C型肝炎ウイルスの受容体結合と侵入に関する構造的洞察

Ashish Kumar¹, Reafa A Hossain¹, Samantha A Yost²

¹Structural Virology Section, Laboratory of Infectious Diseases, National Institute of Allergy and Infectious Diseases, National Institutes of Health, Bethesda, MD, USA.

Nature

|September 16, 2021

まとめ

C型肝炎ウイルス (HCV) の侵入には,CD81受容体へのE2グリコタンパク質結合が含まれます. 低pHとCD81結合はE2の形状変化を誘導し,ウイルスの膜融合を促進する.

科学分野:

ウイルス学
構造生物学
細胞生物学

背景:

C型肝炎ウイルス (HCV) は慢性肝疾患,肝硬変,肝がんを引き起こし,世界中で7千万人以上が感染しています.
HCVエンベロープのグリコタンパク質E1とE2はウイルスの侵入を媒介するが,正確なメカニズムは不明である.
中和抗体はしばしば,CD81受容体の大きな細胞外ループ (CD81-LEL) とのE2グリコタンパク質の相互作用を標的とする.

研究の目的:

HCVの侵入の構造的および分子的メカニズムを解明する.
HCV E2とCD81-LELの相互作用におけるpHとCD81結合の役割を調査する.
E2媒介膜融合の構造的基礎を決定する.

主な方法:

E2複合体の構造を決定するために,X線結晶学を用いた.
主要なE2残留物に関する変異性研究が行われました.
リポソーム漂流試験は,E2と膜の相互作用を評価した.

主要な成果:

低pHはCD81-LELのE2グリコタンパク質への結合を強化する.
結晶構造は,CD81-LEL結合時にE2の形状の変化を明らかにし,残基418-422を移動させ,内部ループ (520-539) を拡張した.
特定のE2残留物 (Tyr529, Trp531, Ile422) は,低pHとCD81-LELによって促進される膜相互作用に不可欠です.

結論:

酸性化とCD81-LEL結合は,E2の形状変化を誘導する.
この形状の変化は,膜融合のためのE2をプライムし,HCVの侵入における重要なステップを表します.
この発見は,HCVと宿主細胞膜の相互作用の分子モデルを提供する.

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