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

Anup Arumughan, Yvette Roske, Carolin Barth, Laura Lleras Forero, Kenny Bravo-Rodriguez, Alexandra Redel, Simona Kostova, Erik McShane, Robert Opitz, Katja Faelber, Kirstin Rau, Thorsten Mielke, Oliver Daumke, Matthias Selbach, Elsa Sanchez-Garcia, Oliver Rocks, Daniela Panáková, Udo Heinemann () and Erich E. Wanker ()
Additional contact information
Anup Arumughan: Max Delbrück Center for Molecular Medicine
Yvette Roske: Max Delbrück Center for Molecular Medicine
Carolin Barth: Max Delbrück Center for Molecular Medicine
Laura Lleras Forero: Max Delbrück Center for Molecular Medicine
Kenny Bravo-Rodriguez: Max-Planck-Institute for Coal Research
Alexandra Redel: Max Delbrück Center for Molecular Medicine
Simona Kostova: Max Delbrück Center for Molecular Medicine
Erik McShane: Max Delbrück Center for Molecular Medicine
Robert Opitz: Max Delbrück Center for Molecular Medicine
Katja Faelber: Max Delbrück Center for Molecular Medicine
Kirstin Rau: Max Delbrück Center for Molecular Medicine
Thorsten Mielke: Max Planck Institute for Molecular Genetics
Oliver Daumke: Max Delbrück Center for Molecular Medicine
Matthias Selbach: Max Delbrück Center for Molecular Medicine
Elsa Sanchez-Garcia: Max-Planck-Institute for Coal Research
Oliver Rocks: Max Delbrück Center for Molecular Medicine
Daniela Panáková: Max Delbrück Center for Molecular Medicine
Udo Heinemann: Max Delbrück Center for Molecular Medicine
Erich E. Wanker: Max Delbrück Center for Molecular Medicine

Nature Communications, 2016, vol. 7, issue 1, 1-13

Abstract: 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.

Date: 2016
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DOI: 10.1038/ncomms13047

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