期刊
ACS CHEMICAL BIOLOGY
卷 11, 期 8, 页码 2112-2116出版社
AMER CHEMICAL SOC
DOI: 10.1021/acschembio.6b00350
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资金
- National Cancer Institute, National Institutes of Health, under Chemical Biology Consortium [HHSN261200800001E, 29XS127TO15]
- National Institute of Aging, National Institutes of Health [R01AG044515]
- LA BioMed Seed Grant program [20826-01]
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.
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