Common Mode of Remodeling AAA ATPases p97/CDC48 by Their Disassembling Cofactors ASPL/PUX1

• Published in: Structure (London) Vol. 27; no. 12; pp. 1830 - 1841.e3
• Main Authors: Banchenko, Sofia, Arumughan, Anup, Petrović, Saša, Schwefel, David, Wanker, Erich E., Roske, Yvette, Heinemann, Udo
• Format: Journal Article
• Language: English
• Published: United States Elsevier Ltd 03-12-2019
• Subjects: CDC48; p97 ATPase regulation; PUX1; structural remodeling; ubiquitin regulatory-X domain; p97 ATPase regulation; PUX1; ubiquitin regulatory-X domain; CDC48; structural remodeling
• ISSN: 0969-2126; 1878-4186
• DOI: 10.1016/j.str.2019.10.001

The hexameric ring structure of the type II AAA+ ATPases is considered as stable and permanent. Recently, the UBX domain-containing cofactors Arabidopsis thaliana PUX1 and human alveolar soft part sarcoma locus (ASPL) were reported to bind and disassemble the cognate AAA+ ATPases AtCDC48 and human p97. Here, we present two crystal structures related to these complexes: a truncated AtCDC48 (AtCDC48-ND1) and a hybrid complex containing human p97-ND1 and the UBX domain of plant PUX1 (p97-ND1:PUX1-UBX). These structures reveal close similarity between the human and plant AAA+ ATPases, but also highlight differences between disassembling and non-disassembling AAA+ ATPase cofactors. Based on an AtCDC48 disassembly assay with PUX1 and known crystal structures of the p97-bound human cofactor ASPL, we propose a general ATPase disassembly model. Thus, our structural and biophysical investigations provide detailed insight into the mechanism of AAA+ ATPase disassembly by UBX domain cofactors and suggest a general mode of regulating the cellular activity of these molecular machines.
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•Crystal structures of plant ATPase AtCDC48-ND1 and human-plant hybrid complex p97-ND1:PUX1•PUX1 binds p97-ND1 via a conserved cis-Pro touch-turn motif of its UBX domain•Closed lariat structure in PUX1 involved in binding and disassembly of ATPases•Different thermostability of AtCDC48 and p97 affects the disassembly by PUX1
AAA+ ATPases are regulated by disassembling cofactors including ASPL or PUX1. Banchenko et al. determined crystal structures of the plant AAA+ ATPase AtCDC48-ND1 and of plant PUX1-UBX bound to the human AAA+ ATPase p97-ND1. Structural and biochemical data support a general mechanism of regulating the cellular activity of these molecular machines.