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Structural and biochemical studies of human lysine methyltransferase Smyd3 reveal the important functional roles of its post-SET and TPR domains and the regulation of its activity by DNA binding.

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Xu S, Wu J, Sun B, Zhong C, Ding J
OpenAccess logo Nucleic Acids Res 39 4438-49 (2011)
Related entries: 3oxg, 3oxl

Cited: 50 times
EuropePMC logo PMID: 21266482

Abstract

The SET- and MYND-domain containing (Smyd) proteins constitute a special subfamily of the SET-containing lysine methyltransferases. Here we present the structure of full-length human Smyd3 in complex with S-adenosyl-L-homocysteine at 2.8 Å resolution. Smyd3 affords the first example that other region(s) besides the SET domain and its flanking regions participate in the formation of the active site. Structural analysis shows that the previously uncharacterized C-terminal domain of Smyd3 contains a tetratrico-peptide repeat (TPR) domain which together with the SET and post-SET domains forms a deep, narrow substrate binding pocket. Our data demonstrate the important roles of both TPR and post-SET domains in the histone lysine methyltransferase (HKMT) activity of Smyd3, and show that the hydroxyl group of Tyr239 is critical for the enzymatic activity. The characteristic MYND domain is located nearby to the substrate binding pocket and exhibits a largely positively charged surface. Further biochemical assays show that DNA binding of Smyd3 can stimulate its HKMT activity and the process may be mediated via the MYND domain through direct DNA binding.

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Articles - 3oxf mentioned but not cited (1)

  1. Structural and biochemical studies of human lysine methyltransferase Smyd3 reveal the important functional roles of its post-SET and TPR domains and the regulation of its activity by DNA binding. Xu S, Wu J, Sun B, Zhong C, Ding J. Nucleic Acids Res 39 4438-4449 (2011)


Reviews citing this publication (14)

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Articles citing this publication (33)

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  2. Lysine methyltransferase Smyd2 regulates Hsp90-mediated protection of the sarcomeric titin springs and cardiac function. Voelkel T, Andresen C, Unger A, Just S, Rottbauer W, Linke WA. Biochim Biophys Acta 1833 812-822 (2013)
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  4. Structure of human SMYD2 protein 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 286 38725-38737 (2011)
  5. The Smyd Family of Methyltransferases: Role in Cardiac and Skeletal Muscle Physiology and Pathology. Tracy C, Warren JS, Szulik M, Wang L, Garcia J, Makaju A, Russell K, Miller M, Franklin S. Curr Opin Physiol 1 140-152 (2018)
  6. Cooperation between SMYD3 and PC4 drives a distinct transcriptional program in cancer cells. Kim JM, Kim K, Schmidt T, Punj V, Tucker H, Rice JC, Ulmer TS, An W. Nucleic Acids Res 43 8868-8883 (2015)
  7. Structure-Based Design of a Novel SMYD3 Inhibitor that Bridges the SAM-and MEKK2-Binding Pockets. Van Aller GS, Graves AP, Elkins PA, Bonnette WG, McDevitt PJ, Zappacosta F, Annan RS, Dean TW, Su DS, Carpenter CL, Mohammad HP, Kruger RG. Structure 24 774-781 (2016)
  8. C-terminal domain of SMYD3 serves as a unique HSP90-regulated motif in oncogenesis. Brown MA, Foreman K, Harriss J, Das C, Zhu L, Edwards M, Shaaban S, Tucker H. Oncotarget 6 4005-4019 (2015)
  9. SMYD3 overexpression was a risk factor in the biological behavior and prognosis of gastric carcinoma. Liu Y, Luo X, Deng J, Pan Y, Zhang L, Liang H. Tumour Biol 36 2685-2694 (2015)
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  11. The human histone chaperone sNASP interacts with linker and core histones through distinct mechanisms. Wang H, Ge Z, Walsh ST, Parthun MR. Nucleic Acids Res 40 660-669 (2012)
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  13. The lysine methyltransferase SMYD3 interacts with hepatitis C virus NS5A and is a negative regulator of viral particle production. Eberle CA, Zayas M, Stukalov A, Pichlmair A, Alvisi G, Müller AC, Bennett KL, Bartenschlager R, Superti-Furga G. Virology 462-463 34-41 (2014)
  14. SMYD3 promoter hypomethylation is associated with the risk of colorectal cancer. Li B, Pan R, Zhou C, Dai J, Mao Y, Chen M, Huang T, Ying X, Hu H, Zhao J, Zhang W, Duan S. Future Oncol 14 1825-1834 (2018)
  15. Structural and functional analysis of the DEAF-1 and BS69 MYND domains. Kateb F, Perrin H, Tripsianes K, Zou P, Spadaccini R, Bottomley M, Franzmann TM, Buchner J, Ansieau S, Sattler M. PLoS One 8 e54715 (2013)
  16. Host factor SMYD3 is recruited by Ebola virus nucleoprotein to facilitate viral mRNA transcription. Chen J, He Z, Yuan Y, Huang F, Luo B, Zhang J, Pan T, Zhang H, Zhang J. Emerg Microbes Infect 8 1347-1360 (2019)
  17. LncRNA LTSCCAT promotes tongue squamous cell carcinoma metastasis via targeting the miR-103a-2-5p/SMYD3/TWIST1 axis. Liu M, Liu Q, Fan S, Su F, Jiang C, Cai G, Wang Y, Liao G, Lei X, Chen W, Bi J, Cheng W, Zhao L, Ruan Y, Li J. Cell Death Dis 12 144 (2021)
  18. Explaining the autoinhibition of the SMYD enzyme family: A theoretical study. Al-Shar'i NA, Alnabulsi SM. J Mol Graph Model 68 147-157 (2016)
  19. Dynamic methylation of histone H3K18 in differentiating Theileria parasites. Cheeseman K, Jannot G, Lourenço N, Villares M, Berthelet J, Calegari-Silva T, Hamroune J, Letourneur F, Rodrigues-Lima F, Weitzman JB. Nat Commun 12 3221 (2021)
  20. Molecular Dynamics Simulation Reveals Correlated Inter-Lobe Motion in Protein Lysine Methyltransferase SMYD2. Spellmon N, Sun X, Sirinupong N, Edwards B, Li C, Yang Z. PLoS One 10 e0145758 (2015)
  21. QM/MM MD and free energy simulations of G9a-like protein (GLP) and its mutants: understanding the factors that determine the product specificity. Chu Y, Yao J, Guo H. PLoS One 7 e37674 (2012)
  22. SET and MYND Domain-Containing Protein 3 (SMYD3) Polymorphism as a Risk Factor for Susceptibility and Poor Prognosis in Ovarian Cancer. Liu TT, Xu H, Gao WP, Zhang SX, Zhou XH, Tang J, Liu QN. Med Sci Monit 22 5131-5140 (2016)
  23. SMYD3 promotes epithelial ovarian cancer metastasis by downregulating p53 protein stability and promoting p53 ubiquitination. Zhang L, Jin Y, Yang H, Li Y, Wang C, Shi Y, Wang Y. Carcinogenesis 40 1492-1503 (2019)
  24. Discovery of an Allosteric Ligand Binding Site in SMYD3 Lysine Methyltransferase. Talibov VO, Fabini E, FitzGerald EA, Tedesco D, Cederfeldt D, Talu MJ, Rachman MM, Mihalic F, Manoni E, Naldi M, Sanese P, Forte G, Lepore Signorile M, Barril X, Simone C, Bartolini M, Dobritzsch D, Del Rio A, Danielson UH. Chembiochem 22 1597-1608 (2021)
  25. Function of the MYND Domain and C-Terminal Region in Regulating the Subcellular Localization and Catalytic Activity of the SMYD Family Lysine Methyltransferase Set5. Jaiswal D, Turniansky R, Moresco JJ, Ikram S, Ramaprasad G, Akinwole A, Wolf J, Yates JR, Green EM. Mol Cell Biol 40 e00341-19 (2020)
  26. New open conformation of SMYD3 implicates conformational selection and allostery. Spellmon N, Sun X, Xue W, Holcomb J, Chakravarthy S, Shang W, Edwards B, Sirinupong N, Li C, Yang Z. AIMS Biophys 4 1-18 (2017)
  27. The Methyltransferase Smyd1 Mediates LPS-Triggered Up-Regulation of IL-6 in Endothelial Cells. Shamloul A, Steinemann G, Roos K, Liem CH, Bernd J, Braun T, Zakrzewicz A, Berkholz J. Cells 10 3515 (2021)
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  29. Mechanism of the Conformational Change of the Protein Methyltransferase SMYD3: A Molecular Dynamics Simulation Study. Sun J, Li Z, Yang N. Int J Mol Sci 22 7185 (2021)
  30. Prognostic significance of stromal SMYD3 expression in colorectal cancer of TNM stage I-III. Liu N, Sun S, Yang X. Int J Clin Exp Pathol 10 8901-8907 (2017)
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  32. Aberrant DNA Methylation Involved in Obese Women with Systemic Insulin Resistance. Zhang SJ, Wang Y, Yang YL, Zheng H. Open Life Sci 13 201-207 (2018)
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