Lysine methylation of VCP by a member of a novel human protein methyltransferase family

Nat Commun. 2012;3:1038. doi: 10.1038/ncomms2041.


Valosin-containing protein (VCP, also called p97) is an essential and highly conserved adenosine triphosphate-dependent chaperone implicated in a wide range of cellular processes in eukaryotes, and mild VCP mutations can cause severe neurodegenerative disease. Here we show that mammalian VCP is trimethylated on Lys315 in a variety of cell lines and tissues, and that the previously uncharacterized protein METTL21D (denoted here as VCP lysine methyltransferase, VCP-KMT) is the responsible enzyme. VCP methylation was abolished in three human VCP-KMT knockout cell lines generated with zinc-finger nucleases. Interestingly, VCP-KMT was recently reported to promote tumour metastasis, and indeed, VCP-KMT-deficient cells displayed reduced growth rate, migration and invasive potential. Finally, we present data indicating that VCP-KMT, calmodulin-lysine methyltransferase and eight uncharacterized proteins together constitute a novel human protein methyltransferase family. The present work provides new insights on protein methylation and its links to human disease.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Adenosine Triphosphatases / chemistry
  • Adenosine Triphosphatases / genetics
  • Adenosine Triphosphatases / metabolism*
  • Amino Acid Motifs
  • Amino Acid Sequence
  • Cell Cycle Proteins / chemistry
  • Cell Cycle Proteins / genetics
  • Cell Cycle Proteins / metabolism*
  • Cell Line
  • Humans
  • Lysine / metabolism*
  • Methylation
  • Methyltransferases / genetics
  • Methyltransferases / metabolism*
  • Molecular Sequence Data
  • Multigene Family*
  • Sequence Alignment
  • Valosin Containing Protein


  • Cell Cycle Proteins
  • Methyltransferases
  • VCPKMT protein, human
  • Adenosine Triphosphatases
  • VCP protein, human
  • Valosin Containing Protein
  • Lysine