Cryo-electron microscopy structures of VCP/p97 reveal a new mechanism of oligomerization regulation

Summary: VCP/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 reveal...

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Autores principales:	Guimei Yu, Yunpeng Bai, Kunpeng Li, Ovini Amarasinghe, Wen Jiang, Zhong-Yin Zhang
Formato:	article
Lenguaje:	EN
Publicado:	Elsevier 2021
Materias:	Biological sciences Biochemistry Structural biology Science Q
Acceso en línea:	https://doaj.org/article/0492c1fabe994643b68f2a33602a0845
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spelling	oai:doaj.org-article:0492c1fabe994643b68f2a33602a08452021-11-20T05:09:47ZCryo-electron microscopy structures of VCP/p97 reveal a new mechanism of oligomerization regulation2589-004210.1016/j.isci.2021.103310https://doaj.org/article/0492c1fabe994643b68f2a33602a08452021-11-01T00:00:00Zhttp://www.sciencedirect.com/science/article/pii/S2589004221012797https://doaj.org/toc/2589-0042Summary: VCP/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.Guimei YuYunpeng BaiKunpeng LiOvini AmarasingheWen JiangZhong-Yin ZhangElsevierarticleBiological sciencesBiochemistryStructural biologyScienceQENiScience, Vol 24, Iss 11, Pp 103310- (2021)
institution	DOAJ
collection	DOAJ
language	EN
topic	Biological sciences Biochemistry Structural biology Science Q
spellingShingle	Biological sciences Biochemistry Structural biology Science Q Guimei Yu Yunpeng Bai Kunpeng Li Ovini Amarasinghe Wen Jiang Zhong-Yin Zhang Cryo-electron microscopy structures of VCP/p97 reveal a new mechanism of oligomerization regulation
description	Summary: VCP/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.
format	article
author	Guimei Yu Yunpeng Bai Kunpeng Li Ovini Amarasinghe Wen Jiang Zhong-Yin Zhang
author_facet	Guimei Yu Yunpeng Bai Kunpeng Li Ovini Amarasinghe Wen Jiang Zhong-Yin Zhang
author_sort	Guimei Yu
title	Cryo-electron microscopy structures of VCP/p97 reveal a new mechanism of oligomerization regulation
title_short	Cryo-electron microscopy structures of VCP/p97 reveal a new mechanism of oligomerization regulation
title_full	Cryo-electron microscopy structures of VCP/p97 reveal a new mechanism of oligomerization regulation
title_fullStr	Cryo-electron microscopy structures of VCP/p97 reveal a new mechanism of oligomerization regulation
title_full_unstemmed	Cryo-electron microscopy structures of VCP/p97 reveal a new mechanism of oligomerization regulation
title_sort	cryo-electron microscopy structures of vcp/p97 reveal a new mechanism of oligomerization regulation
publisher	Elsevier
publishDate	2021
url	https://doaj.org/article/0492c1fabe994643b68f2a33602a0845
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Cryo-electron microscopy structures of VCP/p97 reveal a new mechanism of oligomerization regulation

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