p97 Disease Mutations Modulate Nucleotide-Induced Conformation to Alter Protein–Protein Interactions
Abstract
The AAA+ ATPase p97/VCP adopts at least three conformations that depend on the binding of ADP and ATP and alter the orientation of the N-terminal protein–protein interaction (PPI) domain into "up" and "down" conformations. Point mutations that cause multisystem proteinopathy 1 (MSP1) are found at the interface of the N domain and D1-ATPase domain and potentially alter the conformational preferences of p97. Additionally, binding of "adaptor" proteins to the N-domain regulates p97's catalytic activity. We propose that p97/adaptor PPIs are coupled to p97 conformational states. We evaluated the binding of nucleotides and the adaptor proteins p37 and p47 to wild-type p97 and MSP1 mutants. Notably, p47 and p37 bind 8-fold more weakly to the ADP-bound conformation of wild-type p97 compared to the ATP-bound conformation. However, MSP1 mutants lose this nucleotide-induced conformational coupling because they destabilize the ADP-bound, "down" conformation of the N-domain. Loss in conformation coupling to PPIs could contribute to the mechanism of MSP1.
Additional Information
© 2016 American Chemical Society. This is an open access article published under an ACS AuthorChoice License, which permits copying and redistribution of the article or any adaptations for non-commercial purposes. Received 22 April 2016. Accepted 7 June 2016. Published online 13 June 2016. Published in issue 19 August 2016. The project was funded in part with federal funds from the National Cancer Institute, National Institutes of Health, under Chemical Biology Consortium Contract No. HHSN261200800001E Agreement No. 29XS127TO15, and from the National Institute of Aging, National Institutes of Health, R01AG044515 and from the LA BioMed Seed Grant program (20826-01). TFC is a member of UCLA Jonsson Comprehensive Cancer Center. Author Contributions: The manuscript was written through contributions of all authors. The authors declare no competing financial interest.Attached Files
Published - acschembio.6b00350.pdf
Supplemental Material - cb6b00350_si_001.pdf
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Additional details
- PMCID
- PMC5224236
- Eprint ID
- 114046
- Resolver ID
- CaltechAUTHORS:20220323-565696000
- HHSN261200800001E
- NIH
- 29XS127TO15
- NIH
- R01AG044515
- NIH
- 20826-01
- LA BioMed Seed Grant
- UCLA Jonsson Comprehensive Cancer Center
- Created
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2022-03-24Created from EPrint's datestamp field
- Updated
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2022-03-24Created from EPrint's last_modified field