Cooperative subunit dynamics modulate p97 function

Significance Mutations in the highly conserved hexameric p97 enzyme are associated with a series of diseases affecting muscle, bone, and brain, and have been linked to changes to the orientation of the N-terminal domain (NTD) in each p97 subunit. Although studies have focused on p97 constructs where all protomers are WT or all contain a disease-causing mutation, a strong body of evidence suggests that p97 molecules are heterogeneous, containing a mixture of these subunits in patients. We have used solution NMR to study such heterohexameric structures, showing that the NTD conformation of a disease mutant can be somewhat remedied by WT neighbors, leading to a partial restoration of interactions with adaptor molecules. The mechanism of this allosteric process is investigated.