Chemical and Biochemical Perspectives of Protein Lysine Methylation

Chem Rev. 2018 Jul 25;118(14):6656-6705. doi: 10.1021/acs.chemrev.8b00008. Epub 2018 Jun 21.

Abstract

Protein lysine methylation is a distinct posttranslational modification that causes minimal changes in the size and electrostatic status of lysine residues. Lysine methylation plays essential roles in regulating fates and functions of target proteins in an epigenetic manner. As a result, substrates and degrees (free versus mono/di/tri) of protein lysine methylation are orchestrated within cells by balanced activities of protein lysine methyltransferases (PKMTs) and demethylases (KDMs). Their dysregulation is often associated with neurological disorders, developmental abnormalities, or cancer. Methyllysine-containing proteins can be recognized by downstream effector proteins, which contain methyllysine reader domains, to relay their biological functions. While numerous efforts have been made to annotate biological roles of protein lysine methylation, limited work has been done to uncover mechanisms associated with this modification at a molecular or atomic level. Given distinct biophysical and biochemical properties of methyllysine, this review will focus on chemical and biochemical aspects in addition, recognition, and removal of this posttranslational mark. Chemical and biophysical methods to profile PKMT substrates will be discussed along with classification of PKMT inhibitors for accurate perturbation of methyltransferase activities. Semisynthesis of methyllysine-containing proteins will also be covered given the critical need for these reagents to unambiguously define functional roles of protein lysine methylation.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't
  • Review

MeSH terms

  • Coenzymes / chemistry
  • Coenzymes / metabolism
  • Histone Demethylases / chemistry
  • Histone Demethylases / metabolism
  • Histone-Lysine N-Methyltransferase / chemistry
  • Histone-Lysine N-Methyltransferase / classification
  • Histone-Lysine N-Methyltransferase / metabolism*
  • Humans
  • Lysine / chemistry*
  • Lysine / metabolism
  • Protein Domains
  • Protein Processing, Post-Translational
  • Substrate Specificity

Substances

  • Coenzymes
  • Histone Demethylases
  • Histone-Lysine N-Methyltransferase
  • Lysine