VCPKMT (METTL21D) is a highly specific protein lysine methyltransferase that catalyzes the trimethylation of lysine 315 (Lys315) in valosin-containing protein (VCP/p97), a crucial AAA+ ATPase 12. The enzyme functions by first disassembling p97 hexamers into monomeric units, making the buried Lys315 residue accessible for methylation 2. This process is facilitated by the adaptor protein ASPL, which structurally remodels p97 to expose the target lysine residue 3. Structural studies reveal that VCPKMT recognizes monomeric p97 through specific molecular interactions involving the N/D1 domains 2. While trimethylation of Lys315 may decrease VCP ATPase activity, knockout studies in mice demonstrate that VCPKMT is dispensable for normal development and survival under unstressed conditions 1. Notably, VCPKMT expression has been associated with cancer progression, as it was identified as part of a three-gene signature predictive of positive surgical margins in tongue squamous cell carcinomas 4. The enzyme appears to be highly substrate-specific, with VCP being its primary target 1.