The AAA+ ATPase p97, a cellular multi-tool
File(s)
Published version
Accepted version
Author(s)
freemont, P
Stach, L
Type
Journal Article
Abstract
The AAA+ (ATPases associated with diverse cellular activities) ATPase p97 is essential to a wide range of cellular functions, including endoplasmic reticulum-associated degradation, membrane fusion, NF-κB (nuclear factor kappa-light-chain-enhancer of activated B cells) activation and chromatin-associated processes, which are regulated by ubiquitination. p97 acts downstream from ubiquitin signaling events and utilizes the energy from ATP hydrolysis to extract its substrate proteins from cellular structures or multiprotein complexes. A multitude of p97 cofactors have evolved which are essential to p97 function. Ubiquitin-interacting domains and p97-binding domains combine to form bi-functional cofactors, whose complexes with p97 enable the enzyme to interact with a wide range of ubiquitinated substrates. A set of mutations in p97 have been shown to cause the multisystem proteinopathy inclusion body myopathy associated with Paget's disease of bone and frontotemporal dementia. In addition, p97 inhibition has been identified as a promising approach to provoke proteotoxic stress in tumors. In this review, we will describe the cellular processes governed by p97, how the cofactors interact with both p97 and its ubiquitinated substrates, p97 enzymology and the current status in developing p97 inhibitors for cancer therapy.
Date Issued
2017-08-17
Date Acceptance
2017-07-21
Citation
Biochemical Journal, 2017, 474 (17), pp.2953-2976
ISSN
1470-8728
Publisher
Portland Press
Start Page
2953
End Page
2976
Journal / Book Title
Biochemical Journal
Volume
474
Issue
17
Copyright Statement
© 2017 The Author(s). This is an open access article published by Portland Press Limited on behalf of the Biochemical Society and distributed under the Creative Commons Attribution License 4.0 (CC BY).
Sponsor
Cancer Research UK
Grant Number
13449
Subjects
Adenosine Triphosphatases
Allosteric Regulation
Animals
Antineoplastic Agents
Binding Sites
Chromatin Assembly and Disassembly
Coenzymes
Drugs, Investigational
Endoplasmic Reticulum-Associated Degradation
Enzyme Inhibitors
Humans
Membrane Fusion
Models, Biological
Molecular Conformation
NF-kappa B p50 Subunit
Nuclear Proteins
Protein Conformation
Ubiquitination
06 Biological Sciences
11 Medical And Health Sciences
03 Chemical Sciences
Biochemistry & Molecular Biology
Publication Status
Published