Mechanism of histone lysine methyl transfer revealed by the structure of SET7/9-AdoMet

Taewoo Kwon, Jeong Ho Chang, Eunyee Kwak, Chang Wook Lee, Andrzej Joachimiak, Young Chang Kim, Jae Woon Lee, Yunje Cho

Research output: Contribution to journalArticle

96 Scopus citations

Abstract

The methylation of lysine residues of histones plays a pivotal role in the regulation of chromatin structure and gene expression. Here, we report two crystal structures of SET7/9, a histone methyltransferase (HMTase) that transfers methyl groups to Lys4 of histone H3, in complex with S-adenosyl-L-methionine (AdoMet) determined at 1.7 and 2.3 Å resolution. The structures reveal an active site consisting of: (i) a binding pocket between the SET domain and a c-SET helix where an AdoMet molecule in an unusual conformation binds; (ii) a narrow substrate-specific channel that only unmethylated lysine residues can access; and (iii) a catalytic tyrosine residue. The methyl group of AdoMet is directed to the narrow channel where a substrate lysine enters from the opposite side. We demonstrate that SET7/9 can transfer two but not three methyl groups to unmodified Lys4 of H3 without substrate dissociation. The unusual features of the SET domain-containing HMTase discriminate between the un- and methylated lysine substrate, and the methylation sites for the histone H3 tail.

Original languageEnglish (US)
Pages (from-to)292-303
Number of pages12
JournalEMBO Journal
Volume22
Issue number2
DOIs
StatePublished - Jan 15 2003

Keywords

  • 9 histone methyltransferase
  • Compact form of AdoMet
  • Post-SET helix
  • SET domain
  • SET7
  • Substrate-specific channel

ASJC Scopus subject areas

  • Neuroscience(all)
  • Molecular Biology
  • Biochemistry, Genetics and Molecular Biology(all)
  • Immunology and Microbiology(all)

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    Kwon, T., Chang, J. H., Kwak, E., Lee, C. W., Joachimiak, A., Kim, Y. C., Lee, J. W., & Cho, Y. (2003). Mechanism of histone lysine methyl transfer revealed by the structure of SET7/9-AdoMet. EMBO Journal, 22(2), 292-303. https://doi.org/10.1093/emboj/cdg025