The Histidine Methyltransferase Universe: Characterization of METTL9 and CARNMT1 – Two Novel Protein Histidine Methyltransferases

Abstract

The proteins in all living organism are composed of 20 primary amino acids. These can be modified by a variety of chemical modifications. One of the most important ones is methylation, which can occur on some of the amino acids. Such methylations play an important role in optimizing and regulating the function of the proteins and changes in such methylations can lead to human disease. One less characterized protein methylation is that on the amino acid residue histidine, even though it has become recently evident that histidine methylation is abundant and important. Specific enzymes called methyltransferases attach methyl groups (-CH3) to histidine residues and the present thesis has focused on characterizing two histidine methyltransferases. The first, METTL9, is of particular interest because it has diverse substrates in humans and other eukaryotes relevant to zinc homeostasis and immunity. For the second enzyme, CARNMT1, we found evidence that it also has multiple substrates in humans, but more investigations are needed to elucidate its biological function. Our discoveries explore a small part of the growing universe of histidine methylation, and set the stage for future studies on this fascinating but largely unexplored protein modification.