Hereditary inclusion body myopathy-linked p97/VCP mutations in the NH 2 domain and the D1 ring modulate p97/VCP ATPase activity and D2 ring conformation

Abstract

Hereditary inclusion body myopathy associated with early-onset Paget disease of bone and frontotemporal dementia (hIBMPFTD) is a degenerative disorder caused by single substitutions in highly conserved residues of p97/VCP. All mutations identified thus far cluster within the NH2 domain or the D1 ring, which are both required for communicating conformational changes to adaptor protein complexes. In this study, biochemical approaches were used to identify the consequences of the mutations R155P and A232E on p97/VCP structure. Assessment of p97/VCP oligomerization revealed that p97R155P and p97A232E formed hexameric ring-shaped structures of ∼600 kDa. p97R155P and p97A232E exhibited an ∼3-fold ..