7BPA

Human AAA+ ATPase VCP mutant - T76A, AMP-PNP-bound form, Conformation I

7BPA の概要

• エントリーDOI: 10.2210/pdb7bpa/pdb
• 関連するPDBエントリー: 7BP8 7BP9
• EMDBエントリー: 30147 30148 30149
• 分子名称: Transitional endoplasmic reticulum ATPase, ADENOSINE-5'-DIPHOSPHATE, PHOSPHOAMINOPHOSPHONIC ACID-ADENYLATE ESTER (3 entities in total)
• 機能のキーワード: complex, atpase, unfoldase, protein transportation, cell cycle
• 由来する生物種: Homo sapiens (Human)
• タンパク質・核酸の鎖数: 6
• 化学式量合計: 542041.12

構造登録者

Yang, C.,Zhang, H. (登録日: 2020-03-21, 公開日: 2021-03-31, 最終更新日: 2025-09-17)

主引用文献

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

実験手法

ELECTRON MICROSCOPY (3.3 Å)