期刊
JOURNAL OF MOLECULAR CELL BIOLOGY
卷 3, 期 5, 页码 293-300出版社
OXFORD UNIV PRESS
DOI: 10.1093/jmcb/mjr015
关键词
Smyd2; Smyd proteins; SET family; histone lysine methyltransferase; epigenetics
类别
资金
- Ministry of Science and Technology of China [2007CB914302, 2011CB966301]
- National Natural Science Foundation of China [30730028]
- Chinese Academy of Sciences [SIBS2008002]
- Science and Technology Commission of Shanghai Municipality [10JC1416500]
- SA-SIBS
The SET- and myeloid-Nervy-DEAF-1 (MYND)-domain containing (Smyd) lysine methyltransferases 1-3 share relatively high sequence similarity but exhibit divergence in the substrate specificity. Here we report the crystal structure of the full-length human Smyd2 in complex with S-adenosyl-L-homocysteine (AdoHcy). Although the Smyd1-3 enzymes are similar in the overall structure, detailed comparisons demonstrate that they differ substantially in the potential substrate-binding site. The binding site of Smyd3 consists mainly of a deep and narrow pocket, while those of Smyd1 and Smyd2 consist of a comparable pocket and a long groove. In addition, Smyd2, which has lysine methyltransferase activity on histone H3-lysine 36, exhibits substantial differences in the wall of the substrate-binding pocket compared with those of Smyd1 and Smyd3 which have activity specifically on histone H3-lysine 4. The differences in the substrate-binding site might account for the observed divergence in the specificity and methylation state of the substrates. Further modeling study of Smyd2 in complex with a p53 peptide indicates that mono-methylation of p53-Lys(372) might result in steric conflict of the methyl group with the surrounding residues of Smyd2, providing a structural explanation for the inhibitory effect of the SET7/9-mediated mono-methylation of p53-Lys(372) on the Smyd2-mediated methylation of p53-Lys(370).
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