Open Accessp97 Disease Mutations Modulate Nucleotide-Induced Conformation to Alter Protein–Protein Interactions
Author(s) -
Stacie L. Bulfer,
TsuiFen Chou,
Michelle R. Arkin
Publication year - 2016
Publication title -
acs chemical biology
Language(s) - Uncategorized
Resource type - Journals
SCImago Journal Rank - 1.899
H-Index - 111
eISSN - 1554-8937
pISSN - 1554-8929
DOI - 10.1021/acschembio.6b00350
Subject(s) - signal transducing adaptor protein , mutant , nucleotide , atpase , aaa proteins , plasma protein binding , protein structure , microbiology and biotechnology , cyclic nucleotide binding domain , point mutation , biochemistry , adenosine triphosphate , conformational change , chemistry , binding domain , biology , biophysics , binding site , enzyme , signal transduction , gene
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.