Mechanistic basis of the increased methylation activity of the SETD2 protein lysine methyltransferase towards a designed super-substrate peptide

Abstract

The SET-domain containing protein 2 (SETD2) is a protein lysine methyltransferase that has been shown to methylate the super-substrate peptide ssK36 100 times faster than the corresponding natural H3K36 peptide. Here, a combination of molecular dynamics simulations and biochemical experiments are applied to identify the mechanisms responsible for the increased activity of SETD2 towards ssK36.