Shank

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SHANK3から転送)

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林 真理子
慶應義塾大学 医学部
DOI:10.14931/bsd.1089 原稿受付日:2012年5月28日 原稿完成日:2012年6月6日
担当編集委員:柚崎 通介(慶應義塾大学 医学部生理学)

SH3 and multiple ankyrin repeat domains 1
Identifiers
Symbols SHANK1; SPANK-1; SSTRIP; synamon
External IDs OMIM604999 MGI3613677 HomoloGene22949 GeneCards: SHANK1 Gene
Orthologs
Species Human Mouse
Entrez 50944 243961
Ensembl ENSG00000161681 ENSMUSG00000038738
UniProt Q9Y566 D3YZU1
RefSeq (mRNA) NM_016148.2 NM_001034115.1
RefSeq (protein) NP_057232.2 NP_001029287.1
Location (UCSC) Chr 19:
51.17 – 51.22 Mb
Chr 7:
51.57 – 51.61 Mb
PubMed search [1] [2]
SH3 and multiple ankyrin repeat domains 2
Identifiers
Symbols SHANK2; AUTS17; CORTBP1; CTTNBP1; ProSAP1; SHANK; SPANK-3
External IDs OMIM603290 MGI2671987 HomoloGene105965 GeneCards: SHANK2 Gene
RNA expression pattern
PBB GE SHANK2 213307 at tn.png
PBB GE SHANK2 213308 at tn.png
PBB GE SHANK2 215829 at tn.png
More reference expression data
Orthologs
Species Human Mouse
Entrez 22941 210274
Ensembl ENSG00000162105 ENSMUSG00000037541
UniProt Q9UPX8 Q80Z38
RefSeq (mRNA) NM_012309.3 XM_001002370
RefSeq (protein) NP_036441.2 XP_001002370
Location (UCSC) Chr 11:
70.31 – 70.96 Mb
Chr 7:
143.99 – 144.23 Mb
PubMed search [3] [4]
SH3 and multiple ankyrin repeat domains 3
Identifiers
Symbols SHANK3; DEL22q13.3; PROSAP2; PSAP2; SCZD15; SPANK-2
External IDs OMIM606230 MGI1930016 HomoloGene75163 GeneCards: SHANK3 Gene
RNA expression pattern
PBB GE SHANK3 gnf1h01748 s at tn.png
PBB GE SHANK3 gnf1h02526 x at tn.png
PBB GE SHANK3 gnf1h02529 at tn.png
More reference expression data
Orthologs
Species Human Mouse
Entrez 85358 58234
Ensembl ENSG00000251322 ENSMUSG00000022623
UniProt F2Z3L0 Q4ACU6
RefSeq (mRNA) NM_001080420.1 NM_021423.3
RefSeq (protein) NP_001073889.1 NP_067398.2
Location (UCSC) Chr 22:
51.11 – 51.17 Mb
Chr 15:
89.33 – 89.39 Mb
PubMed search [5] [6]

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、2000個以上のアミノ酸からなる巨大な足場タンパク質である。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 (Src homology 3)ドメインPDZ (PSD-95, Dlg, Zo-1)ドメイン、プロリンリッチ配列、SAM (Sterile alpha motif)ドメインからなる。それぞれのドメインが相互作用するタンパク質を持つので、結合タンパク質は多岐にわたる。自閉症との関連が指摘されている。 

構造

 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ドメイン、PDZ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 = Somatostatin receptor-interacting protein (SSTRIP) = Synamon
  • Shank2 = CortBP1 (Cortactin-binding protein 1) = ProSAP1 (Proline-rich synapse-associated protein 1) = SPANK-3
  • Shank3 = ProSAP2 = SPANK-2
図1.Shank ドメイン構造と選択的スプライシング産物
Ank:アンキリンリピート
SH3:SH3ドメイン
PDZ:PDZドメイン
Pro rich:プロリンリッチ配列
SAM:SAMドメイン

発現

 Shank1, Shank2, Shank3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部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]

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結合タンパク質である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小脳顆粒細胞にShankを導入すると、 NMDA型グルタミン酸受容体AMPA型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部の骨格となると考えられる[4]

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ドメイン本来のタンパク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。

Shankと相互作用するタンパク質

図4 Shank PDZ ドメインとβPIXとの相互作用 PDB 3l4f [8]

受容体・膜タンパク質

 いずれも、C末端(C-terminus)がShankのPDZドメインに結合する。

シナプス足場タンパク質

低分子量GTP結合タンパク質を制御するタンパク質

  • IRSp53

アクチン結合タンパク質

  • IRSp53

その他のタンパク質

Shank遺伝子の異常

 自閉症との関連については、ヒトにおける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、Shank2、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] [33] [34]。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[35]。 

関連項目

参考文献

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    Characterization of the Shank family of synaptic proteins. Multiple genes, alternative splicing, and differential expression in brain and development. The Journal of biological chemistry, 274(41), 29510-8. [PubMed:10506216] [WorldCat] [DOI]
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