7BP8

Human AAA+ ATPase VCP mutant - T76A, ADP-bound form

Summary for 7BP8

• Entry DOI: 10.2210/pdb7bp8/pdb
• EMDB information: 30147
• Descriptor: Transitional endoplasmic reticulum ATPase, ADENOSINE-5'-DIPHOSPHATE (2 entities in total)
• Functional Keywords: complex, atpase, unfoldase, protein transportation, cell cycle
• Biological source: Homo sapiens (Human)
• Total number of polymer chains: 6
• Total formula weight: 541567.15

Authors

Yang, C.,Zhang, H. (deposition date: 2020-03-21, release date: 2021-03-31, Last modification date: 2024-05-29)

Primary citation

Zhu, K.,Cai, Y.,Si, X.,Ye, Z.,Gao, Y.,Liu, C.,Wang, R.,Ma, Z.,Zhu, H.,Zhang, L.,Li, S.,Zhang, H.,Yue, J.
The phosphorylation and dephosphorylation switch of VCP/p97 regulates the architecture of centrosome and spindle.
Cell Death Differ., 2022

PubMed Abstract: The proper orientation of centrosome and spindle is essential for genome stability; however, the mechanism that governs these processes remains elusive. Here, we demonstrated that polo-like kinase 1 (Plk1), a key mitotic kinase, phosphorylates residue Thr76 in VCP/p97 (an AAA-ATPase), at the centrosome from prophase to anaphase. This phosphorylation process recruits VCP to the centrosome and in this way, it regulates centrosome orientation. VCP exhibits strong co-localization with Eg5 (a mitotic kinesin motor), at the mitotic spindle, and the dephosphorylation of Thr76 in VCP is required for the enrichment of both VCP and Eg5 at the spindle, thus ensuring proper spindle architecture and chromosome segregation. We also showed that the phosphatase, PTEN, is responsible for the dephosphorylation of Thr76 in VCP; when PTEN was knocked down, the normal spread of VCP from the centrosome to the spindle was abolished. Cryo-EM structures of VCP and VCP, which represent dephosphorylated and phosphorylated states of VCP, respectively, revealed that the Thr76 phosphorylation modulates VCP by altering the inter-domain and inter-subunit interactions, and ultimately the nucleotide-binding pocket conformation. Interestingly, the tumor growth in nude mice implanted with VCP-reconstituted cancer cells was significantly slower when compared with those implanted with VCP-reconstituted cancer cells. Collectively, our findings demonstrate that the phosphorylation and dephosphorylation switch of VCP regulates the architecture of centrosome and spindle for faithful chromosome segregation.

PubMed: 35430615
DOI: 10.1038/s41418-022-01000-4

Experimental method

ELECTRON MICROSCOPY (3.9 Å)