title: Structure of human lysine methyltransferase Smyd2 reveals insights into the substrate divergence in Smyd proteins.
abstract: 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).
authors: State Key Laboratory of Molecular Biology and Research Center for Structural Biology, Institute of Biochemistry and Cell Biology, Shanghai Institutes for Biological Sciences, Chinese Academy of Sciences, China.
authors: Shutong
authors: S
authors: Xu
authors: Chen
authors: C
authors: Zhong
authors: Tianlong
authors: T
authors: Zhang
authors: Jianping
authors: J
authors: Ding
mesh_terms: D000595:Amino Acid Sequence; D001665:Binding Sites; D018360:Crystallography, X-Ray; D004268:DNA-Binding Proteins / Q000737:chemistry / Q000378:metabolism; D011495:Histone-Lysine N-Methyltransferase / Q000737:chemistry* / Q000378:metabolism*; D006657:Histones / Q000737:chemistry / Q000378:metabolism; D006801:Humans; D007527:Isoenzymes / Q000737:chemistry / Q000378:metabolism; D008239:Lysine / Q000737:chemistry / Q000378:metabolism; D008958:Models, Molecular; D008969:Molecular Sequence Data; D009124:Muscle Proteins / Q000737:chemistry / Q000378:metabolism; D017434:Protein Structure, Tertiary; D012435:S-Adenosylhomocysteine / Q000737:chemistry / Q000378:metabolism; D013379:Substrate Specificity; D014157:Transcription Factors / Q000737:chemistry / Q000378:metabolism; D016159:Tumor Suppressor Protein p53 / Q000737:chemistry / Q000378:metabolism
chemical_list: D004268:DNA-Binding Proteins; D006657:Histones; D007527:Isoenzymes; D009124:Muscle Proteins; C484340:SMYD1 protein, human; D014157:Transcription Factors; D016159:Tumor Suppressor Protein p53; D012435:S-Adenosylhomocysteine; D011495:Histone-Lysine N-Methyltransferase; C512569:SMYD2 protein, human; C506278:SMYD3 protein, human; D008239:Lysine