3tg4 | pdb_00003tg4
Structure of SMYD2 in complex with SAM
Structural highlights
Function[SMYD2_HUMAN] Protein-lysine N-methyltransferase that methylates both histones and non-histone proteins. Specifically methylates histone H3 'Lys-4' (H3K4me) and dimethylates histone H3 'Lys-36' (H3K36me2). Has also methyltransferase activity toward non-histone proteins such as p53/TP53 and RB1. Monomethylates 'Lys-370' of p53/TP53, leading to decreased DNA-binding activity and subsequent transcriptional regulation activity of p53/TP53. Monomethylates 'Lys-860' of RB1/RB.[1] [2] [3] [4] Publication Abstract from PubMedSMYD2 belongs to a sub-family of histone lysine methyltransferase (HKMT) and was recently identified to methylate tumor suppressor p53 and Rb. Here we report that SMYD2 prefers to methylate p53 K370 than histone substrates in vitro. Consistently, the level of endogenous p53 K370 mono-methylation is significantly elevated when SMYD2 is overexpressed in vivo. We have solved the high resolution crystal structures of the full length SMYD2 protein in binary complex with its cofactor SAM and in ternary complex with cofactor product S-adenosylhomocysteine (AdoHcy) and p53 substrate peptide (368-375), respectively. P53 peptide binds to a deep pocket of the interface between catalytic SET (1-282) and C-terminal domain (CTD) with a unpredecent U-shaped conformation. Subtle conformational change exists around p53 binding site between the binary and ternary structures, in particular, the tetratrico-peptide repeat (TPR) motif of the CTD. In addition, a unique EDEE motif between the loop of anti-parallel beta7 and beta8 sheets of the SET core not only interacts with p53 substrate but also forms hydrogen bond network with residues from CTD. These observations suggest that the TPR and EDEE motif may play an important role in determining p53 substrate binding specificity. This is further verified by the results that deletion of the CTD domain drastically reduces the methylation activity of SMYD2 to p53 protein. Meanwhile, mutation of EDEE residues impairs both the binding and the enzymatic activity of SMYD2 to p53 K370. These data together reveal the molecular basis of SMYD2 in specifically recognizing and regulating functions of p53 tumor suppressor through K370 mono-methylation. Structure of human SMYD2 reveals the basis of p53 tumor suppressor methylation.,Wang L, Li L, Zhang H, Luo X, Dai J, Zhou S, Gu J, Zhu J, Atadja P, Lu C, Li E, Zhao K J Biol Chem. 2011 Aug 31. PMID:21880715[5] From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine. See AlsoReferences
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