STINGの冷凍-EM構造は,周期的なGMP-AMPによる活性化のメカニズムを明らかにします

Guijun Shang¹, Conggang Zhang², Zhijian J Chen^3,4,5

¹Department of Pharmacology, University of Texas Southwestern Medical Center, Dallas, TX, USA.

Nature

|March 8, 2019

まとめ

サイクルGMP- AMP合成酵素 (cGAS) は,cGAMP経由でインターフェロン遺伝子刺激剤 (STING) を活性化する. この研究はSTINGを明らかにします.

科学分野:

免疫学
分子生物学
構造生物学

背景:

I型インターフェロンと炎症性サイトカインを誘発します
サイクルGMP- AMP合成酵素 (cGAS) は,インターフェロン刺激遺伝子 (STING) を活性化するcGAMPを産生する.
STINGは内プラズマ網膜タンパク質で生まれながらの免疫シグナル伝達に不可欠です

研究の目的:

cGAMPによるSTING活性化のメカニズムを解明する.
リガンド結合時にSTINGの形状の変化の構造的基礎を決定する.
STING オリゴメリゼーションと信号伝達におけるその役割を理解する.

主な方法:

クリオ電子顕微鏡 (cryo-EM) で,ヒトと鶏のSTINGの構造を決定する.
非活性二次体,cGAMP結合二次体,および四次体状態でのSTINGの分析
提案された活性化モデルを検証するための構造ベースの変異分析.

主要な成果:

ヒトと鶏の全身STINGの冷凍-EM構造を決定した.
トランスメブランとサイトプラズマ領域の統合された二次元組成を明らかにした
示すcGAMP結合は,リガンド結合ドメインの180°の回転を誘導し,テトラマー形成と高次元のオリゴマーを生成する.

結論:

cGAMPがSTINGと結合すると,ドメインの形状の変化と回転が生じます.
この回転はSTINGのオリゴメリゼーションを誘発し,テトラメアと活性化に不可欠な高階構造を形成する.
この発見は,STING媒介の先天性免疫シグナル伝達の構造モデルを提供する.

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