Structural and functional analysis of p47 cofactor binding on the p97 disease mutant

Human p97/VCP (valosin-containing protein) is a hexameric AAA+ (ATPase associated with diverse cellular activities) ATPase plays a pivotal role in the regulation of multiple cellular activities by interacting with various cofactor proteins. Critical roles of p97 involve ubiquitin-dependent protein quality control and regulation of membrane fusion in the Golgi apparatus in the presence of cofactor p47. Heterozygous missense mutations of p97 have been implicated in numerous neurodegenerative diseases, such as IBMPFD (Inclusion body myopathy with early-onset Paget’s disease and frontotemporal dementia) and ALS (amyotrophic lateral sclerosis). The disease mutations of the p97 are mostly clustered on the Ndomain or the connection between N and D1-domain. The single amino acid mutation of R155H on the N-domain is the highest mutated sites, leading to a rare degenerative disease multisystem proteinopathy 1 (MSP1) and resulting in abnormal ATPase activity and cofactor dysregulation. The structural details of the interaction between p97 and p47 cofactor. Our study aims to characterize the protein interactions and identify the key complex structure to answer disease relevance of the p97 -p47 complex.