Structural and Functional Analysis of Disease-Linked p97 ATPase Mutant Complexes.
IBMPFD/ALS is a genetic disorder caused by a single amino acid mutation on the p97 ATPase, promoting ATPase activity and cofactor dysregulation. The disease mechanism underlying p97 ATPase malfunction remains unclear. To understand how the mutation alters the ATPase regulation, we assembled a full-length p97R155H with its p47 cofactor and first visualized their structures using single-particle cryo-EM. More than one-third of the population was the dodecameric form. Nucleotide presence dissociates the dodecamer into two hexamers for its highly elevated function. The N-domains of the p97R155H mutant all show up configurations in ADP- or ATPγS-bound states. Our functional and structural analyses showed that the p47 binding is likely to impact the p97R155H ATPase activities via changing the conformations of arginine fingers. These functional and structural analyses underline the ATPase dysregulation with the miscommunication between the functional modules of the p97R155H.
['Nandi|Purbasha|P|0000-0002-8047-2029', 'Li|Shan|S|0000-0002-0829-1821', 'Columbres|Rod Carlo A|RCA|', 'Wang|Feng|F|', 'Williams|Dewight R|DR|', 'Poh|Yu-Ping|YP|', 'Chou|Tsui-Fen|TF|', 'Chiu|Po-Lin|PL|0000-0001-8608-7650']
D057180:Frontotemporal Dementia D006801:Humans D046529:Microscopy, Electron, Transmission D008958:Models, Molecular D049288:Muscular Dystrophies, Limb-Girdle D009154:Mutation D018979:Myositis, Inclusion Body D010001:Osteitis Deformans D011487:Protein Conformation D052067:Soluble N-Ethylmaleimide-Sensitive Factor Attachment Proteins D000074405:Valosin Containing Protein
p97 ATPase IBMPFD p47 cofactor single-particle cryo-EM arginine finger p97R155H mutation