDPIATFQQLDQEYKINSRL CTTGCGGAATAAACACAAAATTCACGTCCAAGGAACCGATCTTCCTGACCCAAT QNILDAGFQMPTPIQMQAIPVM TGCTACATTTCAGCAACTTGACCAGGAATATAAAATCAATTCTCGACTACTTCA HGRELLASAPTGSGKTLAFSIP GAACATTCTAGATGCAGGTTTCCAAATGCCTACGCCAATCCAAATGCAAGCCAT LMQLKQPANKGFRALIISPTRE CCCAGTTATGCTGCATGGTCGGGAACTTCTGGCTTCTGCTCCAACTGGATCTGG ASQIHRELIKISEGTGFRIHMI to to AAAAACATTAGCTTTTAGCATTCCTATTTTAATGCAGCTGAAACAACCCGCAAA KAAVAAKKFGPKSSKKFDILVT

Ul TAAAGGCTTCAGAGCCCTGATTATATCACCAACACGAGAACTTGCCAGCCAGAT PNRLIYLLKQDPPGIDLASVEW TCACAGAGAGTTAATAAAAATTTCTGAGGGAACAGGATTCAGGATACACATGAT WDESDKLLKMQTGSETSWLPF CCACAAAGCAGCAGTGGCAGCCAAGAAATTTGGACCTAAATCATCTAAAAAGTT WPAHPTRSEEPMFSATFAYDVE TGATATTCTTGTGACTACTCCAAATCGACTAATCTATTTATTAAAGCAAGATCC WCNSTWTMSSVCPLEARNSAVE CCCCGGAATCGACCTAGCAAGTGTTGAGTGGCTTGTAGTAGACGAATCAGATAA VEQELLFVGSETGKLLAVRELV ACTGTTGAAGATGCAAACTGGTTCAGAGACCAGCTGGCTTCCATTTTCCTGGCC KGFNPPVLVFVQSIERAKELFH TGCACATCCCACAAGGTCCGAAGAGCCTATGTTCAGTGCAACTTTTGCATATGA LIYEGINVDVIHAERTQQQRDN TGTTGAACAGTGGTGCAACTCAACCTGGACAATGTCATCAGTGTGTCCATTGGA VHSFRAGKIWVLICTALLARGI AGCAAGGAATTCTGCAGTAGAAACTGTAGAACAAGAGCTTCTCTTTGTTGGATC FKGVNLVINYDFPTSSVEYIHR TGAGACCGGAAAACTTCTGGCCGTGAGAGAACTTGTTAAAAAGGGTTTCAATCC GRTGRAGNKGKAITFFTEDDKP ACCTGTTCTTGTTTTTGTTCAGTCCATTGAAAGGGCTAAAGAACTTTTTCATGA LRSVANVIQQAGCPVPEYIKGF GCTCATATATGAAGGTATTAATGTGGATGTTATTCATGCAGAGAGAACACAACA KLLSKQKKKMIKKPLERESIST ACAGAGAGATAACACAGTCCACAGTTTCAGAGCAGGAAAAATCTGGGTTCTGAT PKCFLEKAKDKQKKVTGQNSKK TTGTACAGCCTTGCTAGCAAGAGGGATTGATTTTAAAGGTGTGAACTTGGTGAT VALEDKS* CAACTATGACTTTCCAACTAGCTCAGTGGAATATATCCACAGGATAGGTCGAAC TGGAAGAGCAGGGAATAAGGGAAAAGCAATTACATTTTTCACTGAGGATGATAA GCCATTATTAAGAAGCGTTGCTAATGTTATACAGCAGGCTGGGTGTCCTGTACC AGAATACATAAAAGGTTTTCAGAAACTACTAAGCAAACAAAAGAAAAAGATGAT TAAGAAACCATTGGAAAGGGAGAGCATTAGTACAACTCCAAAATGTTTCTTAGA

AAAAGCTAAGGATAAACAGAAAAAGGTCACTGGTCAGAACAGCAAGAAGAAAGT AGCTCTTGAAGACAAAAGTTAA

Human prey3640 391 ACAGACATTTTCCACAGCCAGCGTAGGAACAGCTCCTCCAAATATGGGGGCTTC 1129 QTFSTASVGTAPPNMGASFGSP Melatoni CTTTGGGAGCCCAACGTTTAGCTCAACTGTTCCAAGCACAGCCTCTCCAATGAA FSSTVPSTASPMNTVPPPPIPP n la CACAGTCCCGCCGCCACCAATTCCTCCAATTCCAGCGATGCCATCTCTGCCACC PAMPSLPPMPSIPPIPVPPPVP receptor AATGCCATCCATTCCCCCAATTCCAGTTCCTCCTCCAGTACCTACATTGCCTCC LPPVPPVPPIPPVPSVPPMTPL v4 TGTGCCTCCTGTGCCCCCGATTCCCCCAGTTCCTTCTGTGCCACCCATGACCCC PMSGMPPLNPPPVAPLPAGMNG ACTGCCACCCATGTCGGGCATGCCGCCCTTGAATCCGCCACCTGTGGCACCTCT GAPMNLNNNLNPMFLGPLNPVN ACCTGCTGGAATGAATGGCTCTGGAGCACCTATGAATTTGAACAATAATCTGAA IQMNSQSSVKPLPINPDDLYVS TCCTATGTTTCTTGGTCCGTTGAATCCTGTTAACCCTATCCAGATGAACTCTCA HGMPFSAMENDVRDFFHGLRVD GAGCAGTGTGAAGCCACTCCCCATCAACCCTGATGATCTGTATGTCAGTGTGCA VHLLKDHVGRNNGNGLVKFLSP TGGAATGCCCTTTTCTGCAATGGAAAATGATGTCAGAGATTTTTTTCATGGGCT DTFEALKRNRMLMIQRYVEVSP CCGTGTTGATGCAGTGCATTTGTTGAAAGATCATGTAGGTCGAAATAATGGGAA TERQVIVAAGGHITFKQNMGPSG TGGATTGGTTAAGTTTCTCTCCCCTCAAGATACATTTGAAGCTTTGAAACGAAA THPPPQT PRSKSPSGQKRSRS CAGAATGCTGATGATTCAACGCTATGTGGAAGTTAGCCCTGCCACAGAAAGACA SPHEAGFCVYLKGLPFEAENKH GTGGGTAGCTGCTGGAGGCCATATCACTTTTAAGCAAAATATGGGACCTTCTGG IDFFKKLDIVEDSIYIAYGPNG ACAAACTCATCCCCCTCCTCAGACACTTCCCAGGTCAAAATCGCCCAGTGGGCA ATGEGFVEFRNEADYKAALCRH GAAAAGATCAAGGTCAAGATCACCACATGAGGCTGGTTTTTGTGTTTACTTGAA QYMGNRFIQVHPITKKGMLEKI AGGGCTACCATTTGAAGCAGAAAACAAACATGTCATTGATTTTTTTAAAAAGCT MIRKRLQNFSYDQREMILNPEG GGATATTGTGGAAGATAGTATTTATATAGCTTATGGACCCAATGGGAAAGCAAC VNSAKVCAHITNIPFSITKMDV TGGCGAAGGCTTTGTAGAGTTCAGAAATGAGGCTGACTATAAGGCTGCTCTGTG QFLEGIPVDENAVHVLVDNNGQ TCGTCATAAACAGTACATGGGCAATCGCTTTATTCAAGTTCATCCAATTACTAA LGQALVQFKNEDDARKTERLHR GAAAGGTATGCTAGAAAAGATAGATATGATTCGAAAAAGACTGCAGAACTTCAG KLNGREAFVHWTLEDMREIEK CTATGACCAGAGGGAAATGATACTAAATCCAGAGGGGGATGTCAACTCTGCCAA PPAQGKKGLKMPVPGNPAVPGM AGTCTGTGCCCACATAACAAATATTCCATTCAGCATTACAAAGATGGATGTTCT NAGLPGVGLPSAGLPGAGLPST TCAGTTCCTAGAAGGAATCCCAGTGGATGAAAATGCTGTACATGTTCTTGTTGA LPGSAITSAGLPGAGMPSAGIP TAACAATGGGCAAGGTCTAGGACAGGCATTGGTTCAGTTTAAAAATGAAGATGA AGGEEHAFLTVGSKEANNGPPF TGCACGTAAGACTGAACGCTTACACCGTAAAAAACTTAATGGGAGAGAAGCTTT FPGNFGGSNAFGPPIPPPGLGG TGTTCATGTAGTTACCCTAGAAGATATGAGAGAGATTGAGAAAAATCCCCCTGC AFGDARPGMPSVGNSGLPGLGL CCAAGGAAAAAAGGGATTAAAGATGCCTGTGCCAGGTAATCCTGCAGTTCCAGG VPGFGGGPNNLSGPSGFGGGPQ AATGCCCAATGCGGGACTGCCCGGTGTGGGACTGCCCAGTGCAGGACTTCCCGG FGNGPGSLGGPPGFGSGPPGLG TGCAGGCCTGCCCAGCACAGGACTGCCTGGTTCAGCAATAACCAGTGCAGGACT APGHLGGPPAFGPGPGPGPGPG GCCTGGTGCGGGAATGCCCAGTGCAGGAATACCTAGTGCAGGAGGTGAAGAGCA IHIGGPPGFASSSGKPGPTVIK TGCCTTCCTGACTGTAGGATCAAAGGAAGCCAATAATGGGCCTCCATTTAACTT QNMPFTVSIDEILDFFYGYQVI TCCTGGTAATTTTGGTGGATCAAATGCCTTTGGGCCACCAATCCCTCCTCCAGG GSVCLKYNEKGMPTGEAMVAFE ATTAGGAGGCGGGGCCTTTGGTGATGCTAGGCCTGGTATGCCTTCAGTTGGAAA RDEATAAVIDLNDRPIGSRKVK CAGTGGTTTGCCTGGTCTAGGACTGGATGTTCCGGGTTTTGGAGGTGGACCAAA VLG*

CAATTTAAGTGGGCCATCGGGATTTGGAGGGGGCCCTCAGAATTTTGGAAATGG CCCTGGTAGCTTAGGCGGTCCCCCGGGGTTTGGAAGTGGCCCTCCTGGTCTTGG

TGAATTACNTGNNNTTGAAAATTGNNCTAAANGATCA

Human prey3809 396 CAGGCTGGCCCAGGCTGGCTACCGGGCTGTGGCCATTGACCTGCCAGGTCTGGG 1134 RLAQAGYRAVAIDLPGLGHSKE Melatoni GCACTCCAAGGAAGCAGCAGCCCCTGCCCCTATTGGGGAGCTGGCCCCTGGCAG AAPAPIGELAPGSFLAAWDAL n la CTTCCTGGCGGCTGTGGTGGATGCCTTGGAGCTGGGCCCCCCGGTTGTGATCAG LGPPWISPSLSGMYSLPFLTA receptor TCCATCACTGAGTGGCATGTACTCCCTGCCCTTCCTCACGGCCCCTGGCTCCCA GSQLPGFVPVAPICTDKINAAN v4 GCTCCCGGGCTTTGTGCCAGTGGCCCCCATCTGCACTGACAAAATCAATGCTGC ASVKTPALIVYGDQDPMGQTSF CAACTATGCCAGTGTGAAGACTCCAGCTCTGATTGTATATGGAGACCAGGACCC HLKQLPNHRVLIMKGAGHPCYL CATGGGTCAGACCAGCTTTGAGCACCTGAAGCAGCTGCCCAACCACCGGGTGCT KPEEWHTGLLDFLQGLQ* GATCATGAAGGGGGCGGGGCACCCCTGTTACCTGGACAAACCAGAGGAGTGGCA TACAGGGCTGCTGGACTTCCTGCAGGGGCTCCAGTGA

Human prey3798 397 GTACCAGATGCCTCCAGGATCTTTGCCACCGGTTCCTTCTTCAGTGCAGTCACC 1135 YQMPPGSLPPVPSSVQSPAQQQ Melatoni GGCACAGCAGCAGGTACCTGCCAGACCTGGGGCTCCCTCTGTTCAAGTGCCATC PARPGAPSVQVPSPFLLQNQYE n la TCCTTTTCTACTTCAAAACCAATATGAGCCTGTTCAGCCCCACTGGTTTTACTG VQPHWFYCKEVEYKQLWMPFSV receptor CAAGGAGGTAGAATACAAACAACTGTGGATGCCTTTTAGTGTGTTCGACTCTTT DSLNLEEIYNSVQPDPESWLG v4 GAATCTTGAAGAAATCTATAATTCAGTTCAGCCAGATCCGGAGAGCGTGGTTCT DGGRYDVYLYDRIRKAAYWEEE TGGCACGGATGGAGGGCGCTACGATGTTTACCTCTATGACCGAATAAGGAAGGC AEVRRCTWFYKGDTDSRFIPYT TGCCTACTGGGAAGAGGAGCCAGCCGAAGTGAGACGCTGTACTTGGTTTTACAA EFSEKLEAEYKKAVTTNQWHRR GGGGGACACAGATAGTCGATTTATTCCCTATACTGAGGAGTTCAGTGAAAAACT EFPSGETIVMHNPKVIVQFQPS AGAGGCTGAATATAAAAAAGCTGTAACCACTAATCAGTGGCACCGAAGATTAGA VPDEWGTTQDGQTRPRWKRGI GTTTCCAAGTGGAGAGACAATTGTTATGCACAATCCAAAGGTTATTGTTCAGTT DNLDEIPDGEMPQVDHLVFWH CCAGCCCTCCTCAGTGCCAGATGAATGGGGCACCACGCAAGATGGACAGACAAG IGPVCDLRFRSIIECVDDFRW GCCCAGGGTTGTAAAGCGTGGAATTGATGATAACCTTGATGAAATTCCCGACGG LKLLRTHFKKSLDDGKVSRVEF GGAGATGCCTCAAGTTGACCATTTGGTGTTTGTGGTGCATGGCATTGGACCTGT PVHWHSSLGGDATGVDRNIKKI GTGTGACTTACGCTTTAGGAGCATTATTGAGTGTGTGGATGATTTTAGGGTGGT LPSIGRFRHFTNETLLDILFYN TTCTCTCAAATTGCTGCGGACACATTTCAAGAAATCTTTAGATGACGGGAAAGT PTYCQTIVEKVGMEINHLHALF AAGCAGAGTGGAGTTCCTTCCAGTTCATTGGCATAGTTCTTTGGGTGGGGACGC SRNPDFKGGVSVAGHSLGSLIL CACAGGTGTGGACAGGAATATTAAGAAAATCACTTTGCCAAGTATTGGTCGATT DILSNQKDLNLSKCPGPLAVAN TCGTCACTTTACCAATGAAACTTTGCTAGATATTTTATTTTATAACAGCCCCAC WKQLHFQEKQMPEEPKLTLDE CTACTGTCAGACAATTGTGGAAAAAGTAGGAATGGAGATAAACCATCTGCATGC YDLWENKEVLTLQETLEALSL ACTCTTTATGAGTCGGAACCCAGACTTCAAAGGAGGTGTCTCTGTTGCTGGTCA EYFSTFEKEKIDMESLLMCTVD CAGTTTAGGTTCTTTAATATTGTTTGACATCCTGTCTAATCAAAAAGATTTGAA LKEMGIPLGPRKKIANFVEHKA TTTATCAAAGTGCCCTGGACCTCTTGCTGTTGCTAATGGAGTTGTGAAGCAGCT KLKKAASEKKAVAATSTKGQEQ ACATTTTCAGGAAAAGCAGATGCCTGAAGAGCCAAAGCTGACTTTGGATGAGTC AQKTKDMASLPSESNEPKRKLP GTATGACCTTGTTGTTGAAAATAAAGAAGTCCTAACTTTGCAAGAAACTCTGGA GACVSSVCVNYESFEVGAGQVS AGCACTTAGCCTCTCTGAATATTTTAGCACTTTTGAAAAGGAAAAGATTGATAT AYNSLDFEPEIFFALGSPIAMF GGAGTCCCTGCTTATGTGTACAGTTGATGACCTGAAGGAAATGGGGATACCCCT TIRGVDRIDENYSLPTCKGFFN TGGACCCAGAAAGAAGATAGCTAACTTTGTAGAACATAAAGCAGCCAAACTGAA YHPLDPVAYRLEPMIVPDLDLK AAAAGCAGCGTCAGAAAAGAAGGCAGTGGCGGCCACTTCTACAAAAGGACAAGA VLIPHHKGRKRLHLELKESLSR GCAAAGTGCCCAGAAGACTAAAGACATGGCTTCCCTCCCCTCAGAATCCAATGA GSDLKQGFISSLKSAWQTLNEF

receptor TAAGAATTNAGAAAATTNATTTATAAAATGAGANAATNNTTGNGTNTGTGGNTT XWXWXXXXFC*RCXXGLGGXLW v4 TGGTGNTGNCNTTGNTTTTGTTGACGGTGCNAAGANGGNTTGGGGGGATNGTTA VGGGLTHWXXXXGGWXXXXMXX TGGGGCGTGGGGGGGGGGCTGACGCATTGGNCGNAATNNNGNGGCGGCTGGGNN XXXXXXGXXXXXGXXTXXXXXX GNGNATNGNATGNNNGNGNCNNCGNTGGNNGNGNNTGNNGGNGNTCNGGNNGNA XXXXGEX TGNGGGAGNNGNACNNNNCNGGNGNCGNGTANGGAAGNGNGGNGGNGNGGGGAG NGN

Human prey84331 407 GACGAAAAAGGCATCTTGTCTGTTAACCACAGCTTGCTTTAATAGAATCCTGGG 1145 DEKGILSVNHSLL* *NPGRVIG Melatoni AGGGTGATTGGGACTTTTTAGTATTACAACCTTAGTGTCATTGAGGAGGATTTT F*YYNLSVIEEDFGLVSGLSFI n la GGTCTAGTTAGTGGGCTGAGTTTCATATACCTCTCCCTCCATGTGCAGGTTTGT LSLHVQVC*DNW*FLII*NT*V receptor TAAGATAATTGGTAGTTTTTAATAATATAAAATACTTAAGTTGAAATACAAAAG IQKCGNNY* ILARILGELHN*W v4 TGTGGCAACAATTATTAAATATTGGCTAGAATTCTAGGAGAGTTACACAACTAG SMFRK*MACLRKSFCVQSSLKS TGGAAGTCCATGTTTAGAAAATAAATGGCTTGTTTAAGGAAAAGTTTTTGTGTC RFLPGT*HHMEIDALVRVLAIL CAAAGCTCCTTAAAGTCAGAGAGATTTCTACCTGGTACTTAACATCATATGGAA SISCILFSSLFLYRDKVSLCCP ATTGATGCTTTAGTGAGGGTGTTGGCTATCCTATTGTCAATTTCCTGCATCCTT WSCSWAQAVLPPRSPKVPGLQV TTTTCTTCTTTATTTTTGTATAGAGACAAGGTCTCGCTATGTTGCCCAGGC1GG ATVPSLSFFHYTKRLNLVSSKL TCTTGTTCCTGGGCTCAAGCAGTCCTCCCGCCTCGGTCTCCCAAAGTGCCGGGA DKDGMHRRPLGALR*LSHSSKI TTACAGGTGTGAGCCACTGTGCCCAGCTTATCCTTTTTTCATTACACAAAAAGA LGCIL*IFPA*DVYLRNKVRKM CTGAATTTGGTTAGTTCTAAGTTGGAAGATAAAGATGGTATGCACAGGAGGCCC ASQPLVYLLAGMDP*GSRRELG TTGGGAGCCCTCAGATAACTTTCTCATTCTTCCAAAATCAGGCTGGGATGCATT EEGVKLVSFKARVILPQILKNT CTGTAAATTTTCCCTGCCTAGGATGTATACCTGAGGAATAAGGTAAGGAAGATG ESSCWGTCYY*KDLDNLSSESY TCAGCAAGTCAGCCTCTGGTTTACCTGCTAGCTGGCATGGATCCTTAAGGAAGC TLYLWHINPHCLILWLNLSFHQ AGGAGGGAGTTGGGAAGAGAGGAAGGGGTGAAGTTGGTATCTTTTAAAGCGAGA CQRTFFSAQPCLRVCHLKREAS GTGATTTTACCTCAGATTTTGAAGAATACTAAGGAATCCAGTTGTTGGGGTACA YCCPDCSVLTTYQTRW*GTKVH TGCTATTATTAGAAGGATCTAGATAATTTGTCCTCTGAGTCATACTTGACATTG WKSSLHHQ**AVTEWNSLNEMK TACCTGTGGCACATCAATCCGCACTGTTTGATACTCTGGCTGAATCTCAGCTTT GLLQWH*GWSLNPVLTTRLTLQ CACCAACATTGTCAAAGGACCTTTTTTAGTGCCCAGCCATGCCTAAGAGTGTGT TQNPSKAFHFL*WHSDPL*FDP CATCTGAAGAGGGAAGCATCTGCATACTGCTGTCCTGATTGCTCAGTCCTCACT LQLEPLLLFRMNIFL*PWTTST ACCTACCAGACCCGTTGGTAAGGTACAAAAGTACATGCTTGGAAAAGCAGTCTG VTSHIGLI*NMTSLN*DVM*V* CACCACCAGTGATAAGCTGTGACAGAGTGGAACAGCCTCAATGAAATGAAGGAA TQQISKTAHKM*NMSKIFDTDY GGATTGCTACAGTGGCATTAAGGATGGTCTCTTAATCCTGTGTTAACCACTAGA LKYMCWVK*NALK TTAACTTTACAATCAACTCAAAATCCTTCAAAGGCTTTCCACTTTCTTTAGTGG CATTCAGACCCCCTCTAGTTTGACCCCTACCTCCAACTTGAACCTCTGTTACTC TTCCGTATGAACATTTTCCTCTAGCCCTGGACTACTAGTACCGAAGTCACTAGT CACATAGGACTCATTTGAAATATGACTAGTCTCAATTGAGATGTAATGTAAGTG TAAAATACACAGCAGATTTCTAAGACAGCACACAAAATGTAAAATATGTCAAAA ATATTTGATACTGATTACATGTTGAAATATATGTGTTGGGTTAAATAAAATGCA TTAAAGTT

Human prey94831 408 TCAAAACTACTCAAAACCTGCTCCATCACCCCAGCATNCTTTGATTTAGGATTA 1146 SKLLKTCSITPAXFDLGLIVLF Melatoni ATAGTCCTGTTTTAGAAATGAAGGTTTTGAAAGGTCTTACTGTCCTCCTTTCTN K*RF*KVLLSSFLLADI*T*XQ

n la TTGGCCGACATTTGAACCTGANTNCAGATNTTTTTCTTTTTCTTTTTTCTTTTT FFFFFFLFXCFLXXFDXXXGXW receptor NCNTGCTTCTTGTNTTNTTTTGATTTNANAANNGGGNGNTGGGGGAGGGAAGCN REAHXR*XAXGXEKGGXXXXXT v4 CACGNCCGNTAGAANGCCAGNGGGNGNGAAAAGGGGGGGNGAGNNNCCNNGCNG SXXGXRRGXVXXGGXXXXVXRR ACCNNNAGTNNATNCGGNNGGAGACGCGGNNCGGTNTNGNGCGGGGGNCNGNNN XLAXPXXXXXXSXXXXAGEXXX GNAGNGGTNGNCCGGCGNTGGGNGCTNGCNCANCCAGNGNTNNTATNCNCNNNT XGXTXTSSXGXXXXPGXXXXXR TCNGNCTNNNTNNNAGCAGGCGAGNTTTNNNGCCNGTNGGGCNGGACGNANACN TCTTCNCNNGGNCNTNCGNTTNCGCCGGGGNNGGNNNGGANGNTACGGGN

Human prey3596 409 CCACTCAGCACATTCAACGCATTCTACACATTCTGCTCATTCAACGCATGCCGG 1147 HSAHSTHSTHSAHSTHAGHAGH Melatoni ACATGCAGGTCACACGTCACTTCCACAGTGCATTAATCCGTTCACCAACTTACC SLPQCINPFTNLPHTPRYYDIL n la CCATACTCCTCGATACTATGATATTCTAAAGAAACGTCTTCAGCTCCCTGTTTG KRLQLPVWEYKDRFTDILGRHQ receptor GGAATACAAGGATAGGTTTACAGATATTCTGGGTAGACATCAGTCCTTTGTACT FVLVGETGSGKTTQIPHRCVEY v4 GGTTGGTGAGACTGGGTCTGGTAAAACAACACAAATTCCACACCGGTGTGTGGA RSLPGPKRGVACTQPRRVAAMS GTACATGCGATCATTACCAGGACCCAAGAGAGGAGTTGCCTGTACCCAACCCAG AQRVADEMDVMLGQEVGYSIRF GAGAGTGGCTGCAATGAGTGTGGCTCAGAGAGTTGCTGATGAGATGGATGTGAT DCSSAKTFFMYMTDGMLLREAM GTTGGGCCAGGAAGTTGGTTACTCCATTCGATTTGAAGACTGCAGTAGTGCAAA DPLLERYGVIILDEAHERTLAT AACATTTTTTATGTATATGACTGATGGGATGTTACTTCGTGAAGCTATGAATGA ILMGVLKEWRQRSDLKVIVMS TCCCCTCCTGGAGCGTTATGGTGTAATAATTCTTGATGAGGCTCATGAGAGGAC TLDAGKFQIYFDNCPLLTIPGR ACTGGCTACAGATATTCTAATGGGTGTTCTGAAGGAAGTTGTAAGACAGAGATC HPVEIFYTPEPERDYLEAAIRT AGATTTAAAGGTTATAGTTATGAGCGCTACTCTAGATGCAGGAAAATTCCAGAT IQIHMCEEEEGDLLLFLTGQEE TTACTTTGATAACTGTCCTCTCCTAACTATTCCTGGGCGTACACATCCTGTTGA DEACKRIKREVDDLGPEVGDIK GATCTTCTATACTCCAGAACCAGAGAGAGATTATCTTGAAGCAGCAATTCGAAC IPLYSTLPPQQQQRIFEPPPPK AGTTATCCAGATTCATATGTGTGAAGAGGAAGAGGGAGATCTTCTTCTTTTCTT QNGAIGRKVWSTNIAETSLTI AACTGGTCAAGAGGAAATTGATGAAGCCTGTAAGAGAATAAAGCGTGAAGTTGA GWFVIDPGFAKQKVYNPRIRV TGATTTGGGCCCTGAAGTTGGTGACATTAAAATCATTCCATTGTATTCTACACT SLLVTAISKASAQQRAGRAGRT TCCACCTCAGCAGCAGCAACGCATTTTTGAGCCTCCACCTCCCAAAAAACAGAA PGKCFRLYTEKAYKTEMQDNTY TGGAGCAATTGGAAGAAAGGTAGTTGTGTCAACTAACATAGCAGAGACGTCTTT EILRSNLGSWLQLKKLGIDDL GACAATAGATGGTGTGGTGTTTGTGATTGATCCTGGATTTGCGAAACAGAAGGT HFDFMDPPAPETLMRALELLNY CTACAATCCTCGAATCAGAGTTGAGTCCCTTTTGGTGACAGCTATTAGTAAAGC AALNDDGDLTELGSMMAEFPLD TTCAGCTCAGCAAAGGGCTGGTCGAGCTGGACGTACCAGACCTGGAAAATGCTT QLAKMVIASCDYNCSNEVLSIT CAGACTTTACACAGAGAAAGCTTATAAAACAGAAATGCAGGATAACACCTATCC MLSVPQCFVRPTEAKKAADEAK TGAGATTTTGCGTTCTAATTTAGGATCAGTTGTGTTACAATTGAAGAAACTTGG RFAHIDGDHLTLLNVYHAFKQN TATTGATGACTTGGTACATTTTGATTTTATGGATCCACCAGCTCCTGAAACTCT ESVQWCYDNFINYRSLMSADNV GATGAGAGCCCTGGAACTTTTGAATTACCTGGCTGCTTTAAATGATGATGGAGA QQLSRIMDRFNLPRRSTDFTSR TCTGACTGAATTGGGATCCATGATGGCAGAGTTTCCTCTAGATCCACAGCTCGC YYINIRKALVTGYFMQVAHLER AAAAATGGTTATTGCAAGTTGTGACTACAACTGTTCTAATGAGGTCCTATCTAT GHYLTVKDNQWQLHPSTVLDH TACTGCTATGTTGTCAGTCCCACAGTGTTTTGTTCGCCCCACGGAGGCCAAGAA PEWVLYNEFVLTTKNYIRTCTD AGCCGCAGATGAGGCCAAGATGAGATTTGCCCACATAGATGGAGATCATCTGAC KPEWLVKIAPQYYDMSNFPQCE ACTGCTGAACGTCTACCATGCTTTTAAACAAAATCATGAATCGGTTCAGTGGTG KRQLDRIIAQTSIQGIFTVLNS TTATGACAACTTCATTAACTACAGGTCCCTGATGTCCGCGGACAATGTACGCCA LRTEVIERTALKDE*

GCAGCTATCTCGAATTATGGACAGATTTAATTTGCCTCGTCGAAGTACTGACTT TACAAGCAGGGACTATTATATTAATATAAGAAAAGCTTTGGTTACTGGGTATTT TATGCAGGTGGCACATTTAGAACGAACAGGGCATTACTTAACTGTGAAAGATAA CCAGGTGGTTCAGTTGCATCCCTCTACTGTTCTTGACCACAAACCTGAATGGGT GCTTTATAATGAGTTTGTTCTAACAACAAAGAATTACATCCGGACATGTACAGA CATCAAGCCAGAATGGTTGGTGAAAATTGCCCCTCAATATTATGACATGAGCAA TTTCCCACAGTGTGAAGCAAAGAGACAGTTGGACCGCATCATTGCCCAAACTTC AATCCAAGGAATATTCACAGTACTGAATTCAGTGCTTAGAACTGAAGTTATTGA GAGGACAGCTTTAAAAGATGAATGA

Human prey94836 410 AACAAACATGCTGAACCACCTATGGGAATCAAAACACACCCCCACTCTGATGGT 1148 NKHAEPPMGIKTHPHSDGEAGL Melatoni GAAGCTGGGCTCCCAGTAGTGCAGGAGGTGTGGGGGCTCCCTCGAACACTGACT WQEVWGLPRTLTFSSLPCHLC n la TTCTCCTCCCTCCCCTGCCACCTCTGTCCTCACCTTGTGGCCAGAATACAACCC HLVARIQPWSWQGSSLRPDAAD receptor TGGAGTTGGCAAGGCTCCTCCCTGCGCCCTGATGCCGCAGACTCTGCAACCTTC ATFMLPAASSLSSLEGGQEPVD v4 ATGCTGCCCGCTGCCTCCTCCCTCAGCTCTCTGGAGGGCGGCCAGGAGCCCGTG KIMSFPKSPFPARSHFDVSGTV GATATAAAGATCATGAGTTTCCCAAAGAGCCCCTTTCCAGCCCGAAGCCACTTT GLRVTSPSGQLIPVKNLSENIE GATGTCAGCGGGACTGTCGGTGGCCTCCGTGTGACCAGCCCTAGTGGTCAACTC LLPRHSQRHSQPTVLNLTSPEA ATACCTGTGAAGAATCTGTCGGAGAATATCGAGATCCTGCTGCCCCGGCATTCA WVNVTSGEATLGIQLHWRPDIA CAAAGACACAGCCAGCCGACCGTGTTGAACCTGACCAGTCCTGAAGCTTTGTGG TLSLGYGYHPNKSSYDAQTHLV GTGAACGTGACTTCAGGGGAGGCAACCTTGGGGATCCAGCTGCACTGGAGACCG MVAPDELPTWILSPQDLRFGEG t GACATTGCACTCACGCTTAGCCTGGGCTATGGCTACCACCCCAACAAGAGCAGC YYLTWPESDLEPAPGRDLTVG

Ul TACGATGCCCAAACTCACCTCGTACCAATGGTGGCTCCAGATGAGCTGCCCACG TTFLSHCVFWDEVQETWDDSGC TGGATCCTGAGCCCACAGGACCTGCGTTTTGGAGAAGGGGTCTACTATTTGACT VGPRTSPYQTHCLCNHLTFFGS GTGGTCCCTGAGTCTGACCTGGAGCCAGCCCCCGGCAGGGACCTCACGGTTGGC FLVMPNAIDVHQTAELFATFED ATCACCACCTTCCTGTCTCACTGTGTGTTCTGGGATGAGGTCCAGGAGACTTGG PVWTTVGCLCWYVLWIWAR GACGACTCAGGATGCCAGGTGGGGCCTCGGACCAGCCCCTACCAGACACACTGC KDAQDQAKVKVTVLEDNDPFAQ CTCTGCAACCACCTCACTTTCTTCGGAAGCACGTTCCTGGTGATGCCCAATGCC HYLVTVYTGHRRGAATSSKVTV ATCGACGTCCACCAGACTGCTGAGCTCTTTGCCACCTTTGAGGACAACCCTGTG LYGLDGEREPHHLADPDTPVFE GTCGTGACCACCGTGGGCTGCCTGTGTGTGGTCTACGTGCTGGTGGTGATCTGG GAVDAFLLSTLFPLGELRSLRL GCGAGGAGGAAGGACGCTCAGGATCAGGCCAAGGTGAAGGTCACAGTGCTGGAA HDNSGDRPSWYVSRVLVYDLVM GACAATGATCCCTTTGCTCAGTACCACTACCTGGTGACAGTCTACACAGGACAC RKWYFLCNSWLSINVGDCVLDK CGACGAGGGGCAGCCACGTCCTCAAAGGTGACTGTCACCCTGTATGGCCTGGAT FPVATEQDRKQFSHLFFMKTSA GGAGAGAGAGAGCCCCACCACCTGGCTGATCCTGACACTCCGGTTTTTGAGCGA FQDGHIWYSIFSRCARSSFTRV GGAGCAGTGGATGCCTTCCTCCTCTCCACCCTGTTCCCCCTGGGAGAACTGCGG RVSCCFSLLLCTMLTSIMFWGV AGCCTCCGGCTGTGGCATGACAACTCAGGGGACCGGCCATCGTGGTATGTGAGC KDPAEQKMDLGKIEFTWQEVMI CGGGTGCTGGTCTATGACCTGGTGATGGACCGGAAGTGGTATTTCCTGTGCAAC LESSILMFPINLLIVQIFQNTR TCCTGGCTATCCATCAATGTTGGAGATTGCGTCCTCGACAAGGTGTTTCCTGTG RVAKEQNTGKWDRGSPNLTPSP GCCACGGAGCAGGACAGAAAACAATTCAGCCACCTGTTTTTCATGAAGACTTCC PMEDGLLTPEAVTKDVSRIVSS GCGGGCTTCCAGGATGGACACATCTGGTATTCGATCTTCAGCCGCTGCGCTCGC FKALKVPSPALGWDSVNLMDIN AGCAGCTTCACCCGCGTCCAGAGGGTGTCCTGCTGCTTCTCCCTGCTGCTGTGC LLALVEDVIYPQNTSGQVFWEE

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GAACGGGAAAGTCCAGCACTGCCGTATCCACTCCCGGCAAGATGCTGGGACCCC FLTDNLVFDSLYDLITHYQQVP CAAGTTCTTCTTGACAGACAACCTCGTCTTTGACTCCCTCTATGACCTCATCAC RCNEFEMRLSEPVPQTNAHESK GCACTACCAGCAGGTGCCCCTGCGCTGTAATGAGTTTGAGATGCGACTTTCAGA WYHASLTRAQAEHMLMRVPRDG GCCTGTCCCACAGACCAACGCCCACGAGAGCAAAGAGTGGTACCACGCGAGCCT FLVRKRNEPNSYAISFRAEGKI GACCAGAGCACAGGCTGAGCACATGCTAATGCGCGTCCCTCGTGATGGGGCCTT HCRVQQEGQTVMLGNSEFDSLV CCTGGTGCGGAAGCGGAATGAACCCAACTCATATGCCATCTCTTTCCGGGCTGA LISYYEKHPLYRKMKLRYPINE GGGCAAGATCAAGCATTGCCGTGTCCAGCAAGAGGGCCAGACAGTGATGCTAGG ALEKIGTAEPDYGALYEGRNPG GAACTCGGAGTTCGACAGCCTTGTTGACCTCATCAGCTACTATGAGAAACACCC YVEANPMPTFKCAVKALFDYKA GCTATACCGCAAGATGAAGCTGCGCTATCCCATCAACGAGGAGGCACTGGAGAA REDELTFIKSAlIQNVEKQEGG GATTGGCACAGCTGAGCCTGACTACGGGGCCCTGTATGAGGGACGCAACCCTGG WRGDYGGKKQLWFPSNYVEEMV CTTCTATGTAGAGGCAAACCCTATGCCAACTTTCAAGTGTGCAGTCAAAGCCCT PVALEPEREHLDENSPLGDLLR CTTTGACTACAAGGCCCAGAGGGAGGACGAGCTGACCTTCATCAAGAGCGCCAT VLDVPACQIAIRPEGKNNRLFV CATCCAGAATGTGGAGAAGCAAGAGGGAGGCTGGTGGCGAGGGGACTACGGAGG SISMASVAHWSLDVAADSQEEL GAAGAAGCAGCTGTGGTTCCCATCAAACTACGTGGAAGAGATGGTCAACCCCGT DWVKKIREVAQTADARLTEGKI GGCCCTGGAGCCGGAGAGGGAGCACTTGGACGAGAACAGCCCCCTAGGGGACTT ERRKKIALELSELWYCRPVPF GCTGCGGGGGGTCTTGGATGTGCCGGCTTGTCAGATTGCCATCCGTCCTGAGGG EEKIGTERACYRDMSSFPETKA CAAGAACAACCGGCTCTTCGTCTTCTCCATCAGCATGGCGTCGGTGGCCCACTG KYVNKAKGKKFLQYNRLQLSRI GTCCCTGGATGTTGCTGCCGACTCACAGGAGGAGCTGCAGGACTGGGTGAAAAA PKGQRLDSSNYDPLPMWICGSQ GATCCGTGAAGTGGCCCAGACAGCAGACGCCAGGCTCACTGAAGGGAAGATAAT VALNFQTPDKPMQMNQALFMTG to GGAACGGAGGAAGAAGATTGCCCTGGAGCTCTCTGAACTTGTCGTCTACTGCCG HCGYVLQPSTMRDEAFDPFDKS

4- oe GCCTGTTCCCTTTGATGAAGAGAAGATTGGCACAGAACGTGCTTGCTACCGGGA LRGLEPCAISIEVLGARHLPKN CATGTCATCCTTCCCGGAAACCAAGGCTGAGAAATACGTGAACAAGGCCAAAGG RGIVCPFVEIEVAGAEYDSTKQ CAAGAAGTTCCTTCAGTACAATCGACTGCAGCTCTCCCGCATCTACCCCAAGGG TEFWDNGLNPVWPAKPFHFQI CCAGCGACTGGATTCCTCCAACTACGATCCTTTGCCCATGTGGATCTGTGGCAG NPEFAFLRFWYEEDMFSDQNF TCAGCTTGTGGCCCTCAACTTCCAGACCCCTGACAAGCCTATGCAGATGAACCA AQATFPVKGLKTGYRAVPLKNN GGCCCTCTTCATGACGGGCAGGCACTGTGGCTACGTGCTGCAGCCAAGCACCAT SEDLELASLLIKIDIFPAKENG GCGGGATGAGGCCTTCGACCCCTTTGACAAGAGCAGCCTCCGCGGGCTGGAGCC LSPFSGTSLRERGSDASGQLFH ATGTGCCATCTCTATTGAGGTGCTGGGGGCCCGACATCTGCCAAAGAATGGCCG RAREGSFESRYQQPFEDFRISQ AGGCATTGTGTGTCCTTTTGTGGAGATTGAGGTGGCTGGAGCTGAGTATGACAG HLADHFDSRERRAPRRTRVNGD CACCAAGCAGAAGACAGAGTTTGTGGTGGACAATGGACTCAACCCTGTATGGCC RL* AGCCAAGCCCTTCCACTTCCAGATCAGTAACCCTGAATTTGCCTTTCTGCGCTT CGTGGTGTATGAGGAAGACATGTTTAGTGACCAGAATTTCCTGGCTCAGGCTAC TTTCCCAGTAAAAGGCCTGAAGACAGGATACAGAGCAGTGCCTTTGAAGAACAA CTACAGTGAGGACCTGGAGTTGGCCTCCCTGCTGATCAAGATTGACATTTTCCC TGCCAAGGAGAATGGTGACCTCAGTCCCTTCAGTGGTACGTCCCTGCGGGAGCG GGGCTCAGATGCCTCAGGCCAGCTGTTTCATGGCCGAGCCCGGGAAGGCTCCTT TGAATCCCGCTACCAGCAGCCGTTTGAGGACTTCCGCATCTCCCAGGAGCATCT CGCAGACCATTTTGACAGTCGAGAACGAAGGGCCCCAAGAAGGACTCGGGTCAA TGGAGACAACCGCCTCTAG

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GAGGGCTTCTCGCATGGGTGGATCCAGAGGCGTGTGTGCCGACACCTTCTCACT RVCRHLLTHLSWVITLIDDN*C CACCTTTCCTGGGTCATCACCCTGATAGACGATAACTGATGTGACCTCTCCACT LSTVCLGF*AEELMARRLQLRA GTCTGCCTCGGATTCTAAGCAGAAGAGCTGATGGCCAGAAGGCTCCAGCTCAGA TTAAFTGLFIV GCCTCCACTACTGCTGCTTTCACCGGACTCTTCATAGTCTG

Human 10 prey33232 544 ACGTGGGAACTGCCAAACCAAACTGCACGACATCGACGGCGTACCTCACCTCAT 1282 RGNCQTKLHDIDGVPHLILIAS hGITl vl CCTCATCGCCTCCCGAGACATCGCGGCTGGGGAGGAGCCCCTGTATGACTATGG DIAAGEEPLYDYGDRSKASIEA GGACCGCAGCAAGGCTTCCATTGAAGCCCACCCATGGCTGAAGCATTAA PWLKH*

Human 10 preyl7072 545 GCTTACAGCAAAGGAGAAGAAGACACAGTTGGATGATAGGACAAAAATCACTGA 1283 LTAKEKKTQLDDRTKITELFAV hGITl vl GCTTTTTGCCGTGGCCCTTCCTCAGTTATTAGCAAAATACTCTGTAGATGCAGA LPQLLAKYSVDAEKVTNLLQLP AAAGGTGACTAACTTGTTGCAGTTGCCTCAGTACTTTGATTTGGAAATATATAC YFDLEIYTTGRLENDLDALLRQ CACTGGACGATTAGAAAACGATTTGGATGCCTTATTGCGACAGATCCGGAATAT RNIVEKHTDTDVLEACSKTYHA TGTAGAGAAGCACACAGATACAGATGTTTTGGAAGCATGTTCTAAAACTTACCA CNEEFTIFNRVDISRSQLIDEL TGCACTCTGTAATGAAGAGTTCACAATCTTCAACAGAGTAGATATTTCAAGAAG DKFNRLLEDFLQEGEEPDΞDDA TCAACTGATAGATGAATTGGCAGATAAATTTAACCGGCTTCTTGAAGATTTTCT QVLSTLKRITAFHNAHDLSKRD GCAAGAGGGTGAAGAACCTGATGAAGATGATGCATATCAGGTATTGTCAACPTT FACNYKLLKTGIENGDMPEQIV GAAGAGGATCACTGCTTTTCATAATGCCCATGACCTTTCAAAGAGGGATTTATT HALQCTHYVILWQLAKITESSS TGCTTGTAATTACAAACTCTTGAAAACTGGAATCGAAAATGGAGACATGCCTGA KEDLLRLKKQMRVFCQICQHYL GCAGATTGTTATTCACGCACTGCAGTGTACTCACTATGTAATCCTTTGGCAACT NVNTTVKEQAFTILCDILMIFS TGCTAAGATAACTGAAAGCAGCTCTACAAAGGAGGACTTGCTGCGTTTAAAGAA QIMSGGRDMLEPLVYTPDSSLQ to

-4 ACAAATGAGAGTATTTTGTCAGATATGTCAACATTACCTGACCAACGTGAATAC ELLSFILDHVFIEQDDDNNSAD -4 TACTGTTAAGGAACAGGCCTTCACTATTCTGTGTGATATTTTGATGATCTTCAG QQEDEASKIEALHKRRNLLAAF CCATCAGATTATGTCAGGAGGGCGTGACATGTTAGAGCCATTAGTGTATACCCC KLIVYTWEMNTAADIFKQYMK TGATTCTTCATTGCAGTCTGAGTTGCTCAGCTTTATTTTGGATCATGTCTTCAT YNDYGDIIKETMSKTRQIDKIQ TGAACAGGATGATGATAATAATAGTGCAGATGGTCAGCAAGAGGATGAAGCCAG AKTLILSLQQLFNEMIQENGYN TAAAATTGAAGCTCTGCACAAGAGAAGAAATTTACTTGCAGCATTTTGTAAGCT DRSSSTFSGIKELARRFALTFG AATTGTATATACTGTGGTGGAGATGAATACAGCTGCAGATATCTTCAAACAGTA DQLKTREAIAMLHKDGIEFAFK TATGAAGTATTATAATGACTATGGAGATATCATCAAAGAAACAATGAGTAAAAC PNPQGESHPPLNLAFLDILSEF AAGGCAGATAGACAAAATTCAGTGTGCTAAGACCCTTATTCTCAGTCTGCAACA SKLLRQDKRTVYVYLEKFMTFQ GCTTTTTAATGAAATGATACAAGAAAATGGCTATAATTTTGATAGATCATCCTC SLRREDVWLPLMSYRNSLLAGG TACATTTAGTGGCATAAAAGAACTTGCTCGACGTTTTGCTTTAACTTTTGGACT DDTMSVISGISSRGSTVRSKKS TGATCAGTTGAAAACAAGAGAAGCCATTGCCATGCTACACAAAGATGGCATAGA PSTGKRKWEGMQLSLTEESSS ATTTGCTTTTAAAGAGCCTAATCCGCAAGGGGAGAGCCATCCACCTTTAAATTT DSMWLTREQTLH GGCATTTCTTGATATTCTGAGTGAATTTTCTTCTAAACTACTTCGACAAGACAA AAGAACAGTGTATGTTTACTTGGAAAAGTTCATGACCTTTCAGATGTCACTCCG AAGAGAGGATGTGTGGCTTCCACTGATGTCTTACCGAAATTCTTTGCTAGCTGG TGGTGATGATGACACCATGTCAGTCATTAGTGGAATCAGCAGCCGGGGGTCAAC AGTACGGAGTAAAAAATCAAAACCATCTACAGGAAAACGGAAAGTGGTTGAGGG CATGCAGCTTTCACTCACTGAAGAAAGTAGTAGTAGTGACAGTATGTGGTTAAC GAGAGAACAAACACTGCAC

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AATCGCNCNCAGTTATNGGGAAAGAGGTNCAAAGGAGNCATAGTCCAACCGTGC CAACNNCCANGANGGGCNTGANCNCC

Human 10 prey21907 605 GATAGTTGA 1343 DS* hGITl vl

Human 10 prey33364 606 ATGAGCAACATCTGTCAGAGGCTCTGGGAGTACCTAGAACCCTATCTCCCCTGT 1344 MSNICQRLWEYLEPYLPCLSTE hGITl vl TTGTCCACGGAGGCAGACAAGTCAACCGTGATTGAAAATCCAGGGGCCCTTTGC DKSTVIENPGALCSPQSQRHGH TCTCCCCAGTCACAGAGGCATGGCCACTACTTTGTGGCTTTGTTTGATTACCAG FVALFDYQARTAEDLSFRAGDK GCTCGGACTGCTGAGGACTTGAGCTTCCGAGCAGGTGACAAACTTCAAGTTCTG QVLDTLHEGWWFARHLEKRRDG GACACTTTGCATGAGGGCTGGTGGTTTGCCAGACACTTGGAGAAAAGACGAGAT SQQLQGYIPSNYVAEDRSLQAE GGCTCCAGTCAGCAACTACAAGGCTATATTCCTTCTAACTACGTGGCTGAGGAC WFFGAIGRSDAEKQLLYSENKT AGAAGCCTACAGGCAGAGCCGTGGTTCTTTGGAGCAATCGGAAGATCAGATGCA SFLIRESESQKGEFSLSVLDGA GAGAAACAACTATTATATTCAGAAAACAAGACCGGTTCCTTTCTAATCAGAGAA VKHYRIKRLDEGGFFLTRRRIF AGTGAAAGCCAAAAAGGAGAATTCTCTCTTTCAGTTTTAGATGGAGCAGTTGTA TLNEFVSHYTKTSDGLCVKLGK AAACACTACAGAATTAAAAGACTGGATGAAGGGGGATTTTTTCTCACGCGAACA CLKIQVPAPFDLSYKTVDQWEI AGAATCTTTTCAACACTGAACGAATTTGTGAGCCACTACACCAAGACAAGTGAC RNSIQLLKRLGSGQFGEVWEGL GGCCTGTGTGTCAAGCTGGGGAAACCATGCTTAAAGATCCAGGTCCCAGCTCCA NNTTPVAVKTLKPGSMDPNDFL TTTGATTTGTCGTATAAAACCGTGGACCAATGGGAGATAGACCGCAACTCCATA EAQIMKNLRHPKLIQLYAVCTL CAGCTTCTGAAGCGATTGGGATCTGGTCAGTTTGGCGAAGTATGGGAAGGTCTG DPIY11TELMRHGSLQEYLQND TGGAACAATACCACTCCAGTAGCAGTGAAAACATTAAAACCAGGTTCAATGGAT GSKIHLTQQVDMAAQVASGMAY CCAAATGACTTCCTGAGGGAGGCACAGATAATGAAGAACCTAAGACATCCAAAG ESRNYIHRDLAARNVLVGEHNI CTTATCCAGCTTTATGCTGTTTGCACTTTAGAAGATCCAATTTATATTATTACA KVADFGLARVFKVDNEDIYESR GAGTTGATGAGACATGGAAGTCTGCAAGAATATCTCCAAAATGACACTGGATCA EIKLPVKWTAPEAIRSNKFSIK AAAATCCATCTGACTCAACAGGTAGACATGGCGGCACAGGTTGCCTCTGGAATG DVWSFGILLYEIITYGKMPYSG GCCTATCTGGAGTCTCGGAACTACATTCACAGAGATCTGGCTGCCAGAAATGTC TGAQVIQMLAQNYRLPQPSNCP CTCGTTGGTGAACATAATATCTACAAAGTAGCAGATTTTGGACTTGCCAGAGTT QFYNIMLECWNAEPKERPTFET TTTAAGGTAGATAATGAAGACATCTATGAATCTAGACACGAAATAAAGCTGCCG RWKLEDYFETDSSYSDANNFIR GTGAAGTGGACTGCGCCCGAAGCCATTCGTAGTAATAAATTCAGCATTAAGTCC GATGTATGGTCATTTGGAATCCTTCTTTATGAAATCATTACTTATGGCAAAATG CCTTACAGTGGTATGACAGGTGCCCAGGTAATCCAGATGTTGGCTCAAAACTAT AGACTTCCGCAACCATCCAACTGTCCACAGCAATTTTACAACATCATGTTGGAG TGCTGGAATGCAGAGCCTAAGGAACGACCTACATTTGAGACACTGCGTTGGAAA CTTGAAGACTATTTTGAAACAGACTCTTCATATTCAGATGCAAATAACTTCATA AGATGA

Human 10 prey33367 607 GTTCACTGTGAAACTCTGCGTATTGGGAAGGCCTGGCCTCAGTCATCAGGCCAG 1345 VHCETLRIGKAWPQSSGQERYW hGITl vl GAGAGGTACTGGACGCCGCGCACGCACTCGTCTGCCAGCGAGGCCCAAAGGGGA PRTHSSASEAQRGSLAELSVAA AGCCTAGCGGAGCTCAGTGTGGCAGCTGCTGGCCTCTGGGCCGACTGTGATCAA GLWADCDQPLYDCPMCGLICTN CCACTCTATGATTGTCCTATGTGTGGGCTCATATGTACAAATTACCATATTCTN HILXXHXGLHLXEDXLXGAXGW NAGGANCATGNTGGCTTGCATTTGNAAGAAGACAGNCTTTGNGGGGCGNNTGGA XTCSXG TGGANCGNCACGTGTTCTGNTGGAN

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GATGAGCGGAGCACCTTGCTGGACATGTCCTCCATTTTCCACCAGAAGGCCGAA EVLHHQRHVRTIWQHRKVRLHQ AAGTATATGAGCAACGTGGATTCATGGTGTAAAGCTTGCGGTGAGGTAGACCTT LQLCVFQQEVQQVLDWIENHGE CCCTCAGAGCTGCAGGACCTAGAAGATGCCATTCATCACCACCAGGGAATATAT FLSKHTGVGKSLHRARALQKRH GAACATATCACTCTTGCTTATTCTGAGGTCAGCCAAGATGGGAAGTCGCTCCTT DFEEVAQNTYTNADKLLEAAEQ GACAAGCTCCAGCGGCCCTTGACTCCCGGCAGCTCCGATTCCCTGACAGCCTCT AQTGECDPEEIYQAAHQLEDRI GCCAACTACTCCAAGGCCGTGCACCATGTCCTGGATGTCATCCACGAGGTGCTG DFVRRVEQRKILLDMSVSFHTH CACCACCAGCGGCACGTGAGAACAATCTGGCAACACCGCAAGGTCCGGCTGCAT KELWTWLEELQKELLDDVYAES CAGAGGCTGCAGCTGTGTGTTTTCCAGCAGGAAGTTCAGCAGGTGCTAGACTGG EAVQDLIKRFGQQQQTTLQVTV ATCGAGAACCACGGAGAAGCATTTCTGAGCAAACATACAGGTGTGGGGAAATCT VIKEGEDLIQQLRDSAISSNKT CTTCATCGGGCCAGAGCATTGCAGAAACGTCATGAAGATTTTGAAGAAGTGGCA HNSSINHIETVLQQLDEAQSQM CAGAACACATACACCAATGCGGATAAATTACTGGAAGCAGCAGAACAGCTGGCT ELFQERKIKLELFLHVRIFERD CAGACTGGGGAATGTGACCCCGAAGAGATTTATCAGGCTGCCCATCAGCTGGAA IDIISDLESWNDELSQQMNDFD GACCGGATTCAAGATTTCGTTCGGCGTGTTGAGCAGCGAAAGATCCTACTGGAC EDLTIAFQRLQHHADKALTMNN ATGTCAGTGTCCTTTCACACCCATGTGAAAGAGCTGTGGACGTGGCTGGAGGAG TFDVIHQGQDLLQYVNEVQASG CTGCAGAAGGAGCTGCTGGACGACGTGTATGCCGAGTCGGTGGAGGCCGTGCAG ELLCDRDVDMATRVQDLLEFLH GACCTCATCAAGCGCTTTGGCCAGCAGCAGCAGACCACCCTGCAGGTGACTGTC KQQELDLAAEQHRKHLEQCVQL AACGTGATCAAGGAAGGGGAGGACCTCATCCAGCAGCTCAGGGACTCTGCCATC HLQAEVKQVLGWIRNGESMLNA TCCAGTAACAAGACCCCCCACAACAGCTCCATCAACCACATTGAGACGGTGCTG LITASSLQEAEQLQREHEQFQH CAGCAGCTGGACGAGGCGCAGTCGCAGATGGAGGAGCTCTTCCAGGAGCGCAAG IEKTHQSALQVQQKAEAMLQAN

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© ATCAAGCTGGAGCTCTTCCTGCACGTGCGCATCTTCGAGAGGGACGCCATCGAC YDMDMIRDCAEKVASHWQQLML to ATTATCTCAGACCTCGAGTCTTGGAATGATGAGCTTTCTCAGCAAATGAATGAC MEDRLKLVNASVAFYKTSEQVC TTCGACACAGAAGATCTCACGATTGCAGAGCAGCGCCTCCAGCACCATGCAGAC VLESLEQEYKREEDWCGGADKL AAAGCCTTGACCATGAACAACTTGACTTTTGACGTCATCCACCAAGGGCAAGAT PNSETDHVTPMISKHLEQKEAF CTTCTGCAGTATGTCAATGAGGTCCAGGCCTCTGGTGTGGAGCTGCTGTGTGAT KACTLARRNADVFLKYLHRNSV AGAGATGTAGACATGGCAACTCGGGTCCAGGACCTGCTGGAGTTTCTTCATGAA MPGMVTHIKAPEQQVKNILNEL AAACAGCAGGAATTGGATTTAGCCGCAGAGCAGCATCGGAAACACCTGGAGCAG QRENRVLHYWTMRKRRLDQCQQ TGCGTGCAGCTGCGCCACCTGCAGGCAGAAGTGAAACAGGTGCTGGGTTGGATC WFERSAKQALEWIHDNGEFYL CGCAACGGAGAGTCCATGTTAAATGCCGGACTTATCACAGCCAGCTCGTTACAA THTSTGSSIQHTQELLKEHEEF GAGGCAGAGCAGCTCCAGCGAGAGCACGAGCAGTTCCAGCATGCCATTGAGAAA ITAKQTKERVKLLIQLADGFCE ACACATCAGAGCGCGCTGCAGGTGCAGCAGAAGGCAGAAGCCATGCTACAGGCC GHAHAAEIKKCVTAVDKRYRDF AACCACTACGACATGGACATGATCCGGGACTGCGCCGAGAAGGTGGCGTCTCAC LRMEKYRTSLEKALGISSDSNK TGGCAACAGCTCATGCTCAAGATGGAAGATCGCCTCAAGCTCGTCAACGCCTCT SKSLQLDIIPASIPGSEVKLRD GTCGCTTTCTACAAAACCTCAGAGCAGGTCTGCAGCGTCCTCGAGAGCCTGGAA AHELNEEKRKSARRKEFIMAEL CAGGAGTACAAGAGAGAAGAAGACTGGTGTGGCGGGGCGGATAAGCTGGGCCCA QTEKAYVRDLRECMDTYLWEMT AACTCTGAGACGGACCACGTGACGCCCATGATCAGCAAGCACCTGGAGCAGAAG GVEEIPPGIVNKELIIFGNMQE GAGGCATTCCTGAAGGCTTGCACCCTTGCTCGGAGGAATGCAGACGTCTTCCTG YEFHNNIFLKELEKYEQLPEDV AAATACCTGCACAGGAACAGCGTGAACATGCCAGGAATGGTGACGCACATCAAA HCFVTWADKFQMYVTYCKNKPD GCTCCTGAACAGCAAGTGAAAAATATCTTGAATGAACTCTTCCAACGGGAGAAC TQLI EHAGSYFDEIQQRHGLA AGGGTATTGCATTACTGGACCATGAGGAAGAGACGGCTGGACCAGTGTCAGCAG SISSYLIKPVQRITKYQLLLKE

TACGTGGTCTTTGAGAGGAGTGCCAAGCAGGCTTTGGAATGGATCCATGACAAT LTCCEEGKGEIKDGLEVMLSVP GGCGAGTTCTACCTTTCCACACACACCTCCACGGGCTCCAGTATACAGCACACC RANDAMHLSMLEGFDENIESQG CAGGAGCTCCTGAAAGAGCACGAGGAGTTCCAGATAACTGCAAAGCAAACCAAA LILQESFQVWDPKTLIRKGRER GAGAGAGTGAAGCTATTGATACAGCTGGCTGATGGCTTTTGTGAAAAAGGGCAT LFLFEMSLVFSKEVKDSSGRSK GCCCATGCGGCAGAGATAAAAAAATGTGTTACTGCTGTGGATAAGAGGTACAGA LYKSKLFTSELGVTEHVEGDPC GATTTCTCTCTGCGGATGGAGAAGTACAGGACCTCTTTGGAAAAAGCCCTGGGG FALWVGRTPTSDNKIVLKASSI ATTTCTTCAGATTCCAACAAATCGAGTAAAAGTCTCCAGCTAGATATCATTCCA NKQDWIKHIREVIQERTIHLKG GCCAGTATCCCTGGCTCAGAGGTGAAACTTCGAGATGCTGCTCATGAACTTAAT LKEPIHIPKTAPATRQKGRRDG GAAGAGAAGCGGAAATCTGCCCGCAGGAAAGAGTTCATAATGGCTGAGCTCATT DLDSQGDGSSQPDTISIASRTS CAAACTGAAAAGGCTTATGTAAGAGACCTCCGGGAATGTATGGATACGTACCTG NTLDSDKLSGGCELTWIHDFT TGGGAAATGACCAGTGGCGTGGAAGAGATTCCACCTGGCATTGTAAACAAAGAA CNSNELTIRRGQTVEVLERPHD CTCATCATCTTCGGAAACATGCAAGAAATCTACGAATTTCATAATAACATATTC PDWCLVRTTDRSPAAEGLVPCG CTAAAGGAGCTGGAAAAATATGAACΛGTTGCCAGAGGATGTTGGACATTGTTTT LCIAHSRSSMEMΞGIFNHKDSL GTTACTTGGGCAGACAAGTTTCAGATGTATGTCACATATTGCAAAAATAAGCCT VSSNDASPPASVASLQPHMIGA GATTCTACTCAGCTGATATTGGAACATGCAGGGTCCTATTTTGACGAGATACAG SSPGPKRPGNTLRKWLTSPVRR CAGCGACATGGATTAGCCAATTCCATTTCTTCCTACCTTATTAAACCAGTTCAG SSGKADGHVKKLAHKHKKSREV CGAATAACGAAATATCAGCTCCTTTTAAAAGAGCTGCTGACGTGCTGTGAGGAA KSADAGSQKDSDDSAATPQDET GGAAAGGGAGAGATTAAAGATGGCCTGGAGGTGATGCTCAGCGTGCCGAAGCGA EERGRNEGLSSGTLSKSSSSGM GCCAATGACGCCATGCACCTCAGCATGCTGGAAGGGTTTGATGAAAACATTGAG SCGEEEGEEGADAVPLPPPMAI

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Ul TTAATTCGAAAGGGTCGAGAACGGCATCTCTTCCTTTTTGAAATGTCCTTAGTA SSETPSAAELVSAIEELVKSKM TTTAGTAAAGAAGTGAAAGATTCCAGTGGGAGAAGCAAGTACCTTTATAAAAGC LEDRPSSLLVDQGDSSSPSFNP AAATTGTTTACCTCAGAGTTGGGTGTCACAGAACATGTTGAAGGAGACCCTTGC DNSLLSSSSPIDEMEERKSSSL AAATTTGCACTGTGGGTGGGGAGAACACCAACTTCAGATAATAAAATTGTCCTT RRHYVLQELVETERDYVRDLGY AAGGCTTCCAGCATAGAGAACAAGCAGGACTGGATAAAGCATATCCGCGAAGTC VEGYMALMKEDGVPDDMKGKDK ATCCAGGAGCGGACGATCCACCTGAAGGGAGCCCTGAAGGAGCCCATTCACATC VFGNIHQIYDWHRDFFLGELEK CCTAAGACCGCTCCCGCCACAAGACAGAAGGGAAGGAGGGATGGAGAGGATCTG LEDPEKLGSLFVKHERRLHMYI GACAGCCAAGGAGACGGCAGCAGCCAGCCTGATACGATTTCCATCGCCTCACGG YCQNKPKSEHIVSEYIDTFFED ACGTCTCAGAACACGCTGGACAGCGATAAGCTCTCTGGTGGCTGTGAGCTGACA KQRLGHRLQLTDLLIKPVQRIM GTGGTGATCCATGACTTCACCGCTTGCAACAGCAACGAGCTGACCATCCGACGG YQLLLKDFLKYSKKASLDTSEL GGCCAGACCGTGGAAGTTCTGGAGCGGCCGCATGACAAGCCTGACTGGTGTCTG RAVEVMCIVPRRCNDMMNVGRL GTGCGGACCACTGACCGCTCCCCAGCGGCAGAAGGCCTGGTCCCCTGTGGTTCA GFDGKIVAQGKLLLQDTFLVTD CTGTGCATCGCCCACTCCAGAAGTAGCATGGAAATGGAGGGCATCTTCAACCAC DAGLLPRCRERRIFLFEQIVIF AAAGACTCGCTCTCCGTCTCCAGCAATGACGCCAGTCCACCCGCATCCGTGGCT EPLDKKKGFSMPGFLFKNSIKV TCCCTCCAGCCCCACATGATCGGGGCCCAGAGCTCGCCGGGCCCCAAGCGGCCG CLCLEENVENDPCKFALTSRTG GGCAACACCCTGCGCAAGTGGCTCACCAGCCCCGTGCGGCGGCTCAGCAGCGGC WETFILHSSSPSVRQTWIHEI AAGGCCGACGGGCACGTGAAGAAGCTGGCGCACAAGCACAAGAAGAGCCGCGAG QILENQRNFLNALTSPIEYQRN GTCCGCAAGAGCGCCGACGCCGGCTCGCAGAAGGACTCCGACGACAGTGCGGCC SGGGGGGGSGAAAGVGAAAAAG ACCCCGCAGGACGAGACGGTCGAGGAGAGAGGCCGGAACGAGGGCCTGAGCAGC PVAAAATVAAPAAAAAPPARAG

GGTACTCTCTCCAAATCCTCCTCCTCGGGGATGCAGAGCTGTGGAGAAGAGGAA GPPGSPSLSDTTPPCWSPLQPR GGCGAGGAGGGGGCCGACGCCGTGCCCCTGCCGCCACCCATGGCCATCCAGCAG RQRQTRCQSESSSSS ISTMLV CACAGCCTCCTCCAGCCAGACTCACAGGATGACAAGGCCTCTTCTCGGTTATTA HDYTAVKEDEINVYQGEWQIL GTCCGCCCCACCAGCTCCGAAACACCGAGTGCAGCCGAGCTCGTCAGTGCAATT SNQQNMFLVFRAATDQCPAAEG GAGGAACTCGTGAAAAGCAAGATGGCACTGGAGGATCGCCCCAGCTCACTCCTT IPGFVLGHTSAVIVENPDGTLK GTTGACCAGGGAGATAGTAGCAGCCCTTCCTTCAACCCTTCGGATAATTCCCTT STSWHTALRLRKKSEKKDKDGK CTCTCTTCCTCCTCGCCCATTGATGAGATGGAAGAAAGGAAATCCAGCTCTTTA EGKLENGYRKSREGLSNKVSVK AAGAGAAGACACTACGTTTTGCAAGAACTAGTGGAGACAGAGCGTGACTATGTG LNPNYIYDVPPEFVIPLSEVTC CGGGACCTTGGCTATGTGGTTGAGGGCTACATGGCACTTATGAAAGAAGATGGT TGETWLRCRVCGRPKASITWK GTTCCTGATGACATGAAAGGAAAAGACAAAATTGTGTTCGGCAACATCCATCAG PEHNTLNNDGHYSISYSDLGEA ATTTACGACTGGCACAGAGACTTTTTTTTAGGAGAGTTAGAGAAGTGCCTTGAA LKIVGVTTEDDGIYTCIAVNDM GATCCAGAAAAACTAGGATCCCTTTTTGTTAAACACGAGAGAAGGTTGCACATG SASSSASLRVLGPGMDGIMVTW TACATAGCTTATTGTCAAAATAAACCAAAGTCTGAGCACATTGTCTCAGAATAC DNFDSFYSEVAELGRGRFSWK ATTGATACCTTTTTTGAGGACTTAAAGCAGCGTCTTGGCCACAGGTTACAGCTC CDQKGTKRAVATKFVNKKLMKR ACAGATCTGTTGATCAAACCAGTGCAGAGAATCATGAAGTATCAGCTGTTACTG QVTHELGILQS QHPLLVGLLD AAGGACTTCCTCAAGTATTCCAAAAAGGCCAGCCTGGATACATCAGAATTAGAG FETPTSYILVLEMADQGRLLDC AGAGCTGTGGAAGTCATGTGCATAGTACCCAGGCGGTGCAACGACATGATGAAC VRWGSLTEGKIRAHLGEVLEAV GTGGGGCGGCTGCAAGGATTCGACGGGAAAATCGTTGCCCAGGGTAAACTGCTC YLHNCRIAHLDLKPENILVDES TTGCAGGACACATTCTTGGTCACAGACCAAGATGCAGGACTTCTGCCTCGCTGC AKPTIKLADFGDAVQLNTT YI

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© AGAGAGAGGCGCATCTTCCTCTTTGAGCAGATCGTCATATTCAGCGAACCACTT QLLGNPEFAAPEII GNPVSLT GATAAAAAGAAGGGCTTCTCCATGCCGGGATTCCTGTTTAAGAACAGTATCAAG DTWSVGVLTYVLLSGVSPFLDD GTGAGTTGCCTTTGCCTGGAGGAAAATGTGGAAAATGATCCCTGTAAATTTGCT VEETCLNICRLDFSFPDDYFKG CTGACATCGAGGACGGGTGACGTGGTAGAGACCTTCATTTTGCATTCATCTAGT SQKAKEFVCFLLQEDPAKRPSA CCAAGTGTCCGGCAAACTTGGATCCATGAAATCAACCAAATTTTAGAAAACCAG LALQEQWLQAGNGRSTGVLDTS CGCAATTTTTTAAATGCCTTGACATCGCCAATCGAGTACCAGAGGAACCACAGC LTSFIERRKHQNDVRPIRSIKN GGGGGCGGCGGCGGCGGCGGCAGCGGGGCAGCGGCGGGGGTGGGGGCAGCGGCG LQSRLLPRV* GCGGCGGGGCCCCCAGTGGCGGCAGCGGCCACAGTGGCGGCCCCAGCAGCTGCG GCGGCGCCCCCAGCACGAGCAGGAGCCGGCCCTCCCGGATCCCCCAGCCTGTCC GACACCACCCCCCCGTGCTGGTCTCCTCTGCAGCCTCGAGCCAGGCAGAGGCAG ACAAGATGTCAGAGTGAAAGCAGCAGCAGTAGCAACATCTCCACCATGTTGGTG ACACACGATTACACGGCAGTGAAGGAGGATGAGATCAACGTCTACCAAGGAGAG GTCGTTCAAATTCTGGCCAGCAACCAGCAGAACATGTTTCTGGTGTTCCGAGCC GCCACTGACCAGTGCCCCGCAGCTGAGGGCTGGATTCCAGGCTTTGTCCTGGGC CACACCAGTGCAGTCATCGTGGAGAACCCGGACGGGACTCTCAAGAAGTCAACA TCTTGGCACACAGCACTCCGTTTAAGGAAAAAATCTGAGAAAAAAGATAAAGAC GGCAAAAGGGAAGGCAAGTTAGAGAACGGTTATCGGAAGTCACGGGAAGGACTC AGCAACAAGGTATCTGTGAAGCTTCTCAATCCCAACTACATTTATGACGTTCCC CCAGAATTCGTCATTCCATTGAGTGAGGTCACGTGTGAGACAGGGGAGACCGTT GTTCTTAGATGTCGAGTCTGTGGCCGCCCCAAAGCCTCAATTACCTGGAAGGGC

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AAAAAGGAATCAACCCCAGGAAGTAATTATTTACAACGATTTTCCCAAATTTTG LGWTNALLFSNCSHLFSISPSC TACAATCTGTCCTGGAAAGCAAACCCCTTTTAAAATCTAATGTCTGGGCTTTGA LLSLMNAPRFSKAM*KSRHCP* GTATTAGCTCATTTAGGGTGGACAAATGCATTACTGTTTTCAAACTGCTCACAT CVICFFVLRYAQFPNQL*VPV* TTATTCAGTATTTCTCCAAGTTGCTATCTACTCAGCCTTATGAATGCCCCTCGC RGRFYLSKGEI*NLH*KDNFTF TTTTCTAAGGCCATGTGAAAATCACGGCACTGCCCTTAGCCTTGTGTCATCTGC ASLNETFFFL*VYFSTQFQNTN TTTTTCGTTCTGCGATATGCCCAGTTCCCAAATCAATTATAGGTACCTGTTTAG IFTLIFNVSLNIYNVASFKIFS GAGAGAGGAAGATTTTACCTCTCAAAGGGTGAGATTTGAAATTTACACTAAAAA KITFIIPLCACYW*QA*FII*Y* GACAACTTTACATTTAATGCTTCACTTAATGAGACATTCTTTTTTTTATAAGTC NMLFYLTVNKYVLIYIC*YAYS TATTTTTCTACTCAGTTTCAGAACACTAATCTGATTTTCACTCTGATTTTTAAC KKWT*GPRRFHFIHPGQIQ*RL GTTTCTTTAAATATTTATAATGTAGCTTCTTTCAAAATATTTTCATGAAAAATT V*IHNFLTRCRACS*ISNLLML ACTTTTATTATACCATTATGTGCATGTTATTGGTAGCAGGCATAGTTTATTATT PREEKL*LNVDLLITRRLCEKI TAGTACTGAAACATGCTCTTTTACCTAACAGTAAACAAGTATGTTTTGATATAT VYIYMICRSHFFYQALFSLQSH ATCTGTTAATATGCTTATAGTGGTAAGAAATGGACTTGAGGTCCC GGAGATTT LTVCNSWFMLMIDKYPVFVTFS CATTTTATTCACCCTGGTCAGATACAATAAAGGCTATGAGTATAAATACATAAC YHCNDNLSHVYTCNFL.-SFP*S TTCCTAACCAGGTGTAGGGCATGTTCATGAATATCAAATCTTTTGATGCTGGAC FNIFSILCP*CCFC*Q*SLSFF CCAAGAGAGGAAAAGTTGTAGCTAAATGTTGATTTACTTATAACTAGACGTCTA SYIFISSS*ICPVEASGPRHDF TGTGAGAAAATATATGTATACATATATATGATATGCAGAAGTCACTTTTTTTAT TPKYFTETFFK*GKYFIYQMVH CAGGCTTTATTCTCCTTACAAAGCCACAGTTTAACTGTCTGCAACAGTTGGTTT ^♦WLIASFFFSSKKCQVFKIIYL ATGTTAATGATAGACAAATACCCAGTGTTTGTTACTTTTTCCAACTACCACTGT KMKSAlLNF*RKDLTCFFSI*T

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I—' AATGATAATCTTTCTCACGTATATACATGCAACTTCTTGGCTTCATTTCCATGA FVLY*SLNYQEKNQNFIPMI**

© AGCTGTTTCAATATATTCAGTATACTTTGTCCTTAATGCTGCTTCTGTTAACAG *GIG*LT*WRMCQIFSSNATFS TGATCTCTTTCTTTTTTTCATTCTTATATCTTCATTAGTTCATCATAAATCTGT YN*NSVI*LIPLNFDVRSI*AP CCAGTTGAGGCCTCAGGACCACGGCATGATTTCATGACTCCGAAGTATTTTACA MIWHASHFSVK*IQYQSTLWV GAAACATTTTTTAAATAAGGGAAATATTTTATATACCAGATGGTTCACAAGTGA LLSFMVDLLMGKKYIKSNRILY TGGCTCATAGCTAGTTTTTTTTTTTCTTCTAAAAAATGTCAGGTTTTTAAAATC YVKIEHLPEVSGLDHSPGSFPS ATTTACCTTATTAAAATGAAAAGTGCCATACTTAACTTTTAAAGGAAAGACCTG SCAV*PWTRRFISLGLYFSICK ACTTGCTTTTTCTCTATTTAGACTGTTTTTGTACTTTACTAATCTTTAAACTAT SGCSR*WLRALPVPRCLGPKTP CAGGAAAAAAACCAAAACTTTATACCAATGATTTAGTAATTTTGAGGCATAGGG LCWSCQRVGAISCFRYKIGLSI TAGCTTACGTAGTGGAGGATGTGCCAAATATTCTCTTCAAATGCCACCTTCTCA FVHLIASKRPFCYTVLFF*FYG ATTTATAACTAAAATAGTGTTATCTGACTAATTCCTCTGAATTTTGATGTAAGA GYCNNVLFLAM*LQTDILLMS* TCTATATAGGCCCCCAAAATGATCGTAGTACATGCCAGTCATTTCTCAGTGAAA ICI*YIIDEILLLCNILWLRIC TAAATACAATACCAGAGTACATTATGGGTTTTATTGCTTTCTTTTATGGTAGAC ASY*P*YCDHYLEICPMERIKA CTGTTAATGGGGAAAAAATACATCAAATCAAATAGAATCTTATATCTGTATGTT TSQLACSQI*KKFH*KHHCFQK AAAATAGAGCACTTACCTGAAGTCAGTGGCCTGGATCATAGCCCTGGATCATTT KK CCCAGTCTGTCCTGTGCTGTGTGACCTTGGACAAGGCGCTTCATCTCTCTGGGC CTCTATTTCTCCATTTGTAAAACAAGTGGCTGCAGTAGATGATGGCTGAGAGCC CTTCCTGTTCCCAGATGCCTTGGTCCAAAGACCCCACCCCTCTGCTGGTCCTGC CAACGTGTTGGTGCTATAAGCTGCTTCAGATATAAAATTGGTTTATCTATAATG TTTGTTCATTTAATAGCTTCTAAAAGGCCTTTTTGTTATACAGTGCTTTTTTTC

TATATGACTGATGGGATGTTACTTCGTGAAGCTATGAATGATCCCCTCCTGGAG FQIYFDNCPLLTIPGRTHPVEI CGTTATGGTGTAATAATTCTTGATGAGGCTCATGAGAGGACACTGGCTACAGAT YTPEPERDYLEAAIRTVIQIHM ATTCTAATGGGTGTTCTGAAGGAAGTTGTAAGACAGAGATCAGATTTAAAGGTT EEEEGDLLLFLTGQEEIDEACK ATAGTTATGAGCGCTACTCTAGATGCAGGAAAATTCCAGATTTACTTTGATAAC IKREVDDLGPEVGDIKIIPLYS TGTCCTCTCCTAACTATTCCTGGGCGTACACATCCTGTTGAGATCTTCTATACT LPPQQQQRIFEPPPPKKQNGAI CCAGAACCAGAGAGAGATTATCTTGAAGCAGCAATTCGAACAGTTATCCAGATT RKVWSTNIAETSLTIDGWFV CATATGTGTGAAGAGGAAGAGGGAGATCTTCTTCTTTTCTTAACTGGTCAAGAG DPGFAKQKVYNPRIRVESLLVT GAAATTGATGAAGCCTGTAAGAGAATAAAGCGTGAAGTTGATGATTTGGGCCCT ISKASAQQRAGRAGRTRPGKCF GAAGTTGGTGACATTAAAATCATTCCATTGTATTCTACACTTCCACCTCAGCAG LYTEKAYKTEMQDNTYPEILRS CAGCAACGCATTTTTGAGCCTCCACCTCCCAAAAAACAGAATGGAGCAATTGGA LGSWLQLKKLGIDDLVHFDFM AGAAAGGTAGTTGTGTCAACTAACATAGCAGAGACGTCTTTGACAATAGATGGT PPAPETLMRALELLNYLAALND GTGGTGTTTGTGATTGATCCTGGATTTGCGAAACAGAAGGTCTACAATCCTCGA GDLTELGSMMAEFPLDPQLAKM ATCAGAGTTGAGTCCCTTTTGGTGACAGCTATTAGTAAAGCTTCAGCTCAGCAA IASCDYNCSNEVIJΓITAMLSVP AGGGCTGGTCGAGCTGGACGTACCAGACCTGGAAAATGCTTCAGACTTTACACA CFVRPTEAKKAADEAKMRFAHI GAGAAAGCTTATAAAACAGAAATGCAGGATAACACCTATCCTGAGATTTTGCGT GDHLTLLNVYHAFKQNHESVQW TCTAATTTAGGATCAGTTGTGTTACAATTGAAGAAACTTGGTATTGATGACTTG YDNFINYRSLMSADNVRQQLSR GTACATTTTGATTTTATGGATCCACCAGCTCCTGAAACTCTGATGAGAGCCCTG MDRFNLPRRSTDFTSRDYYINI GAACTTTTGAATTACCTGGCTGCTTTAAATGATGATGGAGATCTGACTGAATTG KALVTGYFMQVAHLERTGHYLT GGATCCATGATGGCAGAGTTTCCTCTAGATCCACAGCTCGCAAAAATGGTTATT KDNQWQLHPSTVLDHKPEWVL GCAAGTTGTGACTACAACTGTTCTAATGAGGTCCTATCTATTACTGCTATGTTG NEFVLTTKNYIRTCTDIKPEWL TCAGTCCCACAGTGTTTTGTTCGCCCCACGGAGGCCAAGAAAGCCGCAGATGAG KIAPQYYDMSNFPQCEAKRQLD GCCAAGATGAGATTTGCCCACATAGATGGAGATCATCTGACACTGCTGAACGTC IIAQTSIQGIFTVLNSVLRTEV TACCATGCTTTTAAACAAAATCATGAATCGGTTCAGTGGTGTTATGACAACTTC ERTALKDE* ATTAACTACAGGTCCCTGATGTCCGCGGACAATGTACGCCAGCAGCTATCTCGA ATTATGGACAGATTTAATTTGCCTCGTCGAAGTACTGACTTTACAAGCAGGGAC TATTATATTAATATAAGAAAAGCTTTGGTTACTGGGTATTTTATGCAGGTGGCA CATTTAGAACGAACAGGGCATTACTTAACTGTGAAAGATAACCAGGTGGTTCAG TTGCATCCCTCTACTGTTCTTGACCACAAACCTGAATGGGTGCTTTATAATGAG TTTGTTCTAACAACAAAGAATTACATCCGGACATGTACAGACATCAAGCCAGAA TGGTTGGTGAAAATTGCCCCTCAATATTATGACATGAGCAATTTCCCACAGTGT GAAGCAAAGAGACAGTTGGACCGCATCATTGCCCAAACTTCAATCCAAGGAATA TTCACAGTACTGAATTCAGTGCTTAGAACTGAAGTTATTGAGAGGACAGCTTTA AAAGATGAATGA

Human 11 preyl5125 651 GGAGTTGCTGAATTCCACCCCAGAATCCCACCCAG 1389 ELLNSTPESHP hGITl v4

Human 11 preyl2722 652 TACCGAGCACGGGCGCTGGAACTAGAGGCCGAGGTGGCAGAGATGCGACAGATG 1390 YRARALELEAEVAEMRQMLQSE hGITl v4 TTGCAGTCAGAGCATCCATTTGTGAATGGAGTTGAGAAGCTGGTGCCAGACTCT PFVNGVEKLVPDSLYVPFKEPS CTGTATGTTCCTTTCAAAGAGCCCAGCCAGAGCCTGCTGGAAGAGATGTTCCTG SLLEEMFLTVPESHRKPLKRSS ACTGTGCCGGAATCACATAGAAAGCCTCTCAAGCGCAGCAGCAGTGAGACGATC ETILSSLAGSDIVKGHEETCIR

CTCAGCAGCTTGGCAGGGAGTGACATCGTGAAGGGCCACGAGGAGACCTGCATC AKAVKQRGISLLHEVDTQYSAL AGGAGGGCCAAGGCTGTGAAACAGAGGGGCATCTCCCTTCTGCACGAAGTGGAC VKYEELLKKCQEEQDSLSHKAV ACGCAGTACAGCGCCCTGAAGGTGAAGTATGAAGAGTTGCTGAAGAAGTGCCAA TSRAAAKDLTGVNAQSEPVASG GAGGAACAGGACTCCCTGTCACACAAGGCTGTGCAGACCTCCAGGGCTGCAGCC ELASVNPEPVSSPTTPPEYKAL AAGGACCTGACTGGAGTGAACGCCCAGTCTGAGCCTGTTGCCAGCGGCTGGGAA KEIFSCIKKTKQEIDEQRTKYR CTGGCCTCTGTCAACCCAGAGCCCGTGAGTTCCCCTACAACACCTCCAGAATAC LSSHS*LNL*LYY*FAYCLSPL AAAGCGTTGTTTAAGGAGATCTTTAGTTGCATCAAGAAAACTAAGCAGGAAATA PIQTSVCRL GATGAACAGAGAACAAAATACCGATCACTCTCCTCTCATTCTTAATTGAACCTC TAGCTCTACTACTAATTTGCCTATTGCCTATCGCCTCTCTCTCCCATTCAGACA AGTGTTTGTAGACTCT

Human 11 preyl857 653 ATGGCAGGAGAGCTGGCTGACAAAAAGGACCGTGATGCATCACCTTCCAAGGAG 1391 MAGELADKKDRDASPSKEERKR hGITl v4 GAAAGGAAGCGATCACGGACTCCTGACAGAGAGCGGGATAGAGACCGGGACCGG RTPDRERDRDRDRKSSPSKDRK AAGTCTTCCCCATCTAAAGATAGAAAGCGGCΛTCGTTCAAGGGATAGACGTCGA HRSRDRRR3GSRSRSRSRSKSA GGAGGCAGCCGTTCTCGCTCTCGTTCCCGTTCCAAATCTGCAGAAAGAGAACGA RERRHKERERDKERDRNKKDRD CGGCACAAAGAACGAGAACGAGATAAGGAGCGGGATCGGAATAAGAAGGACCGA DKDGHRRDKDRKRSSLSPGRGK GATCGAGACAAGGATGGGCACAGACGGGACAAGGACCGTAAACGATCCAGCTTA FKSRKDRDSKKDEEDEHGDKKL TCTCCTGGTCGAGGAAAAGACTTTAAATCTCGGAAGGACAGAGACTCTAAGAAG AQPLSLEELLAKKKAEEEAEAK GATGAAGAGGATGAACATGGTGATAAGAAGCTTAAGGCCCAGCCATTATCCCTG KFLSKAEREAEALKRRQQEVEE GAGGAGCTTCTGGCCAAGAAAAAGGCTGAGGAAGAAGCTGAGGCTAAGCCCAAG QRMLEEERKKRKQFQDLGRKML

Ul

I—' TTCCTCTCTAAAGCAGAACGAGAGGCTGAAGCTCTAAAGCGACGGCAGCAGGAG DPQERERRERRERMERETNGNE Ul GTGGAAGAGCGGCAGAGGATGCTTGAAGAAGAGAGGAAGAAAAGGAAACAGTTC EEGRQKIREEKDKSKELHAIKE CAAGACTTGGGCAGGAAGATGTTGGAAGATCCTCAGGAACGGGAACGTCGGGAA YLGGIKKRRRTRHLNDRKFVFE CGCAGGGAGAGGATGGAACGGGAGACCAATGGAAATGAGGATGAGGAAGGGCGG DASEETSIDYNPLYKERHQVQL CAGAAGATCCGGGAAGAGAAGGATAAGAGCAAGGAACTGCATGCCATTAAGGAG GRGFIAGIDFKQQKREQSRFYG CGTTACCTGGGTGGCATCAAAAAGCGGCGCCGAACGAGACATCTCAATGACCGG LMEKRRTLEEKEQEEARLRKLR AAATTTGTTTTTGAGTGGGATGCATCTGAGGAGACATCCATTGACTACAACCCC KEAKQRWDDRHWSQKKLDEMTD CTGTACAAAGAACGGCACCAGGTGCAGTTGTTAGGGCGAGGCTTCATTGCAGGC DWRIFREDYSITTKGGKIPNPI ATTGACTTCAAGCAGCAGAAGCGAGAGCAGTCACGTTTCTATGGAGACCTAATG SWKDSSLPPHILEVIDKCGYKE GAGAAGAGGCGAACCCTGGAAGAAAAGGAGCAGGAGGAGGCAAGACTCCGCAAA TPIQRQAIPIGLQNRDIIGVAE CTTCGTAAGAAGGAAGCCAAGCAGCGCTGGGATGATCGTCATTGGTCTCAGAAA GSGKTAAFLIPLLVWITTLPKI AAGTTAGATGAGATGACGGACAGGGACTGGCGGATCTTCCGTGAGGACTACAGC RIEESDQGPYAIILAPTRELAQ ATCACCACCAAAGGTGGCAAGATCCCCAATCCCATCCGATCCTGGAAAGACTCT IEEETIKFGKPLGIRTVAVIGG TCTCTGCCCCCACACATCTTGGAGGTCATTGATAAGTGTGGCTACAAGGAACCA SREDQGFRLRMGCEIVIATPGR ACACCTATCCAGCGTCAGGCAATTCCCATTGGGCTACAGAATCGTGACATCATT IDVLENRYLVLSRCTYWLDEA GGTGTGGCTGAGACTGGCAGTGGCAAGACAGCAGCCTTCCTCATCCCTCTGCTG RMIDMGFEPDVQKILEHMPVSN GTCTGGATCACCACACTTCCCAAAATTGACAGGATCGAAGAGTCAGACCAAGGC KPDTDEAEDPEKMLANFESGKH CCTTATGCCATCATCCTGGCTCCCACCCGTGAGTTGGCTCAACAGATTGAGGAA YRQTVMFTATMPPAVERLARSY GAGACCATCAAGTTTGGGAAACCGCTAGGTATCCGCACTGTGGCTGTCATTGGT RRPAWYIGSAGKPHERVEQKV GGCATCTCCAGAGAAGACCAGGGCTTCAGGCTGCGCATGGGTTGTGAGATTGTG LMSESEKRKKLLAILEQGFDPP

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TCTTCCCCTGCACCATCCACTGGAAAAGTAGAAGCAGCACTAAATGAAAATACT EPVIFCLDFIKIQLDEPDHDPV TGCAGAGCAGAGCGTGAACTACGAAGCATTCCAGAAGACTCAGAGTTAAATACA IILNTSDLTKCEWCNVRKLPW GTTACATTGCCAAGAAAAGCAAGAATGAAAGACCAGTTTGGCAATTCTATTATC LQAIPAVYQKLSIQLQMNKEDK AACACACCTCTGAAACGTCGTAAAGTGTTTTCTCAAGAACCTCCAGATGCTTTA WNDCKGVNKLTNLEEQYIILIF GCTTTAAGCTGCCAAAGTTCCTTTGACAGTGTCATTTTAAACTGTCGAAGTATA NGLDPPANMVFESIINEIGIKN CGAGTAGGAACACTCTTCCGGCTGTTAATAGAGCCTGTAATTTTTTGTTTAGAT ISNFFAKIPFEEANGRLVACTR TTTATCAAGATACAGCTAGACGAACCAGACCATGATCCTGTAGAGATTATATTA YEESIKGSCGQKENKIKTVSFE AATACCTCTGATCTAACTAAATGTGAATGGTGTAATGTCCGAAAATTACCTGTA KIQLRSKQEFQFFDEEEETGEN GTGTTTCTTCAAGCAATTCCAGCAGTTTATCAAAAGCTGAGCATCCAACTGCAA TIFIGPVEKLIVYPPPPAKGGI ATGAATAAGGAGGATAAAGTTTGGAATGATTGTAAAGGAGTAAATAAATTAACA VTNEDLHCLNEGEFLNDVIIDF AATTTAGAAGAACAATATATAATTTTAATTTTTCAAAATGGCCTTGATCCTCCG LKYLVLEKLKKEDADRIHIFSS GCAAATATGGTATTTGAAAGTATCATTAATGAAATTGGTATAAAGAATAACATC FYKRLNQRERRNHETTNLSIQQ TCCAATTTTTTTGCGAAAATTCCCTTTGAAGAAGCTAATGGCAGACTTGTTGCC RHGRVKTWTRHVDIFEKDFIFV TGTACAAGAACCTATGAAGAGAGCATCAAAGGAAGTTGTGGGCAAAAGGAAAAC LNEAAHWFLAWCFPGLEKPKY AAAATTAAAACTGTATCATTTGAATCTAAAATACAACTTAGAAGCAAACAAGAA PNPHYHENAVTQKCSTVEDSCI TTTCAGTTTTTTGATGAAGAAGAAGAAACTGGAGAAAACCACACCATCTTCATT SSASEMESCSQNSSAKPVIKKM GGCCCAGTAGAAAAGTTGATAGTATATCCACCACCTCCAGCTAAGGGAGGCATC NKKHCIAVIDSNPGQEESDPRY TCTGTTACCAATGAGGACCTGCACTGTCTAAATGAAGGAGAATTTTTAAATGAT RNICSVKYSVKKINHTASENEE GTTATTATAGACTTTTATTTGAAATACTTGGTGCTTGAAAAACTGAAGAAGGAA NKGESTSQKVADRTKSENGLQN

Ul to GACGCTGACCGAATTCATATATTCAGTTCTTTTTTCTATAAACGCCTTAATCAG SLSSTHHTDGLSKIRLNYSDES

© AGAGAGAGGAGAAATCATGAAACAACTAATCTGTCAATACAGCAAAAACGGCAT EAGKMLEDELVDFSEDQDNQDD GGGAGAGTAAAAACATGGACCCGGCACGTAGATATTTTTGAGAAGGATTTTATT SDDGFLADDNCSSEIGQWHLKP TTTGTACCCCTTAATGAAGCTGCACACTGGTTTTTGGCTGTTGTTTGTTTCCCC ICKQPCILLMDSLRGPSRSNW GGTTTGGAAAAACCAAAGTATGAACCTAATCCTCATTACCATGAAAATGCTGTC ILREYLEVEWEVKKGSKRSFSK ATACAGAAATGTTCAACTGTAGAGGACAGTTGTATTTCTTCTTCAGCCAGTGAA VMKGSNPKVPQQNNFSDCGVYV ATGGAGAGTTGTTCACAAAACTCTTCTGCCAAGCCTGTAATTAAGAAGATGCTA QYVESFFENPILSFELPMNLAN AACAAAAAACATTGCATAGCTGTAATTGATTCCAATCCTGGGCAGGAAGAAAGT FPPPRMRTKREEIRNIILKLQE GACCCTCGTTATAAGAGAAACATATGCAGTGTAAAATACAGTGTGAAAAAAATA QSKEKRKHKDTYSTEAPLGEGT AATCATACTGCGAGTGAAAATGAAGAATTCAATAAAGGAGAATCTACATCCCAG QCVNSISD* AAAGTTGCTGATAGGACTAAAAGTGAGAATGGCCTACAGAATGAAAGTTTAAGT TCCACACATCATACAGATGGCTTAAGCAAAATCAGACTAAACTATAGCGATGAA TCACCTGAAGCTGGTAAAATGCTTGAAGATGAACTCGTCGACTTCTCAGAAGAT CAGGATAACCAGGATGATAGCAGTGACGATGGATTCCTCGCTGATGACAACTGC AGTTCAGAAATAGGACAGTGGCATTTAAAGCCTACTATCTGTAAACAACCTTGT ATCCTACTTATGGACTCACTCCGAGGCCCTTCTCGGTCAAATGTTGTCAAAATT TTAAGAGAGTATTTAGAAGTGGAATGGGAAGTTAAAAAAGGAAGCAAAAGAAGT TTTTCCAAAGATGTTATGAAGGGCTCTAATCCAAAAGTACCACAGCAAAACAAC TTCAGTGACTGTGGTGTATATGTATTGCAGTATGTAGAGAGCTTTTTTGAGAAT CCAATTCTCAGTTTTGAACTACCTATGAATTTGGCAAACTGGTTTCCTCCACCA

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ACGATGCATGCGGTGGGTGAGGGGGCAGATCAGACGCTGCTCCAGAAACTTCAG EESRVKHQVEYLGLKENIRVRR ATGCAGATTGGGAGTCATGAGCACTTCAACAGTTGGAACCAAGGCTTCATCATT GYAYRRIFQKFLQRYAILTKAT CATCATTATGCTGGGAAGGTATCCTATGACATGGATGGCTTTTGTGAAAGGAAC PSWQGEEKQGVLHLLQSVNMDS CGGGATGTGCTTTTTATGGATCTCATCGAGCTTATGCAGAGCAGCGAGCTGCCT QFQLGRSKVFIKAPESLFLLEE TTCATAAAGTCTTTATTTCCGGAAAATCTGCAGGCTGACAAGAAAGGGCGCCCA RERKYDGYARVIQKSWRKFVAR ACTACTGCCGGAAGCAAAATAAAGAAACAAGCCAATGACCTTGTGAGCACCCTG KYVQMREEASDLLLNKKERRRN ATGAAATGTACGCCCCACTACATTCGCTGCATCAAGCCAAACGAAACCAAGAAG INRNFIGDYIGMEEHPELQQFV CCCAGAGACTGGGAGGAAAGCAGGGTAAAGCATCAAGTCGAATATTTGGGTCTG KREKIDFADTVTKYDRRFKGVK AAAGAGAACATTCGAGTGAGAAGAGCTGGCTATGCCTATCGGCGCATCTTCCAA DLLLTPKCLYLIGREKVKQGPD AAATTCCTACAGAGGTATGCCATTCTGACCAAAGCCACCTGGCCTTCTTGGCAG GLVKEVLKRKIEIERILSVSLS GGAGAGGAGAAGCAAGGCGTCCTGCACCTGCTGCAGTCGGTCAACATGGACAGC MQDDIFILHEQEYDSLLESVFK GACCAGTTCCAGCTGGGGAGGAGTAAAGTGTTCATCAAAGCCCCCGAGTCTCTA EFLSLLAKRYEEKTQKQLPLKF TTTCTTTTAGAΛGAGATGAGAGAGAGAAAGTATGATGGGTATGCTCGAGTGATA NTLELKLKKENWGPGVQGAGSR CAGAAATCATGGAGGAAATTCGTGGCCCGGAAGAAATACGTTCAAATGAGAGAA VQFHQGFGDLAVLKPSNKVLQV GAAGCCTCAGACCTCTTATTGAACAAGAAGGAGAGAAGGAGAAACAGTATTAAC IGPGLPKNSRPTRRNTTQNTGY AGGAACTTTATAGGGGATTATATTGGGATGGAAGAGCACCCAGAACTCCAGCAG SGTQNANYPVRAAPPPPGYHQN TTCGTGGGCAAGAGGGAGAAGATTGATTTCGCAGACACAGTCACCAAGTATGAC VIRNQYVPYPHAPGSQRSIQKS AGGAGGTTCAAGGGTGTAAAGCGAGACCTGCTCCTTACCCCAAAGTGCTTGTAC YTSMARPPLPRQQSTSSDRVSQ TTAATCGGACGAGAAAAAGTCAAACAGGGCCCAGACAAGGGCCTGGTGAAAGAA PESLDFLKVPDQGAAGVRRQTT

Ul to GTCCTGAAGCGGAAAATCGAGATAGAACGGATCTTGTCTGTGTCCCTCAGTACT RPPPAGGRPKPQPKPKPQVPQC

Ul ATGCAGGATGACATTTTTATTCTCCATGAGCAAGAGTATGACAGTTTGCTTGAA ALYAYDAQDTDELSFNANDIID TCTGTCTTCAAAACTGAATTCCTAAGCCTCTTAGCAAAGCGTTACGAGGAGAAG IKEDPSGWWTGRLRGKPGLFPN ACCCAGAAGCAACTACCTCTGAAATTCAGCAATACGCTTGAACTGAAGTTGAAA YVTKI* AAGGAAAACTGGGGCCCTGGAGTGCAGGGTGCGGGCTCCCGGCAAGTGCAGTTC CACCAAGGGTTTGGGGACCTGGCTGTCCTCAAGCCCAGTAACAAAGTGCTGCAG GTCAGCATCGGACCTGGACTGCCCAAGAACTCCCGTCCTACCAGAAGGAACACT ACCCAAAATACAGGTTATTCCAGTGGGACTCAAAATGCCAACTACCCAGTGAGA GCTGCCCCTCCTCCCCCAGGATACCATCAGAACGGAGTCATCAGAAACCAGTAT GTGCCATATCCCCATGCTCCTGGAAGCCAGAGGTCCATTCAGAAAAGCCTGTAC ACCTCCATGGCCCGCCCGCCCTTGCCTCGGCAGCAGTCTACCAGTTCAGACCGA GTGTCACAGACGCCAGAGAGCCTGGATTTCCTCAAGGTCCCGGACCAGGGAGCT GCAGGGGTCAGGAGACAAACAACCAGTCGGCCTCCCCCAGCTGGGGGCAGACCC AAGCCCCAGCCCAAGCCCAAGCCTCAGGTTCCACAGTGCAAGGCTTTGTATGCC TATGACGCTCAGGACACAGACGAACTCAGCTTTAATGCCAATGACATTATTGAT ATTATCAAAGAAGATCCTTCTGGCTGGTGGACGGGTCGACTACGAGGCAAGCCA GGGCTGTTCCCCAACAACTATGTGACCAAGATCTGA

Human 11 prey3634 683 CATCTTGGAACCTGTAGGCCTGCAGGAGGAGGCAGAACTGCCAGCCAAGATCCT 1421 ILEPVGLQEEAELPAKILVEF hGITl v4 GGTTGAGTTTGTGGTGGACTCTCAGAAGAAAGACAAGCTGCTCTGCAGCCAGCT DSQKKDKLLCSQLQVADFLQNI TCAGGTAGCGGATTTCCTGCAGAACATCCTGGCTCAGGAGGACACTGCTAAGGG AQEDTAKGLDPLASEDTSRQKA

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TCACTTCCCCAGGAAGCATTTGAAAAGTACCAGACAC

Human 11 prey4752 691 CATCGTGATGTCTTATTTAAGGGGAACGTGTGGGCTATTTAGGCTTTATGACCC 1429 HRDVLFKGNVWAl*AL*P*SRN hGITl v4 TGAAGTAGGAACCAGATGTCGGATACAGTTCACTTTAGCTACCCCCAAGTGTTA MSDTVHFSYPQVLWARSEESST TGGGCCCGGAGCGAGGAGAGTAGCACTCTTGTGCGGGATATTGATTTCACGGAG VRDIDFTEDGGQGTPI*GGSSM GATGGTGGTCAAGGGACCCCTATCTGAGGGGGGTCATCCATGGGGACGAGAAGG TRRDLTVMCYVR*MALCTMYC* GATTTGACTGTAATGTGCTATGTACGGTAAATGGCTTTATGTACTATGTACTGT WVGLLVS*WVRGGFGVAVDV** TAAGGGTGGGTAGGTTTGTTGGTATCCTAGTGGGTGAGGGGTGGCTTTGGAGTT RVDCCTCL*AWGGGFDVDWVFM GCAGTTGATGTGTGATAGTTGAGGGTTGATTGCTGTACTTGCTTGTAAGCATGG YRWSSIYGTVQYSWWLAVMYEI GGAGGGGGTTTTGATGTGGATTGGGTTTTTATGTACTACAGGTGGTCAAGTATT SGC*WVSQYLGGTQICFPMKEQ TATGGTACCGTACAATATTCATGGTGGCTGGCAGTAATGTACGAAATACATAGC IV*IRILALGANGGVKDFFSDL GGTTGTTGATGGGTGAGTCAATACTTGGGTGGTACCCAAATCTGCTTCCCCATG LEKGFHLRFTRLVY*FILQGQA AAAGAACAGAGAATAGTTTAAATTAGAATCTTAGCTTTGGGTGCTAATGGTGGA LSILFSIREIVGIRIRIWKYS GTTAAAGACTTTTTCTCTGATTTGTCCTTGGAAAAAGGTTTTCATCTCCGGTTT DATCPMMVKG*LTGCPPIQVRM ACAAGACTGGTGTATTAGTTTATACTACAAGGACAGGCCCATTTGAGTATTTTG RSAARSQ*SDWLSGRNIMLCCL TTTTCAATTAGGGAGATAGTTGGTATTAGGATTAGGATTGTTGTGAAGTATAGT IWRMGIIARMRMDSNRARTPPS ACGGATGCTACTTGTCCAATGATGGTAAAAGGGTAGCTTACTGGTTGTCCTCCG LGTDRRIV*ANRKYHSGLMWGG ATTCAGGTTAGAATGAGGAGGTCTGCGGCTAGGAGTCAATAAAGTGATTGGCTT FKGLARV*LSGSPRRSGENSVN AGTGGGCGAAATATTATGCTTTGTTGTTTGGATATATGGAGGATGGGGATTATT IKERRKRSKPRASLIV**GWKV GCTAGGATGAGGATGGATAGTAATAGGGCAAGGACGCCTCCTAGTTTGTTAGGG LSEWEVIPRGLFDPVSCKNRRW

Ul to ACGGATCGGAGAATTGTGTAGGCGAATAGGAAATATCATTCGGGCTTGATGTGG VARAAIMKGKMK*KVKNRVRVG oe GGAGGGGTGTTTAAGGGGTTGGCTAGGGTATAATTGTCTGGGTCGCCTAGGAGG STE*PPQIH*TRSVPMYGMADS TCTGGTGAGAATAGTGTTAATGTCATTAAGGAGAGAAGGAAGAGAAGTAAGCCG FVI VAPQNDIWPHGRT*PMKA AGGGCGTCTTTGATTGTGTAGTAAGGGTGGAAGGTGATTTTATCGGAATGGGAG AIVASRRIMPMFQVSE*RNDP* GTGATTCCTAGGGGGTTGTTTGATCCCGTTTCGTGCAAGAATAGGAGGTGGAGT RPRPMCRKRQIKNIEAPLA*R* GTTGCTAGGGCTGCAATAATGAAGGGCAAGATGAAGTGAAAGGTAAAGAATCGT MIQP*FTSRVMWAIDEKAVEAS GTGAGGGTGGGACTGTCTACTGAGTAGCCTCCTCAGATTCATTGAACTAGGTCT E*CMARNSPWIWRIRQAPRSE GTCCCAATGTATGGGATGGCGGATAGTAAGTTTGTAATTACTGTGGCCCCTCAG KFHHAEMLDGVGRSMNEWLINF AATGATATTTGGCCTCACGGGAGGACATAGCCTATGAAGGCTGTTGCTATAGTT RGLVLRIGVIGVLWEIQRWFF GCAAGCAGGAGGATAATGCCGATGTTTCAGGTTTCTGAGTAGAGAAATGATCCG SLVWWRARIMMYALFLLSVG TAATATAGGCCTCGCCCGATGTGTAGGAAGAGGCAGATAAAGAATATTGAGGCG VMGFVGFSSKPSPIYGGLVLIV CCATTGGCGTGAAGGTAGCGGATGATTCAGCCATAATTTACGTCTCGAGTGATG GWGCVIILNFGGGYMGLIVFL TGGGCGATTGATGAAAAGGCGGTTGAGGCGTCTGGTGAGTAGTGCATGGCTAGG YLGGMMWFGYTTAMAIEEYPE AATAGTCCTGTGGTGATTTGGAGGATCAGGCAGGCGCCAAGGAGTGAGCCGAAG WGSGVEVLVSVLVGLAMEVGLV TTTCATCATGCGGAGATGTTGGATGGGGTGGGGAGGTCGATGAATGAGTGGTTA WVKEYDGVWWNFNSVGS*11 ATTAATTTTATTAGGGGGTTAGTTTTGCGTATTGGGGTCATTGGTGTTCTTGTA EGEGSGLIREDPIGAGALYDYG GTTGAAATACAACGATGGTTTTTCATATCATTGGTCGTGGTTGTAGTCCGTGCG *LVWTG*TLFVGVYIVIEIAR AGAATAATGATGTATGCTTTGTTTCTGTTGAGTGTGGGTTTAGTAATGGGGTTT NRLCD*E*G*DEWEEEREEVKF GTGGGGTTTTCTTCTAAGCCTTCTCCTATTTATGGGGGTTTAGTATTGATTGTT YAFLG*GDDGGGDLVL*NCFR* AGCGGTGTGGTCGGGTGTGTTATTATTCTGAATTTTGGGGGAGGTTATATGGGT LF*SG*V*EE*GQVLARKKA*I

TTAATAGTTTTTTTAATTTATTTAGGGGGAATGATGGTTGTCTTTGGATATACT DCAVCDARVESEYVGEIKCA*W ACAGCGATGGCTATTGAGGAGTATCCTGAGGCATGGGGGTCAGGGGTTGAGGTC FYFKFVG*WEV*GC*KS *ESD TTGGTGAGTGTTTTAGTGGGGTTAGCGATGGAGGTAGGATTGGTGCTGTGGGTG EGCEF*VEGDCCLEGGCGGNW AAAGAGTATGATGGGGTGGTGGTTGTGGTAAACTTTAATAGTGTAGGAAGCTGA NEKSCE*ASGCQAFNGV**GGV ATAATTTATGAAGGAGAGGGGTCAGGGTTGATTCGGGAGGATCCTATTGGTGCG FVNVSKGGEARLTC*GEKNYSS GGGGCTTTGTATGATTATGGGCGTTGATTAGTAGTAGTTACTGGTTGAACATTG IGACQGGSDESNR*GSGVCV*Y TTTGTTGGTGTATATATTGTAATTGAGATTGCTCGGGGGAATAGGTTATGTGAT CGFDDWFGVETCEERYSC*C* TAGGAGTAGGGTTAGGATGAGTGGGAAGAAGAAAGAGAGGAAGTAAAGTTTAAT ANGEGG* SERYGFE*SSYFSNI TATGCCTTTTTGGGTTGAGGTGATGATGGAGGTGGAGATTTGGTGCTGTGAAAT FIVKWDDGPGAHK*YGFEEGV TGTTTTAGGTAATAGCTTTTCTAGTCAGGTTAGGTCTAGGAGGAGTAGGGGCAG TDVQEC * VWLVDADCNYYES * L GTTTTGGCTCGTAAGAAGGCCTAGATAGGGGATTGTGCGGTGTGTGATGCTAGG * SGEGYDFFDVILCKGADCCEQ GTAGAATCCGAGTATGTTGGAGAAATAAAATGTGCATAGTGGGGATTTTATTTT GDSA*A*C*SLD*WAIFC*GVE AAGTTTGTTGGTTAGGTAGTTGAGGTCTAGGGCTGTTAGAAGTCCTACGAAAGT DE*EDSCYNYSA*VE*G*DWGG GACAGCGAGGGCTGTGAGTTTTAGGTAGAGGGGGATTGTTGTTTGGAAGGGGGA FYG*GESGVET*LG*FACCC*E TGCGGGGGAAATGTTGTTAGTAATGAGAAATCCTGCGAATAGGCTTCCGGCTGC A**WGEAWISV*KGYLLWVS*V CAGGCGTTTAATGGGGTTTAGTAGGGTGGGGTTATTTTCGTTAATGTTAGTAAG V*DKSC*GEDETDIADTW*DC GGTGGGGAAGCGAGGTTGACCTGTTAGGGTGAGAAGAATTATTCGAGTGCTATA NGCCVGICSGVSSTDEQEGYNS GGCGCTTGTCAGGGAGGTAGCGATGAGAGTAATAGATAGGGCTCAGGCGTTTGT ALSADEQLE*WSGN*D*YGN* GTATGATATGTTTGCGGTTTCGATGATGTGGTCTTTGGAGTAGAAACCTGTGAG DE*IFEELINVWV*VYISQ*EF

Ul to GAAAGGTATTCCTGCTAATGCTAGGCTGCCAATGGTGAGGGAGGTTGAAGTGAG DGPCNEQCYRDEYYGEW*FEA

VO AGGTATGGTTTTGAGTAGTCCTCCTATTTTTCGAATATCTTGTTCATTGTTAAG GELGCLGCGSVSVRDNNFLV*A GTTGTGGATGATGGACCCGGAGCACATAAATAGTATGGCTTTGAAGAAGGCGTG EYCCGEETDNKGGCDNGFYIMG GGTACAGATGTGCAGGAATGCTAGGTGTGGTTGGTTGATGCCGATTGTAACTAT *VFFVRVNEGGKDGGN*GSQG* TATGAGTCCTAGTTGACTTGAAGTGGAGAAGGCTACGATTTTTTTGATGTCATT GYSSVHGYYFYLELHQNFWGLR TTGTGTAAGGGCGCAGACTGCTGCGAACAGAGTGGTGATAGCGCCTAAGCATAG MDSCYPLKVEKAMLLDMGA*VS TGTTAGAGTTTGGATTAGTGGGCTATTTTCTGCTAGGGGGTGGAAGCGGATGAG SCELSR*IRGRKPLLSDSQSDV TAAGAAGATTCCTGCTACAACTATAGTGCTTGAGTGGAGTAGGGCTGAGACTGG VKLYLQEENPVMMSGLRDRRRM GGTGGGGCCTTCTATGGCTGAGGGGAGTCAGGGGTGGAGACCTAATTGGGCTGA DRCMNMRVFSRVNEGFMLLMWW TTTGCCTGCTGCTGCTAGGAGGAGGCCTAGTAGTGGGGTGAGGCTTGGATTAGC SEPHCVWNM*REYRAVTSMLS GTTTAGAAGGGCTATTTGTTGTGGGTCTCATGAGTTGGAGTGTAGGATAAATCA VSRRVIFDQENWTSTESSPSR TGCTAAGGCGAGGATGAAACCGATATCGCCGATACGGTTGTATAGGATTGCTTG IVGGKARLARLARSHQKAISGS AATGGCTGCTGTGTTGGCATCTGCTCGGGCGTATCATCAACTGATGAGCAAGAA V*SP*ERIMMRL*VRS*FEFAR GGATATAATTCCTACGCCCTCTCAGCCGATGAACAGTTGGAATAGGTTGTTAGC NSNEDVSPWAIMRMTAPVKLQG GGTAACTAAGATTAGTATGGTAATTAGGAAGATGAGTAGATATTTGAAGAACTG WMRMAVTTRAMWLIEEYAMSDF ATTAATGTTTGGGTCTGAGTTTATATATCACAGTGAGAATTCTATGATGGACCA SVCRRQMELVIIMPHRDSTRKG TGTAACGAACAATGCTACAGGGATGAATATTATGGAGAAGTAGTCTAGTTTGAA AMCFVRGLRMSVRRIIP*PPSF GCTTAGGGAGAGCTGGGTTGTTTGGGTTGTGGCTCAGTGTCAGTTCGAGATAAT STAASTIDPAMGASTWALGSHK AACTTCTTGGTCTAGGCACATGAATATTGTTGTGGGGAAGAGACTGATAATAAA SP*RGIFTIKAIV*ASHIKLLA GGTGGATGCGACAATGGATTTTACATAATGGGGGTATGAGTTTTTTTTGTTAGG EFDSSWAVRVSSRMFSEPRVL*

GTTAACGAGGGTGGTAAGGATGGGGGGAATTAGGGAAGTCAGGGTTAGGGTGGT *ISAMSRGREPTRV*NRKYVPA TATAGTAGTGTGCATGGTTATTACTTTTATTTGGAGTTGCACCAAAATTTTTGG RRSGWLPHRVMIAKVGISWSK GGCCTAAGACCAATGGATAGCTGTTATCCTTTAAAAGTTGAGAAAGCCATGTTG I*NMISSVAVNVIIKEICREIS TTAGACATGGGGGCATGAGTTAGCAGTTCTTGTGAGCTTTCTCGGTAAATAAGG ER*SFFRDSGSLDKWRWLAMIV GGTCGTAAGCCTCTGTTGTCAGATTCACAATCTGATGTTTTGGTTAAACTATAT GRSQWSIRRGWRGSEEKVGE TTACAAGAGGAAAACCCGGTAATGATGTCGGGGTTGAGGGATAGGAGGAGAATG LNRLLLIWLKNSRGMMLIIRLW GGGGATAGGTGTATGAACATGAGGGTGTTTTCTCGTGTGAATGAGGGTTTTATG WLIQIMCFLESHVSGSNIIVG TTGTTAATGTGGTGGGTGAGTGAGCCCCATTGTGTTGTGGTAAATATGTAGAGG ISFSIGVGLGYVRSLGHMCWRL GAGTATAGGGCTGTGACTAGTATGTTGAGTCCTGTAAGTAGGAGAGTGATATTT LVGLGPPLLRRRQRLVWQ*AQY GATCAGGAGAACGTGGTTACTAGCACAGAGAGTTCTCCCAGTAGGTTAATAGTG LRGSGC*GL*E*L* *TAIVLFL GGGGGTAAGGCGAGGTTAGCGAGGCTTGCTAGAAGTCATCAAAAAGCTATTAGT GIVGRI*GVSDILVFLEVRW*M GGGAGTAGAGTTTGAAGTCCTTGAGAGAGGATTATGATGCGACTGTGAGTGCGT V*YLCK*GAFGKYDYHNLMSRN TvGTAGTTTGAGTTTGCTAGGCAGAATAGTAATGAGGATGTAAGCCCGTGGGCG SFCLNYIPIRFSLILFWTHRP ATTATGAGAATGACTGCGCCGGTGAAGCTTCAGGGGGTTTGGATGAGAATGGCT LGLG**LIRGMT*LLVAG*LFV GTTACTACGAGGGCTATGTGGCTGATTGAAGAGTATGCAATGAGCGATTTTAGG LMVGVKGGQFLDQIIRR**LLR TCTGTTTGTCGTAGGCAGATGGAGCTTGTTATAATTATGCCTCATAGGGATAGT ILWRKGRGRGI*GRSRTRKGWI ACAAGGAAGGGGTAGGCTATGTGTTTTGTCAGGGGGTTGAGAATGAGTGTGAGG LCSR*VVWKM**LLWRLGGC CGTATTATACCATAGCCGCCTAGTTTTAAGAGTACTGCGGCAAGTACTATTGAC LLKLRRSLLLFFECCQN*LIGS CCAGCGATGGGGGCTTCGACATGGGCTTTAGGGAGTCATAAGTGGAGTCCGTAA RYYLY*KSKTLINRWRHTEIVK

Ul Ul AGAGGTATCTTTACTATAAAAGCTATTGTGTAAGCTAGTCATATTAAGTTGTTG HLQNASIRRRLRSQSDVWM*SE

© GCTCAGGAGTTTGATAGTTCTTGGGCAGTGAGAGTGAGTAGTAGAATGTTTAGT LVGG*SR**GKLSQ**REVRGS GAGCCTAGGGTGTTGTGAGTGTAAATTAGTGCGATGAGTAGGGGAAGGGAGCCT WLQKMLSRRCRRKW*RETRSTL ACTAGGGTGTAGAATAGGAAGTATGTGCCTGCGTTCAGGCGTTCTGGCTGGTTG LVGG*NRDPVKL**AVLELFGF CCTCATCGGGTGATGATAGCCAAGGTGGGGATAAGTGTGGTTTCGAAGAAGATA CFLLDYGELR*LILLMRVIRMC TAAAATATGATTAGTTCTGTGGCTGTGAATGTTATAATTAAGGAGATTTGTAGG GVGLLGDLAG*CLLGASALLIG GAGATTAGTATAGAGAGGTAGAGTTTTTTTCGTGATAGTGGTTCACTGGATAAG *GLGWSGKRLRKILRRKKLLR* TGGCGTTGGCTTGCCATGATTGTGAGGGGTAGGAGTCAGGTAGTTAGTATTAGG IGLSRIEGLFGQWCGGLGMCF AGGGGGGTTGTTAGGGGGTCGGAGGAAAAGGTTGGGGAACAGCTAAATAGGTTG VLHRAIIGIWLVCWLVGLV*GA TTGTTGATTTGGTTAAAAAATAGTAGAGGGATGATGCTAATAATTAGGCTGTGG WSGSEITWLGRRSLGGLRGPLL GTGGTTGTGTTGATTCAAATTATGTGTTTTTTGGAAAGTCATGTCAGTGGTAGT VMGWVLLYDRHVIGGSLCVWQ AATATAATTGTTGGGACGATTAGTTTTAGCATTGGAGTAGGTTTAGGTTATGTA EAY*KCENVGLD*GDSDF*DSQ CGTAGTCTAGGCCATATGTGTTGGAGATTGAGACTAGTAGGGCTAGGCCCACCG N*NCEDDKCRGKVNG*YC*GGA CTGCTTCGCAGGCGGCAAAGACTAGTATGGCAATAGGCACAATATTGGCTAAGA N*VHE*VACSNVSG*AYGQGYW GGGAGTGGGTGTTGAGGGTTATGAGAGTAGCTATAATGAACAGCGATAGTATTA NE*ADGFDNN*YGDKGCRCALW TTCCTTCTAGGCATAGTAGGGAGGATATGAGGTGTGAGCGATATACTAGTATTC EVG*GIFNLRAKAYNHCARS*G CTAGAAGTGAGATGGTAAATGCTAGTATAATATTTATGTAAATGAGGGGCATTT GHG*VYR*LGGWCK*VRQESEE GGTAAATATGATTATCATAATTTAATGAGTCGAAATCATTCGTTTTGTTTAAAC SCGNKND*GY*YKRSGSSFSW TATATACCAATTCGGTTCAGTCTAATCCTTTTTGTAGTCACTCATAGGCCAGAC GYHLF*G*FD*SLLGGD*SWD TTAGGGCTAGGATGATGATTAATAAGAGGGATGACATAACTATTAGTGGCAGGT IFGGGDQ*RGK*NDQYCGG*A*

TAGTTGTTTGTAGGGCTCATGGTAGGGGTAAAAGGAGGGCAATTTCTAGATCAA CGGNE*SEQIFVHFGSQGLL*F ATAATAAGAAGGTAATAGCTACTAAGAAGAATTTTATGGAGAAAGGGACGCGGG IFMGFGEGGRW*FVFNIFSWVM CGGGGGATATAGGGTCGAAGCCGCACTCGTAAGGGGTGGATTTTTCTATGTAGC NSVRSMGVIMVGHTWFSWGIS CGTTGAGTTGTGGTAGTCAAAATGTAATAATTATTAGTAGTAAGGCTAGGAGGG *RGVGSLNL*LKRLMLS*LYSG TGTTGATTATTAAAATTAAGGCGAAGTTTATTACTCTTTTTTGAATGTTGTCAA *RG*RGCYRVNTGPISKIFRGI AACTAGTTAATTGGAAGTTAACGGTACTATTTATACTAAAAGAGTAAGACCCTC SRTMGMKLWFAPQISEH*P*YT ATCAATAGATGGAGACATACAGAAATAGTCAAACCACATCTACAAAATGCCAGT GRVAVKWWFRRPGIASVFKPN ATCAGGCGGCGGCTTCGAAGCCAAAGTGATGTTTGGATGTAAAGTGAAATATTA GTAHECKTSCDVIIIRMGASIG GTTGGCGGATGAAGCAGATAGTGAGGAAAGTTGAGCCAATAATGACGTGAAGTC TTRLSTSRSRRSPGSRNNGGSM CGTGGAAGCCTGTGGCTACAAAAAATGTTGAGCCGTAGATGCCGTCGGAAATGG ELKISPP*SVYS*VQYHWWPID TGAAGGGAGACTCGAAGTACTCTGAGGCTTGTAGGAGGGTAAAATAGAGACCCA MVREGSLTSSVM*RMRRDGRAM GTAAAATTGTAATAAGCAGTGCTTGAATTATTTGGTTTCGGTTGTTTTCTATTA TRMMAGRIVQTVSIS*ASEMLV GACTATGGTGAGCTCAGGTGATTGATACTCCVGATGCGAGTAATACGGATGTGT VSFWSVRKRAYRTRKQIRKMI TTAGGAGTGGGACTTCTAGGGGATTTAGCGGGGTGATGCCTGTTGGGGGCCAGT RA*S*KVISSSMIGEVASCRPT GCCCTCCTAATTGGGGGGTAGGGGCTAGGCTGGAGTGGTAAAAGGCTCAGAAAA AACAIKIYRI*PII*L*QSYEM ATCCTGCGAAGAAAAAAACTTCTGAGGTAATAAATAGGATTATCCCGTATCGAA FLIPF*KSHGGHGVGLKPALGG GGCCTTTTTGGACAGGTGGTGTGTGGTGGCCTTGGTATGTGCTTTCTCGTGTTA IPSFFV*ILCIRVLRMCGRVGG CATCGCGCCATCATTGGTATATGGTTAGTGTGTTGGTTAGTAGGCCTAGTATGA HIVTPGLWRVLLLLGLFASKRR GGAGCGTTATGGAGTGGAAGTGAAATCACATGGCTAGGCCGGAGGTCATTAGGA LKS*KLLILLLLEK*MSLQMIG

Ul Ul GGGCTGAGAGGGCCCCTGTTAGGGGTCATGGGCTGGGTTTTACTATATGATAGG FMWCMHRGSPSNVGAFRIGRES CATGTGATTGGTGGGTCATTATGTGTTGTCGTGCAGGTAGAGGCTTACTAGAAG VGRKLDLRR*I***NGFWRRFG TGTGAAAACGTAGGCTTGGATTAAGGCGACAGCGATTTCTAGGATAGTCAGTAG GCSLRIGEISE*SLL*WQIQLL AATTAGAATTGTGAAGATGATAAGTGTAGAGGGAAGGTTAATGGTTGATATTGC IGHSGSGLQRSTCRWRCLVMS TAGGGTGGCGCTTCCAATTAGGTGCATGAGTAGGTGGCCTGCAGTAATGTTAGC LIQCQSGHLR*KER*ILGLRAL GGTTAGGCGTACGGCCAGGGCTATTGGTTGAATGAGTAGGCTGATGGTTTCGAT QIISYCFRGVWRVS*IL*RRWG AATAACTAGTATGGGGATAAGGGGTGTAGGTGTGCCTTGTGGTAAGAAGTGGGC R*LW*RR*NMLVCLRLFLL*IY TAGGGCATTTTTAATCTTAGAGCGAAAGCCTATAATCACTGTGCCCGCTCATAA VLTR*TLGSQLIS*LRPYLCIQ GGGGATGGCCATGGCTAGGTTTATAGATAGTTGGGTGGTTGGTGTAAATGAGTG VLFFRSSKLQYGRLFRSLVG*E AGGCAGGAGTCCGAGGAGGTTAGTTGTGGCAATAAAAATGATTAAGGATACTAG KLQGDRKIRIGVGIEWGLLLRR TATAAGAGATCAGGTTCGTCCTTTAGTGTTGTGTATGGTTATCATTTGTTTTGA RRRWC*GCGLLW**CQQLGLG GGTTAGTTTGATTAGTCATTGTTGGGTGGTGATTAGTCGGTTGTTGATGAGATA IGEVGLL*LGRIRRRGAFGIGL TTTGGAGGTGGGGATCAATAGAGGGGGAAATAGAATGATCAGTACTGCGGCGGG QGVLY* *LL**N*WPLR*RRHL TAGGCCTAGGATTGTGGGGGCAATGAATGAAGCGAACAGATTTTCGTTCATTTT GVRRRWLGLRRLQGGSSSLLRE GGTTCTCAGGGTTTGTTATAATTTTTTATTTTTATGGGCTTTGGTGAGGGAGGT RLFNLFLLRPPL*QMRAGVGER AGGTGGTAGTTTGTGTTTAATATTTTTAGTTGGGTGATGAGGAATAGTGTAAGG VRVRSLCCLCGETPYRGHRLLG AGTATGGGGGTAATTATGGTGGGCCATACGGTAGTATTTAGTTGGGGCATTTCA LVSCQSLRL*WVLL*RRLLQMH CTGTAAAGAGGTGTTGGTTCTCTTAATCTTTAACTTAAAAGGTTAATGCTAAGT L*R*RCRCGRYLEGCLAGPARL TAGCTTTACAGTGGGCTCTAGAGGGGGTAGAGGGGGTGCTATAGGGTAAATACG *GGLELCLGLQLMRRIIGIVFQ GGCCCTATTTCAAAGATTTTTAGGGGAATTAATTCTAGGACGATGGGCATGAAA LCGL*RIVNGRRTSVGVR*NG*

CTGTGGTTTGCTCCACAGATTTCAGAGCATTGACCGTAGTATACCCCCGGTCGT KHWTVNLKTGVRPLFTSSEVIF GTAGCGGTGAAAGTGGTTTGGTTTAGACGTCCGGGAATTGCATCTGTTTTTAAG LNCKFEEAASNLPGLLPPFFPA CCTAATGTGGGGACAGCTCATGAGTGCAAGACGTCTTGTGATGTAATTATTATA GEVD*SQLIRVLSC*LSVCGFK CGAATGGGGGCTTCAATCGGGAGTACTACTCGATTGTCAACGTCAAGGAGTCGC HWSSKGLA*LKWLICVQLMQSG AGGTCGCCTGGTTCTAGGAATAATGGGGGAAGTATGTAGGAGTTGAAGATTAGT LQSLAVTEIKYCNLLRALKALG CCGCCGTAGTCGGTGTACTCGTAGGTTCAGTACCATTGGTGGCCAATTGATTTG YLT*ISIRLLV*KGR*VGVAW* ATGGTAAGGGAGGGATCGTTGACCTCGTCTGTTATGTAAAGGATGCGTAGGGAT R*VWGGMGWVLYVQTVILFLRC GGGAGGGCGATGAGGACTAGGATGATGGCGGGCAGGATAGTTCAGACGGTTTCT IWGW*LRWSRLGVGRSRG*GG ATTTCCTGAGCGTCTGAGATGTTAGTATTAGTTAGTTTTGTTGTGAGTGTTAGG WWL*WWG* *GYCFL*ILR*WPI AAAAGGGCATACAGGACTAGGAAGCAGATAAGGAAAATGATTATGAGGGCGTGA AKSRLAGAGLLGRGGWMELRVL TCATGAAAGGTGATAAGCTCTTCTATGATAGGGGAAGTAGCGTCTTGTAGACCT MLACFRCEIWGSWCWSLS*W ACTTGCGCTGCATGTGCCATTAAGATATATAGGATTTAGCCTATAATTTAACTT MR**LG*YK*LN*EWLC*GCTV TGACAAAGTTATGAAATGGTTTTTCTAATACCTTTTTGAAAAAGTCATGGAGGC LLLFILCG*LRSMLRFCVAGFG CATGGGGTTGGCTTGAAACCAGCTTTGGGGGGTTCGATTCCTTCCTTΓTTTGTC IHLNCLL*WIRLRE*GEGLRLV TAGATTTTATGTATACGGGTTCTTCGAATGTGTGGTAGGGTGGGGGGCATCCAT ERFGI*LRWGLVFVM*EEAGRM ATAGTCACTCCAGGTTTATGGAGGGTTCTTCTACTATTAGGACTTTTCGCTTCG EGCLG*PLGLRSERGLFLVLLL AAGCGAAGGCTTCTCAAATCATGAAAATTATTAATATTACTGCTGTTAGAGAAA LL*LLMMSIDW*YWLWFIVRRV TGAATGAGCCTACAGATGATAGGATGTTTCATGTGGTGTATGCATCGGGGTAGT C*RG*LLEGLWMRLLA*GNT*W CCGAGTAACGTCGGGGCATTCCGGATAGGCCGAGAAAGTGTTGTGGGAAGAAAG LLWNEGLFFWLELE*KLACLFL

Ul Ul TTAGATTTACGCCGATGAATATGATAGTGAAATGGATTTTGGCGTAGGTTTGGT LLR*KISASLAL**VCLQRW*S to CTAGGGTGTAGCCTGAGAATAGGGGAAATCAGTGAATGAAGCCTCCTATGATGG *RVGPGD*LVREGYNQHFRGMG CAAATACAGCTCCTATTGATAGGACATAGTGGAAGTGGGCTACAACGTAGTACG IAYLADLTLGWGVIGGTENFGF TGTCGTGTAGTACGATGTCTAGTGATGAGTTTGCTAATACAATGCCAGTCAGGC GMGSILIVLEIRGFKLLLFTLS CACCTACGGTGAAAAGAAAGATGAATCCTAGGGCTCAGAGCACTGCAGCAGATC *LFYQTYFLGLRGNAGDCNGYG ATTTCATATTGCTTCCGTGGAGTGTGGCGAGTCAGCTAAATACTTTGACGCCGG ISYK*C*GEW*EVFS*EVYEL TGGGGATAGCGATGATTATGGTAGCGGAGGTGAAATATGCTCGTGTGTCTACGT AESGVCCSNS*EQGG*K*GLGD CTATTCCTACTGTAAATATATGGTGTGCTCACACGATAAACCCTAGGAAGCCAA ICCVEFRGECVICCS*EDCSGE TTGATATCATAGCTCAGACCATACCTATGTATCCAAATGGTTCTTTTTTTCCGG VYYNNVCVFGYEE*GEGACGVF AGTAGTAAGTTACAATATGGGAGATTATTCCGAAGCCTGGTAGGATAAGAATAT VEA*D*FGLPFGKVEGGSVGLC AAACTTCAGGGTGACCGAAAAATCAGAATAGGTGTTGGTATAGAATGGGGTCTC CGDKSYYGQGS*WQE*SEVFLC CTCCTCCGGCGGGGTCGAAGAAGGTGGTGTTGAGGTTGCGGTCTGTTAGTAGTA DKGGEVKGA Y**C***NDG*G TAGTGATGCCAGCAGCTAGGACTGGGAGAGATAGGAGAAGTAGGACTGCTGTGA FI*DCLGYCSQCADQGW*V*C TTAGGACGGATCAGACGAAGAGGGGCGTTTGGTATTGGGTTATGGCAGGGGGTT P*SED*VNG*ARGG*NK*EA*V TTATATTGATAATTGTTGTGATGAAATTGATGGCCCCTAAGATAGAGGAGACAC VDQGVGYGEGGS**KSDGES*G CTGCTAGGTGTAAGGAGAAGATGGTTAGGTCTACGGAGGCTCCAGGGTGGGAGT GGDVEGDGRCGGF*GLFGEEFY AGTTCCCTGCTAAGGGAGGGTAGACTGTTCAACCTGTTCCTGCTCCGGCCTCCA VSEGL**PVGAYNVGAFA*LYI CTATAGCAGATGCGAGCAGGAGTAGGAGAGAGGGAGGTAAGAGTCAGAAGCTTA *NFSFGKH*ECHCD*NGYNEE* TGTTGTTTATGCGGGGAAACGCCATATCGGGGGCACCGATTATTAGGGGAACTA VGHGYWKKRN*TSDCKVLSFM GTCAGTTGCCAAAGCCTCCGATTATGATGGGTATTACTATGAAGAAGATTATTA LPGSAILTNPVLGWVWV*Y*VE

CAAATGCATGGGCTGTGACGATAACGTTGTAGATGTGGTCGTTACCTAGAAGGT ISFTGEGAL*SRPYFSCPFVQG TGCCTGGCTGGCCCAGCTCGGCTCGAATAAGGAGGCTTAGAGCTGTGCCTAGGA I*SR*KPTWITPV*TQIT*DFN CTCCAGCTCATGCGCCGAATAATAGGTATAGTGTTCCAATGTCTTTGTGGTTTG *TNEPLIAAAPSGCPDPTSRS* TAGAGAATAGTCAACGGTCGGCGAACATCAGTGGGGGTGAGGTAAAATGGCTGA LLLIWTLE*DCAVIPRVTCSVG GTGAAGCATTGGACTGTAAATCTAAAGACAGGGGTTAGGCCTCTTTTTACCAGC VIGSIEYSSSL*LVKS*HVLLG TCCGAGGTGATTTTCATATTGAATTGCAAATTCGAAGAAGCAGCTTCAAACCTG WVLLRGRPNRNF*CRFGSLGPV CCGGGGCTTCTCCCGCCTTTTTTCCCGGCGGCGGGAGAAGTAGATTGAAGCCAG LLGTVCINKLKLHRVFSSCCVM TTGATTAGGGTGCTTAGCTGTTAACTAAGTGTTTGTGGGTTTAAGTCCCATTGG ASSRAGQFHWLKVRDS*TLVEP TCTAGTAAGGGCTTAGCTTAATTAAAGTGGCTGATTTGCGTTCAGTTGATGCAG IQVPI*GTSDYATFARLGYRGR AGTGGGGTTTTGCAGTCCTTAGCTGTTACAGAAATTAAGTATTGCAACTTACTG TCVTGQAVPLILVMLEVMFLVN AGGGCTTTGAAGGCTCTTGGTCTGTATTTAACCTAAATTTCTATAAGATTATTA RGKICRVPFTFFNLSL*ACLCW GTATAAAAGGGGAGATAGGTAGGAGTAGCGTGGTAAGGGCGATGAGTGTGGGGA DSEGNNDLLVDCRYWAVNCQFS GGAATGGGGTGGGTTTTGTATGTTCAAACTGTCATTTTATTTTTACGTIGTTAG LI*RRLMRRRMFSCYLY*H*FF ATATGGGGAGTAGTGTGATTGAGGTGGAGTAGATTAGGCGTAGGTAGAAGTAGA RVIDWSNWV*GVQLYVWDFLGS GGTTAAGGAGGGTGATGGTGGCTATGATGGTGGGGATGATGAGGCTATTGTTTT C*A*TLS*LVAAFRPTMGVKFF TTGTGAATTCTTCGATAATGGCCCATTTGGGCAAAAAGCCGGTTAGCGGGGGCA LSTRFFPSVQRAVPLWTNS*IY GGCCTCCTAGGGAGAGGAGGGTGGATGGAATTAAGGGTGTTAGTCATGTTAGCT GI*RVLWANLKLN*DSILDNQL TGTTTCAGGTGCGAGATAGTAGTAGGGTCGTGGTGCTGGAGTTTAAGTTGAGTA PGSVGLSPLPINLPTILLHRRV GTAGGAATGCGGTAGTAGTTAGGATAATATAAATAGTTAAATTAAGAATGGTTA SFSCS*VARLVSGVLALALLAK

Ul Ul TGTTAGGGTTGTACGGTAGAACTGCTATTATTCATCCTATGTGGGTAATTGAGG FLVNSLCRRYRG*SLLYYAWL* Ul AGTATGCTAAGATTTTGCGTAGCTGGGTTTGGTTTAATCCACCTCAACTGCCTG FIFPLRYYIYCARFQFLSPILY CTATGATGGATAAGATTGAGAGAGTGAGGAGAAGGCTTACGTTTAGTGAGGGAG GKWFG*GCLWRWSGFGARFSS AGATTTGGTATATGATTGAGATGGGGGCTAGTTTTTGTCATGTGAGAAGAAGCA RSS*VEIS*V*VGCFVLSYTLV GGCCGGATGTCAGAGGGGTGCCTTGGGTAACCTCTGGGACTCAGAAGTGAAAGG PSALSSTLTMLRLVSSI*MRRG GGGCTATTCCTAGTTTTATTGCTATAGCTATTATGATTATTAATGATGAGTATT S*MSFEVYLRRVTGGVYALQGP GATTGGTAGTATTGGTTATGGTTCATTGTCCGGAGAGTATATTGTTGAAGAGGA QLSTLLLVYC*IHLRPLSFIRA TAGCTATTAGAAGGATTATGGATGCGGTTGCTTGCGTGAGGAAATACTTGATGG WFWGRKCSPFLATSWATP*PN CAGCTTCTGTGGAACGAGGGTTTATTTTTTTGGTTAGAACTGGAATAAAAGCTA FTWVLALTL*PSSGFAEDGGI* GCATGTTTATTTCTAGGCCTACTCAGGTAAAAAATCAGTGCGAGCTTAGCGCTG EQEWRLIGVYRLQNRLL*RDM TGATGAGTGTGCCTGCAAAGATGGTAGAGTAGATGACGGGTTGGGCCAGGGGAT HRQVL*VLSCGS*CSGEQFC*F TAATTAGTACGGGAAGGGTATAACCAACATTTTCGGGGTATGGGCCCGATAGCT C*GLGLSIVGYLIPVWVLAIVC TATTTAGCTGACCTTACTTTAGGATGGGGTGTGATAGGTGGCACGGAGAATTTT DMLKPLS*SILCQLEFFTTQVS GGATTCTCAGGGATGGGTTCGATTCTCATAGTCCTAGAAATAAGGGGGTTTAAG SFIGEGVI*NTLYAGFY*LGLI CTCCTATTATTTACTCTATCAAAGTAACTCTTTTATCAGACATATTTCTTAGGT *PRWLARN*PTLGLV*LS*TFV TTGAGGGGGAATGCTGGAGATTGTAATGGGTATGGAGACATATCATATAAGTAA C*RLITAVSRGGVARLSVLSCI TGCTAGGGTGAGTGGTAGGAAGTTTTTTCATAGGAGGTGTATGAGTTGGTCGTA ACLMLVPFDRGDLEGELTGTGM GCGGAATCGGGGGTATGCTGTTCGAATTCATAAGAACAGGGAGGTTAGAAGTAG ACVILLRANRKARTKPICLWGD GGTCTTGGTGACAAAATATGTTGTGTAGAGTTCAGGGGAGAGTGCGTCATATGT SPSKHFQCIALRR*AT*TVGGV TGTTCCTAGGAAGATTGTAGTGGTGAGGGTGTTTATTATAATAATGTTTGTGTA GVWLVRGMGLAAVCVCWVGWAG

TTCGGCTATGAAGAATAGGGCGAAGGGGCCTGCGGCGTATTCGATGTTGAAGCC VLMRLWWEWEGKIMC*LGGDC TGAGACTAGTTCGGACTCCCCTTCGGCAAGGTCGAAGGGGGTTCGGTTGGTCTC KCIPPKDKI*NLVRLVLGFFVF TGCTAGTGTGGAGATAAATCATATTATGGCCAAGGGTCATGATGGCAGGAGTAA VWQRCV*VLWPEAGEGGFGGNF TCAGAGGTGTTCTTGTGTTGTGATAAGGGTGGAGAGGTTAAAGGAGCCACTTAT L*CLCGKWLCRHSIVIIMSYKH TAGTAATGTTGATAGTAGAATGATGGCTAGGGTGACTTCATATGAGATTGTTTG LINTL* *VCSPVILNVGAINNR GGCTACTGCTCGCAGTGCGCCGATCAGGGCGTAGTTTGAGTTTGATGCTCACCC RQESKTDTAT*GAPAPASRNAI TGATCAGAGGATTGAGTAAACGGCTAGGCTAGAGGTGGCTAGAATAAATAGGAG CIPPRRKYQMHGELP*WNRVI GCCTAGGTTGAGGTTGACCAGGGGGTTGGGTATGGGGAGGGGGGTTCATAGTAG L* AAGAGCGATGGTGAGAGCTAAGGTCGGGGCGGTGATGTAGAGGGTGATGGTAGA TGTGGCGGGTTTTAGGGGCTCTTTGGTGAAGAGTTTTATGGCGTCAGCGAAGGG TTGTAGTAGCCCGTAGGGGCCTACAACGTTGGGGCCTTTGCGTAGTTGTATATA GCCTAGAATTTTTCGTTCGGTAAGCATTAGGAATGCCATTGCGATTAGAATGGG TACAATGAGGAGTAGGAGGTTGGCCATGGGTATGTTGTTAAGAAGAGGAATTGA ACCTCTGACTGTAAAGTTTTAAGTTTTATGCGATTACCGGGCTCTGCCATCΓTA ACAAACCCTGTTCTTGGGTGGGTGTGGGTATAATACTAAGTTGAGATGATATCA TTTACGGGGGAAGGCGCTTTGTGAAGTAGGCCTTATTTCTCTTGTCCTTTCGTA CAGGGAGGAATTTGAAGTAGATAGAAACCGACCTGGATTACTCCGGTCTGAACT CAGATCACGTAGGACTTTAATCGTTGAACAAACGAACCTTTAATAGCGGCTGCA CCATCGGGATGTCCTGATCCAACATCGAGGTCGTAAACCCTATTGTTGATATGG

Ul Ul ACTCTAGAATAGGATTGCGCTGTTATCCCTAGGGTAACTTGTTCCGTTGGTCAA GTTATTGGATCAATTGAGTATAGTAGTTCGCTTTGACTGGTGAAGTCTTAGCAT GTACTGCTCGGAGGTTGGGTTCTGCTCCGAGGTCGCCCCAACCGAAATTTTTAA TGCAGGTTTGGTAGTTTAGGACCTGTGGGTTTGTTAGGTACTGTTTGCATTAAT AAATTAAAGCTCCATAGGGTCTTCTCGTCTTGCTGTGTTATGCCCGCCTCTTCA CGGGCAGGTCAATTTCACTGGTTAAAAGTAAGAGACAGCTGAACCCTCGTGGAG CCATTCATACAGGTCCCTATTTAAGGAACAAGTGATTATGCTACCTTTGCACGG TTAGGGTACCGCGGCCGTTAAACATGTGTCACTGGGCAGGCGGTGCCTCTAATA CTGGTGATGCTAGAGGTGATGTTTTTGGTAAACAGGCGGGGTAAGATTTGCCGA GTTCCTTTTACTTTTTTTAACCTTTCCTTATGAGCATGCCTGTGTTGGGTTGAC AGTGAGGGTAATAATGACTTGTTGGTTGATTGTAGATATTGGGCTGTTAATTGT CAGTTCAGTGTTTTAATCTGACGCAGGCTTATGCGGAGGAGAATGTTTTCATGT TACTTATACTAACATTAGTTCTTCTATAGGGTGATAGATTGGTCCAATTGGGTG TGAGGAGTTCAGTTATATGTTTGGGATTTTTTAGGTAGTGGGTGTTGAGCTTGA ACGCTTTCTTAATTGGTGGCTGCTTTTAGGCCTACTATGGGTGTTAAATTTTTT ACTCTCTCTACAAGGTTTTTTCCTAGTGTCCAAAGAGCTGTTCCTCTTTGGACT AACAGTTAAATTTACAAGGGGATTTAGAGGGTTCTGTGGGCAAATTTAAAGTTG AACTAAGATTCTATCTTGGACAACCAGCTATCACCAGGCTCGGTAGGTTTGTCG CCTCTACCTATAAATCTTCCCACTATTTTGCTACATAGACGGGTGTGCTCTTTT AGCTGTTCTTAGGTAGCTCGTCTGGTTTCGGGGGTCTTAGCTTTGGCTCTCCTT

GCAAAGTTATTTCTAGTTAATTCATTATGCAGAAGGTATAGGGGTTAGTCCTTG CTATATTATGCTTGGTTATAATTTTTCATCTTTCCCTTGCGGTACTATATCTAT TGCGCCAGGTTTCAATTTCTATCGCCTATACTTTATTTGGGTAAATGGTTTGGC TAAGGTTGTCTGGTAGTAAGGTGGAGTGGGTTTGGGGCTAGGTTTAGCTCAGAG CGGTCAAGTTAAGTTGAAATCTCCTAAGTGTAAGTTGGGTGCTTTGTGTTAAGC TACACTCTGGTTCGTCCAAGTGCACTTTCCAGTACACTTACCATGTTACGACTT GTCTCCTCTATATAAATGCGTAGGGGTTTTAGTTAAATGTCCTTTGAAGTATAC TTGAGGAGGGTGACGGGCGGTGTGTACGCGCTTCAGGGCCCTGTTCAACTAAGC ACTCTACTCTTAGTTTACTGCTAAATCCACCTTCGACCCTTAAGTTTCATAAGG GCTATCGTAGTTTTCTGGGGTAGAAAATGTAGCCCATTTCTTGCCACCTCATGG GCTACACCTTGACCTAACGTCTTTACGTGGGTACTTGCGCTTACTTTGTAGCCT TCATCAGGGTTTGCTGAAGATGGCGGTATATAGGCTGAGCAAGAGGTGGTGAGG TTGATCGGGGTTTATCGATTACAGAACAGGCTCCTCTAGAGGGATATGAAGCAC CGCCAGGTCCTTTGAGTTTTAAGCTGTGGCTCGTAGTGTTCTGGCGAGCAGTTT TGTTGATTTAACTGTTGAGGTTTAGGGCTAAGCATAGTGGGGTATCTAATCCCA GTTTGGGTCTTAGCTATTGTGTGTTCAGATATGTTAAAGCCACTTTCGTAGTCT ATTTTGTGTCAACTGGAGTTTTTTACAACTCAGGTGAGTTTTAGCTTTATTGGG GAGGGGGTGATCTAAAACACTCTTTACGCCGGCTTCTATTGACTTGGGTTAATC GTGTGACCGCGGTGGCTGGCACGAAATTGACCAACCCTGGGGTTAGTATAGCTT

Ul Ul AGTTAAACTTTCGTTTATTGCTAAAGGTTAATCACTGCTGTTTCCCGTGGGGGT Ul GTGGCTAGGCTAAGCGTTTTGAGCTGCATTGCTGCGTGCTTGATGCTTGTCCCT TTTGATCGTGGTGATTTAGAGGGTGAACTCACTGGAACGGGGATGCTTGCATGT GTAATCTTACTAAGAGCTAATAGAAAGGCTAGGACCAAACCTATTTGTTTATGG GGTGATGTGAGCCCGTCTAAACATTTTCAGTGTATTGCTTTGAGGAGGTAAGCT ACATAAACTGTGGGGGGTGTCTTTGGGGTTTGGTTGGTTCGGGGTATGGGGTTA GCAGCGGTGTGTGTGTGCTGGGTAGGATGGGCGGGGGTTGTATTGATGAGATTA GTAGTATGGGAGTGGGAGGGGAAAATAATGTGTTAGTTGGGGGGTGACTGTTAA AAGTGCATACCGCCAAAAGATAAAATTTGAAATCTGGTTAGGCTGGTGTTAGGG TTCTTTGTTTTTGGGGTTTGGCAGAGATGTGTTTAAGTGCTGTGGCCAGAAGCG GGGGAGGGGGGGTTTGGTGGAAATTTTTTGTTATGATGTCTGTGTGGAAAGTGG CTGTGCAGACATTCAATTGTTATTATTATGTCCTACAAGCATTAATTAATTAAC ACACTTTAGTAAGTATGTTCGCCTGTAATATTGAACGTAGGTGCGATAAATAAT AGGATGAGGCAGGAATCAAAGACAGATACTGCGACATAGGGTGCTCCGGCTCCA GCGTCTCGCAATGCTATCGCGTGCATACCCCCCAGACGAAAATACCAAATGCAT GGAGAGCTCCCGTGAGTGGTTAATAGGGTGATAGACCTGTGATC

Human 11 prey24365 692 CAAAAGCTCCAAAACCTTCTGATTTCTTGACTCTTGAAGGAAGAANCAGTAAAA 1430 QKLQNLLIS*LLKEEXVK*SRW hGITl v4 TAAAGCAGGTGGACAGCGTACTGAAGCATGTGAAGAAGCATCTGCCCCAAAGCA AY*SM*RSICPKAHVKELISWL CATGTGAAGGAGCTTATCAGTTGGCTCGTGGGTCAGGAATTCGAATTAGAAAAA GQEFELEKMESICQARAKELED ATGGAGTCCATATGCCAGGCTCGAGCAAAGGAGCTTGAAGACTCCTTGCAGCAG LQQLLRLQDDHRNLRKWLTNQE

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hGITl v4 AGAAAAATCGGAGAAAATTATAGCAAAATGGATGGGCCAGAAGTAATGATTGAA NYSKMDGPEVMIEQPIPMSKEC CAGCCAATTCCCATGTCCAAAGAGTGTACATTTCAGACATATTTGACAATGCAG FQTYLTMQTIESTVDRKNNLKD ACAATTGAGTCTACAGTGGATCGAAAAAACAATCTCAAAGATCTACAAGAAAGT QESIDTLIGNLERELNKNKLNM ATTGATACTTTGATTGGAAATCTGGAACGTGAGCTCAACAAAAACAAGCTTAAT F*D*GFFFVMS*SFKSVFVLFS ATGAGTTTTTGAGATTGAGGGTTTTTTTTTGTAATGTCTTAAAGTTTCAAATCT TT GTTTTTGTTTTATTTTCTTATACCACCC

Human 11 prey4031 722 GCATGATCCATCAGCGGTTGCAGTTGCTGGAAGTTCATCAGCAGAGGAAATGGT 1460 A*SISGCSCWKFISRGNGHSLG hGITl v4 CACTCTCTTGGTTCAGGCGGGCCTCTTTGACACTGCCATATCACTCTGTCAGAC GGPL*HCHITLSDF*ASLNASL TTTTAAGCTTCCCTTAACGCCAGTCTTTGAAGGGCTTGCCTTCAAATGCATCAA RACLQMHQIAIWRRGSTSRSLG ATTGCAATTTGGAGGAGAGGCAGCACAAGCAGAAGCCTGGGCCTGGCTAGCAGC ASSQSALICHHY*GV*CYR*SM CAATCAGCTCTCATCTGTCATCACTACTAAGGAGTCTAGTGCTACAGATGAAGC TIIHLPGEVQSPE*LVSPLCNQ ATGGCGACTATTATCCACTTACCTGGAGAGGTACAAAGTCCAGAATAACTTGTA ALVSWSASA*LAYKQLQEG*CC TCACCACTGTGTAATCAΛCAAGCTCTTGTCTCATGGAGTGCCTCTGCCTAATTG IASFILKL*PFRRSCGFGVRIC GCTTATAAACAGTTACAAGAAGGTTGATGCTGCTGAATTGCTTCGTTTATACTT CCIGKRTSILRN*VSTVRNSPN AAACTATGACCTTTTAGAAGAAGCTGTGGATTTGGTGTCAGAATATGTGGATGC VASILLY*SASPSSGREQCQQS TGTATTGGGAAAAGGACATCAATACTTCGGAATTGAGTTTCCACTGTCCGCAAC HRTVPENT*QIGGLPAKS**GN AGCCCCAATGGTGTGGCTTCCATACTCCTCTATTGATCAGCTTCTCCAAGCTCT GFIISSDLVIWIVT*PL*PLGA GGGAGAGAACAGTGCCAACAGTCACAACATCGCACTGTCCCAGAAAATACTTGA *DLRLPYRNPVLKADFCNCK*C CAAATTGGAGGACTACCAGCAAAAAGTTGATAAGGCAACACGGGATTTATTATA QHSSLHSAQDRRAEESEDPVLA TCGTCGGACCTTGTGATTTGGATTGTCACCTAGCCTTTGTAACCGCTTGGTGCC GANTISGVQPWSQIAAFVYDSR TCTTAGGACTTAAGACTACCCTACAGGAACCCTGTACTCAAGGCCGATTTTTGT FLEFIFF*TTEDIHYLQIKTHL AACTGTAAATGATGTGTACAACATTCAAGTCTGCATTCTGCACAAGATAGGAGG FPK*LRWGLL*LTTKSSHCKS GCGGAAGAGTCAGAGGACCCTGTGCTTGCTGGTGGTGCTAACACAATTTCTGGT NSSLSPFVF*CNYFGPELTCIF GTTCAACCTTGGTCTCAAATAGCTGCTTTTGTATATGATTCACGAGCTTTTTTA IVHKS**FCVLFIYFGGFI*SS GAGTTTATATTTTTTTAAACTACCGAAGACATTCATTATCTGCAAATTAAGACT EY*IICLD*A*NDDQLIKEDIL CACCTTCACTTTCCAAAATAGCTGAGGGTTGTTGGCTTGTTGTAGCTGACCACC LVLS*S*VNS*LRKNWKSIIYI AAAAGCAGTCACTGCAAATCTTTTAATTCTTCCCTATCACCTTTTGTATTTTAA NRFSE* IVNFYDL* *SSWT*SY TGCAATTATTTTGGTCCAGAACTGACCTGTATTTTCTGTATTGTACACAAAAGC LVS*CIGPKCKLHWSDLEAFML TAATAATTTTGTGTACTTTTTATTTATTTTGGAGGTTTTATATGATCTTCAATT SFGKVKNNKIILDFILYIKIYL GAGTATTAAATAATTTGCCTAGATTAAGCCTAAAATGATGACCAGCTAATTAAA RKQSVYYLLV*PFDPS*VFQKP GAAGATATTTTGAATCTGGTTCTGAGCTAAAGTTGAGTAAATTCTTAGCTAAGA IFILSIPYLHYIL*LTKKKKKK AAAAATTGGAAATCCATCATCTATATTAGCAACAGATTCTCAGAGTAAATTGTT AACTTCTATGATTTATGATAATCAAGCTGGACTTGATCATACAAGTTAGTCTCA TAATGTATTGGACCAAAATGTAAACTTCATTGGTCAGATTTAGAAGCATTCATG CTCACAAGTTTTGGGAAAGTGAAAAATAATAAAATCATCTTGGATTTTATTCTG TATATTAAAATTTATCTTTTAAGGAAACAATCTGTATACTACTTGCTTGTATAG CCTTTTGACCCTTCTTGAGTTTTTCAGAAGCCTTTAATTTTTATACTTTCAATA CCATATTTACATTATATACTTTAATTAACAAAAAAAAAAAAAAAAAAAA

Human 11 prey24248 723 AATATNTTAAACGANANCNNNAAGGANNGCGGGCAGNACCGGCGGGCTGCTGGG 1461 NXLNXXXKXXGQXRRAAGVQAR

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hGITl v4 GACTTGGGTGGCAGAGGAGGGGTCCAAGTTCCAGCAGTGGACATTTCATCTTCT GGVQVPAVDISSSLGGRAVEVQ CTTGGGGGTAGGGCAGTAGAGGTACAGGGCCCATCTCTGGAGAGTGGTGATCAT PSLESGDHGKIKFPTMKVPKFG GGCAAAATTAAATTTCCCACCATGAAAGTGCCGAAATTTGGTGTCTCAACAGGG STGREGQTPKAGLRVSAPEVSV CGTGAGGGCCAGACACCAAAGGCAGGGCTGAGGGTTTCTGCACCTGAAGTCTCT HKGGKPGLTIQAPQLEVSVPSA GTGGGGCACAAGGGCGGCAAGCCAGGCTTGACTATCCAAGCCCCTCAGCTGGAA IEGLEGKLKGPQITGPSLEGDL GTCAGTGTGCCCTCTGCCAATATTGAGGGCCTTGAGGGGAAGCTGAAGGGCCCC LKGAKPQGHIGVDASAPQIGGS CAAATCACTGGGCCATCACTTGAGGGTGACCTAGGCCTGAAAGGTGCCAAGCCA TGPSVEVQAPDIDVQGPGSKLN CAGGGGCACATTGGGGTGGATGCCTCTGCTCCCCAAATTGGGGGTAGCATCACT PKMKVPKFSVSGAKGEETGIDV GGCCCCAGTGTGGAAGTTCAGGCCCCTGACATTGATGTTCAGGGGCCTGGGAGC LPTGEVTVPGVSGDVSLPEIAT AAACTGAATGTGCCCAAGATGAAAGTCCCCAAGTTCTCTGTATCAGGTGCAAAG GLEGKMKGTKVKTPEMIIQKPK GGAGAGGAAACTGGGATTGATGTGACACTGCCTACAGGTGAAGTGACTGTTCCT SMQDVDLSLGSPKLKGDIKVSA GGGGTCTCTGGGGATGTCAGCCTGCCTGAGATTGCTACTGGTGGGCTGGAAGGA GVQGDVKGPQVALKGSRVDIET AAGATGAAAGGTACTAAAGTGAAGACTCCTGAAATGATTATTCAGAAACCTAAA NLEGTLTGPRLGSPSGKTGTCR ATCTCCATGCAGGATGTGGATCTGAGCCTTGGGTCTCCTAAACTGAAAGGAGAT SMSEVDLNVAAPKVKGGVDVTL ATTAAGGTTTCTGCTCCTGGGGTGCAAGGTGATGTTAAAGGCCCTCAAGTGGCA RVEGKVKVPEVDVRGPKVDVSA CTTAAAGGCTCCAGAGTGGACATAGAGACACCAAACCTAGAGGGAACCTTGACA DVEAHGPEWNLKMPKMKMPTFS GGCCCTAGGCTTGGCAGTCCTTCCGGGAAAACCGGAACCTGTAGGATCTCTATG PGAKGEGPDVHMTLPKGDISIS TCAGAAGTAGACTTAAATGTGGCCGCACCTAAAGTGAAAGGGGGTGTAGATGTC PKVNVEAPDVNLEGLGGKLKGP ACACTCCCCAGAGTAGAAGGGAAAGTCAAAGTCCCTGAAGTTGATGTCAGAGGC VKLPDMSVKTPKISMPDVDLHV

Ul Ul CCCAAAGTGGATGTCAGTGCCCCAGATGTCGAAGCGCATGGCCCAGAATGGAAC GTKVKGEYDVTVPKLEGELKGP

© CTGAAAATGCCCAAGATGAAAATGCCCACGTTCAGCACTCCAGGAGCCAAAGGG VDIDAPDVDVHGPDWHLKMPKM GAAGGTCCAGATGTTCATATGACTCTACCCAAAGGAGATATCAGTATTTCAGGG MPKFSVPGFKAEGPEVDVNLPIC CCCAAGGTCAATGTGGAAGCCCCAGATGTCAACTTGGAGGGTCTGGGGGGAAAA DVDISGPKIDVTAPDVSIEEPE CTTAAAGGCCCCGATGTTAAGCTGCCTGATATGAGTGTCAAGACACCAAAGATC KLKGPKFKMPEMNIKVPKISMP TCCATGCCTGATGTAGATTTGCACGTGAAAGGTACAAAGGTGAAGGGAGAGTAT VDLHLKGPNVKGEYDVTMPKVE GATGTAACTGTACCAAAGCTGGAAGGAGAACTCAAAGGCCCAAAAGTGGACATT EIKVPDVELKSAKMDIDVPDVE GATGCCCCAGATGTGGATGTTCATGGCCCAGACTGGCACTTGAAGATGCCCAAG QGPDWHLKMPKMKMPKFSMPGF ATGAAAATGCCCAAATTCAGTGTGCCAGGGTTCAAAGCAGAGGGCCCAGAAGTG AEGPEVDVNLPKADVDISGPKV GATGTGAACCTGCCCAAGGCTGATGTGGACATTTCCGGGCCCAAGATAGATGTT VEVPDVNIEGPEGKLKGPKFKM ACTGCTCCTGATGTGAGCATTGAGGAACCAGAAGGGAAATTGAAAGGGCCCAAG EMNIKAPKISMPDVDLHMKGPK TTTAAGATGCCTGAGATGAACATCAAAGTCCCCAAGATCTCCATGCCTGATGTG KGEYDMTVPKLEGDLKGPKVDV GACTTACATCTGAAAGGCCCTAACGTAAAGGGAGAATATGATGTCACAATGCCA APDVEMQGPDWNLKMPKIKMPK AAGGTTGAAAGTGAGATTAAAGTTCCTGATGTTGAACTTAAAAGTGCCAAAATG SMPSLKGEGPEFDVNLSKANVD GACATTGATGTCCCAGATGTGGAGGTTCAAGGCCCAGACTGGCACCTGAAGATG SAT* CCCAAGATGAAAATGCCCAAGTTCAGCATGCCTGGCTTCAAAGCAGAGGGCCCA GAAGTGGATGTGAACCTGCCCAAGGCTGATGTGGACATCTCAGGACCCAAGGTG GGTGTTGAAGTTCCAGATGTGAATATTGAAGGACCTGAAGGAAAGCTGAAGGGC CCCAAGTTCAAGATGCCAGAGATGAATATCAAGGCCCCCAAGATCTCCATGCCT GATGTGGACTTGCATATGAAAGGTCCTAAAGTAAAGGGAGAATATGATATGACA

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TATCCAAAATGCATGTGTTGCAGATAAGCACAGGCCTCTGGAAATGTCAGCCAA SAKIRVPFLRQWPISKKVARD GATCCGAGTACCATTTTTACGTCAGGTTGTTCCCATTAGTAAAAAGGTAGCCCG RFDDLSGEYNPEVFDKTYQFLN GGACCCTCGCTTTGATGATCTGTCAGGGGAATATAATCCTGAGGTGTTTGACAA IRAKEKELVKKQLKKHLSGEEH AACATACCAATTCTTGAATGACATCCGAGCGAAAGAGAAAGAGCTTGTGAAAAA KLQQLLQRMEQQEMAQQERKQQ ACAGTTGAAGAAGCACCTTTCAGGAGAGGAGCATGAGAAACTGCAGCAACTGCT ELHLALKQERRAQAQQGHRPYF TCAGCGAATGGAGCAGCAAGAAATGGCACAGCAGGAACGAAAGCAACAGCAGGA KKSEQRQLALAEKFKELKRSKK GCTGCACCTGGCCCTGAAGCAAGAACGTCGGGCTCAGGCCCAGCAGGGCCATCG ENFLSRKRRRNAGK GCCATACTTCCTGAAAAAATCTGAGCAGCGCCAGTTGGCACTAGCTGAGAAGTT CAAGGAGCTGAAACGCAGCAAGAAATTGGAGAACTTCTTGAGTCGAAAGAGGCG ACGAAATGCAGGCAAGGA

Human 11 prey4211 767 ATGGGGTTCCTGAAACTGATTGAGATTGAGAACTTTAAGTCGTACAAGGGTCGA 1505 MGFLKLIEIENFKSYKGRQIIG hGITl v4 CAGATTATCGGACCATTTCAGAGGTTCACCGCCATCATTGGACCCAATGGCTCT FQRFTAIIGPNGSGKSNLMDAI GGTAAGTCAAATCTCATGGATGCCATCAGCTTTGTGCTAGGTGAAAAAACCAGC FVLGEKTSNLRVKTLRDLIHGA AACCTGCGGGTAAAGACCCTGCGGGACCTGATCCATGGAGCTCCTGTGGGCAAG VGKPAANRAFVSMVYSEEGAED CCAGCTGCCAACCGGGCCTTTGTCAGCATGGTCTACTCTGAGGAGGGTGCTGAG TFARVIVGGSSEYKINNKWQL GACCGTACCTTTGCCCGTGTCATTGTAGGAGGTTCTTCTGAGTACAAGATCAAC EYSEELEKLGILIKARNFLVFQ AACAAAGTGGTCCAACTACATGAGTACAGTGAGGAATTAGAGAAGTTGGGCATT AVESIAMKNPKERTALFEEISR CTCATCAAAGCTCGTAACTTCCTCGTTTTCCAGGGTGCTGTGGAATCTATTGCC GDVAQEYDKRKKEMVKAEEDTQ ATGAAGAACCCCAAAGAGAGGACAGCTCTATTTGAAGAGATTAGTCGTTCTGGG NYHRKKNIAAERKEAKQEKEEA

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ON GACGTGGCGCAGGAGTATGACAAGCGAAAGAAGGAAATGGTGAAGGCTGAAGAG RYQRLKDEWRAQVQLQLFKLY © GACACACAGTTTAATTACCATCGCAAGAAAAATATTGCGGCTGAACGCAAGGAA NEVEIEKLNKELASKNKEIEKD GCAAAGCAGGAGAAAGAAGAGGCTGACCGGTACCAGCGCCTGAAGGATGAGGTA KRMDKVEDELKEKKKELGKMMR GTACGGGCTCAGGTACAGCTGCAGCTCTTTAAGCTTTACCATAATGAAGTGGAA QQQIEKEIKEKDSELNQKRPQY ATTGAGAAGCTCAACAAGGAACTGGCCTCAAAGAACAAGGAGATCGAGAAGGAC KAKENTSHKIKKLEAAKKSLQN AAGAAGCGTATGGACAAGGTGGAGGATGAACTGAAGGAGAAGAAGAAGGAGCTG QKHYKKRKGDMDELEKEMLSVE GGCAAAATGATGCGGGAGCAGCAGCAGATTGAGAAGGAGATCAAGGAGAAGGAC ARQEFEERMEEESQSQGRDLTL TCAGAATTGAACCAGAAGCGGCCTCAGTACATCAAAGCCAAGGAGAACACCTCC ENQVKKYHRLKEEASKRAATLA CACAAAATCAAGAAGCTGGAAGCAGCCAAGAAGTCTCTGCAGAATGCTCAGAAG ELEKFNRDQKADQDRLDLEERK CACTACAAGAAGCGTAAAGGTGACATGGATGAGCTGGAGAAGGAGATGCTGTCA VETEAKIKQKLREIEENQKRIE GTGGAGAAGGCTCGGCAGGAGTTTGAAGAACGGATGGAAGAAGAGAGTCAGAGT LEEYITTSKQSLEEQKKLEGEL CAGGGCAGAGATTTGACGTTGGAGGAGAATCAGGTGAAGAAATACCACCGGTTG EEVEMAKRRIDEINKELNQVME AAAGAAGAAGCCAGCAAGAGAGCAGCTACCCTGGCCCAGGAGCTGGAGAAATTC LGDARIDRQESSRQQRKAEIME AATCGAGACCAGAAAGCTGACCAGGACCGTCTGGATCTGGAAGAACGGAAGAAA IKRLYPGSVYGRLIDLCQPTQK GTAGAGACAGAGGCCAAGATCAAGCAAAAGCTGCGGGAAATTGAAGAGAATCAG YQIAVTKVLGKNMDAIIVDSEK AAGCGGATTGAGAAACTGGAGGAATACATCACCACTAGCAAGCAGTCCCTAGAA GRDCIQYIKEQRGEPETFLPLD GAGCAGAAGAAGCTAGAGGGGGAGCTGACAGAGGAGGTGGAGATGGCCAAGCGG LEVKPTDEKLRELKGAKLVIDV CGTATTGATGAAATCAATAAGGAGCTGAACCAGGTGATGGAGCAGCTAGGGGAT RYEPPHIKKALQYACGNALVCD GCCCGCATCGACCGCCAGGAGAGCAGCCGCCAGCAGCGAAAGGCAGAGATAATG VEDARRIAFGGHQRHKTVALDG GAAAGCATCAAGCGCCTTTACCCTGGCTCTGTGTACGGCCGCCTCATTGACCTA LFQKSGVISGGASDLKAKARRW

TGCCAGCCCACACAAAAGAAGTATCAGATTGCTGTAACCAAGGTTTTGGGCAAG EKAVDKLKEKKERLTEELKEQM AACATGGATGCCATTATTGTGGACTCGGAGAAGACAGGCCGGGACTGTATTCAG AKRKEAELRQVQSQAHGLQMRL TATATCAAGGAGCAGCGTGGGGAGCCTGAGACCTTCTTGCCTCTTGACTACCTG YSQSDLEQTKTRHLALNLQEKS GAGGTGAAGCCTACAGATGAGAAACTCCGGGAGCTGAAGGGGGCCAAGCTAGTG LESELANFGPRINDIKRIIQSR ATTGATGTGATTCGCTATGAGCCACCTCATATCAAAAAGGCCCTGCAGTATGCT REMKDLKEKMNQVEDEVFEEFC TGTGGCAATGCCCTTGTCTGTGACAACGTGGAAGATGCCCGCCGCATTGCCTTT EIGVRNIREFEEEKVKRQNEIA GGAGGCCACCAGCGCCACAAGACAGTGGCACTGGATGGAACCCTATTCCAGAAG KRLEFENQKTRLGIQLDFEKNQ TCAGGAGTGATCTCTGGTGGGGCCAGTGACCTGAAGGCCAAGGCACGGCGCTGG KEDQDKVHMWEQTVKKDENEIE GATGAGAAAGCAGTAGACAAGTTGAAAGAGAAGAAGGAGCGCTTGACAGAGGAG LKKEEQRHMKIIDETMAQLQDL CTGAAAGAGCAGATGAAGGCAAAACGGAAAGAGGCAGAGCTGCGTCAGGTGCAG NQHLAKKSEVNDKNHEMEEI K TCTCAGGCCCATGGACTGCAGATGCGGCTCAAGTACTCCCAGAGTGACCTAGAA LGGANKEMTHLQKEVTAIETKL CAGACCAAGACACGACATCTAGCCCTGAATCTGCAGGAAAAATCCAAGCTGGAG QKRSDRHNLLQACKMQDIKLPL AGTGAGCTAGCCAACTTTGGGCCTCGCATTAATGATATCAAGAGGATCATTCAG KGTMDDISQEEGSSQGEDSVSG AGCCGAGAGAGGGAAATGAAAGACTTGAAGGAGAAGATGAACCAGGTAGAGGAT QRISSIYAREALIEIDYGDLCE GAGGTGTTTGAAGAGTTTTGTCGGGAGATTGGTGTGCGCAACATCCGGGAGTTT LKDAQAEEEIKQEMNTLQQKLN GAGGAAGAAAAGGTGAAACGGCAGAATGAAATCGCCAAGAAGCGTTTGGAGTTT QQSVLQRIAAPNMKAMEKLESV GAGAATCAGAAGACTCGCTTGGGCATTCAGTTGGATTTTGAAAAGAACCAACTG DKFQETSDEFEAARKRAKKAKQ AAGGAGGACCAAGATAAAGTACACATGTGGGAGCAGACAGTGAAAAAAGATGAA FEQIKKERFDRFNACFESVATN AATGAGATAGAAAAGCTCAAAAAGGAGGAACAAAGACACATGAAGATCATAGAT DEIYKALSRNSSAQAFLGPENP

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ON GAGACCATGGCTCAGCTACAAGACCTGAAGAATCAGCATCTGGCCAAGAAGTCG EPYLDGINYNCVAPGKRFRPMD GAAGTGAATGACAAGAATCATGAGATGGAGGAGATTCGTAAGAAACTCGGGGGC LSGGEKTVAALALLFAIHSYKP GCCAACAAGGAAATGACCCATTTACAGAAGGAGGTGACAGCCATTGAGACCAAG PFFVLDEIDAALDNTNIGKVAN CTTGAACAGAAGCGCAGTGACCGTCACAACTTGCTACAGGCCTGTAAGATGCAG IKEQSTCNFQAIVISLKEEFYT GACATTAAGTTGCCACTGTCAAAAGGCACCATGGATGATATTAGTCAGGAAGAG AESLIGVYPEQGDCVISKVLTF GGTAGCTCCCAGGGGGAGGACTCAGTGAGTGGTTCACAGAGAATTTCCAGTATC LTKYPDANPNPNEQ* TATGCACGAGAGGCCCTCATTGAGATTGACTACGGTGATCTGTGTGAGGATCTG AAGGATGCCCAGGCTGAGGAAGAGATCAAGCAAGAGATGAACACACTGCAGCAG AAGCTGAATGAGCAGCAGAGTGTGCTTCAGCGTATTGCCGCCCCCAACATGAAG GCCATGGAAAAGCTGGAAAGTGTCCGAGACAAGTTCCAGGAGACCTCAGATGAG TTTGAAGCAGCCCGAAAGCGAGCAAAGAAGGCCAAGCAGGCATTCGAACAGATC AAGAAGGAGCGCTTTGACCGCTTCAATGCTTGTTTTGAATCTGTGGCTACCAAC ATTGATGAGATCTATAAGGCCCTGTCCCGCAATAGCAGTGCCCAGGCATTCCTG GGCCCTGAGAACCCTGAAGAGCCCTACTTGGATGGCATCAACTACAACTGTGTG GCTCCTGGGAAACGCTTCCGGCCTATGGACAACTTGTCAGGCGGGGAGAAGACA GTGGCAGCTCTGGCCCTGCTCTTTGCCATCCACAGCTACAAGCCAGCCCCCTTC TTCGTCCTGGATGAGATTGATGCTGCCTTGGATAACACCAACATTGGCAAGGTG GCAAATTACATCAAGGAGCAGTCGACTTGCAACTTCCAGGCCATCGTCATCTCT CTCAAGGAGGAGTTCTACACCAAGGCCGAGAGCCTCATTGGAGTCTATCCTGAG CAAGGGGACTGTGTGATCAGCAAAGTCCTGACCTTCGACCTCACCAAGTACCCA

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Claims

CLAIMSWhat is claimed is:

1. A complex between two interacting proteins in adipocyte cells as defined in columns 1 and 4 in Table 2.

2. A polynucleotide encoding a polypeptide in adipocyte cells as defined in columns 1 and 4 in Table 2.

3. A recombinant host cell expressing at least one of the interacting polypeptides of said complex of claim 1.

4. A method for selecting a modulating compound in adipocyte cells comprising:

(a) cultivating a recombinant host cell on a selective medium containing a modulating compound and a reporter gene the expression of which is toxic for said recombinant host cell wherein said recombinant host cell is transformed with two vectors: (i) wherein said first vector comprises a polynucleotide encoding a first hybrid polypeptide and a DNA bonding domain; (ii) wherein said second vector comprises a polynucleotide encoding a second hybrid polypeptide and an activating domain that activates said toxic reporter gene when the first and second hybrid polypeptides interact;

(b) selecting said modulating compound which inhibits the growth of said recombinant host cell.

5. A modulating compound obtained from the method of Claim 4.

6. A SID® polypeptide comprising the SEQ ID Nos. 772 to 1509.

7. A SID® polynucleotide comprising the SEQ ID Nos. 34 to 771.

8. A vector comprising the SID® polynucleotide comprising the SEQ ID Nos. 34 to 771.

9. A fragment of said SID® polypeptide according to Claim 6.

10. A variant of said SID® polypeptide according to Claim 6.

1 1 .A fragment of said SID® polynucleotide according to Claim 7.

12. A variant of said SID® polynucleotide according to Claim 7.

13. A vector comprising the SID® polynucleotide according to Claim 11.

14. A vector comprising the SID® polynucleotide according to Claim 12.

15. A recombinant host cell containing the vectors according to Claim 8.

16. A recombinant host cell containing the vectors according to Claim 13.

17. A pharmaceutical composition comprising a modulating compound of claim 5 and a pharmaceutically acceptable carrier.

18. A pharmaceutical composition comprising a SID® polypeptide of SEQ ID

Nos. 772 to 1509 and a pharmaceutically acceptable carrier.

19. A pharmaceutical composition comprising the recombinant host cells of Claim 15 and a pharmaceutically acceptable carrier.

20. A pharmaceutical composition comprising the recombinant host cells of Claim 16 and a pharmaceutically acceptable carrier.

21. A protein chip comprising the polypeptides of Table 2.

22. A record comprising all or part of the data set forth in Tables 1 and 2.