NLRP3炎症体のNEK7認可活性化の構造的メカニズム

Humayun Sharif^1,2, Li Wang^1,2, Wei Li Wang^{1,2,3,4,5,6,7}

¹Department of Biological Chemistry and Molecular Pharmacology, Harvard Medical School, Boston, MA, USA.

Nature

|June 14, 2019

まとめ

ミトキナーゼNEK7は,隣接するNLRP3サブユニットをブリッジしてNLRP3炎症体を活性化します. この構造的な洞察は,NEK7

科学分野:

免疫学
構造生物学
分子生物学

背景:

NLRP3炎症体は様々な危険信号によって活性化される重要な免疫センサーです.
NEK7 (ミトーシス遺伝子のA関連キナーゼ7) は,NLRP3炎症体の組み立てと活性化に不可欠です.

研究の目的:

NEK7媒介のNLRP3炎症体の活性化の構造的基礎を決定する.
炎症体組成を制御する分子相互作用を解明する.

主な方法:

クリオ電子顕微鏡 (cryo-EM) で,非活性なヒトNLRP3とNEK7の構造を解析する.
構造的発見を検証するためのインビトロおよび細胞変異研究.
関連する炎症体 (例えば,NLRC4) に基づく計算モデル化.

主要な成果:

NEK7と複合された非活性ヒトNLRP3の3. 8 Å解像度の冷凍- EM構造が得られた.
NEK7のC末端葉は,NLRP3のレウシンに富んだリピート領域とNACHT領域の両方と相互作用する.
ミュタゲネシスは構造認識インターフェースを確認し,NEK7が介在する重要なNLRP3間のインターフェースを特定しました.

結論:

NEK7は,隣接するNLRP3サブユニットをリンクするために,双方向の相互作用を利用する分子ブリッジとして機能します.
このNEK7媒介の橋渡しメカニズムは,NLRP3炎症体の活性化に不可欠です.
構造的な洞察は,炎症ホルモンの調節と治療目標の理解のための基盤を提供します.

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