JP2005323584A - フォリスタチン変異体ポリペプチド - Google Patents
フォリスタチン変異体ポリペプチド Download PDFInfo
- Publication number
- JP2005323584A JP2005323584A JP2004355293A JP2004355293A JP2005323584A JP 2005323584 A JP2005323584 A JP 2005323584A JP 2004355293 A JP2004355293 A JP 2004355293A JP 2004355293 A JP2004355293 A JP 2004355293A JP 2005323584 A JP2005323584 A JP 2005323584A
- Authority
- JP
- Japan
- Prior art keywords
- cys
- lys
- glu
- follistatin
- leu
- Prior art date
- Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
- Granted
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Abstract
【解決手段】 (a)フォリスタチンドメインIを含み、(b)特定なアミノ酸配列であって、かつ特定なアミノ酸配列と50%以上の相同性を有する配列を含まず、かつ(c)アクチビンの活性の阻害と比較して、GDF-8の活性を選択的に阻害する、ことを特徴とするフォリスタチン変異体ポリペプチド。
【選択図】なし
Description
(1)(a)フォリスタチンドメインIを含み、
(b)式(I):Cys−(X1)a−Cys−(X2)b−Cys−(X3)c−Cys−(X4)d−Cys−(X5)e−Cys−(X6)f−Cys−(X7)g−Cys−(X8)h−Cys−(X9)i−Cys(式中、X1、X2、X3、X4、X5、X6、X7、X8およびX9は、それぞれ独立して同一または異なった、システイン以外の天然に存在するアミノ酸残基を表し、aは2〜6、bは3〜7、cは7〜11、dは0〜4、eは1〜6、fおよびgは8〜12、hは4〜8、iは11〜15の整数をそれぞれ表す。)で表されるアミノ酸配列であって、かつ配列番号2または配列番号29のアミノ酸配列と50%以上の相同性を有する配列を含まず、かつ
(c)アクチビンの活性の阻害と比較して、GDF-8の活性を選択的に阻害する、
ことを特徴とするフォリスタチン変異体ポリペプチド。
(3) さらにフォリスタチンドメインIIIを含まない、(1)または(2)に記載のフォリスタチン変異体ポリペプチド。
(4) 2つ以上のフォリスタチンドメインIを含む、(1)から(3)のいずれかに記載のフォリスタチン変異体ポリペプチド。
(5) さらにN末端ドメインを含む、(1)から(4)のいずれかに記載のフォリスタチン変異体ポリペプチド。
(6) FSI、FSI−FSI、FSI−FSI−FSIII、FSN−FSI、FSN−FSI−FSI、又はFSN−FSI−FSI−FSIII(ここでFSIはフォリスタチンドメインIを示し、FSIIIはフォリスタチンドメインIIIを示し、FSNはN末端ドメインを示し、各ドメイン間は直接またはリンカーポリペプチドで連結している)から選択されるいずれかのドメイン構造を含む(1)または(2)に記載のフォリスタチン変異体ポリペプチド。
(8) 配列番号4の30〜166番目のアミノ酸配列を含む、(7)に記載のフォリスタチン変異体ポリペプチド。
(9) フォリスタチンのドメインのアミノ酸配列のN末端またはC末端に他のポリペプチドが融合している、(1)から(8)の何れかに記載のフォリスタチン変異体ポリペプチド。
(10) 配列番号6、8または10のアミノ酸配列からなるポリペプチド。
(12) 配列番号5、7または9の塩基配列を含む(11)に記載のポリヌクレオチド。
(13) (11)または(12)に記載のポリヌクレオチドを含むベクター。
(14) (13)に記載のベクターを宿主細胞に導入して得られる形質転換細胞。
(15) (14)に記載の形質転換細胞を培地中で培養し、該細胞で発現した(1)から(10)のいずれかに記載のポリペプチドを培地または該細胞中に蓄積させ、培地または該細胞から該ポリペプチドを採取することを特徴とする、該ポリペプチドの製造方法。
(17) (1)から(10)のいずれかに記載のポリペプチド、(11)または(12)に記載のポリヌクレオチドまたは(13)に記載のベクターを含有する医薬組成物。
(18) (1)から(10)のいずれかに記載のポリペプチド、(11)または(12)に記載のポリヌクレオチドまたは(13)に記載のベクターを有効成分として含有する、骨格筋増加剤。
(19) (1)から(10)のいずれかに記載のポリペプチド、(11)または(12)に記載のポリヌクレオチドまたは(13)に記載のベクターを有効成分として含有する、脂肪減少剤。
(20) (1)から(10)のいずれかに記載のポリペプチド、(11)または(12)に記載のポリヌクレオチドまたは(13)に記載のベクターを有効成分として含有する、筋萎縮症状の治療剤または予防剤。
(22) 筋萎縮を伴う疾患が、遺伝性の筋ジストロフィー、筋萎縮性側索硬化症、脊髄小脳変性症またはパーキンソン病である(21)に記載の治療剤または予防剤。
(23) (11)または(12)に記載のポリヌクレオチドを含む外来遺伝子を導入したトランスジェニック非ヒト哺乳動物。
(24) 非ヒト動物に(1)から(10)のいずれかに記載のポリペプチド、(11)または(12)に記載のポリヌクレオチドまたは(13)に記載のベクターを投与して、該非ヒト動物の筋肉を増加させる方法。
(25) 非ヒト動物に(1)から(10)のいずれかに記載のポリペプチド、(11)または(12)に記載のポリヌクレオチドまたは(13)に記載のベクターを投与して、該非ヒト動物の脂肪を減少させる方法。
本発明における変異体を作製する場合の、元になるフォリスタチンはどの動物種のものでもよいが、哺乳類または鳥類のフォリスタチン、例えばヒト、マウス、ラット、ウシ、ブタ、ヒツジ、ウマ、ニワトリ等のフォリスタチンが好ましく、特にヒトフォリスタチンが好ましい。また、mRNAのスプライシングの違いあるいは翻訳後のプロセシングにより、C末端のアミノ酸配列が異なる分子があるが、どれでもよい。具体的には、配列番号4の30〜344番目のアミノ酸配列からなるヒトフォリスタチン、NCBIの蛋白質データベース登録番号P47931のアミノ酸配列の30〜344番目の配列からなるマウスフォリスタチン、NCBIの蛋白質データベース登録番号NP 032072のアミノ酸配列の30〜343番目の配列からなるマウスフォリスタチン、NCBIの蛋白質データベース登録番号P21674のアミノ酸配列の30〜344番目の配列からなるラットフォリスタチン、NCBIの蛋白質データベース登録番号P50291のアミノ酸配列の30〜344番目の配列からなるウシフォリスタチン、NCBIの蛋白質データベース登録番号P10669のアミノ酸配列の30〜344番目の配列からなるブタフォリスタチン、NCBIの蛋白質データベース登録番号P31514のアミノ酸配列の30〜344番目の配列からなるヒツジフォリスタチン、NCBIの蛋白質データベース登録番号O62650のアミノ酸配列の30〜344番目の配列からなるウマフォリスタチン、NCBIの蛋白質データベース登録番号NP 990531のアミノ酸配列の29〜343番目の配列からなるニワトリフォリスタチン、これらのフォリスタチンのC末端の27アミノ酸または12アミノ酸が欠失した配列からなるポリペプチド、また、天然に存在する、これらのポリペプチドの遺伝子のアレル変異や1塩基多型の遺伝子がコードするポリペプチドがあげられる。
以下に、本発明のフォリスタチン変異体の作製方法、活性評価方法およびその使用方法について説明する。
(1)フォリスタチン変異体ポリペプチドをコードするDNAの構築
1.に記載した条件に基づき、アクチビンの活性の阻害と比較して、GDF-8を選択的に阻害するフォリスタチン変異体ポリペプチドの構造を設計し、該ポリペプチドをコードするDNAを以下のようにして構築する。
(1)で作製したフォリスタチン変異体ポリペプチドをコードするDNAを宿主細胞に応じた適当な発現用ベクターに挿入して、フォリスタチン変異体発現ベクターを作製する。
宿主細胞としては、細菌等の原核生物、酵母等の真核微生物、動物細胞、昆虫細胞、植物細胞等、フォリスタチン変異体ポリぺプチドを発現できるものであればいずれも用いることができるが、フォリスタチン変異体発現ベクターを導入した細胞(以下、形質転換細胞ともいう)が発現するフォリスタチン変異体ポリペプチドが正しい高次構造を保ち、GDF-8特異的な阻害活性を保持するためには、動物細胞や昆虫細胞などで発現させるのが好ましい。
(2)で作製した形質転換細胞が大腸菌等の原核生物あるいは酵母等の真核生物である場合、該細胞を培養する培地はは、該細胞が資化し得る炭素源、窒素源、無機塩類等を含有し、形質転換体の培養を効率的に行える培地であれば天然培地、合成培地のいずれを用いてもよい。炭素源としては、該生物が資化し得るものであればよく、グルコース、フラクトース、スクロース、これらを含有する糖蜜、デンプンあるいはデンプン加水分解物等の炭水化物、酢酸、プロピオン酸等の有機酸、エタノール、プロパノールなどのアルコール類等を用いることができる。窒素源としては、アンモニア、塩化アンモニウム、硫酸アンモニウム、酢酸アンモニウム、リン酸アンモニウム等の無機酸もしくは有機酸のアンモニウム塩、その他の含窒素化合物、並びに、ペプトン、肉エキス、酵母エキス、コーンスチープリカー、カゼイン加水分解物、大豆粕および大豆粕加水分解物、各種発酵菌体、およびその消化物等を用いることができる。無機塩としては、リン酸水素二カリウム、リン酸二水素カリウム、リン酸マグネシウム、硫酸マグネシウム、塩化ナトリウム、硫酸第一鉄、硫酸マンガン、硫酸銅、炭酸カルシウム等を用いることができる。
本発明のフォリスタチン変異体ポリペプチドが「GDF-8の活性を選択的に阻害する」とは、「アクチビンの活性の阻害と比較して、GDF-8の活性を選択的に阻害する」ことを意味する。「アクチビンの活性の阻害と比較して、GDF-8の活性を選択的に阻害する」とは、請求項3に記載の方法で、同じ濃度のフォリスタチン変異体ポリペプチドについて、アクチビンの活性の阻害とGDF-8の活性の阻害を測定したときに、GDF-8の活性は50%以上、好ましくは60%以上、より好ましくは70%以上、さらに好ましくは80%以上阻害するのに対し、アクチビンの活性の阻害は50%未満、好ましくは30%以下、より好ましくは10%以下であるか、さらに好ましくは阻害せず、アクチビンの活性の阻害と比較して、GDF-8の活性をより強く阻害することを意味する。
本発明のフォリスタチン変異体ポリペプチドは、アクチビンの活性の阻害と比較して、GDF-8の活性を選択的に阻害するフォリスタチン変異体ポリペプチドであり、アクチビンの活性は阻害せず、GDF-8の活性を選択的に阻害するものが好ましい。以下のように、本発明のフォリスタチン変異体ポリペプチドの活性(アクチビンの活性の阻害と比較してGDF-8の活性を選択的に阻害する活性)は、例えば、アクチビンおよびGDF-8が有する転写促進活性をレポーターアッセイにより測定することにより確認できる。
本発明のフォリスタチン変異体ポリペプチド、該ポリペプチドを投与した生体内で発現するための該ポリペプチドをコードするポリヌクレオチドおよび該ポリヌクレオチドを含むベクターは、アクチビンの活性の阻害と比較して、GDF-8の活性を選択的に阻害するので、GDF-8が発症あるいは進行に関与する症状や疾患の治療や予防に用いることができ、しかも、アクチビンの阻害による副作用が少ないことが期待される。このような症状や疾患としては、例えば、疾患や老化、寝たきり等に伴う骨格筋の減少や萎縮、皮下脂肪や内臓脂肪等の脂肪の増加、悪液質、筋萎縮を伴う疾患、II型糖尿病、肥満および後天性免疫不全症候群などをあげることができる。筋萎縮を伴う疾患としては、デュシェンヌ型筋ジストロフィー等の遺伝性の筋ジストロフィー、および筋萎縮性側索硬化症、脊髄小脳変性症およびパーキンソン病等の神経の変性により二次的に筋萎縮を呈する疾患等をあげることができる。
投与形態としては、例えば錠剤、注射剤などがあげられる。
有効成分として使用するDNA(以下、対象DNAとも称する)の断片を調製する。該DNA断片をウイルスベクター内のプロモーターの下流に挿入することにより、組換えウイルスベクターを造成する。
ウイルスベクターとしては、上記パッケージング細胞において組換えウイルスが生産でき、標的細胞で対象DNAを転写できる位置にプロモーターを含有しているものが用いられる。プラスミドベクターとしてはMFG〔Proc. Natl. Acad. Sci. USA, 92, 6733 (1995)〕、pBabePuro〔Nucleic Acids Res., 18, 3587 (1990)〕、LL-CG、CL-CG、CS-CG、CLG〔J. Virol., 72, 8150 (1998)〕、pAdex1〔Nucleic Acids Res., 23, 3816 (1995)〕などが用いられる。プロモーターとしては、ヒト組織中で機能するものであればいずれも用いることができ、例えば、サイトメガロウイルス(CMV)のIE(immediate early)遺伝子のプロモーター、SV40の初期プロモーター、レトロウイルスのプロモーター、メタロチオネインプロモーター、ヒートショック蛋白質プロモーター、SRαプロモーターなどをあげることができる。また、ヒトCMVのIE遺伝子のエンハンサーをプロモーターと共に用いてもよい。
当該分野で公知の非ウイルス遺伝子移入法には、リン酸カルシウム共沈法〔Virology, 52, 456 (1973); Science, 209, 1414 (1980)〕、マイクロインジェクション法〔Proc. Natl. Acad. Sci. USA,77, 5399 (1980); Proc. Natl. Acad. Sci. USA,77, 7380 (1980); Cell, 27, 223 (1981); Nature, 294, 92 (1981)〕、リポソームを介した膜融合−介在移入法〔Proc. Natl. Acad. Sci. USA,84, 7413 (1987); Biochemistry, 28, 9508 (1989); J. Biol. Chem., 264, 12126 (1989); Hum. Gene Ther., 3, 267 (1992); Science, 249, 1285 (1990); Circulation, 83, 2007 (1992)〕あるいは直接DNA取り込みおよび受容体を介したDNA移入法〔Science, 247, 1465 (1990); J. Biol. Chem., 266, 14338 (1991); Proc. Natl. Acad. Sci. USA,87, 3655 (1991); J. Biol. Chem., 264, 16985 (1989); BioTechniques, 11, 474 (1991); Proc. Natl. Acad. Sci. USA,87, 3410 (1990); Proc. Natl. Acad. Sci. USA,88, 4255 (1991); Proc. Natl. Acad. Sci. USA,87, 4033 (1990); Proc. Natl. Acad. Sci. USA,88, 8850 (1991); Hum. Gene Ther., 3, 147 (1991)〕などをあげることができる。
本発明のフォリスタチン変異体ポリペプチドをコードするポリヌクレオチドを含む外来遺伝子を非ヒト哺乳動物に導入することにより、トランスジェニック非ヒト哺乳動物を作製することができる。上記トランスジェニック非ヒト哺乳動物においては、本発明のフォリスタチン変異体ポリペプチドが過剰発現しており、好ましくは骨格筋量が増大していることを特徴とする。当該トランスジェニック非ヒト哺乳動物は、骨格筋の形成機構の研究や、骨格筋の異常を伴う疾患の研究の際に使用するモデル動物として有用である。
(1)導入遺伝子の調製
本発明のフォリスタチン変異体ポリペプチドをコードするDNAを対象動物に導入する際には、導入の対象動物の細胞内で当該DNAを発現させうるプロモーターの下流に当該DNAを連結した遺伝子構築物を用いるのが一般に有利である。導入させる遺伝子は、常法により、例えば、下記の通り調製することができる。
本発明のトランスジェニック非ヒト哺乳動物は、フォリスタチン変異体ポリペプチドをコードするDNAを対象動物に導入することによって作製できる。具体的には、該遺伝子を対象となる非ヒト哺乳動物の受精卵、胚性幹細胞、体細胞、精子、未受精卵へ導入することによって、目的とするフォリスタチン変異体ポリペプチドをコードするDNAが胚芽細胞を含むすべての細胞の染色体上に組み込まれたトランスジェニック非ヒト哺乳動物を得ることによって作出できる。受精卵、胚性幹細胞、体細胞、精子、未受精卵における該遺伝子の導入は、対象非ヒト哺乳動物の胚芽細胞および体細胞を含む全ての細胞の染色体上に存在するように確保されることが好ましい。遺伝子導入後の作出動物の胚芽細胞において該導入遺伝子が存在することは、作出動物の子孫がその胚芽細胞および体細胞の全てに該導入遺伝子を有することを意味する。
本発明のフォリスタチン変異体ポリペプチド、該ポリペプチドを投与した生体内で発現するための該ポリペプチドをコードするポリヌクレオチドおよび該ポリヌクレオチドを含むベクターをウシ、ブタ、ヒツジ、ニワトリ等の非ヒト動物に投与することにより、該非ヒト動物の骨格筋を増加させ、脂肪を低下させることができる。また、5に記載した方法と同様にして、本発明のフォリスタチン変異体ポリペプチドをコードするDNAを導入したトランスジェニック非ヒト動物を作製することにより、、該非ヒト動物の骨格筋を増加させ、脂肪を低下させることができる。特に非ヒト動物が家畜である場合、以上のようにして肉の量が多く、脂肪の少ない家畜を作製することができるので、肉の生産量を増加でき、また脂肪の少ない良質肉の生産をすることができる。また骨格筋の増加から、家畜の労働力を改良することができる。
以下、本発明の実施例を示すが、これにより本発明の範囲が限定されるものではない。
ヒト精巣cDNAライブラリー〔クロンテック(Clontech)社製〕から、ブタフォリスタチン前駆体cDNAをプローブとしたハイブリダイゼーションによりクローン化された、ヒトフォリスタチン前駆体cDNA〔Proc. Natl. Acad. Sci. USA, 85, 4218, (1988)〕を、プラスミドpUC19(宝酒造社製)中のEcoRI部位とXbaI部位の間に挿入し、フォリスタチン変異体用の鋳型pUC19/FSを作製した。
(1)COS-7細胞への発現ベクターの導入と培養
実施例1で得られたフォリスタチン変異体ポリペプチド発現ベクターpcDNA3 (A+B)、pcDNA3 (B)、pcDNA3 (A+B+C)、pcDNA3 (A+B+D)を用いてフォリスタチン変異体ポリペプチドの動物細胞での発現を以下のようにして行った。
(1)で得られた4種類のフォリスタチン変異体ポリペプチドそれぞれを発現するCOS-7細胞の約60 mlの培養上清を20 mmol/L Tris-HCl (pH7.2), 0.3 mol/L NaCl, 0.03% 3-[(3-コールアミドプロピル)ジメチルアンモニオ]-1-プロパンスルホネート(CHAPS)で平衡化した2 mlの硫酸化セルロファインカラム(生化学工業社製)に通塔した。その後、計20 mlの20 mmmol/L Tris-HCl (pH7.2), 0.3 mol/L NaCl, 0.03% CHAPS、続いて計6 mlの20 mmmol/L Tris-HCl (pH7.2), 0.5 mol/L NaCl, 0.03% CHAPSでカラムを洗浄した。その後、計10mlの20mmmol/L Tris-HCl (pH7.2), 1.0mol/L NaCl, 0.03% CHAPSを用いて吸着タンパク質をカラムから溶出させた。この溶出液をウルトラフリー-15(Ultrafree-15)遠心式フィルターユニット(バイオマックス-10メンブレン装着ユニット;ミリポア社製)を用いて添付の説明書に従って濃縮し、200μlのフォリスタチン変異体ポリペプチド溶液を得た。
HEK293細胞(ATCC番号:CRL-1573)を24ウェルプレートに5×104細胞/ウェルで播種し、10%FCS、ペニシリン(100単位/ml)およびストレプトマイシン(100μg/ml)を添加した高グルコース含有DMEM培地(シグマーアルドリッチ社製)(以下、血清含有DMEM培地とする)1 ml中で24時間培養した。リン酸緩衝生理食塩水(PBS)で洗浄し、レポータープラスミド(CAGA)12-MLP-Luc〔EMBO J., 17, 3091 (1998)〕(3μg/ウェル)および内部標準プラスミドCMV-β-gal(1μg/ウェル)をトランスフェクションした。トランスフェクションはプラスミドとカチオン性リポソーム(Transfast;プロメガ社製)の混合液を添加した血清不含DMEM培地(200μl)中で、細胞を2時間37℃で培養することにより行った。さらに血清含有DMEM培地(1 ml)を添加し、37℃で24時間培養した。
標準化ルシフェラーゼ活性 = RLU/OD
実施例1で作製したpcDNA3 (A+B)をEcoRIおよびSacIで切断して得られる、フォリスタチン変異体ポリペプチドFS1-1をコードするDNAを含むEcoRI-SacI断片を、ベクターpSP72(プロメガ社製)のEcoRI部位およびSacI部位の間に挿入した。得られたプラスミドをEcoRIおよびSmaIで切断して得られる、フォリスタチン変異体ポリペプチドFS1-1をコードするDNAを含むEcoRI-SacI断片を、MDAF2ベクター〔Proc. Natl. Acad. Sci. USA, 98, 9306 (2001)〕のミオシン軽鎖のプロモーターの下流に存在するEcoRI部位およびSacI部位の間に挿入し、プラスミドMDAF2-FS1-1を得た。
さらに、このようにして得られたトランスジェニックマウスの、皮下脂肪および内臓脂肪の量を測定し、フォリスタチン変異体ポリペプチドがこれらの脂肪量に与える影響を調べた。皮下脂肪としては鼠径部の皮下脂肪、内臓脂肪としては腎臓周囲の脂肪、それぞれの重量を測定し、体重に対する割合(%)を量の指標とした。その結果、トランスジェニックマウスでは、皮下脂肪量および内臓脂肪量ともに、野生型マウスと比較して著しく減少していることがわかった。例として、図20に12週齢のメスのトランスジェニックマウスおよび12週齢のメスの野生型マウスそれぞれの、体重に対する皮下脂肪量(%)および内臓脂肪量(%)を示した。野生型マウスは3匹の平均値を示した。また、オスのトランスジェニックマウスでも同様に、皮下脂肪量および内臓脂肪量の著しい減少が見られた。なお、トランスジェニックマウスでは、骨格筋の増加と脂肪の減少以外の異常は観察されなかった。
(1)フォリスタチン変異体ポリペプチドとイムノグロブリン定常領域との融合蛋白質の発現ベクターの作製
フォリスタチン変異体ポリペプチドFS1およびFS1-1それぞれとイムノグロブリンの定常領域との融合蛋白質の発現ベクターを以下のようにして作製した。
実施例1で作製したpGEM-T Easy (B)を鋳型にして、プライマーとして配列番号27および28に示した塩基配列を有する合成DNA(ジェンセット社製)をそれぞれ10 pmolずつ用いて、実施例1の遺伝子増幅断片Aと同様の条件でPCRを行い、反応液をアガロースゲル電気泳動にて分画し、5'端にKpnIサイト、3'端にBamHIサイトがそれぞれ付加されたFS1をコードする増幅断片を回収した。得られた増幅断片をKpnIおよびBamHIで切断し、CD5-IgG1ベクター〔Cell, 61, 1303 (1990)〕を制限酵素KpnIおよびBamHIで切断して得られるヒトIgG1定常領域をコードするゲノム配列を含むKpnI-BamHI断片と連結し、FS1のC末端にヒトIgG1の定常領域が融合した融合蛋白質(以下、FS1-Fcとよぶ)発現プラスミドpcDNA3 FS1-Fcを作製した。CD5-IgG1ベクターでは、ベクターpcDNA3のプロモーターの下流のXhoIサイト−XbaIサイト間にヒトIgG1定常領域をコードする配列が挿入されているので、pcDNA3 FS1-Fcは、pcDNA3のプロモーターの下流に、FS1-Fcをコードする配列が挿入された構造を有する。
CHO-K1(ATCC番号:CCL-61)細胞にpcDNA3 FS1-FcまたはpcDNA3 FS1-1-Fcそれぞれをリポソーム試薬Transfast(プロメガ社製)を用いて導入した後、安定に導入した遺伝子が組み込まれたシングルクローンを得た。それぞれのシングルクローンをFCSを10%添加したαMEM培地10 mlに懸濁し、10 cm径細胞培養ディッシュに播種した。5% CO2インキュベーター内で37℃、コンフルエントになるまで培養した後、EX-CELL 301培地(JRHバイオサイエンシズ社製)へ培地交換して、細胞培養ディッシュ6枚で1週間培養し、培養上清約60 mlを回収した。
(2)で得られたFS1-Fc、FS1-1-Fcそれぞれを発現するCHO-K1細胞の培養上清に1/10量のヘパリンセルロファイン(生化学工業社製)を加えて、室温で2時間混合し、蛋白質を吸着させた。ヘパリンセルロファインを洗浄バッファー〔20 mmmol/L Tris-HCl (pH7.4), 0.15 mol/L NaCl〕で洗浄後、溶出バッファー〔20 mmmol/L Tris-HCl (pH7.4), 1.5 mol/L NaCl〕を用いて吸着蛋白質を溶出させた。得られた溶出液から、イムノグロブリンの定常領域と特異的に結合するプロテインA固定化レジンを用いて、常法に従って、FS1-Fc溶液およびFS1-1-Fc溶液それぞれを得た。
(a)緩衝液のみ、(b)FS1-Fc(20 μg/ml)(c)アクチビン(15 ng/ml)、(d)アクチビン(15 ng/ml)とFS1-Fc(20 μg/ml)、(e)GDF-8(15 ng/ml)、(f)GDF-8(15 ng/ml)とFS1-Fc(10 μg/ml)および(g)GDF-8(15 ng/ml)とFS1-Fc(20 μg/ml)それぞれの条件で、実施例3と同様にしてレポーターアッセイにより、FS1-FcのアクチビンおよびGDF-8機能阻害活性の検定を行った。図21に示すように、FS1-FcはGDF-8による標準化ルシフェラーゼ活性の上昇をほぼ完全に阻害したのに対して、アクチビンによる標準化ルシフェラーゼ活性の上昇はほとんど阻害しなかった。
<110> Techno Network Shikoku Co., Ltd.
<110> Kyowa Hakko Kogyo Co., Ltd.
<120> follistatin mutant polypeptide
<130> A41939A
<150> JP 2004-120023
<151> 2004-04-15
<160> 29
<170> PatentIn version 3.2
<210> 1
<211> 70
<212> PRT
<213> Artificial
<220>
<223> follistatin domain I consensus sequence
<220>
<221> misc feature
<222> (2)..(2)
<223> Xaa is Glu or Asp
<220>
<221> misc feature
<222> (13)..(13)
<223> Xaa is Arg or Lys
<220>
<221> misc feature
<222> (69)..(69)
<223> Xaa is Lys or Arg
<220>
<223> Inventor: Tsuchida, Kunihiro; Murakami, Tatsuya
<400> 1
Cys Xaa Asn Val Asp Cys Gly Pro Gly Lys Lys Cys Xaa Met Asn Lys
1 5 10 15
Lys Asn Lys Pro Arg Cys Val Cys Ala Pro Asp Cys Ser Asn Ile Thr
20 25 30
Trp Lys Gly Pro Val Cys Gly Leu Asp Gly Lys Thr Tyr Arg Asn Glu
35 40 45
Cys Ala Leu Leu Lys Ala Arg Cys Lys Glu Gln Pro Glu Leu Glu Val
50 55 60
Gln Tyr Gln Gly Xaa Cys
65 70
<210> 2
<211> 72
<212> PRT
<213> Artificial
<220>
<223> follistatin domain II consensus sequence
<220>
<221> misc feature
<222> (5)..(5)
<223> Xaa can be any naturally occurring amino acid except cysteine
<220>
<221> misc feature
<222> (33)..(33)
<223> Xaa can be any naturally occurring amino acid except cysteine
<220>
<221> misc feature
<222> (35)..(35)
<223> Xaa can be any naturally occurring amino acid except cysteine
<220>
<221> misc feature
<222> (38)..(38)
<223> Xaa can be any naturally occurring amino acid except cysteine
<220>
<221> misc feature
<222> (45)..(45)
<223> Xaa can be any naturally occurring amino acid except cysteine
<220>
<221> misc feature
<222> (48)..(48)
<223> Xaa can be any naturally occurring amino acid except cysteine
<400> 2
Cys Arg Asp Val Xaa Cys Pro Gly Ser Ser Thr Cys Val Val Asp Gln
1 5 10 15
Thr Asn Asn Ala Tyr Cys Val Thr Cys Asn Arg Ile Cys Pro Glu Pro
20 25 30
Xaa Ser Xaa Glu Gln Xaa Leu Cys Gly Asn Asp Gly Xaa Thr Tyr Xaa
35 40 45
Ser Ala Cys His Leu Arg Lys Ala Thr Cys Leu Leu Gly Arg Ser Ile
50 55 60
Gly Leu Ala Tyr Glu Gly Lys Cys
65 70
<210> 3
<211> 1035
<212> DNA
<213> Homo sapiens
<220>
<221> CDS
<222> (1)..(1035)
<220>
<221> sig peptide
<222> (1)..(87)
<400> 3
atg gtc cgc gcg agg cac cag ccg ggt ggg ctt tgc ctc ctg ctg ctg 48
Met Val Arg Ala Arg His Gln Pro Gly Gly Leu Cys Leu Leu Leu Leu
1 5 10 15
ctg ctc tgc cag ttc atg gag gac cgc agt gcc cag gct ggg aac tgc 96
Leu Leu Cys Gln Phe Met Glu Asp Arg Ser Ala Gln Ala Gly Asn Cys
20 25 30
tgg ctc cgt caa gcg aag aac ggc cgc tgc cag gtc ctg tac aag acc 144
Trp Leu Arg Gln Ala Lys Asn Gly Arg Cys Gln Val Leu Tyr Lys Thr
35 40 45
gaa ctg agc aag gag gag tgc tgc agc acc ggc cgg ctg agc acc tcg 192
Glu Leu Ser Lys Glu Glu Cys Cys Ser Thr Gly Arg Leu Ser Thr Ser
50 55 60
tgg acc gag gag gac gtg aat gac aac aca ctc ttc aag tgg atg att 240
Trp Thr Glu Glu Asp Val Asn Asp Asn Thr Leu Phe Lys Trp Met Ile
65 70 75 80
ttc aac ggg ggc gcc ccc aac tgc atc ccc tgt aaa gaa acg tgt gag 288
Phe Asn Gly Gly Ala Pro Asn Cys Ile Pro Cys Lys Glu Thr Cys Glu
85 90 95
aac gtg gac tgt gga cct ggg aaa aaa tgc cga atg aac aag aag aac 336
Asn Val Asp Cys Gly Pro Gly Lys Lys Cys Arg Met Asn Lys Lys Asn
100 105 110
aaa ccc cgc tgc gtc tgc gcc ccg gat tgt tcc aac atc acc tgg aag 384
Lys Pro Arg Cys Val Cys Ala Pro Asp Cys Ser Asn Ile Thr Trp Lys
115 120 125
ggt cca gtc tgc ggg ctg gat ggg aaa acc tac cgc aat gaa tgt gca 432
Gly Pro Val Cys Gly Leu Asp Gly Lys Thr Tyr Arg Asn Glu Cys Ala
130 135 140
ctc cta aag gca aga tgt aaa gag cag cca gaa ctg gaa gtc cag tac 480
Leu Leu Lys Ala Arg Cys Lys Glu Gln Pro Glu Leu Glu Val Gln Tyr
145 150 155 160
caa ggc aga tgt aaa aag act tgt cgg gat gtt ttc tgt cca ggc agc 528
Gln Gly Arg Cys Lys Lys Thr Cys Arg Asp Val Phe Cys Pro Gly Ser
165 170 175
tcc aca tgt gtg gtg gac cag acc aat aat gcc tac tgt gtg acc tgt 576
Ser Thr Cys Val Val Asp Gln Thr Asn Asn Ala Tyr Cys Val Thr Cys
180 185 190
aat cgg att tgc cca gag cct gct tcc tct gag caa tat ctc tgt ggg 624
Asn Arg Ile Cys Pro Glu Pro Ala Ser Ser Glu Gln Tyr Leu Cys Gly
195 200 205
aat gat gga gtc acc tac tcc agt gcc tgc cac ctg aga aag gct acc 672
Asn Asp Gly Val Thr Tyr Ser Ser Ala Cys His Leu Arg Lys Ala Thr
210 215 220
tgc ctg ctg ggc aga tct att gga tta gcc tat gag gga aag tgt atc 720
Cys Leu Leu Gly Arg Ser Ile Gly Leu Ala Tyr Glu Gly Lys Cys Ile
225 230 235 240
aaa gca aag tcc tgt gaa gat atc cag tgc act ggt ggg aaa aaa tgt 768
Lys Ala Lys Ser Cys Glu Asp Ile Gln Cys Thr Gly Gly Lys Lys Cys
245 250 255
tta tgg gat ttc aag gtt ggg aga ggc cgg tgt tcc ctc tgt gat gag 816
Leu Trp Asp Phe Lys Val Gly Arg Gly Arg Cys Ser Leu Cys Asp Glu
260 265 270
ctg tgc cct gac agt aag tcg gat gag cct gtc tgt gcc agt gac aat 864
Leu Cys Pro Asp Ser Lys Ser Asp Glu Pro Val Cys Ala Ser Asp Asn
275 280 285
gcc act tat gcc agc gag tgt gcc atg aag gaa gct gcc tgc tcc tca 912
Ala Thr Tyr Ala Ser Glu Cys Ala Met Lys Glu Ala Ala Cys Ser Ser
290 295 300
ggt gtg cta ctg gaa gta aag cac tcc gga tct tgc aac tcc att tcg 960
Gly Val Leu Leu Glu Val Lys His Ser Gly Ser Cys Asn Ser Ile Ser
305 310 315 320
gaa gac acc gag gaa gag gag gaa gat gaa gac cag gac tac agc ttt 1008
Glu Asp Thr Glu Glu Glu Glu Glu Asp Glu Asp Gln Asp Tyr Ser Phe
325 330 335
cct ata tct tct att cta gag tgg taa 1035
Pro Ile Ser Ser Ile Leu Glu Trp
340
<210> 4
<211> 344
<212> PRT
<213> Homo sapiens
<220>
<221> SIGNAL
<222> (1)..(29)
<400> 4
Met Val Arg Ala Arg His Gln Pro Gly Gly Leu Cys Leu Leu Leu Leu
1 5 10 15
Leu Leu Cys Gln Phe Met Glu Asp Arg Ser Ala Gln Ala Gly Asn Cys
20 25 30
Trp Leu Arg Gln Ala Lys Asn Gly Arg Cys Gln Val Leu Tyr Lys Thr
35 40 45
Glu Leu Ser Lys Glu Glu Cys Cys Ser Thr Gly Arg Leu Ser Thr Ser
50 55 60
Trp Thr Glu Glu Asp Val Asn Asp Asn Thr Leu Phe Lys Trp Met Ile
65 70 75 80
Phe Asn Gly Gly Ala Pro Asn Cys Ile Pro Cys Lys Glu Thr Cys Glu
85 90 95
Asn Val Asp Cys Gly Pro Gly Lys Lys Cys Arg Met Asn Lys Lys Asn
100 105 110
Lys Pro Arg Cys Val Cys Ala Pro Asp Cys Ser Asn Ile Thr Trp Lys
115 120 125
Gly Pro Val Cys Gly Leu Asp Gly Lys Thr Tyr Arg Asn Glu Cys Ala
130 135 140
Leu Leu Lys Ala Arg Cys Lys Glu Gln Pro Glu Leu Glu Val Gln Tyr
145 150 155 160
Gln Gly Arg Cys Lys Lys Thr Cys Arg Asp Val Phe Cys Pro Gly Ser
165 170 175
Ser Thr Cys Val Val Asp Gln Thr Asn Asn Ala Tyr Cys Val Thr Cys
180 185 190
Asn Arg Ile Cys Pro Glu Pro Ala Ser Ser Glu Gln Tyr Leu Cys Gly
195 200 205
Asn Asp Gly Val Thr Tyr Ser Ser Ala Cys His Leu Arg Lys Ala Thr
210 215 220
Cys Leu Leu Gly Arg Ser Ile Gly Leu Ala Tyr Glu Gly Lys Cys Ile
225 230 235 240
Lys Ala Lys Ser Cys Glu Asp Ile Gln Cys Thr Gly Gly Lys Lys Cys
245 250 255
Leu Trp Asp Phe Lys Val Gly Arg Gly Arg Cys Ser Leu Cys Asp Glu
260 265 270
Leu Cys Pro Asp Ser Lys Ser Asp Glu Pro Val Cys Ala Ser Asp Asn
275 280 285
Ala Thr Tyr Ala Ser Glu Cys Ala Met Lys Glu Ala Ala Cys Ser Ser
290 295 300
Gly Val Leu Leu Glu Val Lys His Ser Gly Ser Cys Asn Ser Ile Ser
305 310 315 320
Glu Asp Thr Glu Glu Glu Glu Glu Asp Glu Asp Gln Asp Tyr Ser Phe
325 330 335
Pro Ile Ser Ser Ile Leu Glu Trp
340
<210> 5
<211> 678
<212> DNA
<213> Artificial
<220>
<223> FS-1-1
<220>
<221> CDS
<222> (1)..(678)
<400> 5
ggg aac tgc tgg ctc cgt caa gcg aag aac ggc cgc tgc cag gtc ctg 48
Gly Asn Cys Trp Leu Arg Gln Ala Lys Asn Gly Arg Cys Gln Val Leu
1 5 10 15
tac aag acc gaa ctg agc aag gag gag tgc tgc agc acc ggc cgg ctg 96
Tyr Lys Thr Glu Leu Ser Lys Glu Glu Cys Cys Ser Thr Gly Arg Leu
20 25 30
agc acc tcg tgg acc gag gag gac gtg aat gac aac aca ctc ttc aag 144
Ser Thr Ser Trp Thr Glu Glu Asp Val Asn Asp Asn Thr Leu Phe Lys
35 40 45
tgg atg att ttc aac ggg ggc gcc ccc aac tgc atc ccc tgt aaa gaa 192
Trp Met Ile Phe Asn Gly Gly Ala Pro Asn Cys Ile Pro Cys Lys Glu
50 55 60
acg tgt gag aac gtg gac tgt gga cct ggg aaa aaa tgc cga atg aac 240
Thr Cys Glu Asn Val Asp Cys Gly Pro Gly Lys Lys Cys Arg Met Asn
65 70 75 80
aag aag aac aaa ccc cgc tgc gtc tgc gcc ccg gat tgt tcc aac atc 288
Lys Lys Asn Lys Pro Arg Cys Val Cys Ala Pro Asp Cys Ser Asn Ile
85 90 95
acc tgg aag ggt cca gtc tgc ggg ctg gat ggg aaa acc tac cgc aat 336
Thr Trp Lys Gly Pro Val Cys Gly Leu Asp Gly Lys Thr Tyr Arg Asn
100 105 110
gaa tgt gca ctc cta aag gca aga tgt aaa gag cag cca gaa ctg gaa 384
Glu Cys Ala Leu Leu Lys Ala Arg Cys Lys Glu Gln Pro Glu Leu Glu
115 120 125
gtc cag tac caa ggc aga tgt aaa aag ctt tgt gag aac gtg gac tgt 432
Val Gln Tyr Gln Gly Arg Cys Lys Lys Leu Cys Glu Asn Val Asp Cys
130 135 140
gga cct ggg aaa aaa tgc cga atg aac aag aag aac aaa ccc cgc tgc 480
Gly Pro Gly Lys Lys Cys Arg Met Asn Lys Lys Asn Lys Pro Arg Cys
145 150 155 160
gtc tgc gcc ccg gat tgt tcc aac atc acc tgg aag ggt cca gtc tgc 528
Val Cys Ala Pro Asp Cys Ser Asn Ile Thr Trp Lys Gly Pro Val Cys
165 170 175
ggg ctg gat ggg aaa acc tac cgc aat gaa tgt gca ctc cta aag gca 576
Gly Leu Asp Gly Lys Thr Tyr Arg Asn Glu Cys Ala Leu Leu Lys Ala
180 185 190
aga tgt aaa gag cag cca gaa ctg gaa gtc cag tac caa ggc aga tgt 624
Arg Cys Lys Glu Gln Pro Glu Leu Glu Val Gln Tyr Gln Gly Arg Cys
195 200 205
aaa aag act tgt gaa gat atc tcg agg caa tca cta gag ggc cct att 672
Lys Lys Thr Cys Glu Asp Ile Ser Arg Gln Ser Leu Glu Gly Pro Ile
210 215 220
cta tag 678
Leu
225
<210> 6
<211> 225
<212> PRT
<213> Artificial
<220>
<223> FS-1-1
<400> 6
Gly Asn Cys Trp Leu Arg Gln Ala Lys Asn Gly Arg Cys Gln Val Leu
1 5 10 15
Tyr Lys Thr Glu Leu Ser Lys Glu Glu Cys Cys Ser Thr Gly Arg Leu
20 25 30
Ser Thr Ser Trp Thr Glu Glu Asp Val Asn Asp Asn Thr Leu Phe Lys
35 40 45
Trp Met Ile Phe Asn Gly Gly Ala Pro Asn Cys Ile Pro Cys Lys Glu
50 55 60
Thr Cys Glu Asn Val Asp Cys Gly Pro Gly Lys Lys Cys Arg Met Asn
65 70 75 80
Lys Lys Asn Lys Pro Arg Cys Val Cys Ala Pro Asp Cys Ser Asn Ile
85 90 95
Thr Trp Lys Gly Pro Val Cys Gly Leu Asp Gly Lys Thr Tyr Arg Asn
100 105 110
Glu Cys Ala Leu Leu Lys Ala Arg Cys Lys Glu Gln Pro Glu Leu Glu
115 120 125
Val Gln Tyr Gln Gly Arg Cys Lys Lys Leu Cys Glu Asn Val Asp Cys
130 135 140
Gly Pro Gly Lys Lys Cys Arg Met Asn Lys Lys Asn Lys Pro Arg Cys
145 150 155 160
Val Cys Ala Pro Asp Cys Ser Asn Ile Thr Trp Lys Gly Pro Val Cys
165 170 175
Gly Leu Asp Gly Lys Thr Tyr Arg Asn Glu Cys Ala Leu Leu Lys Ala
180 185 190
Arg Cys Lys Glu Gln Pro Glu Leu Glu Val Gln Tyr Gln Gly Arg Cys
195 200 205
Lys Lys Thr Cys Glu Asp Ile Ser Arg Gln Ser Leu Glu Gly Pro Ile
210 215 220
Leu
225
<210> 7
<211> 480
<212> DNA
<213> Artificial
<220>
<223> FS-1
<220>
<221> CDS
<222> (1)..(480)
<400> 7
ggg aac tgc tgg ctc cgt caa gcg aag aac ggc cgc tgc cag gtc ctg 48
Gly Asn Cys Trp Leu Arg Gln Ala Lys Asn Gly Arg Cys Gln Val Leu
1 5 10 15
tac aag acc gaa ctg agc aag gag gag tgc tgc agc acc ggc cgg ctg 96
Tyr Lys Thr Glu Leu Ser Lys Glu Glu Cys Cys Ser Thr Gly Arg Leu
20 25 30
agc acc tcg tgg acc gag gag gac gtg aat gac aac aca ctc ttc aag 144
Ser Thr Ser Trp Thr Glu Glu Asp Val Asn Asp Asn Thr Leu Phe Lys
35 40 45
tgg atg att ttc aac ggg ggc gcc ccc aac tgc atc ccc tgt aaa gaa 192
Trp Met Ile Phe Asn Gly Gly Ala Pro Asn Cys Ile Pro Cys Lys Glu
50 55 60
acg tgt gag aac gtg gac tgt gga cct ggg aaa aaa tgc cga atg aac 240
Thr Cys Glu Asn Val Asp Cys Gly Pro Gly Lys Lys Cys Arg Met Asn
65 70 75 80
aag aag aac aaa ccc cgc tgc gtc tgc gcc ccg gat tgt tcc aac atc 288
Lys Lys Asn Lys Pro Arg Cys Val Cys Ala Pro Asp Cys Ser Asn Ile
85 90 95
acc tgg aag ggt cca gtc tgc ggg ctg gat ggg aaa acc tac cgc aat 336
Thr Trp Lys Gly Pro Val Cys Gly Leu Asp Gly Lys Thr Tyr Arg Asn
100 105 110
gaa tgt gca ctc cta aag gca aga tgt aaa gag cag cca gaa ctg gaa 384
Glu Cys Ala Leu Leu Lys Ala Arg Cys Lys Glu Gln Pro Glu Leu Glu
115 120 125
gtc cag tac caa ggc aga tgt aaa aag ctt atc gat acc gtc gac ctc 432
Val Gln Tyr Gln Gly Arg Cys Lys Lys Leu Ile Asp Thr Val Asp Leu
130 135 140
gag cat gca tct aga ggg ccc tat tct ata gtg tca cct aaa tgc tag 480
Glu His Ala Ser Arg Gly Pro Tyr Ser Ile Val Ser Pro Lys Cys
145 150 155
<210> 8
<211> 159
<212> PRT
<213> Artificial
<220>
<223> FS-1
<400> 8
Gly Asn Cys Trp Leu Arg Gln Ala Lys Asn Gly Arg Cys Gln Val Leu
1 5 10 15
Tyr Lys Thr Glu Leu Ser Lys Glu Glu Cys Cys Ser Thr Gly Arg Leu
20 25 30
Ser Thr Ser Trp Thr Glu Glu Asp Val Asn Asp Asn Thr Leu Phe Lys
35 40 45
Trp Met Ile Phe Asn Gly Gly Ala Pro Asn Cys Ile Pro Cys Lys Glu
50 55 60
Thr Cys Glu Asn Val Asp Cys Gly Pro Gly Lys Lys Cys Arg Met Asn
65 70 75 80
Lys Lys Asn Lys Pro Arg Cys Val Cys Ala Pro Asp Cys Ser Asn Ile
85 90 95
Thr Trp Lys Gly Pro Val Cys Gly Leu Asp Gly Lys Thr Tyr Arg Asn
100 105 110
Glu Cys Ala Leu Leu Lys Ala Arg Cys Lys Glu Gln Pro Glu Leu Glu
115 120 125
Val Gln Tyr Gln Gly Arg Cys Lys Lys Leu Ile Asp Thr Val Asp Leu
130 135 140
Glu His Ala Ser Arg Gly Pro Tyr Ser Ile Val Ser Pro Lys Cys
145 150 155
<210> 9
<211> 936
<212> DNA
<213> Artificial
<220>
<223> FS-1-1-3
<220>
<221> CDS
<222> (1)..(936)
<400> 9
ggg aac tgc tgg ctc cgt caa gcg aag aac ggc cgc tgc cag gtc ctg 48
Gly Asn Cys Trp Leu Arg Gln Ala Lys Asn Gly Arg Cys Gln Val Leu
1 5 10 15
tac aag acc gaa ctg agc aag gag gag tgc tgc agc acc ggc cgg ctg 96
Tyr Lys Thr Glu Leu Ser Lys Glu Glu Cys Cys Ser Thr Gly Arg Leu
20 25 30
agc acc tcg tgg acc gag gag gac gtg aat gac aac aca ctc ttc aag 144
Ser Thr Ser Trp Thr Glu Glu Asp Val Asn Asp Asn Thr Leu Phe Lys
35 40 45
tgg atg att ttc aac ggg ggc gcc ccc aac tgc atc ccc tgt aaa gaa 192
Trp Met Ile Phe Asn Gly Gly Ala Pro Asn Cys Ile Pro Cys Lys Glu
50 55 60
acg tgt gag aac gtg gac tgt gga cct ggg aaa aaa tgc cga atg aac 240
Thr Cys Glu Asn Val Asp Cys Gly Pro Gly Lys Lys Cys Arg Met Asn
65 70 75 80
aag aag aac aaa ccc cgc tgc gtc tgc gcc ccg gat tgt tcc aac atc 288
Lys Lys Asn Lys Pro Arg Cys Val Cys Ala Pro Asp Cys Ser Asn Ile
85 90 95
acc tgg aag ggt cca gtc tgc ggg ctg gat ggg aaa acc tac cgc aat 336
Thr Trp Lys Gly Pro Val Cys Gly Leu Asp Gly Lys Thr Tyr Arg Asn
100 105 110
gaa tgt gca ctc cta aag gca aga tgt aaa gag cag cca gaa ctg gaa 384
Glu Cys Ala Leu Leu Lys Ala Arg Cys Lys Glu Gln Pro Glu Leu Glu
115 120 125
gtc cag tac caa ggc aga tgt aaa aag ctt tgt gag aac gtg gac tgt 432
Val Gln Tyr Gln Gly Arg Cys Lys Lys Leu Cys Glu Asn Val Asp Cys
130 135 140
gga cct ggg aaa aaa tgc cga atg aac aag aag aac aaa ccc cgc tgc 480
Gly Pro Gly Lys Lys Cys Arg Met Asn Lys Lys Asn Lys Pro Arg Cys
145 150 155 160
gtc tgc gcc ccg gat tgt tcc aac atc acc tgg aag ggt cca gtc tgc 528
Val Cys Ala Pro Asp Cys Ser Asn Ile Thr Trp Lys Gly Pro Val Cys
165 170 175
ggg ctg gat ggg aaa acc tac cgc aat gaa tgt gca ctc cta aag gca 576
Gly Leu Asp Gly Lys Thr Tyr Arg Asn Glu Cys Ala Leu Leu Lys Ala
180 185 190
aga tgt aaa gag cag cca gaa ctg gaa gtc cag tac caa ggc aga tgt 624
Arg Cys Lys Glu Gln Pro Glu Leu Glu Val Gln Tyr Gln Gly Arg Cys
195 200 205
aaa aag act tgt gaa gat atc cag tgc act ggt ggg aaa aaa tgt tta 672
Lys Lys Thr Cys Glu Asp Ile Gln Cys Thr Gly Gly Lys Lys Cys Leu
210 215 220
tgg gat ttc aag gtt ggg aga ggc cgg tgt tcc ctc tgt gat gag ctg 720
Trp Asp Phe Lys Val Gly Arg Gly Arg Cys Ser Leu Cys Asp Glu Leu
225 230 235 240
tgc cct gac agt aag tcg gat gag cct gtc tgt gcc agt gac aat gcc 768
Cys Pro Asp Ser Lys Ser Asp Glu Pro Val Cys Ala Ser Asp Asn Ala
245 250 255
act tat gcc agc gag tgt gcc atg aag gaa gct gcc tgc tcc tca ggt 816
Thr Tyr Ala Ser Glu Cys Ala Met Lys Glu Ala Ala Cys Ser Ser Gly
260 265 270
gtg cta ctg gaa gta aag cac tcc gga tct tgc aac tcc att tcg gaa 864
Val Leu Leu Glu Val Lys His Ser Gly Ser Cys Asn Ser Ile Ser Glu
275 280 285
gac acc gag gaa gag gag gaa gat gaa gac cag gac tac agc ttt cct 912
Asp Thr Glu Glu Glu Glu Glu Asp Glu Asp Gln Asp Tyr Ser Phe Pro
290 295 300
ata tct tct att cta gag tgg taa 936
Ile Ser Ser Ile Leu Glu Trp
305 310
<210> 10
<211> 311
<212> PRT
<213> Artificial
<220>
<223> FS-1-1-3
<400> 10
Gly Asn Cys Trp Leu Arg Gln Ala Lys Asn Gly Arg Cys Gln Val Leu
1 5 10 15
Tyr Lys Thr Glu Leu Ser Lys Glu Glu Cys Cys Ser Thr Gly Arg Leu
20 25 30
Ser Thr Ser Trp Thr Glu Glu Asp Val Asn Asp Asn Thr Leu Phe Lys
35 40 45
Trp Met Ile Phe Asn Gly Gly Ala Pro Asn Cys Ile Pro Cys Lys Glu
50 55 60
Thr Cys Glu Asn Val Asp Cys Gly Pro Gly Lys Lys Cys Arg Met Asn
65 70 75 80
Lys Lys Asn Lys Pro Arg Cys Val Cys Ala Pro Asp Cys Ser Asn Ile
85 90 95
Thr Trp Lys Gly Pro Val Cys Gly Leu Asp Gly Lys Thr Tyr Arg Asn
100 105 110
Glu Cys Ala Leu Leu Lys Ala Arg Cys Lys Glu Gln Pro Glu Leu Glu
115 120 125
Val Gln Tyr Gln Gly Arg Cys Lys Lys Leu Cys Glu Asn Val Asp Cys
130 135 140
Gly Pro Gly Lys Lys Cys Arg Met Asn Lys Lys Asn Lys Pro Arg Cys
145 150 155 160
Val Cys Ala Pro Asp Cys Ser Asn Ile Thr Trp Lys Gly Pro Val Cys
165 170 175
Gly Leu Asp Gly Lys Thr Tyr Arg Asn Glu Cys Ala Leu Leu Lys Ala
180 185 190
Arg Cys Lys Glu Gln Pro Glu Leu Glu Val Gln Tyr Gln Gly Arg Cys
195 200 205
Lys Lys Thr Cys Glu Asp Ile Gln Cys Thr Gly Gly Lys Lys Cys Leu
210 215 220
Trp Asp Phe Lys Val Gly Arg Gly Arg Cys Ser Leu Cys Asp Glu Leu
225 230 235 240
Cys Pro Asp Ser Lys Ser Asp Glu Pro Val Cys Ala Ser Asp Asn Ala
245 250 255
Thr Tyr Ala Ser Glu Cys Ala Met Lys Glu Ala Ala Cys Ser Ser Gly
260 265 270
Val Leu Leu Glu Val Lys His Ser Gly Ser Cys Asn Ser Ile Ser Glu
275 280 285
Asp Thr Glu Glu Glu Glu Glu Asp Glu Asp Gln Asp Tyr Ser Phe Pro
290 295 300
Ile Ser Ser Ile Leu Glu Trp
305 310
<210> 11
<211> 27
<212> DNA
<213> Artificial
<220>
<223> primer for fragment A
<400> 11
gcaagctttg tgagaacgtg gactgtg 27
<210> 12
<211> 37
<212> DNA
<213> Artificial
<220>
<223> primer for fragment A
<400> 12
gcctcgagat atcttcacaa gtctttttac atctgcc 37
<210> 13
<211> 29
<212> DNA
<213> Artificial
<220>
<223> primer for fragment B
<400> 13
cggaattcat ggtccgcgcg aggcaccag 29
<210> 14
<211> 24
<212> DNA
<213> Artificial
<220>
<223> primer for fragment B
<400> 14
cgaagctttt tacatctgcc ttgg 24
<210> 15
<211> 765
<212> DNA
<213> Artificial
<220>
<223> FS-1-1 with signal peptide
<220>
<221> CDS
<222> (1)..(765)
<220>
<221> sig peptide
<222> (1)..(87)
<400> 15
atg gtc cgc gcg agg cac cag ccg ggt ggg ctt tgc ctc ctg ctg ctg 48
Met Val Arg Ala Arg His Gln Pro Gly Gly Leu Cys Leu Leu Leu Leu
1 5 10 15
ctg ctc tgc cag ttc atg gag gac cgc agt gcc cag gct ggg aac tgc 96
Leu Leu Cys Gln Phe Met Glu Asp Arg Ser Ala Gln Ala Gly Asn Cys
20 25 30
tgg ctc cgt caa gcg aag aac ggc cgc tgc cag gtc ctg tac aag acc 144
Trp Leu Arg Gln Ala Lys Asn Gly Arg Cys Gln Val Leu Tyr Lys Thr
35 40 45
gaa ctg agc aag gag gag tgc tgc agc acc ggc cgg ctg agc acc tcg 192
Glu Leu Ser Lys Glu Glu Cys Cys Ser Thr Gly Arg Leu Ser Thr Ser
50 55 60
tgg acc gag gag gac gtg aat gac aac aca ctc ttc aag tgg atg att 240
Trp Thr Glu Glu Asp Val Asn Asp Asn Thr Leu Phe Lys Trp Met Ile
65 70 75 80
ttc aac ggg ggc gcc ccc aac tgc atc ccc tgt aaa gaa acg tgt gag 288
Phe Asn Gly Gly Ala Pro Asn Cys Ile Pro Cys Lys Glu Thr Cys Glu
85 90 95
aac gtg gac tgt gga cct ggg aaa aaa tgc cga atg aac aag aag aac 336
Asn Val Asp Cys Gly Pro Gly Lys Lys Cys Arg Met Asn Lys Lys Asn
100 105 110
aaa ccc cgc tgc gtc tgc gcc ccg gat tgt tcc aac atc acc tgg aag 384
Lys Pro Arg Cys Val Cys Ala Pro Asp Cys Ser Asn Ile Thr Trp Lys
115 120 125
ggt cca gtc tgc ggg ctg gat ggg aaa acc tac cgc aat gaa tgt gca 432
Gly Pro Val Cys Gly Leu Asp Gly Lys Thr Tyr Arg Asn Glu Cys Ala
130 135 140
ctc cta aag gca aga tgt aaa gag cag cca gaa ctg gaa gtc cag tac 480
Leu Leu Lys Ala Arg Cys Lys Glu Gln Pro Glu Leu Glu Val Gln Tyr
145 150 155 160
caa ggc aga tgt aaa aag ctt tgt gag aac gtg gac tgt gga cct ggg 528
Gln Gly Arg Cys Lys Lys Leu Cys Glu Asn Val Asp Cys Gly Pro Gly
165 170 175
aaa aaa tgc cga atg aac aag aag aac aaa ccc cgc tgc gtc tgc gcc 576
Lys Lys Cys Arg Met Asn Lys Lys Asn Lys Pro Arg Cys Val Cys Ala
180 185 190
ccg gat tgt tcc aac atc acc tgg aag ggt cca gtc tgc ggg ctg gat 624
Pro Asp Cys Ser Asn Ile Thr Trp Lys Gly Pro Val Cys Gly Leu Asp
195 200 205
ggg aaa acc tac cgc aat gaa tgt gca ctc cta aag gca aga tgt aaa 672
Gly Lys Thr Tyr Arg Asn Glu Cys Ala Leu Leu Lys Ala Arg Cys Lys
210 215 220
gag cag cca gaa ctg gaa gtc cag tac caa ggc aga tgt aaa aag act 720
Glu Gln Pro Glu Leu Glu Val Gln Tyr Gln Gly Arg Cys Lys Lys Thr
225 230 235 240
tgt gaa gat atc tcg agg caa tca cta gag ggc cct att cta tag 765
Cys Glu Asp Ile Ser Arg Gln Ser Leu Glu Gly Pro Ile Leu
245 250
<210> 16
<211> 254
<212> PRT
<213> Artificial
<220>
<223> FS-1-1 with signal peptide
<220>
<221> SIGNAL
<222> (1)..(29)
<400> 16
Met Val Arg Ala Arg His Gln Pro Gly Gly Leu Cys Leu Leu Leu Leu
1 5 10 15
Leu Leu Cys Gln Phe Met Glu Asp Arg Ser Ala Gln Ala Gly Asn Cys
20 25 30
Trp Leu Arg Gln Ala Lys Asn Gly Arg Cys Gln Val Leu Tyr Lys Thr
35 40 45
Glu Leu Ser Lys Glu Glu Cys Cys Ser Thr Gly Arg Leu Ser Thr Ser
50 55 60
Trp Thr Glu Glu Asp Val Asn Asp Asn Thr Leu Phe Lys Trp Met Ile
65 70 75 80
Phe Asn Gly Gly Ala Pro Asn Cys Ile Pro Cys Lys Glu Thr Cys Glu
85 90 95
Asn Val Asp Cys Gly Pro Gly Lys Lys Cys Arg Met Asn Lys Lys Asn
100 105 110
Lys Pro Arg Cys Val Cys Ala Pro Asp Cys Ser Asn Ile Thr Trp Lys
115 120 125
Gly Pro Val Cys Gly Leu Asp Gly Lys Thr Tyr Arg Asn Glu Cys Ala
130 135 140
Leu Leu Lys Ala Arg Cys Lys Glu Gln Pro Glu Leu Glu Val Gln Tyr
145 150 155 160
Gln Gly Arg Cys Lys Lys Leu Cys Glu Asn Val Asp Cys Gly Pro Gly
165 170 175
Lys Lys Cys Arg Met Asn Lys Lys Asn Lys Pro Arg Cys Val Cys Ala
180 185 190
Pro Asp Cys Ser Asn Ile Thr Trp Lys Gly Pro Val Cys Gly Leu Asp
195 200 205
Gly Lys Thr Tyr Arg Asn Glu Cys Ala Leu Leu Lys Ala Arg Cys Lys
210 215 220
Glu Gln Pro Glu Leu Glu Val Gln Tyr Gln Gly Arg Cys Lys Lys Thr
225 230 235 240
Cys Glu Asp Ile Ser Arg Gln Ser Leu Glu Gly Pro Ile Leu
245 250
<210> 17
<211> 567
<212> DNA
<213> Artificial
<220>
<223> FS-1 with signal peptide
<220>
<221> CDS
<222> (1)..(567)
<220>
<221> sig peptide
<222> (1)..(87)
<400> 17
atg gtc cgc gcg agg cac cag ccg ggt ggg ctt tgc ctc ctg ctg ctg 48
Met Val Arg Ala Arg His Gln Pro Gly Gly Leu Cys Leu Leu Leu Leu
1 5 10 15
ctg ctc tgc cag ttc atg gag gac cgc agt gcc cag gct ggg aac tgc 96
Leu Leu Cys Gln Phe Met Glu Asp Arg Ser Ala Gln Ala Gly Asn Cys
20 25 30
tgg ctc cgt caa gcg aag aac ggc cgc tgc cag gtc ctg tac aag acc 144
Trp Leu Arg Gln Ala Lys Asn Gly Arg Cys Gln Val Leu Tyr Lys Thr
35 40 45
gaa ctg agc aag gag gag tgc tgc agc acc ggc cgg ctg agc acc tcg 192
Glu Leu Ser Lys Glu Glu Cys Cys Ser Thr Gly Arg Leu Ser Thr Ser
50 55 60
tgg acc gag gag gac gtg aat gac aac aca ctc ttc aag tgg atg att 240
Trp Thr Glu Glu Asp Val Asn Asp Asn Thr Leu Phe Lys Trp Met Ile
65 70 75 80
ttc aac ggg ggc gcc ccc aac tgc atc ccc tgt aaa gaa acg tgt gag 288
Phe Asn Gly Gly Ala Pro Asn Cys Ile Pro Cys Lys Glu Thr Cys Glu
85 90 95
aac gtg gac tgt gga cct ggg aaa aaa tgc cga atg aac aag aag aac 336
Asn Val Asp Cys Gly Pro Gly Lys Lys Cys Arg Met Asn Lys Lys Asn
100 105 110
aaa ccc cgc tgc gtc tgc gcc ccg gat tgt tcc aac atc acc tgg aag 384
Lys Pro Arg Cys Val Cys Ala Pro Asp Cys Ser Asn Ile Thr Trp Lys
115 120 125
ggt cca gtc tgc ggg ctg gat ggg aaa acc tac cgc aat gaa tgt gca 432
Gly Pro Val Cys Gly Leu Asp Gly Lys Thr Tyr Arg Asn Glu Cys Ala
130 135 140
ctc cta aag gca aga tgt aaa gag cag cca gaa ctg gaa gtc cag tac 480
Leu Leu Lys Ala Arg Cys Lys Glu Gln Pro Glu Leu Glu Val Gln Tyr
145 150 155 160
caa ggc aga tgt aaa aag ctt atc gat acc gtc gac ctc gag cat gca 528
Gln Gly Arg Cys Lys Lys Leu Ile Asp Thr Val Asp Leu Glu His Ala
165 170 175
tct aga ggg ccc tat tct ata gtg tca cct aaa tgc tag 567
Ser Arg Gly Pro Tyr Ser Ile Val Ser Pro Lys Cys
180 185
<210> 18
<211> 188
<212> PRT
<213> Artificial
<220>
<223> FS-1 with signal peptide
<220>
<221> SIGNAL
<222> (1)..(29)
<400> 18
Met Val Arg Ala Arg His Gln Pro Gly Gly Leu Cys Leu Leu Leu Leu
1 5 10 15
Leu Leu Cys Gln Phe Met Glu Asp Arg Ser Ala Gln Ala Gly Asn Cys
20 25 30
Trp Leu Arg Gln Ala Lys Asn Gly Arg Cys Gln Val Leu Tyr Lys Thr
35 40 45
Glu Leu Ser Lys Glu Glu Cys Cys Ser Thr Gly Arg Leu Ser Thr Ser
50 55 60
Trp Thr Glu Glu Asp Val Asn Asp Asn Thr Leu Phe Lys Trp Met Ile
65 70 75 80
Phe Asn Gly Gly Ala Pro Asn Cys Ile Pro Cys Lys Glu Thr Cys Glu
85 90 95
Asn Val Asp Cys Gly Pro Gly Lys Lys Cys Arg Met Asn Lys Lys Asn
100 105 110
Lys Pro Arg Cys Val Cys Ala Pro Asp Cys Ser Asn Ile Thr Trp Lys
115 120 125
Gly Pro Val Cys Gly Leu Asp Gly Lys Thr Tyr Arg Asn Glu Cys Ala
130 135 140
Leu Leu Lys Ala Arg Cys Lys Glu Gln Pro Glu Leu Glu Val Gln Tyr
145 150 155 160
Gln Gly Arg Cys Lys Lys Leu Ile Asp Thr Val Asp Leu Glu His Ala
165 170 175
Ser Arg Gly Pro Tyr Ser Ile Val Ser Pro Lys Cys
180 185
<210> 19
<211> 1023
<212> DNA
<213> Artificial
<220>
<223> FS-1-1-3 with signal peptide
<220>
<221> CDS
<222> (1)..(1023)
<220>
<221> sig peptide
<222> (1)..(87)
<400> 19
atg gtc cgc gcg agg cac cag ccg ggt ggg ctt tgc ctc ctg ctg ctg 48
Met Val Arg Ala Arg His Gln Pro Gly Gly Leu Cys Leu Leu Leu Leu
1 5 10 15
ctg ctc tgc cag ttc atg gag gac cgc agt gcc cag gct ggg aac tgc 96
Leu Leu Cys Gln Phe Met Glu Asp Arg Ser Ala Gln Ala Gly Asn Cys
20 25 30
tgg ctc cgt caa gcg aag aac ggc cgc tgc cag gtc ctg tac aag acc 144
Trp Leu Arg Gln Ala Lys Asn Gly Arg Cys Gln Val Leu Tyr Lys Thr
35 40 45
gaa ctg agc aag gag gag tgc tgc agc acc ggc cgg ctg agc acc tcg 192
Glu Leu Ser Lys Glu Glu Cys Cys Ser Thr Gly Arg Leu Ser Thr Ser
50 55 60
tgg acc gag gag gac gtg aat gac aac aca ctc ttc aag tgg atg att 240
Trp Thr Glu Glu Asp Val Asn Asp Asn Thr Leu Phe Lys Trp Met Ile
65 70 75 80
ttc aac ggg ggc gcc ccc aac tgc atc ccc tgt aaa gaa acg tgt gag 288
Phe Asn Gly Gly Ala Pro Asn Cys Ile Pro Cys Lys Glu Thr Cys Glu
85 90 95
aac gtg gac tgt gga cct ggg aaa aaa tgc cga atg aac aag aag aac 336
Asn Val Asp Cys Gly Pro Gly Lys Lys Cys Arg Met Asn Lys Lys Asn
100 105 110
aaa ccc cgc tgc gtc tgc gcc ccg gat tgt tcc aac atc acc tgg aag 384
Lys Pro Arg Cys Val Cys Ala Pro Asp Cys Ser Asn Ile Thr Trp Lys
115 120 125
ggt cca gtc tgc ggg ctg gat ggg aaa acc tac cgc aat gaa tgt gca 432
Gly Pro Val Cys Gly Leu Asp Gly Lys Thr Tyr Arg Asn Glu Cys Ala
130 135 140
ctc cta aag gca aga tgt aaa gag cag cca gaa ctg gaa gtc cag tac 480
Leu Leu Lys Ala Arg Cys Lys Glu Gln Pro Glu Leu Glu Val Gln Tyr
145 150 155 160
caa ggc aga tgt aaa aag ctt tgt gag aac gtg gac tgt gga cct ggg 528
Gln Gly Arg Cys Lys Lys Leu Cys Glu Asn Val Asp Cys Gly Pro Gly
165 170 175
aaa aaa tgc cga atg aac aag aag aac aaa ccc cgc tgc gtc tgc gcc 576
Lys Lys Cys Arg Met Asn Lys Lys Asn Lys Pro Arg Cys Val Cys Ala
180 185 190
ccg gat tgt tcc aac atc acc tgg aag ggt cca gtc tgc ggg ctg gat 624
Pro Asp Cys Ser Asn Ile Thr Trp Lys Gly Pro Val Cys Gly Leu Asp
195 200 205
ggg aaa acc tac cgc aat gaa tgt gca ctc cta aag gca aga tgt aaa 672
Gly Lys Thr Tyr Arg Asn Glu Cys Ala Leu Leu Lys Ala Arg Cys Lys
210 215 220
gag cag cca gaa ctg gaa gtc cag tac caa ggc aga tgt aaa aag act 720
Glu Gln Pro Glu Leu Glu Val Gln Tyr Gln Gly Arg Cys Lys Lys Thr
225 230 235 240
tgt gaa gat atc cag tgc act ggt ggg aaa aaa tgt tta tgg gat ttc 768
Cys Glu Asp Ile Gln Cys Thr Gly Gly Lys Lys Cys Leu Trp Asp Phe
245 250 255
aag gtt ggg aga ggc cgg tgt tcc ctc tgt gat gag ctg tgc cct gac 816
Lys Val Gly Arg Gly Arg Cys Ser Leu Cys Asp Glu Leu Cys Pro Asp
260 265 270
agt aag tcg gat gag cct gtc tgt gcc agt gac aat gcc act tat gcc 864
Ser Lys Ser Asp Glu Pro Val Cys Ala Ser Asp Asn Ala Thr Tyr Ala
275 280 285
agc gag tgt gcc atg aag gaa gct gcc tgc tcc tca ggt gtg cta ctg 912
Ser Glu Cys Ala Met Lys Glu Ala Ala Cys Ser Ser Gly Val Leu Leu
290 295 300
gaa gta aag cac tcc gga tct tgc aac tcc att tcg gaa gac acc gag 960
Glu Val Lys His Ser Gly Ser Cys Asn Ser Ile Ser Glu Asp Thr Glu
305 310 315 320
gaa gag gag gaa gat gaa gac cag gac tac agc ttt cct ata tct tct 1008
Glu Glu Glu Glu Asp Glu Asp Gln Asp Tyr Ser Phe Pro Ile Ser Ser
325 330 335
att cta gag tgg taa 1023
Ile Leu Glu Trp
340
<210> 20
<211> 340
<212> PRT
<213> Artificial
<220>
<223> FS-1-1-3 with signal peptide
<220>
<221> SIGNAL
<222> (1)..(29)
<400> 20
Met Val Arg Ala Arg His Gln Pro Gly Gly Leu Cys Leu Leu Leu Leu
1 5 10 15
Leu Leu Cys Gln Phe Met Glu Asp Arg Ser Ala Gln Ala Gly Asn Cys
20 25 30
Trp Leu Arg Gln Ala Lys Asn Gly Arg Cys Gln Val Leu Tyr Lys Thr
35 40 45
Glu Leu Ser Lys Glu Glu Cys Cys Ser Thr Gly Arg Leu Ser Thr Ser
50 55 60
Trp Thr Glu Glu Asp Val Asn Asp Asn Thr Leu Phe Lys Trp Met Ile
65 70 75 80
Phe Asn Gly Gly Ala Pro Asn Cys Ile Pro Cys Lys Glu Thr Cys Glu
85 90 95
Asn Val Asp Cys Gly Pro Gly Lys Lys Cys Arg Met Asn Lys Lys Asn
100 105 110
Lys Pro Arg Cys Val Cys Ala Pro Asp Cys Ser Asn Ile Thr Trp Lys
115 120 125
Gly Pro Val Cys Gly Leu Asp Gly Lys Thr Tyr Arg Asn Glu Cys Ala
130 135 140
Leu Leu Lys Ala Arg Cys Lys Glu Gln Pro Glu Leu Glu Val Gln Tyr
145 150 155 160
Gln Gly Arg Cys Lys Lys Leu Cys Glu Asn Val Asp Cys Gly Pro Gly
165 170 175
Lys Lys Cys Arg Met Asn Lys Lys Asn Lys Pro Arg Cys Val Cys Ala
180 185 190
Pro Asp Cys Ser Asn Ile Thr Trp Lys Gly Pro Val Cys Gly Leu Asp
195 200 205
Gly Lys Thr Tyr Arg Asn Glu Cys Ala Leu Leu Lys Ala Arg Cys Lys
210 215 220
Glu Gln Pro Glu Leu Glu Val Gln Tyr Gln Gly Arg Cys Lys Lys Thr
225 230 235 240
Cys Glu Asp Ile Gln Cys Thr Gly Gly Lys Lys Cys Leu Trp Asp Phe
245 250 255
Lys Val Gly Arg Gly Arg Cys Ser Leu Cys Asp Glu Leu Cys Pro Asp
260 265 270
Ser Lys Ser Asp Glu Pro Val Cys Ala Ser Asp Asn Ala Thr Tyr Ala
275 280 285
Ser Glu Cys Ala Met Lys Glu Ala Ala Cys Ser Ser Gly Val Leu Leu
290 295 300
Glu Val Lys His Ser Gly Ser Cys Asn Ser Ile Ser Glu Asp Thr Glu
305 310 315 320
Glu Glu Glu Glu Asp Glu Asp Gln Asp Tyr Ser Phe Pro Ile Ser Ser
325 330 335
Ile Leu Glu Trp
340
<210> 21
<211> 24
<212> DNA
<213> Artificial
<220>
<223> primer for fragment D
<400> 21
ccggaattct gtcaaaagtc ttgc 24
<210> 22
<211> 39
<212> DNA
<213> Artificial
<220>
<223> primer for fragment D
<400> 22
ccggaattcc tcgagtcaca cgaagttctc ttcctcctc 39
<210> 23
<211> 1017
<212> DNA
<213> Artificial
<220>
<223> FS-1-1-2' with signal peptide
<220>
<221> CDS
<222> (1)..(1017)
<220>
<221> sig peptide
<222> (1)..(87)
<400> 23
atg gtc cgc gcg agg cac cag ccg ggt ggg ctt tgc ctc ctg ctg ctg 48
Met Val Arg Ala Arg His Gln Pro Gly Gly Leu Cys Leu Leu Leu Leu
1 5 10 15
ctg ctc tgc cag ttc atg gag gac cgc agt gcc cag gct ggg aac tgc 96
Leu Leu Cys Gln Phe Met Glu Asp Arg Ser Ala Gln Ala Gly Asn Cys
20 25 30
tgg ctc cgt caa gcg aag aac ggc cgc tgc cag gtc ctg tac aag acc 144
Trp Leu Arg Gln Ala Lys Asn Gly Arg Cys Gln Val Leu Tyr Lys Thr
35 40 45
gaa ctg agc aag gag gag tgc tgc agc acc ggc cgg ctg agc acc tcg 192
Glu Leu Ser Lys Glu Glu Cys Cys Ser Thr Gly Arg Leu Ser Thr Ser
50 55 60
tgg acc gag gag gac gtg aat gac aac aca ctc ttc aag tgg atg att 240
Trp Thr Glu Glu Asp Val Asn Asp Asn Thr Leu Phe Lys Trp Met Ile
65 70 75 80
ttc aac ggg ggc gcc ccc aac tgc atc ccc tgt aaa gaa acg tgt gag 288
Phe Asn Gly Gly Ala Pro Asn Cys Ile Pro Cys Lys Glu Thr Cys Glu
85 90 95
aac gtg gac tgt gga cct ggg aaa aaa tgc cga atg aac aag aag aac 336
Asn Val Asp Cys Gly Pro Gly Lys Lys Cys Arg Met Asn Lys Lys Asn
100 105 110
aaa ccc cgc tgc gtc tgc gcc ccg gat tgt tcc aac atc acc tgg aag 384
Lys Pro Arg Cys Val Cys Ala Pro Asp Cys Ser Asn Ile Thr Trp Lys
115 120 125
ggt cca gtc tgc ggg ctg gat ggg aaa acc tac cgc aat gaa tgt gca 432
Gly Pro Val Cys Gly Leu Asp Gly Lys Thr Tyr Arg Asn Glu Cys Ala
130 135 140
ctc cta aag gca aga tgt aaa gag cag cca gaa ctg gaa gtc cag tac 480
Leu Leu Lys Ala Arg Cys Lys Glu Gln Pro Glu Leu Glu Val Gln Tyr
145 150 155 160
caa ggc aga tgt aaa aag ctt tgt gag aac gtg gac tgt gga cct ggg 528
Gln Gly Arg Cys Lys Lys Leu Cys Glu Asn Val Asp Cys Gly Pro Gly
165 170 175
aaa aaa tgc cga atg aac aag aag aac aaa ccc cgc tgc gtc tgc gcc 576
Lys Lys Cys Arg Met Asn Lys Lys Asn Lys Pro Arg Cys Val Cys Ala
180 185 190
ccg gat tgt tcc aac atc acc tgg aag ggt cca gtc tgc ggg ctg gat 624
Pro Asp Cys Ser Asn Ile Thr Trp Lys Gly Pro Val Cys Gly Leu Asp
195 200 205
ggg aaa acc tac cgc aat gaa tgt gca ctc cta aag gca aga tgt aaa 672
Gly Lys Thr Tyr Arg Asn Glu Cys Ala Leu Leu Lys Ala Arg Cys Lys
210 215 220
gag cag cca gaa ctg gaa gtc cag tac caa ggc aga tgt aaa aag act 720
Glu Gln Pro Glu Leu Glu Val Gln Tyr Gln Gly Arg Cys Lys Lys Thr
225 230 235 240
tgt gaa gat atc gaa ttc tgt caa aag tct tgc gct cag gta gtg tgc 768
Cys Glu Asp Ile Glu Phe Cys Gln Lys Ser Cys Ala Gln Val Val Cys
245 250 255
ccg cgt ccc cag tcg tgc ctt gtg gat cag acc ggc agc gca cac tgc 816
Pro Arg Pro Gln Ser Cys Leu Val Asp Gln Thr Gly Ser Ala His Cys
260 265 270
gtg gtg tgt cgc gct gcg ccc tgc cca gta cct tcc aac ccc ggc caa 864
Val Val Cys Arg Ala Ala Pro Cys Pro Val Pro Ser Asn Pro Gly Gln
275 280 285
gaa ctc tgt ggc aac aac aac gtt acc tac atc tcg tcg tgt cac ctg 912
Glu Leu Cys Gly Asn Asn Asn Val Thr Tyr Ile Ser Ser Cys His Leu
290 295 300
cgc cag gcc act tgc ttc ctg ggc cgc tcc att ggg gtt cgg cac cca 960
Arg Gln Ala Thr Cys Phe Leu Gly Arg Ser Ile Gly Val Arg His Pro
305 310 315 320
ggc atc tgc aca ggt ggc ccc aaa gta cca gca gag gag gaa gag aac 1008
Gly Ile Cys Thr Gly Gly Pro Lys Val Pro Ala Glu Glu Glu Glu Asn
325 330 335
ttc gtg tga 1017
Phe Val
<210> 24
<211> 338
<212> PRT
<213> Artificial
<220>
<223> FS-1-1-2' with signal peptide
<220>
<221> SIGNAL
<222> (1)..(29)
<400> 24
Met Val Arg Ala Arg His Gln Pro Gly Gly Leu Cys Leu Leu Leu Leu
1 5 10 15
Leu Leu Cys Gln Phe Met Glu Asp Arg Ser Ala Gln Ala Gly Asn Cys
20 25 30
Trp Leu Arg Gln Ala Lys Asn Gly Arg Cys Gln Val Leu Tyr Lys Thr
35 40 45
Glu Leu Ser Lys Glu Glu Cys Cys Ser Thr Gly Arg Leu Ser Thr Ser
50 55 60
Trp Thr Glu Glu Asp Val Asn Asp Asn Thr Leu Phe Lys Trp Met Ile
65 70 75 80
Phe Asn Gly Gly Ala Pro Asn Cys Ile Pro Cys Lys Glu Thr Cys Glu
85 90 95
Asn Val Asp Cys Gly Pro Gly Lys Lys Cys Arg Met Asn Lys Lys Asn
100 105 110
Lys Pro Arg Cys Val Cys Ala Pro Asp Cys Ser Asn Ile Thr Trp Lys
115 120 125
Gly Pro Val Cys Gly Leu Asp Gly Lys Thr Tyr Arg Asn Glu Cys Ala
130 135 140
Leu Leu Lys Ala Arg Cys Lys Glu Gln Pro Glu Leu Glu Val Gln Tyr
145 150 155 160
Gln Gly Arg Cys Lys Lys Leu Cys Glu Asn Val Asp Cys Gly Pro Gly
165 170 175
Lys Lys Cys Arg Met Asn Lys Lys Asn Lys Pro Arg Cys Val Cys Ala
180 185 190
Pro Asp Cys Ser Asn Ile Thr Trp Lys Gly Pro Val Cys Gly Leu Asp
195 200 205
Gly Lys Thr Tyr Arg Asn Glu Cys Ala Leu Leu Lys Ala Arg Cys Lys
210 215 220
Glu Gln Pro Glu Leu Glu Val Gln Tyr Gln Gly Arg Cys Lys Lys Thr
225 230 235 240
Cys Glu Asp Ile Glu Phe Cys Gln Lys Ser Cys Ala Gln Val Val Cys
245 250 255
Pro Arg Pro Gln Ser Cys Leu Val Asp Gln Thr Gly Ser Ala His Cys
260 265 270
Val Val Cys Arg Ala Ala Pro Cys Pro Val Pro Ser Asn Pro Gly Gln
275 280 285
Glu Leu Cys Gly Asn Asn Asn Val Thr Tyr Ile Ser Ser Cys His Leu
290 295 300
Arg Gln Ala Thr Cys Phe Leu Gly Arg Ser Ile Gly Val Arg His Pro
305 310 315 320
Gly Ile Cys Thr Gly Gly Pro Lys Val Pro Ala Glu Glu Glu Glu Asn
325 330 335
Phe Val
<210> 25
<211> 309
<212> PRT
<213> Artificial
<220>
<223> FS-1-1-2'
<400> 25
Gly Asn Cys Trp Leu Arg Gln Ala Lys Asn Gly Arg Cys Gln Val Leu
1 5 10 15
Tyr Lys Thr Glu Leu Ser Lys Glu Glu Cys Cys Ser Thr Gly Arg Leu
20 25 30
Ser Thr Ser Trp Thr Glu Glu Asp Val Asn Asp Asn Thr Leu Phe Lys
35 40 45
Trp Met Ile Phe Asn Gly Gly Ala Pro Asn Cys Ile Pro Cys Lys Glu
50 55 60
Thr Cys Glu Asn Val Asp Cys Gly Pro Gly Lys Lys Cys Arg Met Asn
65 70 75 80
Lys Lys Asn Lys Pro Arg Cys Val Cys Ala Pro Asp Cys Ser Asn Ile
85 90 95
Thr Trp Lys Gly Pro Val Cys Gly Leu Asp Gly Lys Thr Tyr Arg Asn
100 105 110
Glu Cys Ala Leu Leu Lys Ala Arg Cys Lys Glu Gln Pro Glu Leu Glu
115 120 125
Val Gln Tyr Gln Gly Arg Cys Lys Lys Leu Cys Glu Asn Val Asp Cys
130 135 140
Gly Pro Gly Lys Lys Cys Arg Met Asn Lys Lys Asn Lys Pro Arg Cys
145 150 155 160
Val Cys Ala Pro Asp Cys Ser Asn Ile Thr Trp Lys Gly Pro Val Cys
165 170 175
Gly Leu Asp Gly Lys Thr Tyr Arg Asn Glu Cys Ala Leu Leu Lys Ala
180 185 190
Arg Cys Lys Glu Gln Pro Glu Leu Glu Val Gln Tyr Gln Gly Arg Cys
195 200 205
Lys Lys Thr Cys Glu Asp Ile Glu Phe Cys Gln Lys Ser Cys Ala Gln
210 215 220
Val Val Cys Pro Arg Pro Gln Ser Cys Leu Val Asp Gln Thr Gly Ser
225 230 235 240
Ala His Cys Val Val Cys Arg Ala Ala Pro Cys Pro Val Pro Ser Asn
245 250 255
Pro Gly Gln Glu Leu Cys Gly Asn Asn Asn Val Thr Tyr Ile Ser Ser
260 265 270
Cys His Leu Arg Gln Ala Thr Cys Phe Leu Gly Arg Ser Ile Gly Val
275 280 285
Arg His Pro Gly Ile Cys Thr Gly Gly Pro Lys Val Pro Ala Glu Glu
290 295 300
Glu Glu Asn Phe Val
305
<210> 26
<211> 12
<212> PRT
<213> Homo sapiens
<400> 26
Glu Gln Pro Glu Leu Glu Val Gln Tyr Gln Gly Arg
1 5 10
<210> 27
<211> 30
<212> DNA
<213> Artificial
<220>
<223> primer for FS1-Fc
<400> 27
aagggtacca tggtccgcgc gaggcaccag 30
<210> 28
<211> 26
<212> DNA
<213> Artificial
<220>
<223> primer for FS1-Fc
<400> 28
tcgggatcca cgcagcgggg tttgtt 26
<210> 29
<211> 73
<212> PRT
<213> Mus musculus
<400> 29
Cys Ala Gln Val Val Cys Pro Arg Pro Gln Ser Cys Leu Val Asp Gln
1 5 10 15
Thr Gly Ser Ala His Cys Val Val Cys Arg Ala Ala Pro Cys Pro Val
20 25 30
Pro Ser Asn Pro Gly Gln Glu Leu Cys Gly Asn Asn Asn Val Thr Tyr
35 40 45
Ile Ser Ser Cys His Leu Arg Gln Ala Thr Cys Phe Leu Gly Arg Ser
50 55 60
Ile Gly Val Arg His Pro Gly Ile Cys
65 70
Claims (25)
- (a)フォリスタチンドメインIを含み、
(b)式(I):Cys−(X1)a−Cys−(X2)b−Cys−(X3)c−Cys−(X4)d−Cys−(X5)e−Cys−(X6)f−Cys−(X7)g−Cys−(X8)h−Cys−(X9)i−Cys(式中、X1、X2、X3、X4、X5、X6、X7、X8およびX9は、それぞれ独立して同一または異なった、システイン以外の天然に存在するアミノ酸残基を表し、aは2〜6、bは3〜7、cは7〜11、dは0〜4、eは1〜6、fおよびgは8〜12、hは4〜8、iは11〜15の整数をそれぞれ表す。)で表されるアミノ酸配列であって、かつ配列番号2または配列番号29のアミノ酸配列と50%以上の相同性を有する配列を含まず、かつ
(c)アクチビンの活性の阻害と比較して、GDF-8の活性を選択的に阻害する、
ことを特徴とするフォリスタチン変異体ポリペプチド。 - フォリスタチンドメインIを含み、フォリスタチンドメインIIを欠失した請求項1に記載のフォリスタチン変異体ポリペプチド。
- さらにフォリスタチンドメインIIIを含まない、請求項1または2に記載のフォリスタチン変異体ポリペプチド。
- 2つ以上のフォリスタチンドメインIを含む、請求項1から3のいずれか1項に記載のフォリスタチン変異体ポリペプチド。
- さらにN末端ドメインを含む、請求項1から4のいずれか1項に記載のフォリスタチン変異体ポリペプチド。
- FSI、FSI−FSI、FSI−FSI−FSIII、FSN−FSI、FSN−FSI−FSI、又はFSN−FSI−FSI−FSIII(ここでFSIはフォリスタチンドメインIを示し、FSIIIはフォリスタチンドメインIIIを示し、FSNはN末端ドメインを示し、各ドメイン間は直接またはリンカーポリペプチドで連結している)から選択されるいずれかのドメイン構造を含む請求項1または2に記載のフォリスタチン変異体ポリペプチド。
- フォリスタチンドメインIが配列番号1のアミノ酸配列からなるポリペプチドである請求項1から6のいずれか1項に記載のフォリスタチン変異体ポリペプチド。
- 配列番号4の30〜166番目のアミノ酸配列を含む、請求項7に記載のフォリスタチン変異体ポリペプチド。
- フォリスタチンのドメインのアミノ酸配列のN末端またはC末端に他のポリペプチドが融合している、請求項1から8の何れか1項に記載のフォリスタチン変異体ポリペプチド。
- 配列番号6、8または10のアミノ酸配列からなるポリペプチド。
- 請求項1から10のいずれか1項に記載のポリペプチドをコードするポリヌクレオチド。
- 配列番号5、7または9の塩基配列を含む請求項11に記載のポリヌクレオチド。
- 請求項11または12に記載のポリヌクレオチドを含むベクター。
- 請求項13に記載のベクターを宿主細胞に導入して得られる形質転換細胞。
- 請求項14に記載の形質転換細胞を培地中で培養し、該細胞で発現した請求項1から10のいずれか1項に記載のポリペプチドを培地または該細胞中に蓄積させ、培地または該細胞から該ポリペプチドを採取することを特徴とする、該ポリペプチドの製造方法。
- 請求項1から10のいずれか1項に記載のポリペプチド、請求項11または12に記載のポリヌクレオチドまたは請求項13に記載のベクターを含有するアクチビンは阻害しないGDF-8選択的な阻害剤。
- 請求項1から10のいずれか1項に記載のポリペプチド、請求項11または12に記載のポリヌクレオチドまたは請求項13に記載のベクターを含有する医薬組成物。
- 請求項1から10のいずれか1項に記載のポリペプチド、請求項11または12に記載のポリヌクレオチドまたは請求項13に記載のベクターを有効成分として含有する、骨格筋増加剤。
- 請求項1から10のいずれか1項に記載のポリペプチド、請求項11または12に記載のポリヌクレオチドまたは請求項13に記載のベクターを有効成分として含有する、脂肪減少剤。
- 請求項1から10のいずれか1項に記載のポリペプチド、請求項11または12に記載のポリヌクレオチドまたは請求項13に記載のベクターを有効成分として含有する、筋萎縮症状の治療剤または予防剤。
- 請求項1から10のいずれか1項に記載のポリペプチド、請求項11または12に記載のポリヌクレオチドまたは請求項13に記載のベクターを有効成分として含有する、悪液質、筋萎縮を伴う疾患、II型糖尿病、肥満または後天性免疫不全症候群の治療剤または予防剤。
- 筋萎縮を伴う疾患が、遺伝性の筋ジストロフィー、筋萎縮性側索硬化症、脊髄小脳変性症またはパーキンソン病である請求項21に記載の治療剤または予防剤。
- 請求項11または12に記載のポリヌクレオチドを含む外来遺伝子を導入したトランスジェニック非ヒト哺乳動物。
- 非ヒト動物に請求項1から10のいずれか1項に記載のポリペプチド、請求項11または12に記載のポリヌクレオチドまたは請求項13に記載のベクターを投与して、該非ヒト動物の筋肉を増加させる方法。
- 非ヒト動物に請求項1から10のいずれか1項に記載のポリペプチド、請求項11または12に記載のポリヌクレオチドまたは請求項13に記載のベクターを投与して、該非ヒト動物の脂肪を減少させる方法。
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JP2004355293A JP4688483B2 (ja) | 2004-04-15 | 2004-12-08 | フォリスタチン変異体ポリペプチド |
EP05734002A EP1748069B1 (en) | 2004-04-15 | 2005-04-15 | Follistatin mutant polypeptide |
CN2005800198613A CN1993463B (zh) | 2004-04-15 | 2005-04-15 | 促滤泡素抑制素突变多肽 |
AT05734002T ATE501250T1 (de) | 2004-04-15 | 2005-04-15 | Mutantes follistatin-polypeptid |
AU2005233474A AU2005233474B2 (en) | 2004-04-15 | 2005-04-15 | Follistatin variant polypeptide |
US11/578,408 US7867973B2 (en) | 2004-04-15 | 2005-04-15 | Follistatin variant polypeptide |
CA002562885A CA2562885A1 (en) | 2004-04-15 | 2005-04-15 | Follistatin variant polypeptide |
KR1020067023962A KR20070039483A (ko) | 2004-04-15 | 2005-04-15 | 폴리스타틴 변이체 폴리펩티드 |
DE602005026796T DE602005026796D1 (de) | 2004-04-15 | 2005-04-15 | Mutantes follistatin-polypeptid |
PCT/JP2005/007662 WO2005100563A1 (ja) | 2004-04-15 | 2005-04-15 | フォリスタチン変異体ポリペプチド |
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EP (1) | EP1748069B1 (ja) |
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KR (1) | KR20070039483A (ja) |
CN (1) | CN1993463B (ja) |
AT (1) | ATE501250T1 (ja) |
AU (1) | AU2005233474B2 (ja) |
CA (1) | CA2562885A1 (ja) |
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JP2016131541A (ja) * | 2015-01-20 | 2016-07-25 | 学校法人藤田学園 | トランスジェニック非ヒト哺乳動物及びその用途 |
JP2021515576A (ja) * | 2018-03-16 | 2021-06-24 | イミュソフト コーポレーション | フォリスタチンを分泌するように遺伝子操作されたb細胞ならびにフォリスタチン関連疾患、状態、障害を処置するために、ならびに筋肉の成長および強度を増強するためにこれを使用する方法 |
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- 2005-04-15 EP EP05734002A patent/EP1748069B1/en not_active Not-in-force
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- 2005-04-15 KR KR1020067023962A patent/KR20070039483A/ko active IP Right Grant
- 2005-04-15 WO PCT/JP2005/007662 patent/WO2005100563A1/ja active Application Filing
- 2005-04-15 DE DE602005026796T patent/DE602005026796D1/de active Active
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Cited By (3)
Publication number | Priority date | Publication date | Assignee | Title |
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JP2016511751A (ja) * | 2013-01-25 | 2016-04-21 | シャイアー ヒューマン ジェネティック セラピーズ インコーポレイテッド | デュシェンヌ筋ジストロフィーの治療におけるフォリスタチン |
JP2016131541A (ja) * | 2015-01-20 | 2016-07-25 | 学校法人藤田学園 | トランスジェニック非ヒト哺乳動物及びその用途 |
JP2021515576A (ja) * | 2018-03-16 | 2021-06-24 | イミュソフト コーポレーション | フォリスタチンを分泌するように遺伝子操作されたb細胞ならびにフォリスタチン関連疾患、状態、障害を処置するために、ならびに筋肉の成長および強度を増強するためにこれを使用する方法 |
Also Published As
Publication number | Publication date |
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WO2005100563A1 (ja) | 2005-10-27 |
CN1993463A (zh) | 2007-07-04 |
US7867973B2 (en) | 2011-01-11 |
DE602005026796D1 (de) | 2011-04-21 |
EP1748069B1 (en) | 2011-03-09 |
KR20070039483A (ko) | 2007-04-12 |
CN1993463B (zh) | 2012-10-03 |
ATE501250T1 (de) | 2011-03-15 |
AU2005233474B2 (en) | 2010-12-09 |
US20080090755A1 (en) | 2008-04-17 |
CA2562885A1 (en) | 2005-10-27 |
JP4688483B2 (ja) | 2011-05-25 |
EP1748069A4 (en) | 2008-04-30 |
AU2005233474A1 (en) | 2005-10-27 |
EP1748069A1 (en) | 2007-01-31 |
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