HPV媒介によるp53分解に必要なE6/E6AP/p53複合体の構造

Denise Martinez-Zapien¹, Francesc Xavier Ruiz², Juline Poirson¹

¹Equipe labellisée Ligue, Biotechnologie et signalisation cellulaire UMR 7242, Ecole Superieure de Biotechnologie de Strasbourg, Boulevard Sébastien Brant, BP 10413, F-67412 Illkirch, France.

Nature

|January 21, 2016

まとめ

ヒトパピローマウイルス (HPV) のオンコタンパク質E6は,E6関連タンパク質1 (E6AP) ユビキチンリガスを乗っ取り,p53腫瘍抑制剤を分解する. 結晶構造は,E6がp53と結合し,HPVによる癌に対する治療戦略を可能にします.

科学分野:

分子生物学
ウイルス学
構造生物学

背景:

腫瘍抑制剤p53はアポトーシスに不可欠であり,がんではしばしば変化する.
高リスクヒトパピローマウイルス (HPV) は,ウイルスオンコタンパク質E6を使用してp53を分解する.
E6は,E6関連タンパク質1 (E6AP) を採用し,p53を分解する必要がありますが,組み立てのメカニズムは不明です.

研究の目的:

HPV-16 E6,E6APとp53の間の三元複合体の構造的基礎を解明する.
E6APによるp53の分解をどのように促進するのかを理解する.
HPV誘発性腫瘍形成に対する治療的介入の開発のための構造的基礎を提供すること.

主な方法:

全長HPV-16 E6,E6AP LxxLLモチーフとp53コアドメイン複合体の結晶構造の決定
E6-p53の相互作用界面を調査するサイト指向型変異.

主要な成果:

結晶構造は,E6AP LxxLLモチーフがE6のp53結合裂け目を誘発することを示す三元複合体を明らかにする.
E6-p53界面での変異はp53の分解を廃止した.
p53のE6結合部位はDNAとタンパク質結合部位とは異なっており,E6が様々なp53の形態を標的とすることが示唆される.

結論:

E6/E6AP/p53複合体の構造は,ウビキチン-プロテアソームシステムとp53経路のウイルスの破壊を説明する.
この構造的な洞察は,HPV媒介の癌発症と戦うための阻害剤の設計に極めて重要です.

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