BIRC6/SMAC複合体によるアポトーシスとオートファギーの調節のための構造的基礎

Julian F Ehrmann^1,2, Daniel B Grabarczyk¹, Maria Heinke¹

¹Research Institute of Molecular Pathology, Vienna BioCenter, Vienna, Austria.

Science (New York, N.Y.)

|February 9, 2023

まとめ

アポトーシスタンパク質6 (BIRC6) のエッセンシャル・インヒビーターは細胞死と自己死を調節する. その構造は,SMACがBIRC6を結合する方法を示しています.

科学分野:

生物化学
分子生物学
細胞生物学

背景:

アポトーシスタンパク質の阻害剤 (IAP) は,カスパスを阻害することによって,プログラム細胞死の重要な調節剤である.
非典型的ユビキチンリガゼBIRC6は,唯一の重要なIAPであり,また,オートファギーを抑制する.
BIRC6の機能を理解することは,アポトーシスとオートファギーの経路を制御する鍵です.

研究の目的:

主要なアポトーシスおよびオートファジータンパク質との複合体におけるBIRC6の構造機能関係を明らかにする.
BIRC6がカスパーゼ9,HTRA2,SMAC,LC3Bとどのように相互作用するかを調査する.
BIRC6がアポトーシスとオートファギーを制御するメカニズムを決定する.

主な方法:

BIRC6複合体の構造を決定するために,冷凍電子顕微鏡 (cryo-EM) が使用されました.
BIRC6はカスパース9,HTRA2,SMAC,LC3Bと併用して構造機能分析を行った.
タンパク質結合とユビキチネーションの活性を評価するために生化学的測定法を使用した.

主要な成果:

Cryo-EMはBIRC6がクライアントタンパク質のための中央腔を持つ大きな半月形の複合体を形成することを明らかにした.
SMACのBIRC6への多価結合は,クライアントタンパク質の結合を阻害することが示された.
SMACによるこの阻害は,BIRC6によるオートファジーとアポプトシス基板の両方のユビキチネーションを阻害する.

結論:

BIRC6/SMAC複合体は,アポトーシスとオートファギーのシグナルを統合する分子ハブとして機能する.
SMACのBIRC6への結合は,そのリガース活性を制御する重要な規制ステップです.
これらの発見は,BIRC6がストレス下での細胞運命をどのように管理するかについての洞察を提供します.

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