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Cell Discov. 2017 Dec 12;3:17045. doi: 10.1038/celldisc.2017.45. eCollection 2017.

Structural basis for nucleotide-modulated p97 association with the ER membrane.

Author information

1
Laboratory of Cell Biology, Center for Cancer Research, National Cancer Institute, National Institutes of Health, Bethesda, MD, USA.
2
Laboratory of Molecular Biology, National Institute of Diabetes and Digestive and Kidney Disease, National Institutes of Health, Bethesda, MD, USA.

Abstract

Association of the cytosolic AAA (ATPases associated with various cellular activities) protein p97 to membranes is essential for various cellular processes including endoplasmic reticulum (ER)-associated degradation. The p97 consists of two ATPase domains and an N domain that interacts with numerous cofactors. The N domain of p97 is known to undergo a large nucleotide-dependent conformation switch, but its physiological relevance is unclear. Here we show p97 is recruited to canine ER membranes predominantly by interacting with VCP-interacting membrane protein (VIMP), an ER-resident protein. We found that the recruitment is modulated through a nucleotide-dependent conformation switch of the N domain in wild-type p97, but this modulation is absent in pathogenic mutants. We demonstrate the molecular mechanism of the modulation by a series of structures of p97, VIMP and their complexes and suggest a physiological role of the nucleotide-dependent N domain conformation switch. The lack of modulation in pathogenic mutants is caused by changes in interactions between the N and D1 domain, as demonstrated by multiple intermediate positions adopted by N domains of mutant p97. Our findings suggest the nucleotide-modulated membrane association may also have a role in other p97-dependent processes.

KEYWORDS:

AAA protein; IBMPFD/MSP; VIMP/SelS; p97-VIMP complex; p97/VCP

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