Research article Special Issues

New open conformation of SMYD3 implicates conformational selection and allostery

  • Received: 23 October 2016 Accepted: 12 December 2016 Published: 20 December 2016
  • SMYD3 plays a key role in cancer cell viability, adhesion, migration and invasion. SMYD3 promotes formation of inducible regulatory T cells and is involved in reducing autoimmunity. However, the nearly “closed” substrate-binding site and poor in vitro H3K4 methyltransferase activity have obscured further understanding of this oncogenically related protein. Here we reveal that SMYD3 can adopt an “open” conformation using molecular dynamics simulation and small-angle X-ray scattering. This ligand-binding-capable open state is related to the crystal structure-like closed state by a striking clamshell-like inter-lobe dynamics. The two states are characterized by many distinct structural and dynamical differences and the conformational transition pathway is mediated by a reversible twisting motion of the C-terminal domain (CTD). The spontaneous transition from the closed to open states suggests two possible, mutually non-exclusive models for SMYD3 functional regulation and the conformational selection mechanism and allostery may regulate the catalytic or ligand binding competence of SMYD3. This study provides an immediate clue to the puzzling role of SMYD3 in epigenetic gene regulation.

    Citation: Nicholas Spellmon, Xiaonan Sun, Wen Xue, Joshua Holcomb, Srinivas Chakravarthy, Weifeng Shang, Brian Edwards, Nualpun Sirinupong, Chunying Li, Zhe Yang. New open conformation of SMYD3 implicates conformational selection and allostery[J]. AIMS Biophysics, 2017, 4(1): 1-18. doi: 10.3934/biophy.2017.1.1

    Related Papers:

  • SMYD3 plays a key role in cancer cell viability, adhesion, migration and invasion. SMYD3 promotes formation of inducible regulatory T cells and is involved in reducing autoimmunity. However, the nearly “closed” substrate-binding site and poor in vitro H3K4 methyltransferase activity have obscured further understanding of this oncogenically related protein. Here we reveal that SMYD3 can adopt an “open” conformation using molecular dynamics simulation and small-angle X-ray scattering. This ligand-binding-capable open state is related to the crystal structure-like closed state by a striking clamshell-like inter-lobe dynamics. The two states are characterized by many distinct structural and dynamical differences and the conformational transition pathway is mediated by a reversible twisting motion of the C-terminal domain (CTD). The spontaneous transition from the closed to open states suggests two possible, mutually non-exclusive models for SMYD3 functional regulation and the conformational selection mechanism and allostery may regulate the catalytic or ligand binding competence of SMYD3. This study provides an immediate clue to the puzzling role of SMYD3 in epigenetic gene regulation.
    加载中
    [1] Spellmon N, Holcomb J, Trescott L, et al. (2015) Structure and function of SET and MYND domain-containing proteins. Int J Mol Sci 16: 1406–1428. doi: 10.3390/ijms16011406
    [2] Hamamoto R, Furukawa Y, Morita M, et al. (2004) SMYD3 encodes a histone methyltransferase involved in the proliferation of cancer cells. Nat Cell Biol 6: 731–740. doi: 10.1038/ncb1151
    [3] Mazur PK, Reynoird N, Khatri P, et al. (2014) SMYD3 links lysine methylation of MAP3K2 to Ras-driven cancer. Nature 510: 283–287. doi: 10.1038/nature13320
    [4] Sarris ME, Moulos P, Haroniti A, et al. (2016) Smyd3 is a transcriptional potentiator of multiple cancer-promoting genes and required for liver and colon cancer development. Cancer Cell 29: 354–366. doi: 10.1016/j.ccell.2016.01.013
    [5] Vieira FQ, Costa-Pinheiro P, Almeida-Rios D, et al. (2015) SMYD3 contributes to a more aggressive phenotype of prostate cancer and targets Cyclin D2 through H4K20me3. Oncotarget 6: 13644–13657. doi: 10.18632/oncotarget.3767
    [6] Van Aller GS, Reynoird N, Barbash O, et al. (2012) Smyd3 regulates cancer cell phenotypes and catalyzes histone H4 lysine 5 methylation. Epigenetics 7: 340–343. doi: 10.4161/epi.19506
    [7] Kim JM, Kim K, Schmidt T, et al. (2015) Cooperation between SMYD3 and PC4 drives a distinct transcriptional program in cancer cells. Nucleic Acids Res 43: 8868–8883. doi: 10.1093/nar/gkv874
    [8] Proserpio V, Fittipaldi R, Ryall JG, et al. (2013) The methyltransferase SMYD3 mediates the recruitment of transcriptional cofactors at the myostatin and c-Met genes and regulates skeletal muscle atrophy. Genes Dev 27: 1299–1312. doi: 10.1101/gad.217240.113
    [9] Cock-Rada AM, Medjkane S, Janski N, et al. (2012) SMYD3 promotes cancer invasion by epigenetic upregulation of the metalloproteinase MMP-9. Cancer Res 72: 810–820. doi: 10.1158/0008-5472.CAN-11-1052
    [10] Luo XG, Zhang CL, Zhao WW, et al. (2014) Histone methyltransferase SMYD3 promotes MRTF-A-mediated transactivation of MYL9 and migration of MCF-7 breast cancer cells. Cancer Lett 344: 129–137. doi: 10.1016/j.canlet.2013.10.026
    [11] Dong SW, Zhang H, Wang BL, et al. (2014) Effect of the downregulation of SMYD3 expression by RNAi on RIZ1 expression and proliferation of esophageal squamous cell carcinoma. Oncol Rep 32: 1064–1070.
    [12] Kunizaki M, Hamamoto R, Silva FP, et al. (2007) The lysine 831 of vascular endothelial growth factor receptor 1 is a novel target of methylation by SMYD3. Cancer Res 67: 10759–10765. doi: 10.1158/0008-5472.CAN-07-1132
    [13] Yoshioka Y, Suzuki T, Matsuo Y, et al. (2016) SMYD3-mediated lysine methylation in the PH domain is critical for activation of AKT1. Oncotarget 7: 75023–75037.
    [14] Doughan M, Spellmon N, Li C, et al. (2016) SMYD proteins in immunity: dawning of a new era. AIMS Biophysics 3: 450–455. doi: 10.3934/biophy.2016.4.450
    [15] Nagata DE, Ting HA, Cavassani KA, et al. (2015) Epigenetic control of Foxp3 by SMYD3 H3K4 histone methyltransferase controls iTreg development and regulates pathogenic T-cell responses during pulmonary viral infection. Mucosal Immunol 8: 1131–1143. doi: 10.1038/mi.2015.4
    [16] Sirinupong N, Brunzelle J, Doko E, et al. (2011) Structural insights into the autoinhibition and posttranslational activation of histone methyltransferase SmyD3. J Mol Biol 406: 149–159. doi: 10.1016/j.jmb.2010.12.014
    [17] Van Aller GS, Graves AP, Elkins PA, et al. (2016) Structure-Based Design of a Novel SMYD3 Inhibitor that Bridges the SAM-and MEKK2-Binding Pockets. Structure 24: 774–781. doi: 10.1016/j.str.2016.03.010
    [18] Xu S, Wu J, Sun B, et al. (2011) 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. Nucleic Acids Res 39: 4438–4449. doi: 10.1093/nar/gkr019
    [19] Brown MA, Foreman K, Harriss J, et al. (2015) C-terminal domain of SMYD3 serves as a unique HSP90-regulated motif in oncogenesis. Oncotarget 6: 4005–4019. doi: 10.18632/oncotarget.2970
    [20] Phillips JC, Braun R, Wang W, et al. (2005) Scalable molecular dynamics with NAMD. J Comput Chem 26: 1781–1802. doi: 10.1002/jcc.20289
    [21] Grant BJ, Rodrigues AP, ElSawy KM, et al. (2006) Bio3d: an R package for the comparative analysis of protein structures. Bioinformatics 22: 2695–2696. doi: 10.1093/bioinformatics/btl461
    [22] Glykos NM (2006) Software news and updates. Carma: a molecular dynamics analysis program. J Comput Chem 27: 1765–1768.
    [23] Wriggers W, Schulten K (1997) Protein domain movements: detection of rigid domains and visualization of hinges in comparisons of atomic coordinates. Proteins 29: 1–14.
    [24] Humphrey W, Dalke A, Schulten K (1996) VMD: visual molecular dynamics. J Mol Graph 14: 33–38. doi: 10.1016/0263-7855(96)00018-5
    [25] Sethi A, Eargle J, Black AA, et al. (2009) Dynamical networks in tRNA:protein complexes. Proc Natl Acad Sci USA 106: 6620–6625. doi: 10.1073/pnas.0810961106
    [26] Jiang Y, Holcomb J, Spellmon N, et al. (2016) Purification of Histone Lysine Methyltransferase SMYD2 and Co-Crystallization with a Target Peptide from Estrogen Receptor alpha. Methods Mol Biol 1366: 207–217. doi: 10.1007/978-1-4939-3127-9_16
    [27] Petoukhov MV, Franke D, Shkumatov AV, et al. (2012) New developments in the program package for small-angle scattering data analysis. J Appl Crystallogr 45: 342–350. doi: 10.1107/S0021889812007662
    [28] Svergun DI (1999) Restoring low resolution structure of biological macromolecules from solution scattering using simulated annealing. Biophys J 76: 2879–2886. doi: 10.1016/S0006-3495(99)77443-6
    [29] Panjkovich A, Svergun DI (2016) Deciphering conformational transitions of proteins by small angle X-ray scattering and normal mode analysis. Phys Chem Chem Phys 18: 5707–5719. doi: 10.1039/C5CP04540A
    [30] Holcomb J, Jiang Y, Lu G, et al. (2014) Structural insights into PDZ-mediated interaction of NHERF2 and LPA(2), a cellular event implicated in CFTR channel regulation. Biochem Biophys Res Commun 446: 399–403. doi: 10.1016/j.bbrc.2014.02.128
    [31] Peserico A, Germani A, Sanese P, et al. (2015) A SMYD3 small-molecule inhibitor impairing cancer cell growth. J Cell Physiol 230: 2447–2460. doi: 10.1002/jcp.24975
    [32] Chandramouli B, Silvestri V, Scarno M, et al. (2016) Smyd3 open & closed lock mechanism for substrate recruitment: The hinge motion of C-terminal domain inferred from mu-second molecular dynamics simulations. Biochim Biophys Acta 1860: 1466–1474. doi: 10.1016/j.bbagen.2016.04.006
    [33] Munz M, Hein J, Biggin PC (2012) The role of flexibility and conformational selection in the binding promiscuity of PDZ domains. PLoS Comput Biol 8: e1002749. doi: 10.1371/journal.pcbi.1002749
    [34] Motlagh HN, Wrabl JO, Li J, et al. (2014) The ensemble nature of allostery. Nature 508: 331–339. doi: 10.1038/nature13001

    © 2017 the Author(s), licensee AIMS Press. This is an open access article distributed under the terms of the Creative Commons Attribution License (http://creativecommons.org/licenses/by/4.0)
  • Reader Comments
通讯作者: 陈斌, bchen63@163.com
  • 1. 

    沈阳化工大学材料科学与工程学院 沈阳 110142

  1. 本站搜索
  2. 百度学术搜索
  3. 万方数据库搜索
  4. CNKI搜索

Metrics

Article views(2111) PDF downloads(946) Cited by(4)

Article outline

Figures and Tables

Figures(4)

/

DownLoad:  Full-Size Img  PowerPoint
Return
Return

Catalog