Cargando…

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

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...

Descripción completa

Detalles Bibliográficos
Autores principales: Yu, Guimei, Bai, Yunpeng, Li, Kunpeng, Amarasinghe, Ovini, Jiang, Wen, Zhang, Zhong-Yin
Formato: Online Artículo Texto
Lenguaje:English
Publicado: Elsevier 2021
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC8571493/
https://www.ncbi.nlm.nih.gov/pubmed/34765927
http://dx.doi.org/10.1016/j.isci.2021.103310
_version_ 1784595032313954304
author Yu, Guimei
Bai, Yunpeng
Li, Kunpeng
Amarasinghe, Ovini
Jiang, Wen
Zhang, Zhong-Yin
author_facet Yu, Guimei
Bai, Yunpeng
Li, Kunpeng
Amarasinghe, Ovini
Jiang, Wen
Zhang, Zhong-Yin
author_sort Yu, Guimei
collection PubMed
description 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 Online
Article
Text
id pubmed-8571493
institution National Center for Biotechnology Information
language English
publishDate 2021
publisher Elsevier
record_format MEDLINE/PubMed
spelling pubmed-85714932021-11-10 Cryo-electron microscopy structures of VCP/p97 reveal a new mechanism of oligomerization regulation Yu, Guimei Bai, Yunpeng Li, Kunpeng Amarasinghe, Ovini Jiang, Wen Zhang, Zhong-Yin iScience Article 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. Elsevier 2021-10-16 /pmc/articles/PMC8571493/ /pubmed/34765927 http://dx.doi.org/10.1016/j.isci.2021.103310 Text en © 2021 The Authors https://creativecommons.org/licenses/by-nc-nd/4.0/This is an open access article under the CC BY-NC-ND license (http://creativecommons.org/licenses/by-nc-nd/4.0/).
spellingShingle Article
Yu, Guimei
Bai, Yunpeng
Li, Kunpeng
Amarasinghe, Ovini
Jiang, Wen
Zhang, Zhong-Yin
Cryo-electron microscopy structures of VCP/p97 reveal a new mechanism of oligomerization regulation
title 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_short 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
topic Article
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC8571493/
https://www.ncbi.nlm.nih.gov/pubmed/34765927
http://dx.doi.org/10.1016/j.isci.2021.103310
work_keys_str_mv AT yuguimei cryoelectronmicroscopystructuresofvcpp97revealanewmechanismofoligomerizationregulation
AT baiyunpeng cryoelectronmicroscopystructuresofvcpp97revealanewmechanismofoligomerizationregulation
AT likunpeng cryoelectronmicroscopystructuresofvcpp97revealanewmechanismofoligomerizationregulation
AT amarasingheovini cryoelectronmicroscopystructuresofvcpp97revealanewmechanismofoligomerizationregulation
AT jiangwen cryoelectronmicroscopystructuresofvcpp97revealanewmechanismofoligomerizationregulation
AT zhangzhongyin cryoelectronmicroscopystructuresofvcpp97revealanewmechanismofoligomerizationregulation