Altered cofactor regulation with disease-associated p97/VCP mutations

摘要: Dominant mutations in p97/VCP (valosin-containing protein) cause a rare multisystem degenerative disease with varied phenotypes that include inclusion body myopathy, Paget’s of bone, frontotemporal dementia, and amyotrophic lateral sclerosis. p97 mutants have altered N-domain conformations, elevated ATPase activity, cofactor association. We now discovered previously unidentified disease-relevant functional property by identifying how the cofactors p37 p47 regulate activity. define as, to our knowledge, first known p97-activating cofactor, which enhances catalytic efficiency (kcat/Km) 11-fold. Whereas both decrease Km ATP p97, increases kcat p97. In contrast, regulation is biphasic, decreased at low levels but increased higher levels. By deleting region lacks homology (amino acids 69–92), we changed from an inhibitory activating similar p37. Our data suggest activity binding N domain. Induced conformation changes affect ADP/ATP D1 domain, turn controls cycling. Most importantly, found D2 domain failed be activated or p47. results show play critical role controlling lack cofactor-regulated communication may contribute p97-associated pathogenesis.