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Quantitative interaction mapping reveals an extended UBX domain in ASPL that disrupts functional p97 hexamers

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Item Type:Article
Title:Quantitative interaction mapping reveals an extended UBX domain in ASPL that disrupts functional p97 hexamers
Creators Name:Arumughan, A. and Roske, Y. and Barth, C. and Lleras Forero, L. and Bravo-Rodriguez, K. and Redel, Al. and Kostova, S. and McShane, E. and Opitz, R. and Faelber, K. and Rau, K. and Mielke, T. and Daumke, O. and Selbach, M. and Sanchez-Garcia, E. and Rocks, O. and Panakova, D. and Heinemann, U. and Wanker, E.E.
Abstract:Interaction mapping is a powerful strategy to elucidate the biological function of protein assemblies and their regulators. Here, we report the generation of a quantitative interaction network, directly linking 14 human proteins to the AAA+ ATPase p97, an essential hexameric protein with multiple cellular functions. We show that the high-affinity interacting protein ASPL efficiently promotes p97 hexamer disassembly, resulting in the formation of stable p97:ASPL heterotetramers. High-resolution structural and biochemical studies indicate that an extended UBX domain (eUBX) in ASPL is critical for p97 hexamer disassembly and facilitates the assembly of p97:ASPL heterotetramers. This spontaneous process is accompanied by a reorientation of the D2 ATPase domain in p97 and a loss of its activity. Finally, we demonstrate that overproduction of ASPL disrupts p97 hexamer function in ERAD and that engineered eUBX polypeptides can induce cell death, providing a rationale for developing anti-cancer polypeptide inhibitors that may target p97 activity.
Source:Nature Communications
ISSN:2041-1723
Publisher:Nature Publishing Group (U.K.)
Volume:7
Page Range:13047
Date:20 October 2016
Official Publication:https://doi.org/10.1038/ncomms13047
PubMed:View item in PubMed

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