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ヒトアセチル-コアカルボキシラーゼの調節のための構造的基礎

Moritz Hunkeler^1,2, Anna Hagmann³, Edward Stuttfeld³

¹Biozentrum, University of Basel, Basel, Switzerland. moritz_hunkeler@dfci.harvard.edu.

|June 15, 2018

まとめ

研究者らは,アセチル-CoAカルボキシラーゼ1 (ACC1) が脂肪酸の生物合成を調節するフィラメントを形成する方法を明らかにした. シトラートはACC1フィラメントを活性化し,BRCA1結合はそれらを無活性化し,新しい酵素調節メカニズムを明らかにします.

科学分野:

生物化学
構造生物学
酵素学

背景:

アセチル-CoAカルボキシラーゼ (ACC) は,アセチル-CoAのATP依存カルボキシラーゼを触媒する脂肪酸バイオシンセシスの重要な酵素である.
人間のACCは,ACC1 (細胞) とACC2 (ミトコンドリア) の2つの同型として存在し,ACC1は脂肪酸合成を調節する.
ACC1の調節には,リン酸化,アロステリックエフェクター,タンパク質の相互作用が含まれており,しばしばフィラメント形成につながりますが,構造的な基礎は不明のままです.

研究の目的:

アセチル-コアカルボキシラーゼ1 (ACC1) のポリメリゼーションとその調節の構造的基礎を解明する.
異なる活性化および抑制されたACC1フィラメント構造を識別する.
大規模な形状の変化による酵素調節の仕組みを理解する.

主な方法:

クリオ電子顕微鏡 (cryo-EM) を用いて,ACC1フィラメントの構造を決定した.
シトラートによるアロステリック活性化が研究された.
BRCA1のBRCTドメインによる抑制を研究した.

主要な成果:

活性化された (ACC-シトラート) と抑制された (ACC1-BRCA1) ACC1フィラメント形態が特定されました.
クリオ-エム構造はこれらの異なるフィラメント状態の分子基盤を明らかにしました
繊維の形成はACC1を特定の形状状態に閉じ,触媒的活動に影響を与えます.

結論:

繊維の形成は,ACC1の重要な規制メカニズムであり,触媒的に活発な状態と不活発な状態の間の切り替えです.
これは,大規模な形状の変化を通じてACC1規制の構造的な理解を提供します.
ACC1の調節に関する洞察は,調節された脂肪酸の生物合成に関連した疾患のための新しい治療戦略を提供することができます.

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