NDLI: 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▿

Content Provider	PubMed Central
Author	Halawani, Dalia Leblanc, Andréa C. Isabelle, Rouiller Michnick, Stephen W. Servant, Marc J. Martin, Latterich
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 increase in ATPase activity compared to wild-type p97 (p97WT) and displayed increased sensitivity to heat-induced upregulation of ATPase activity. Protein fluorescence analysis provided evidence for conformational differences in the D2 rings of both hIBMPFTD mutants. Furthermore, both mutations increased the proteolytic susceptibility of the D2 ring. The solution structures of all p97/VCP proteins revealed a didispersed distribution of a predominant hexameric population and a minor population of large-diameter complexes. ATP binding significantly increased the abundance of large-diameter complexes for p97R155P and p97A232E, but not p97WT or the ATP-binding mutant p97K524A. Therefore, we propose that hIBMPFTD p97/VCP mutants p97R155P and p97A232E possess structural defects that may compromise the mechanism of p97/VCP activity within large multiprotein complexes.
Related Links	http://dx.doi.org/10.1128/mcb.00252-09
Ending Page	4494
Page Count	11
Starting Page	4484
File Format	PDF
ISSN	02707306
e-ISSN	10985549
Journal	Molecular and Cellular Biology
Issue Number	16
Volume Number	29
Language	English
Publisher	American Society for Microbiology (ASM)
Publisher Date	2009-08-15
Access Restriction	Open
Rights Holder	American Society for Microbiology (ASM)
Subject Keyword	Cell Biology Molecular Biology Research in Higher Education
Content Type	Text
Resource Type	Article
Subject	Cell Biology Molecular Biology

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