The general definition of the p97/valosin-containing protein (VCP)-interacting motif (VIM) delineates a new family of p97 cofactors

J Biol Chem. 2011 Nov 4;286(44):38670-8. doi: 10.1074/jbc.M111.274472. Epub 2011 Sep 6.

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.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Adaptor Proteins, Signal Transducing
  • Adaptor Proteins, Vesicular Transport
  • Adenosine Triphosphatases / chemistry*
  • Amino Acid Motifs
  • Amino Acid Sequence
  • Autophagy-Related Proteins
  • Binding Sites
  • Carrier Proteins / chemistry
  • Cell Cycle Proteins / chemistry*
  • Computational Biology / methods
  • HEK293 Cells
  • Humans
  • Magnetic Resonance Spectroscopy / methods
  • Molecular Sequence Data
  • Protein Structure, Tertiary
  • Sequence Homology, Amino Acid
  • Two-Hybrid System Techniques
  • Ubiquitin / chemistry
  • Valosin Containing Protein

Substances

  • Adaptor Proteins, Signal Transducing
  • Adaptor Proteins, Vesicular Transport
  • Autophagy-Related Proteins
  • Carrier Proteins
  • Cell Cycle Proteins
  • UBXN6 protein, human
  • Ubiquitin
  • Adenosine Triphosphatases
  • VCP protein, human
  • Valosin Containing Protein