Vcpkmt, also known as METTL21D, is a valosin-containing protein (VCP) lysine methyltransferase. VCP, an AAA+ ATPase, is involved in diverse cellular processes like membrane fusion and proteolysis. Vcpkmt specifically catalyzes the trimethylation of Lys315 of VCP [1,3,4,5].

A constitutive knockout mouse targeting exon 1-4 of the Vcpkmt gene was generated. In Vcpkmt-/-mice, the methylation of lysine 315 in VCP was completely abolished. Vcpkmt-/-mice were viable, fertile, and had no obvious pathological phenotype, indicating that VCPKMT is not essential for development or survival under unstressed conditions. Also, in vitro methylation assays suggest that VCP is the sole substrate of VCPKMT [2].

In conclusion, Vcpkmt is an enzyme responsible for the methylation of K315 of VCP in vivo. The Vcpkmt knockout mouse model reveals that while Vcpkmt-mediated VCP methylation is dispensable for normal development and survival in mice, it may still have implications in understanding the role of VCP post-translational modifications in disease conditions where stress or specific cellular perturbations are involved [2].

References:

1. Nguyen, Thang Quyet, Koh, Seri, Kwon, Jiin, Kang, Wonchull, Yang, Jin Kuk. 2023. Structural basis for recognition and methylation of p97 by METTL21D, a valosin-containing protein lysine methyltransferase. In iScience, 26, 107222. doi:10.1016/j.isci.2023.107222. https://pubmed.ncbi.nlm.nih.gov/37456834/

2. Fusser, Markus, Kernstock, Stefan, Aileni, Vinay Kumar, Falnes, Pål Ø, Klungland, Arne. 2015. Lysine Methylation of the Valosin-Containing Protein (VCP) Is Dispensable for Development and Survival of Mice. In PloS one, 10, e0141472. doi:10.1371/journal.pone.0141472. https://pubmed.ncbi.nlm.nih.gov/26544960/

3. Petrović, Saša, Roske, Yvette, Rami, Biria, Panáková, Daniela, Heinemann, Udo. 2023. Structural remodeling of AAA+ ATPase p97 by adaptor protein ASPL facilitates posttranslational methylation by METTL21D. In Proceedings of the National Academy of Sciences of the United States of America, 120, e2208941120. doi:10.1073/pnas.2208941120. https://pubmed.ncbi.nlm.nih.gov/36656859/

4. Aileni, Vinay Kumar, Davydova, Erna, Moen, Anders, Falnes, Pål Ø. 2017. A System for Enzymatic Lysine Methylation in a Desired Sequence Context. In ACS omega, 2, 462-469. doi:10.1021/acsomega.6b00486. https://pubmed.ncbi.nlm.nih.gov/28357416/

5. Kernstock, Stefan, Davydova, Erna, Jakobsson, Magnus, Egge-Jacobsen, Wolfgang, Falnes, Pål Ø. . Lysine methylation of VCP by a member of a novel human protein methyltransferase family. In Nature communications, 3, 1038. doi:10.1038/ncomms2041. https://pubmed.ncbi.nlm.nih.gov/22948820/