Targeting of client proteins to the VCP/p97/Cdc48 unfolding machine

Abstract

The AAA+ ATPase p97 (also called VCP or Cdc48) is a major protein unfolding machine with hundreds of clients in diverse cellular pathways that are critical for cell homeostasis, proliferation and signaling. In this review, we summarize recent advances in understanding how diverse client proteins are targeted to the p97 machine to facilitate client degradation or to strip clients from binding partners for regulation. We describe an elaborate system that is governed by at least two types of alternative adapters. The Ufd1-Npl4 adapter along with accessory adapters targets ubiquitylated clients in the majority of pathways and uses ubiquitin as a universal unfolding tag. In contrast, the family of SEP-domain adapters such as p37 can target clients directly to p97 in a ubiquitin-independent manner. Despite the different targeting strategies, both pathways converge by inserting the client into the p97 pore to initiate a peptide threading mechanism through the central channel of p97 that drives client protein unfolding, protein extraction from membranes and protein complex disassembly processes.

DOT1L stimulates MYC/Mondo transcription factor activity by promoting its degradation cycle on chromatin

“…78 VCP is an AAA+ ATPase also known as p97 and Cdc48. 79,80 VCP is an important part of the UPS responsible for the extraction of target proteins from the membranes 79,81 and chromatin. 82,83…”

“…78 VCP is an AAA+ ATPase also known as p97 and Cdc48. 79,80 VCP is an important part of the UPS responsible for the extraction of target proteins from the membranes 79,81 and chromatin. 82,83 To determine whether DOT1L and VCP are present in the same complex, we performed immunoprecipitation experiments with overexpressed DOT1L and VCP.…”

VCP increases or decreases tau seeding using specific cofactors

“…Multiple co-factors generate specificity for VCP’s myriad cellular functions (25,39,40). To identify those which regulated seeding, we individually knocked out or reduced expression of 30 known cofactors in v2L tau biosensor cells (41).…”

Modular DNA origami compartments for the engineering of a protein unfolding and degradation pathway

“…The rst reaction is catalyzed by the valosin-containing protein (VCP)/p97, a protein unfolding machine with a major role in cell homeostasis, proliferation and signaling. 41,42 The second reaction is catalyzed by alpha-chymotrypsin (aCt), a well-studied and robust serine protease of the S1 family. 43 The p97 protein is a member of the ATPases Associated with diverse Activities (AAA) family.…”