Cryo-electron microscopy structures of VCP/p97 reveal a new mechanism of oligomerization regulation
Guimei Yu,
Yunpeng Bai,
Kunpeng Li,
Ovini Amarasinghe,
Wen Jiang,
Zhong-Yin Zhang
Affiliations
Guimei Yu
Departments of Medicinal Chemistry and Molecular Pharmacology and of Chemistry, Center for Cancer Research, and Institute for Drug Discovery, Purdue University, 720 Clinic Drive, West Lafayette, IN 47907, USA
Yunpeng Bai
Departments of Medicinal Chemistry and Molecular Pharmacology and of Chemistry, Center for Cancer Research, and Institute for Drug Discovery, Purdue University, 720 Clinic Drive, West Lafayette, IN 47907, USA
Kunpeng Li
Department of Biological Sciences, Purdue University, 240 S Martin Jischke Drive, West Lafayette, IN 47907, USA
Ovini Amarasinghe
Departments of Medicinal Chemistry and Molecular Pharmacology and of Chemistry, Center for Cancer Research, and Institute for Drug Discovery, Purdue University, 720 Clinic Drive, West Lafayette, IN 47907, USA
Wen Jiang
Department of Biological Sciences, Purdue University, 240 S Martin Jischke Drive, West Lafayette, IN 47907, USA
Zhong-Yin Zhang
Departments of Medicinal Chemistry and Molecular Pharmacology and of Chemistry, Center for Cancer Research, and Institute for Drug Discovery, Purdue University, 720 Clinic Drive, West Lafayette, IN 47907, USA; Corresponding author
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.
