人間のmGlu2とmGlu7のホモ・ヘテロダイマーの構造

Juan Du^1,2,3, Dejian Wang^1,4, Hongcheng Fan^4,5

¹State Key Laboratory of Drug Research, Shanghai Institute of Materia Medica, Chinese Academy of Sciences, Shanghai, China.

Nature

|June 17, 2021

まとめ

メタボトロピックグルタミン酸受容体 (mGluRs) は独特の性質を持つ二重体を形成する. Cryo-EM構造は,mGlu7を強調するサブタイプ特有の二分化および活性化メカニズムを明らかにします.

科学分野:

神経科学
構造生物学
生物化学

背景:

メタボトロピックグルタミン酸受容体 (mGlus) は,シナプス伝達と神経刺激性を調節するために不可欠です.
mGlusはホモディマーとヘテロディマーとして機能し,薬理学的および機能的特性を有する.

研究の目的:

メタボトロピックグルタミン酸受容体 (mGlu) のホモ・ヘテロディメリゼーションの構造的基礎を解明する.
mGlu受容体活性化と亜型特異的相互作用の基礎となる分子機構を調査する.

主な方法:

高解像度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.
不活性なmGlu2およびmGlu7ホモジーマー,活性なmGlu2ホモジーマー,および不活性なmGlu2-mGlu7ヘテロジーマーという4つの異なる構造が解明されました.

主要な成果:

不活性なmGlu2受容体を制限する独特のヘリックスIV媒介インターフェースを持つ亜型依存型二分化モードが特定されました.
詳細な分子洞察は,受容体活性化中のサブユニット間およびサブユニット内の構造変化に得られた.
mGlu2- mGlu7ヘテロダイマーにおけるGタンパク質活性化に mGlu7サブユニットが優位であることが判明した.

結論:

この研究は,mGlu受容体の二分化と活性化に関する前例のない構造的な詳細を提供します.
発見は,クラスAとクラスBと比較して,クラスCのGタンパク質結合受容体の異なるメカニズムを明らかにする.
mGlu ホモ・ヘテロディメリゼーションの洞察は,中央神経系における複雑な役割の理解を深める.

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