Structural and Sequence Motifs of Protein (Histone) Methylation Enzymes

Abstract

With genome sequencing nearing completion for the model organisms used in biomedical research, there is a rapidly growing appreciation that proteomics, the study of covalent modification to proteins, and transcriptional regulation will likely dominate the research headlines in the next decade. Protein methylation plays a central role in both of these fields, as several different residues (Arg, Lys, Gln) are methylated in cells and methylation plays a central role in the "histone code" that regulates chromatin structure and impacts transcription. In some cases, a single lysine can be mono-, di-, or trimethylated, with different functional consequences for each of the three forms. This review describes structural aspects of methylation of histone lysine residues by two enzyme families with entirely different structural scaffolding (the SET proteins and Dot1p) and methylation of protein arginine residues by PRMTs.

Lysine residues in N-terminal and C-terminal regions of human histone H2A are targets for biotinylation by biotinidase

“…These peptides were subjected to enzymatic biotinylation, and peptide-bound biotin was probed using gel electrophoresis and streptavidin peroxidase. Both N [1][2][3][4][5][6][7][8][9] and N 7-14 were good targets for biotinylation by biotinidase but N [12][13][14][15][16][17][18][19][20] was not a good target (Fig. 1, lanes 1 -3).…”

“…2, lane 1). If K9 was substituted with alanine (peptide K9A [1][2][3][4][5][6][7][8][9] ) no biotinylation was detectable (lane 2). In contrast, substitution of K5 with alanine residues (peptide K5A 1-9 ) did not decrease biotinylation (lane 3).…”

“…Lysine (K), arginine (R), serine (S), threonine (T), and glutamate residues in these tails are targets for posttranslational modifications such as acetylation, methylation, ubiquitination, phosphorylation, sumoylation, and poly(ADP-ribosylation) [2]. These covalent modifications play important roles in the epigenetic control of chromatin structure, genomic stability, and gene expression [3][4][5]. Some regions in C-terminal domains (e.g., hinge regions) are also exposed at the nucleosomal surface, and are potential targets for covalent modifications [1].…”

Structural dynamics of protein lysine methylation and demethylation

“…HKMTs can be classified according to the presence or absence and the nature of sequences surrounding the SET domain that are conserved within families [24,25]. Representatives of the major families include SUV, SET1, SET2, EZ, and RIZ (for example, see [26]). The SET7/9 and SET8 proteins do not fit into these families.…”

“…In human, mistargeting of hDOT1L to Hoxa9 (a leukemia-relevant gene) plays an important role in MLL (mixed lineage leukemia)-AF10-mediated leukemogenesish [73]. A sequence analysis [74] suggested that Dot1p possesses AdoMet-binding motifs characteristic of class-I MTases [75], similar to those in protein arginine MTases that modify arginines on many proteins including histones H3 and H4 [20,26]. Class-I MTases such as Dot1p are distinct from and do not contain the SET domain.…”