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Journal Article

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


Mielke,  Thorsten
Microscopy and Cryo-Electron Microscopy (Head: Thorsten Mielke), Scientific Service (Head: Christoph Krukenkamp), Max Planck Institute for Molecular Genetics, Max Planck Society;

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Arumughan, A., Roske, Y., Barth, C., Forero, L. L., Bravo-Rodriguez, K., Redel, A., et al. (2016). Quantitative interaction mapping reveals an extended UBX domain in ASPL that disrupts functional p97 hexamers. Nature Communications, 7: 7:13047. doi:10.1038/ncomms13047.

Cite as: https://hdl.handle.net/11858/00-001M-0000-002E-2422-C
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.