Journal article

Hereditary Inclusion Body Myopathy-Linked p97/VCP Mutations in the NH2 Domain and the D1 Ring Modulate p97/VCP ATPase Activity and D2 Ring Conformation

Dalia Halawani, Andrea C LeBlanc, Isabelle Rouiller, Stephen W Michnick, Marc J Servant, Martin Latterich

MOLECULAR AND CELLULAR BIOLOGY | AMER SOC MICROBIOLOGY | Published : 2009

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 NH(2) 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 p97(R155P) and p97(A232E) formed hexameric ring-shaped structures of approximately 600 kDa. p97(R155P) and p97(A232E..

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Grants

Awarded by CIHR


Funding Acknowledgements

Part of this work was supported by grants from the HFSP, Genome Canada, Silicon Kinetics, and Genocean to M. L.; CIHR grant MOP-86693 to I. R.; CIHR grant MOP-53282 to M. J. S.; and CIHR grant MOP-81146 to A. L. I. R. is the recipient of a CIHR New Investigator award, and M. J. S. is the recipient of an Rx&D/CIHR Health Research Foundation Career Award in Health Sciences. M. L. acknowledges support from the Canada Research Chair Program.