Mechanisms of Substrate Recognition by the Multispecific Protein Lysine Methyltransferase SETD6.

ABSTRACT: The SETD6 protein lysine methyltransferase monomethylates specific lysine residues in a diverse set of substrates which contain the target lysine residue in a highly variable amino acid sequence context. To investigate the mechanism underlying this multispecificity, we analyzed SETD6 substrate recognition using AlphaFold 3 docking and peptide SPOT array methylation experiments. Structural modeling of the SETD6-E2F1 complex suggested that substrate binding alone is insufficient to restrict SETD6 activity to only one lysine residue, pointing to additional sequence readout at the target site. Methylation of mutational scanning peptide SPOT arrays derived from four different SETD6 substrates (E2F1 K117, H2A.Z K7, RELA K310, and H4 K12) revealed sequence preferences of SETD6 at positions -1, +2

SUBMITTER: Ulu GT 

PROVIDER: S-EPMC12565505 | biostudies-literature | 2025 Oct

REPOSITORIES: biostudies-literature