title: The general definition of the p97/valosin-containing protein (VCP)-interacting motif (VIM) delineates a new family of p97 cofactors.
abstract: Cellular functions of the essential, ubiquitin-selective AAA ATPase p97/valosin-containing protein (VCP) are controlled by regulatory cofactors determining substrate specificity and fate. Most cofactors bind p97 through a ubiquitin regulatory X (UBX) or UBX-like domain or linear sequence motifs, including the hitherto ill defined p97/VCP-interacting motif (VIM). Here, we present the new, minimal consensus sequence RX(5)AAX(2)R as a general definition of the VIM that unites a novel family of known and putative p97 cofactors, among them UBXD1 and ZNF744/ANKZF1. We demonstrate that this minimal VIM consensus sequence is necessary and sufficient for p97 binding. Using NMR chemical shift mapping, we identified several residues of the p97 N-terminal domain (N domain) that are critical for VIM binding. Importantly, we show that cellular stress resistance conferred by the yeast VIM-containing cofactor Vms1 depends on the physical interaction between its VIM and the critical N domain residues of the yeast p97 homolog, Cdc48. Thus, the VIM-N domain interaction characterized in this study is required for the physiological function of Vms1 and most likely other members of the newly defined VIM family of cofactors.
authors: Department of Biochemistry, Biocenter, University of Würzburg, Am Hubland, 97074 Würzburg, Germany.
authors: Christopher
authors: C
authors: Stapf
authors: Medical Research Council Centre for Protein Engineering, Hills Road, Cambridge, CB2 2QH, United Kingdom.
authors: Edward
authors: E
authors: Cartwright
authors: Medical Research Council Centre for Protein Engineering, Hills Road, Cambridge, CB2 2QH, United Kingdom.
authors: Mark
authors: M
authors: Bycroft
authors: Miltenyi Biotec GmbH, Friedrich-Ebert-Strasse 68, 51429 Bergisch-Gladbach, Germany.
authors: Kay
authors: K
authors: Hofmann
authors: Department of Biochemistry, Biocenter, University of Würzburg, Am Hubland, 97074 Würzburg, Germany. Electronic address: alexander.buchberger@biozentrum.uni-wuerzburg.de.
authors: Alexander
authors: A
authors: Buchberger
mesh_terms: D048868:Adaptor Proteins, Signal Transducing; D033942:Adaptor Proteins, Vesicular Transport; D000251:Adenosine Triphosphatases / Q000737:chemistry*; D020816:Amino Acid Motifs; D000595:Amino Acid Sequence; D000071183:Autophagy-Related Proteins; D001665:Binding Sites; D002352:Carrier Proteins / Q000737:chemistry; D018797:Cell Cycle Proteins / Q000737:chemistry*; D019295:Computational Biology / Q000379:methods; D057809:HEK293 Cells; D006801:Humans; D009682:Magnetic Resonance Spectroscopy / Q000379:methods; D008969:Molecular Sequence Data; D017434:Protein Structure, Tertiary; D017386:Sequence Homology, Amino Acid; D020798:Two-Hybrid System Techniques; D025801:Ubiquitin / Q000737:chemistry; D000074405:Valosin Containing Protein
chemical_list: D048868:Adaptor Proteins, Signal Transducing; D033942:Adaptor Proteins, Vesicular Transport; D000071183:Autophagy-Related Proteins; D002352:Carrier Proteins; D018797:Cell Cycle Proteins; C533572:UBXN6 protein, human; D025801:Ubiquitin; D000251:Adenosine Triphosphatases; C000614178:VCP protein, human; D000074405:Valosin Containing Protein