RIP1/RIP3ネクロゾームは,プログラムされた死滅のために必要な機能的なアミロイド信号複合体を形成します
Jixi Li1, Thomas McQuade, Ansgar B Siemer
1Department of Biochemistry, Weill Cornell Medical College, New York, NY 10065, USA.
Cell
|July 24, 2012
まとめ
RIP1とRIP3キナーゼはアミロイド繊維を形成し,プログラムされた死滅を引き起こします. ティオフラビンTのような染料でこれらのアミロイド構造を阻害すると,部分的に死滅を阻害し,新しいシグナル伝達機構を明らかにします.
科学分野:
- バイオケミストリー バイオケミストリー
- 細胞生物学 細胞生物学
- 構造生物学 構造生物学とは
背景:
- 腫瘍死滅因子 (TNF) 誘発プログラム死滅には,RIP1とRIP3キナーゼが含まれています.
- RIPのキナーゼシグナル伝達を制御する正確な構造的メカニズムは,まだ完全に理解されていません.
研究 の 目的:
- RIP1およびRIP3キナーゼ複合体の形成の構造的基礎を調査する.
- RIPの同型相互作用モチーフ (RHIMs) がキナーゼアセンブリとシグナル伝達における役割を決定する.
- プログラム性死滅におけるアミロイド構造の潜在的関与を調査する.
主な方法:
- ティオフラビンT (ThT) とコンゴ赤 (CR) の結合分析,円形の二重化,赤外線光譜,X線 difraktion,および固体 NMR を含む生体物理学的技術.
- RIP1とRIP3のRHIM変異体の分析.
- 死細胞からの内生RIP1/RIP3複合体の分離と特徴付け.
- プログラムされた死滅のインビヴォ研究.
主要な成果:
- RIP1とRIP3のRHIMは,ヘテロダイマー性アミロイド繊維の形成を媒介する.
- これらの繊維は,アミロイド核を構成し,その周辺に移動領域がある.
- 固有のRIP1/RIP3複合体はアミロイド特性を有し,超安定である.
- アミロイド染料 (ThT,CR,HBX) は,プログラムされた死滅を部分的に抑制します.
- RHIM変異は,キナーゼ複合体の形成,活性化,プログラム性死滅を妨害する.
結論:
- RIPキナーゼは,プログラムされた死滅のために重要なアミロイド構造に組み合わされます.
- アミロイド形成は,RIPキナーゼ媒介シグナル伝達における重要な構造的イベントである.
- この研究は,アミロイドの既知の機能を,細胞のシグナル伝達複合体へと拡張する.
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