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

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

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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 Building Set 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 Custom Hoodie 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.