Shank

2012年5月27日 (日) 11:12時点におけるMarikohayashi (トーク | 投稿記録)による版

Shank


英:Shank (SH3 and multiple ankyrin repeat domains protein)
同義語:ProSAP (Proline-rich synapse-associated protein), CortBP (Cortactin-binding protein), Somatostatin receptor-interacting protein (SSTRIP), GKAP/SAPAP-interacting protein, SPANK, Synamon 

 Shankは、多くの蛋白質と相互作用する2000個以上のアミノ酸からなる巨大な足場蛋白質である.選択的スプライシングによりさまざまな遺伝子産物が得られるが、最も長いものはアンキリンリピート、SH3ドメイン、PDZドメイン、プロリンリッチ配列、SAMドメインからなる.それぞれのドメインが相互作用する蛋白質を持つので、結合蛋白質は多岐にわたる.自閉症との関連が指摘されている. 

Shankの構造


 
図1 Shank ドメイン構造と選択的スプライシング産物



Shankには異なった遺伝子にコードされるShank1、2、3がある.Shankのドメイン構造はアミノ端から、アンキリンリピート、SH3 (Src homology 3)ドメイン、PDZ (PSD-95, Dlg, Zo-1)ドメイン、1000残基以上に及ぶプロリン、セリン、グリシンに富む配列、SAM (Sterile alpha motif)からなる(図1).選択的スプライシングにより、アンキリンリピートやSH3ドメイン、SAMドメインを欠くものもある.

サブタイプ毎の別名は、

  • Shank1=GKAP/SAPAP-interacting protein=SPANK-1=SSTRIP=Synamon
  • Shank2=CortBP1=ProSAP1=SPANK-3
  • Shank3=ProSAP2=SPANK-2


Shankの発現

いずれのサブタイプも脳に広範に発現している.細胞レベルでは、シナプス後部、特にシナプス後肥厚に多く分布している.

脳以外では、Shank2は腎臓、肝臓に、Shank3は心臓、精巣にも発現している.[1]

Shankの機能

Shankを神経細胞に過剰発現するとスパインの肥大化が起こり、特にShank結合蛋白質であるHomerとの共発現はスパインのを更なる肥大化を引き起こす.[2] さらに、本来、スパインを持たない抑制性の小脳顆粒細胞にShankを導入すると、 NMDA型やAMPA型のグルタミン酸受容体をもつスパインを形成するようになる. [3]

Shank分子間のドメイン間相互作用によりオリゴマーを形成するShankと、両端に2つずつのリガンド結合部位をもつ逆平行4量体を形成するHomerは互いに架橋して、高次のネットワーク構造を形成する.このShankとHomerの高次複合体がシナプス後肥厚の骨格となると考えられる. [4]

Shankの分子内・分子間相互作用


Shank分子内、あるいはShank分子間の相互作用としては、アンキリンリピートとSH3ドメインが相互作用する [5]ほか、PDZドメインはホモ二量体を[6]、SAMドメインは多量体を[7] 形成する.このPDZドメインによるホモ二量体形成には、PDZドメイン本来の蛋白質結合部位は関与しないので、二量体を形成しても、他のPDZリガンドは結合できる(図2).一方、結晶化されたSAMドメインは一周6分子の螺旋状ポリマーを形成しており(図3)、更にこの螺旋が側面で会合して、Zn2+イオンに依存性の二次元の広がりをもつシートを形成する.
但し、SAMドメインの大きさはShank全長の3%にしか相当しないので、上流の長い配列も含めて大きなポリマーを形成できるかどうかは不明である.

 
図2 Shank PDZ ドメインによるダイマー形成とGKAPとの相互作用 [6]

図2 Shank PDZ ドメインによるダイマー形成とGKAPとの相互作用 [6]

図3 Shank SAM ドメインの結晶構造 [7]

 
図3 Shank SAMドメインの結晶構造 [7]


Shankと相互作用する蛋白質


受容体・膜蛋白質

いずれも、カルボキシ端がShankのPDZドメインに結合する.
G protein-coupled alpha-latrotoxin receptor CL1 [8]

Somatostatin receptor subtype 2 [9]

Na+/H+ exchanger 3 [10]

Cystic fibrosis transmembrane conductance regulator [11]

GluA1 [12] 

mGluR1,5 [13]  これらは、Shankに結合するHomerとも相互作用する.

GluR delta 2 [14] 

シナプス足場蛋白質

DLGAP1/GKAP [15]

Homer [16]

IRSp53 [17]

Sharpin [18]

低分子量GTP結合蛋白質を制御する蛋白質

IRSp53

βPIX [19] 

ProSAPiP1 [20]

 
図4 Shank PDZ ドメインとbetaPIXとの相互作用 [21]

 

アクチン結合蛋白質

IRSp53

Cortactin [22] , [23]

Abp1 [24]

Spectrin-alpha [25]

その他の蛋白質

Phospholipse beta 3 [26] 

Dynamin 2 [27]

Dendrite arborization and synapse maturation 1 (Dasm1) [28] 


Shank遺伝子の異常

自閉症との関連については、Shank3の変異が最初に報告されたが、[29]、その後、Shank2 [30], Shank1 [31]についても報告されている。Phelan–McDermid 症候群は染色体22q13部位の欠失によるもので、Shank3 の異常が原因の一つと考えられている.また、Shank3のノックアウトマウスは社会的相互作用の欠如や過剰な毛繕いなど自閉症様の表現型を呈する[32]。さらに、自閉症患者にみられるShank3のC末の欠失変異体は、優性にShank3のプロテアーゼ分解を促進して、シナプスの形成を阻害する[33]。 

関連項目

シナプス後肥厚

自閉症

参考文献

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(執筆者:林 真理子、担当編集委員:柚崎 通介)