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 Lee, Yunje Cho

Research output: Contribution to journalArticle

91 Citations (Scopus)

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
Externally publishedYes

Fingerprint

Methionine
Histones
Lysine
Methylation
Substrates
S-Adenosylmethionine
Gene expression
Chromatin
Tyrosine
Conformations
Catalytic Domain
Crystal structure
Gene Expression
Molecules
histone methyltransferase

Keywords

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

ASJC Scopus subject areas

  • Genetics
  • Cell Biology

Cite this

Kwon, T., Chang, J. H., Kwak, E., Lee, C. W., Joachimiak, A., Kim, Y. C., ... 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

Mechanism of histone lysine methyl transfer revealed by the structure of SET7/9-AdoMet. / Kwon, Taewoo; Chang, Jeong Ho; Kwak, Eunyee; Lee, Chang Wook; Joachimiak, Andrzej; Kim, Young Chang; Lee, Jae; Cho, Yunje.

In: EMBO Journal, Vol. 22, No. 2, 15.01.2003, p. 292-303.

Research output: Contribution to journalArticle

Kwon, T, Chang, JH, Kwak, E, Lee, CW, Joachimiak, A, Kim, YC, Lee, J & Cho, Y 2003, 'Mechanism of histone lysine methyl transfer revealed by the structure of SET7/9-AdoMet', EMBO Journal, vol. 22, no. 2, pp. 292-303. https://doi.org/10.1093/emboj/cdg025
Kwon T, Chang JH, Kwak E, Lee CW, Joachimiak A, Kim YC et al. Mechanism of histone lysine methyl transfer revealed by the structure of SET7/9-AdoMet. EMBO Journal. 2003 Jan 15;22(2):292-303. https://doi.org/10.1093/emboj/cdg025
Kwon, Taewoo ; Chang, Jeong Ho ; Kwak, Eunyee ; Lee, Chang Wook ; Joachimiak, Andrzej ; Kim, Young Chang ; Lee, Jae ; Cho, Yunje. / Mechanism of histone lysine methyl transfer revealed by the structure of SET7/9-AdoMet. In: EMBO Journal. 2003 ; Vol. 22, No. 2. pp. 292-303.
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