title: Lysine methylation of VCP by a member of a novel human protein methyltransferase family.
abstract: 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.
authors.affiliation: Department of Molecular Biosciences, Faculty of Mathematics and Natural Sciences, University of Oslo, Oslo                 0316                 Norway.
authors.forename: Stefan
authors.initials: S
authors.lastname: Kernstock
authors.forename: Erna
authors.initials: E
authors.lastname: Davydova
authors.forename: Magnus
authors.initials: M
authors.lastname: Jakobsson
authors.forename: Anders
authors.initials: A
authors.lastname: Moen
authors.forename: Solveig
authors.initials: S
authors.lastname: Pettersen
authors.forename: Gunhild M
authors.initials: GM
authors.lastname: Mælandsmo
authors.forename: Wolfgang
authors.initials: W
authors.lastname: Egge-Jacobsen
authors.forename: Pål Ø
authors.initials: PØ
authors.lastname: Falnes
mesh_terms: D000251:Adenosine Triphosphatases / Q000737:chemistry / Q000235:genetics / Q000378:metabolism*; D020816:Amino Acid Motifs; D000595:Amino Acid Sequence; D018797:Cell Cycle Proteins / Q000737:chemistry / Q000235:genetics / Q000378:metabolism*; D002460:Cell Line; D006801:Humans; D008239:Lysine / Q000378:metabolism*; D008745:Methylation; D008780:Methyltransferases / Q000235:genetics / Q000378:metabolism*; D008969:Molecular Sequence Data; D005810:Multigene Family; D016415:Sequence Alignment; D000074405:Valosin Containing Protein
chemical_list: D018797:Cell Cycle Proteins; D008780:Methyltransferases; C577899:VCPKMT protein, human; D000251:Adenosine Triphosphatases; C000614178:VCP protein, human; D000074405:Valosin Containing Protein; D008239:Lysine