文章基本信息

标题：Cryo-electron microscopy structures of VCP/p97 reveal a new mechanism of oligomerization regulation
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作者：Guimei Yu ; Yunpeng Bai ; Kunpeng Li 等
期刊名称：iScience
印刷版ISSN：2589-0042
出版年度：2021
卷号：24
期号：11
页码：1-19
DOI：10.1016/j.isci.2021.103310
语种：English
出版社：Elsevier
摘要：SummaryVCP/p97 is an evolutionarily conserved AAA+ ATPase important for cellular homeostasis. Previous studies suggest that VCP predominantly exists as a homohexamer. Here, we performed structural and biochemical characterization of VCP dodecamer, an understudied state of VCP. The structure revealed an apo nucleotide status that has rarely been captured, a tail-to-tail assembly of two hexamers, and the up-elevated N-terminal domains akin to that seen in the ATP-bound hexamer. Further analyses elucidated a nucleotide status-dependent dodecamerization mechanism, where nucleotide dissociation from the D2 AAA domains induces and promotes VCP dodecamerization. In contrast, nucleotide-free D1 AAA domains are associated with the up-rotation of N-terminal domains, which may prime D1 for ATP binding. These results therefore reveal new nucleotide status-dictated intra- and interhexamer conformational changes and suggest that modulation of D2 domain nucleotide occupancy may serve as a mechanism in controlling VCP oligomeric states.Graphical abstractDisplay OmittedHighlights•A cryo-EM structure of VCP dodecamer purified with mammalian cells is resolved•The dodecamer structure reveals an apo nucleotide status•A VCP dodecamerization mechanism has been elucidated•Loss of nucleotide from D2 promotes VCP dodecamer formationBiological sciences; Biochemistry; Structural biology