Mechanism of histone lysine methyl transfer revealed by the structure of SET7/9-AdoMet
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- Mechanism of histone lysine methyl transfer revealed by the structure of SET7/9-AdoMet
- Kwon, Taewoo; Chang, Jeong Ho; Kwak, Eunyee; Lee, Changwook; Joachimiak, Andrzej; Kim, Young Chang; Lee, Jae Woon; Cho, Yunje
- Issue Date
- OXFORD UNIV PRESS
- EMBO JOURNAL, v.22, no.2, pp.292 - 303
- 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 A 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.
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