PDF(Pubmed)
Abstract：
The AAA-type ATPase VPS4 is recruited by proteins of the endosomal sorting complex required for transport III (ESCRT-III) to catalyse membrane constriction and membrane fission. VPS4A accumulates at the cytoplasmic viral assembly complex (cVAC) of cells infected with human cytomegalovirus (HCMV), the site where nascent virus particles obtain their membrane envelope. Here we show that VPS4A is recruited to the cVAC via interaction with pUL71. Sequence analysis, deep-learning structure prediction, molecular dynamics and mutagenic analysis identify a short peptide motif in the C-terminal region of pUL71 that is necessary and sufficient for the interaction with VPS4A. This motif is predicted to bind the same groove of the N-terminal VPS4A Microtubule-Interacting and Trafficking (MIT) domain as the Type 2 MIT-Interacting Motif (MIM2) of cellular ESCRT-III components, and this viral MIM2-like motif (vMIM2) is conserved across β-herpesvirus pUL71 homologues. However, recruitment of VPS4A by pUL71 is dispensable for HCMV morphogenesis or replication and the function of the conserved vMIM2 during infection remains enigmatic. VPS4-recruitment via a vMIM2 represents a previously unknown mechanism of molecular mimicry in viruses, extending previous observations that herpesviruses encode proteins with structural and functional homology to cellular ESCRT-III components.
摘要：
AAA型ATP酶VPS4由转运III（ESCRT-III）所需的内体分选复合物的蛋白质募集，以催化膜收缩和膜裂变。VPS4A在感染人巨细胞病毒（HCMV）的细胞的细胞质病毒组装复合物（cVAC）积累，新生病毒颗粒获得膜包膜的部位。在这里，我们显示VPS4A通过与pUL71的相互作用被招募到cVAC。序列分析,深度学习结构预测，分子动力学和诱变分析鉴定了pUL71C末端区域中的短肽基序，这对于与VPS4A的相互作用是必需和足够的。预测该基序与细胞ESCRT-III组件的2型MIT相互作用基序（MIM2）结合N端VPS4A微管相互作用和运输（MIT）结构域的相同凹槽，这种病毒MIM2样基序（vMIM2）在β-疱疹病毒pUL71同源物中是保守的。然而,pUL71募集VPS4A对于HCMV形态发生或复制是不必要的，感染期间保守的vMIM2的功能仍然是神秘的。通过vMIM2进行的VPS4募集代表了病毒中先前未知的分子模拟机制，扩展了先前的观察，即疱疹病毒编码与细胞ESCRT-III成分具有结构和功能同源性的蛋白质。
