New publication in "Life"

New publication in "Life"

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. Our data revealed amino acid residue preferences at the substrate positions −1, +2, and +3 relative to the target lysine. However, these preferences, were amino acids sequence dependent and variably exploited among different substrates, indicating conformational variability of the enzyme–substrate interface. These findings reveal a versatile mode of peptide recognition by SETD6 in which the readout of each substrate position depends on the overall substrate peptide sequence. These findings can explain the multispecificity of SETD6 and similar mechanisms may underlie substrate selection of other protein methyltransferases.