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Gene Review

Vcp  -  valosin containing protein

Mus musculus

Synonyms: 15S Mg(2+)-ATPase p97 subunit, 3110001E05, AAA ATPase p97, CDC48, TER ATPase, ...
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Disease relevance of Vcp


High impact information on Vcp

  • Here we demonstrate that another member of this family, Cdc48 in yeast and p97 in mammals, is required for the export of ER proteins into the cytosol [2].
  • Mass spectrometry of crosslinked synaptotagmin . p97/VCP revealed interactions near Trp551 and Phe552 [3].
  • The AAA-ATPase p97/VCP facilitates protein dislocation during endoplasmic reticulum-associated degradation (ERAD) [3].
  • Given the D1 and D2 packing arrangement, we propose a ratchet mechanism for p97 during its ATP hydrolysis cycle [4].
  • p97, an abundant hexameric ATPase of the AAA family, is involved in homotypic membrane fusion [4].

Biological context of Vcp


Anatomical context of Vcp


Associations of Vcp with chemical compounds

  • Small-angle X-ray scattering (SAXS) measurements of p97 in the presence of AMP-PNP (ATP state), ADP-AlF(x) (hydrolysis transition state), ADP, or no nucleotide reveal major changes in the positions of the N domains with respect to the hexameric ring during the ATP hydrolysis cycle [10].

Physical interactions of Vcp

  • Wild-type Ube4b also requires N16 to bind VCP, despite a more C-terminal binding site in invertebrate orthologues [11].
  • In order to provide insight into the molecular basis of p97 adaptor binding, we have determined the crystal structure of p97 ND1 domains complexed with p47 C-terminal domain at 2.9 A resolution [6].
  • The crystal structure of the N-terminal domain of PNGase in complex with this motif provides detailed insight into the interaction between p97 and its substrate-processing cofactors [12].
  • We assigned the backbone amides of the p97 N domain and probed both its reciprocal binding surface with Npl4 UBD and its interaction with the p97-binding region of Ufd1 [13].

Other interactions of Vcp

  • We conclude that N-terminal sequences of Wld(S) protein influence the intranuclear location of both ubiquitin proteasome and NAD(+) synthesis machinery and that an evolutionary recent sequence mediates binding of mammalian Ube4b to VCP [11].
  • In the latter, the p97 adaptor protein p47 is of central importance [6].
  • In addition, Ufd1 and Npl4, which complex with p97, also associated with IP(3) receptors upon hormonal stimulation [8].
  • The slow Wallerian degeneration protein, WldS, binds directly to VCP/p97 and partially redistributes it within the nucleus [11].
  • Interaction with Wld(S) targets VCP to discrete intranuclear foci where ubiquitin epitopes can also accumulate [11].

Analytical, diagnostic and therapeutic context of Vcp

  • Here, we report two structures: a crystal structure of the N-terminal and D1 ATPase domains of murine p97 at 2.9 A resolution, and a cryoelectron microscopy structure of full-length rat p97 at 18 A resolution [4].
  • High constitutive VCP protein expression in subconfluent and confluent resting and mildly physiologically stressed MC3T3-E1 cells was confirmed by Western blotting [1].
  • An abundant spot with a M(r) of 94 kDa and a pI of 5.4 was identified as VCP by MALDI/ToF and peptide mass fingerprint analysis [1].


  1. Identification and characterization of valosin-containing protein (VCP/p97) in untransformed osteoblast-like cells. Behnam, K., Murray, S.S., Brochmann, E.J. J. Orthop. Res. (2005) [Pubmed]
  2. The AAA ATPase Cdc48/p97 and its partners transport proteins from the ER into the cytosol. Ye, Y., Meyer, H.H., Rapoport, T.A. Nature (2001) [Pubmed]
  3. Central pore residues mediate the p97/VCP activity required for ERAD. DeLaBarre, B., Christianson, J.C., Kopito, R.R., Brunger, A.T. Mol. Cell (2006) [Pubmed]
  4. Structure of the AAA ATPase p97. Zhang, X., Shaw, A., Bates, P.A., Newman, R.H., Gowen, B., Orlova, E., Gorman, M.A., Kondo, H., Dokurno, P., Lally, J., Leonard, G., Meyer, H., van Heel, M., Freemont, P.S. Mol. Cell (2000) [Pubmed]
  5. VCP, the mammalian homolog of cdc48, is tyrosine phosphorylated in response to T cell antigen receptor activation. Egerton, M., Ashe, O.R., Chen, D., Druker, B.J., Burgess, W.H., Samelson, L.E. EMBO J. (1992) [Pubmed]
  6. Structural basis of the interaction between the AAA ATPase p97/VCP and its adaptor protein p47. Dreveny, I., Kondo, H., Uchiyama, K., Shaw, A., Zhang, X., Freemont, P.S. EMBO J. (2004) [Pubmed]
  7. The mouse p97 (CDC48) gene. Genomic structure, definition of transcriptional regulatory sequences, gene expression, and characterization of a pseudogene. Müller, J.M., Meyer, H.H., Ruhrberg, C., Stamp, G.W., Warren, G., Shima, D.T. J. Biol. Chem. (1999) [Pubmed]
  8. Involvement of the p97-Ufd1-Npl4 complex in the regulated endoplasmic reticulum-associated degradation of inositol 1,4,5-trisphosphate receptors. Alzayady, K.J., Panning, M.M., Kelley, G.G., Wojcikiewicz, R.J. J. Biol. Chem. (2005) [Pubmed]
  9. Inclusion body myopathy-associated mutations in p97/VCP impair endoplasmic reticulum-associated degradation. Weihl, C.C., Dalal, S., Pestronk, A., Hanson, P.I. Hum. Mol. Genet. (2006) [Pubmed]
  10. Conformational changes of p97 during nucleotide hydrolysis determined by small-angle X-Ray scattering. Davies, J.M., Tsuruta, H., May, A.P., Weis, W.I. Structure (Camb.) (2005) [Pubmed]
  11. The slow Wallerian degeneration protein, WldS, binds directly to VCP/p97 and partially redistributes it within the nucleus. Laser, H., Conforti, L., Morreale, G., Mack, T.G., Heyer, M., Haley, J.E., Wishart, T.M., Beirowski, B., Walker, S.A., Haase, G., Celik, A., Adalbert, R., Wagner, D., Grumme, D., Ribchester, R.R., Plomann, M., Coleman, M.P. Mol. Biol. Cell (2006) [Pubmed]
  12. Studies on peptide:N-glycanase-p97 interaction suggest that p97 phosphorylation modulates endoplasmic reticulum-associated degradation. Zhao, G., Zhou, X., Wang, L., Li, G., Schindelin, H., Lennarz, W.J. Proc. Natl. Acad. Sci. U.S.A. (2007) [Pubmed]
  13. Detailed structural insights into the p97-Npl4-Ufd1 interface. Isaacson, R.L., Pye, V.E., Simpson, P., Meyer, H.H., Zhang, X., Freemont, P.S., Matthews, S. J. Biol. Chem. (2007) [Pubmed]
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