Structure and catalytic mechanism of the human histone methyltransferase SET7/9

Abstract

Article:Xiao, B., Jing, C., Wilson, J.R. et al. (7 more authors) (2003) Structure and catalytic mechanism of the human histone methyltransferase SET7/9. Nature, 421 (6923). pp.

Structural dynamics of protein lysine methylation and demethylation

“…Currently known structures of SET proteins include the crystal structures of two SUV family proteins, Neurospora crassa DIM-5 [23,27] (Figure 1a) and Schizosaccharomyces pombe Clr4 [28] (Figure 1b); six human SET7/9 structures in various configurations [29][30][31][32][33][34] (Figure 1c); two human SET8 (or Pr-SET7) structures [35,36] (Figure 1d); an NMR structure of a viral protein that contains only the SET domain (vSET) [37]; and a nonhistone Rubisco MTase [38,39]. These structures revealed that the SET domain forms a novel β-fold with a series of curved β-strands forming several small sheets, packed together with post-SET, pre-SET, or an additional domain (i-SET) inserted into SET domain.…”

“…Comparison of the structure of DIM-5 [27] with that of SET7/9 [32][33][34], and SET8 [35,36], two SET proteins that do not have a cysteine-rich post-SET domain, reveals a remarkable example of convergent evolution. In particular, like DIM-5, these two enzymes rely on residues C-terminal to the SET domain for the formation of a lysine channel, but do so by packing an α-helix, rather than a metal center, onto the active site (Figures 1c-d).…”

“…Five ternary structures, DIM-5 in complex with histone H3 Lys-9 peptide [27], SET7/9 in complex with a peptide containing either histone H3 Lys-4, the tumor suppressor p53 Lys-372, or the TBP-associated factor TAF10 Lys-189 [32][33][34], and SET8 in complex with histone H4 Lys-20 [35,36], revealed the target lysine is inserted into a narrow channel so that the target nitrogen lies in close proximity to the methyl-donor AdoMet at the opposite end of the channel (Figures 3b-c). The aromatic side chains form the channel wall and make van der Waals contacts to the methylene part of the target lysine side chain (Figure 3e).…”

“…Human SET7/9 protein generates exclusively monomethyl Lys-4 of H3 [27,32]. DIM-5 of N. crassa, on the other hand, generates primarily trimethyl Lys-9, which marks chromatin regions for DNA methylation [49].…”

“…DIM-5 and SET7/9 generate distinct products: DIM-5 forms trimethyl-lysine ( Figure 3a) [27,49] and SET7/9 forms only monomethyl-lysine ( Figure 3d) [27,32]. A likely structural explanation for their different product specificities is that residues in the lysine-binding channel of SET7/9 sterically exclude the target lysine side chain with methyl group(s).…”