Structure of human lysine methyltransferase Srnyd2 reveals insights into the substrate divergence in Smyd proteins

• 来源期刊: 分子细胞生物学报（英文版）
• 年，卷（期）: 2011,（5）
• 页码范围: 293-300
• 页数: 8页
• 语种: 中文
• DOI: 10.1093/jmcb/mjr015

摘要

The SET- and myeloid-Nenvy-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-adenosyI-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 poptide indicates that mono-methylation of p53-Lys372 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-Lys372 on the Smyd2-mediated methylation of p53-Lys370.