Structural basis of VCP-VCPIP1-p47 ternary complex in Golgi maintenance

Binita Shah, Moritz Hunkeler, Ariana Bratt, Hong Yue, Isabella Jaen Maisonet, Eric S. Fischer () and Sara J. Buhrlage ()
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Binita Shah: Dana-Farber Cancer Institute
Moritz Hunkeler: Dana-Farber Cancer Institute
Ariana Bratt: Dana-Farber Cancer Institute
Hong Yue: Dana-Farber Cancer Institute
Isabella Jaen Maisonet: Dana-Farber Cancer Institute
Eric S. Fischer: Dana-Farber Cancer Institute
Sara J. Buhrlage: Dana-Farber Cancer Institute

Nature Communications, 2025, vol. 16, issue 1, 1-13

Abstract: Abstract VCP/p97 regulates a wide range of cellular processes, including post-mitotic Golgi reassembly. In this context, VCP is assisted by p47, an adapter protein, and VCPIP1, a deubiquitylase (DUB). However, how they organize into a functional ternary complex to promote Golgi assembly remains unknown. Here, we use cryo-EM to characterize both VCP-VCPIP1 and VCP-VCPIP1-p47 complexes. We show that VCPIP1 engages VCP through two interfaces: one involving the N-domain of VCP and the UBX domain of VCPIP1, and the other involving the VCP D2 domains and a region of VCPIP1 we refer to as VCPID. The p47 UBX domain competitively binds to the VCP N-domain, while not affecting VCPID binding. We show that VCPID is critical for VCP-mediated enhancement of DUB activity and proper Golgi assembly. The ternary structure along with biochemical and cellular data provides new insights into the complex interplay of VCP with its co-factors.

Date: 2025
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DOI: 10.1038/s41467-025-63161-3

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