Protein lysine methylation by seven-β-strand methyltransferases

Abstract

Methylation of biomolecules is a frequent biochemical reaction within the cell, and a plethora of highly specific methyltransferases (MTases) catalyse the transfer of a methyl group from S-adenosylmethionine (AdoMet) to various substrates. The posttranslational methylation of lysine residues, catalysed by numerous lysine (K)-specific protein MTases (KMTs), is a very common and important protein modification, which recently has been subject to intense studies, particularly in the case of histone proteins. The majority of KMTs belong to a class of MTases that share a defining 'SET domain', and these enzymes mostly target lysines in the flexible tails of histones. However, the so-called seven-β-strand (7BS) MTases, characterized by a twisted beta-sheet structure and certain conserved sequence motifs, represent the largest MTase class, and these enzymes methylate a wide range of substrates, including small metabolites, lipids, nucleic acids and proteins. Until recently, the histone-specific Dot1/DOT1L was the only identified eukaryotic 7BS KMT. However, a number of novel 7BS KMTs have now been discovered, and, in particular, several recently characterized human and yeast members of MTase family 16 (MTF16) have been found to methylate lysines in non-histone proteins. Here, we review the status and recent progress on the 7BS KMTs, and discuss these enzymes at the levels of sequence/structure, catalytic mechanism, substrate recognition and biological significance.

The ribosome: A hot spot for the identification of new types of protein methyltransferases

“…In recent years, it has been recognized that proteins of the translational apparatus, including both ribosomal proteins and elongation factors, are major substrates for methylation reactions (5,7,8,19,28). These proteins, and the enzymes that modify them, have been extensively studied from the intersection of two research directions.…”

“…However, it is now clear that methyl groups can stand beside phosphate groups and ubiquitin as major players in controlling the physiological functions of proteins. We are beginning to understand how the much greater diversity of protein methylation reactions can give rise to a greater diversity of function (1,(4)(5)(6)(7)(8). We are also learning the importance of crosstalk between protein and DNA methylation reactions (9) and among protein methylation, phosphorylation, acetylation, and ubiquitination reactions (10)(11)(12).…”

“…However, recent work has emphasized the importance of methylating non-histone substrates at these residues, particularly ribosomal proteins, translation factors, and transcription factors in a wide variety of organisms (7,8,15,18,19). Furthermore, the methylation of lysine and arginine residues represents just the tip of the iceberg in protein methylation -modifications have also been established at histidine, modified histidine (diphthamide), glutamate, glutamine, asparagine, Lisoaspartate, D-aspartate, cysteine, isoprenylcysteine, methionine, N-terminal, and C-terminal residues (1,4 RNA (7,23,24).…”

The lysine methyltransferase SMYD2 methylates the kinase domain of type II receptor BMPR2 and stimulates bone morphogenetic protein signaling

“…With the presence of large number of lysine methyltransferases (KMTs) in mammalian genomes (4,5), it is not surprising that an increasingly larger number of non-histone chromosomal, nuclear and cytoplasmic proteins have been found to be lysine methylated (6)(7)(8)(9). Lysine methylation can be dynamically removed by the action of demethylases (10,11), making it a feasible mechanism for signal transduction.…”

A System for Enzymatic Lysine Methylation in a Desired Sequence Context

“…6−8 The SET domain MTase family, named after its three founding members (Su(var)-39, E(z), and Trithorax), appears to consist exclusively of KMTs, and these enzymes mainly recognize specific motifs in unstructured, short peptide sequences, such as the flexible N-terminal tails of histone proteins. 7 In contrast, the 7BS MTases act on a wide range of substrates, including small metabolites, nucleic acids, and proteins; however, recently, a number of novel human KMTs belonging to this group have been discovered.…”