人間のgα-セクレタゼによるノッチ認識の構造的基礎
Guanghui Yang1, Rui Zhou1, Qiang Zhou1,2
1Beijing Advanced Innovation Center for Structural Biology, Tsinghua-Peking Joint Center for Life Sciences, School of Life Sciences, Tsinghua University, Beijing, China.
Nature
|January 2, 2019
まとめ
研究者はノッチに結合するガンマセクレタスの構造を明らかにし,この酵素が基質を認識する方法を明らかにしました. この発見は,癌におけるノッチ割れを説明し,アミロイド前駆体タンパク質の処理の理解に影響を与える.
科学分野:
- 構造生物学
- 病気 の 分子 機構
- 神経科学
背景:
- ガンマ分泌酵素によるノッチ受容体の異常割れは,様々な癌に関与している.
- Notchのような基質をガンマ分泌酵素が認識し結合する正確なメカニズムは,未だに謎のままである.
- サブストラット認識を理解することは,生理学的および病理学的文脈の両方でガンマ分泌酵素の機能を解読するために重要である.
研究 の 目的:
- ノッチ基板断片との複合体におけるヒトガンマ分泌酵素の高解像度構造を決定する.
- ガンマ分泌酵素による基質認識と結合を制御する分子相互作用を解明する.
- アミロイド前駆体タンパク質などの関連基板に対する分裂機構とその影響に関する構造的洞察を提供すること.
主な方法:
- クリオ電子顕微鏡 (cryo-EM) を使用して,ヒトのガンマ分泌酵素/ノッチ複合体を視覚化しました.
- 2.7 Åの解像度の高解像度構造分析
- 観察された構造的特徴の機能的重要性を確認するための生化学的測定.
主要な成果:
- Notchのトランスメブランヘリクスは,ガンマ分泌酵素の核成分であるプレセニリン1 (PS1) の3つのトランスメブランドメインに囲まれています.
- ハイブリッドのβシート構造は,ノッチ断片のC端のβ鎖とPS1内の基板誘導のβ鎖の間に形成される.
- PS1は基板結合時に重要な形状変化を経験し,基板の結合と割れに積極的な役割を果たしていることを示しています.
結論:
- この研究は,ガンマ分泌酵素がノッチ基質を認識するための構造的基礎を明らかにしている.
- ハイブリッドβシートによって促進されるノッチトランスメブランヘリクスのC端で割れが起こります.
- これらの発見は,アミロイド前駆体タンパク質を含む他の基板とのガンマ分泌酵素の相互作用を理解し,標的治療薬の開発に意味を持つ.
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