p97 Disease Mutations Modulate Nucleotide-Induced Conformation to Alter Protein-Protein Interactions.
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.
Department of Pharmaceutical Chemistry, Small Molecule Discovery Center, University of California , San Francisco, California 94143, United States.
Stacie L
SL
Bulfer
Division of Medical Genetics, Department of Pediatrics, Harbor-UCLA Medical Center and Los Angeles Biomedical Research Institute , Torrance, California 90502, United States.
Tsui-Fen
TF
Chou
Department of Pharmaceutical Chemistry, Small Molecule Discovery Center, University of California , San Francisco, California 94143, United States.
Michelle R
MR
Arkin
D000244:Adenosine Diphosphate / Q000378:metabolism; D000251:Adenosine Triphosphatases / Q000737:chemistry / Q000235:genetics* / Q000378:metabolism; D000255:Adenosine Triphosphate / Q000378:metabolism; D002384:Catalysis; D009687:Nuclear Proteins / Q000737:chemistry / Q000235:genetics* / Q000378:metabolism; D009690:Nucleic Acid Conformation; D017354:Point Mutation; D011485:Protein Binding; D011506:Proteins / Q000378:metabolism*; D020349:Surface Plasmon Resonance
D009687:Nuclear Proteins; D011506:Proteins; D000244:Adenosine Diphosphate; D000255:Adenosine Triphosphate; D000251:Adenosine Triphosphatases; C404942:p97 ATPase