MRAS-SHOC2-PP1Cフォスファタゼ複合体の構造

Zachary J Hauseman¹, Michelle Fodor², Anxhela Dhembi²

¹Novartis Institutes for BioMedical Research, Cambridge, MA, USA. zachary.hauseman@novartis.com.

Nature

|July 13, 2022

まとめ

研究者はMRAS-SHOC2-PP1C複合体の構造を決定し,RAS-MAPK経路の活性化のための多分子メカニズムを明らかにし,癌および発達障害において決定的な役割を果たしました.

科学分野:

分子生物学
構造生物学
細胞シグナリング

背景:

RAS-MAPKシグナリングは細胞増殖に不可欠であり,ヒトの癌では頻繁に変化します.
RAFによるRAS信号の正確なメカニズム,特に中間アクティベーションステップは,まだ完全に理解されていません.
MRAS- SHOC2- PP1Cホロフォスファタゼ複合体は,RAFの脱リン化と活性化において重要な役割を果たし,ラソパシーと癌に関連した変異がある.

研究の目的:

MRAS-SHOC2-PP1Cホロフォスファタゼ複合体の構造的基礎を解明する.
RAS駆動型RAFの活性化に伴う分子メカニズムを理解する.
この複合体の変異が病気の発生にどのように寄与するかを調査する.

主な方法:

MRAS- SHOC2- PP1C複合体の高解像度構造を決定するために,X線結晶学を用いた.
複雑な組み立てとダイナミクスを評価するために生体物理的特徴化技術が使用されました.
決定された構造の文脈内の変異部位の分析.

主要な成果:

結晶構造はSHOC2をエスカフォルドとして示し,MRASとPP1Cを橋渡しし,3つの構成要素の相互作用を容易にします.
複合組成は,他のRASアイソフォームに適用されるメカニズムであるMRASのアクティブ,GTP結合状態によって協力的に駆動されます.
タンパク質とタンパク質のインターフェイスで発症し,複合体の安定性と機能を向上させました.

結論:

この研究は,RAF-14-3-3とSHOC2-PP1Cホロフォスファターゼの採用を含む,RAS-GTPによって誘発されるRAF活性化のための多分子モデルを提示しています.
この発見は,RAS-MAPK経路の調節と,その異常な活性化によって引き起こされる疾患の分子基礎に関する重要な構造的洞察を提供します.
この構造的な理解は,RAS主導の癌やラソパシーに対する標的治療の開発のための基盤を提供します.

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