School of Medicine

Wayne State University School of Medicine

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Title
Associate Professor
Phone
313-577-1294
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We are working on a protein family called SMYD (SET and MYND domain-containing protein family). This protein family methylates both histone and non-histone proteins. It is involved in epigenetic regulation of oncogenes, pro-inflammatory genes, developmental genes, and cell-cycle regulators. It has been linked to cancer, autoimmune disease, cardiovascular disease, and diabetes. Our main research interests are the structure and function of SMYD proteins and molecular mechanism of protein-protein interaction in SMYD-involved signaling pathways. We use X-ray crystallography to solve structure and use small-angle X-ray scattering and computational biology such as molecular dynamics simulation to study structural dynamics. We further use the structure in structure-based drug design and in silico screening of millions of drug-like compounds (virtual screening).

We are looking at how SMYDs methylate chemokine receptors and how this methylation regulates receptors signaling pathways in endothelial progenitor cells. We are testing the hypothesis that SMYD proteins attenuate the inflammatory response through regulating mitochondrial epigenetics and methylation of mtDNA binding factors. We are studying the role of SMYD proteins in chaperone-mediated autophagy and mitophagy and how they are involved in aging and neurodegenerative disease. We are also studying their role in inflammation and immune response and how their nuclear-mitochondrial translocation is related to autoimmune diseases such as inflammatory bowl disease and rheumatoid arthritis.

Graduate
Ph.D. Institute of Biophysics, Chinese Academy of Sciences, Beijing, P. R. China, 1999
Postdoctoral Emory University, Atlanta, GA, 2007 University of California at San Diego, La Jolla, CA, 2002
Interests

Research Areas : Structure and function of epigenetics and mitochondrial epigenetics regulators.

Publications

1. Spellmon, N., Holcomb, J., Niu, A., Choudhary, V., Sun, X., Zhang, Y., Wan, J., Doughan, M., Hayden, S., Hachem, F., Brunzelle, F., Li, C. and Yang, Z. Structural basis of PDZ-mediated chemokine receptor CXCR2 scaffolding by guanine nucleotide exchange factor PDZ-RhoGEF. Biochem Biophys Res Commun, doi: 10.1016/j.bbrc.2017.02.010, (2017).

2. Spellmon, N., Sun, X., Xue, W., Holcomb, J., Chakravarthy, S., Shang, W., Edwards, B., Sirinupong, N., Li, C. and Yang, Z. New open conformation of SMYD3 implicates conformational selection and allostery. AIMS Biophysics, 4(1):1-18, doi: 10.3934/biophy.2017.1.1, (2017).

3. Zaidan, A., Spellmon, N., Choudhary, V., Li, C. and Yang, Z. N-Lysine Methyltransferase SMYD. Encyclopedia of Signaling Molecules, Chapter 101729-1, Springer (2017).

4. Zhao, B., Hu, W., Kumar, S., Gonyo, P., Rana, U., Liu, Z., Wang, B., Duong, WQ., Yang, Z., Williams, CL. and Miao, QR. The Nogo-B receptor promotes Ras plasma membrane localization and activation. Oncogene, January 9, doi: 10.1038/onc.2016.484, (2017).

5. Yu, H., Jiang, Y, Liu, L., Shan, W., Chu, X., Yang, Z. and Yang, ZQ. Integrative genomic and transcriptomic analysis for pinpointing recurrent alterations of plant homeodomain genes and their clinical significance in breast cancer. Oncotarget, December 31, doi: 10.18632/oncotarget.14402, (2016).

6. Doughan, M., Spellmon, N., Li, C. and Yang, Z. SMYD proteins in immunity: dawning of a new era. AIMS Biophysics, 3(4):450-455, (2016).

7. Hou, Y., Guan, X., Yang, Z. and Li, C. Emerging role of cystic fibrosis transmembrane conductance regulator - an epithelial chloride channel in gastrointestinal cancers. World Journal of Gastrointestinal Oncology, 8(3):282-282, (2016).

8. Guan, X., Hou, Y., Sun, F., Yang, Z. and Li, C. Dysregulated Chemokine Signaling in Cystic Fibrosis Lung Disease: A Potential Therapeutic Target. Current Drug Targets, 17(13):1535-44, (2016).

9. Sirinupong, N. and Yang, Z. Epigenetics in Cystic Fibrosis: Epigenetic Targeting of a Genetic Disease. Current Drug Targets, 16(9):976-87, (2015).

10. Jiang, Y., Holcomb, J., Spellmon, N. and Yang, Z. Purification of Histone Lysine Methyltransferase SMYD2 and Co-crystallization with a Target Peptide from Estrogen Receptor α. Methods in Molecular Biology, 1366:207-17, (2015).

11. Sun, X., Spellmon, N., Holcomb, J., Xue, W., Li, C. and Yang, Z. Epigenetic landscape in embryonic stem cell. Stem Cells in Toxicology and Medicine, Wiley (2015).

12. Hou, Y., Guan, X., Farooq, S., Sun, X., Wang, P., Yang, Z., and Li, C. Stem Cell Therapeutics for Cardiovascular Diseases. Stem Cells in Toxicology and Medicine, Wiley (2015).

13. Spellmon, N., Sun, X., Sirinupong, N., Edwards, B., Li, C. and Yang, Z. Molecular Dynamics Simulation Reveals Correlated Inter-Lobe Motion in Protein Lysine Methyltransferase SMYD2. PLoS ONE, 10(12):e0145758, (2015).

14. Yang, Z., Sun, F. and Li, C. Emerging Molecular Targets for the Treatment of Cystic Fibrosis. Current Drug Targets, 16(9):922, (2015).

15. Sirinupong, N. and Yang, Z. Bioactive Food Components as Dietary Intervention for Cystic Fibrosis. Current Drug Targets, 16(9):988-92, (2015).


16. Spellmon, N., Holcomb, J., Trescott, L., Sirinupong, N. and Yang, Z. Structure and Function of SET and MYND Domain-Containing Proteins. International Journal of Molecular Sciences, 16:1406-1428, (2015).

17. Holcomb, J., Spellmon, N., Trescott, L., Sun, F., Li, C. and Yang, Z. PDZ Structure and Implication in Selective Drug Design against Cystic Fibrosis. Current Drug Targets, 16(9):945-50, (2015).

18. Trescott, L., Holcomb, J., Spellmon, N., Mcleod, C., Aljehane, L., Sun, F., Li, C. and Yang, Z. Targeting the Root Cause of Cystic Fibrosis. Current Drug Targets, 16(9):933-44, (2015).

19.  Hou, Y., Wu, Y., Farooq, S.M., Guan, X., Liu, Y., Oblak, J.J., Holcomb, J., Jiang, Y., Strieter, R.M., Lasley, R.D., Arbab, A.S., Sun, F., Li, C. and Yang, Z. A Critical Role of CXCR2 PDZ-mediated Interactions in Endothelial Progenitor Cell Homing and Angiogenesis. Stem Cell Research, 14:133-143, (2014).

20. Margaret, R., Jiang, Y., Holcomb, J., Trescott, L., Spellmon, N., Sirinupong, N. and Yang, Z. SMYD2 Structure and Function: A Multispecificity Protein Lysine Methyltransferase. Journal of Cytology and Molecular Biology, 1(2):7, (2014).

21. Jiang, Y., Holcomb. J., Trescott, L., Rice, M. and Yang, Z. Structural Dissection of Cardiogenic and Myogenic SMYD Proteins. Experimental and Clinical Cardiology, Jul 31, (2014).

22. Yang, Z and Li, C. Is Smyd1 Involved in Vasculature?. Austin Biomark Diagn, 1(1):2, (2014).

23. Abu-Soud, H., Maitra, D., Shaeib, F., Khan, S., Byun, J., Abdulhamid, I., Yang, Z., Saed, G., Diamond, M., Andreana and P., Pennathur, S. Disruption of heme-peptide covalent cross-linking in mammalian peroxidases by hypochlorous acid. Journal of Inorganic Biochemistry, doi: 10.1016/j.jinorgbio.2014.06.018, (2014).

24.  Holcomb, J., Jiang, Y., Guan, X., Trescott, L., Lu, G., Hou, Y., Wang, S., Brunzelle, J., Sirinupong, N., Li, C. and Yang, Z. Crystal Structure of the NHERF1 PDZ2 Domain in Complex with the Chemokine Receptor CXCR2 Reveals Probable Modes of PDZ2 Dimerization. Biochem Biophys Res Commun, 446(1):399-403, (2014).

25. Jiang, Y., Trescott, L., Holcomb, J., Zhang, X., Brunzelle, J., Sirinupong, N., Shi, X. and Yang, Z. Structural Insights into Estrogen Receptor Alpha Methylation by Histone Methyltransferase SMYD2, a Cellular Event Implicated in Estrogen Signaling Regulation. Journal of Molecular Biology, S0022-2836:00101-6, (2014).

26. Jiang, Y., Wang, S., Holcomb, J., Trescott, L., Guan, X., Hou, Y., Brunzelle, J., Sirinupong, N., Li, C. and Yang. Z. Crystallographic Analysis of NHERF1-PLCβ3 Interaction Provides Structural Basis for CXCR2 Signaling in Pancreatic Cancer. Biochem Biophys Res Commun, 446(2):638-43, (2014).

27. Holcomb, J., Jiang, Y., Lu, G., Trescott, L., Brunzelle, J., Sirinupong, N., Li, C., Naren, A. and Yang, Z. Structural Insights into PDZ-mediated Interaction of NHERF2 and LPA2, a Cellular Event Implicated in CFTR Channel Regulation. Biochem Biophys Res Commun, 446(1):399-403, (2014).

28. Jiang, Y., Lu, G., Trescott, L., Hou, Y., Guan, X., Wang, S., Stamenkovich, A., Brunzelle, J., Sirinupong, N., Spaller, M., Li, C. and Yang, Z. New Conformational State of NHERF1-CXCR2 Signaling Complex Captured by Crystal Lattice Trapping. PLoS ONE 8(12):e81904, (2013).

29. Zhang, X., Tanaka, K., Li, J., Yang, J., Peng, D., Jiang, Y., Yang, Z., Barton, M., Wen, H., and Shi, X. Regulation of estrogen receptor α by SMYD2-mediated protein methylation. Proc. Natl. Acad. Sci. USA, 110:17284-9, (2013).

30. Lu, G., Wu, Y., Jiang, Y., Wang, S., Hou, Y., Guan, X., Brunzelle, J., Sirinupong, N., Sheng, S., Li, C. and Yang, Z. Structural Insights into Neutrophilic Migration Revealed by the Crystal Structure of the Chemokine Receptor CXCR2 in Complex with the First PDZ Domain of NHERF1. PLoS ONE 8(10):e76219, (2013).

31. Jiang, Y., Sirinupong, N., Brunzelle, J. and Yang, Z. Crystal structures of histone and p53 methyltransferase SmyD2 reveal a conformational flexibility of the autoinhibitory C-terminal domain. PLoS ONE, 6:e21640, (2011).

32. Sirinupong, N., Brunzelle, J., Doko, E. and Yang, Z. Structural insights into the autoinhibition and posttranslational activation of histone methyltransferase SmyD3. Journal of Molecular Biology, 406:149-159, (2011).

33. Sirinupong, N., Brunzelle, J., Ye, J., Pirzada, A., Nico, L. and Yang, Z. Crystal structure of cardiac-specific histone methyltransferase SmyD1 reveals unusual active site architecture. Journal of Biological Chemistry, 285:40635-40644, (2010).

34. Ooi SK, Qiu C, Bernstein E, Li K, Jia D, Yang, Z., Erdjument-Bromage H, Tempst P, Lin SP, Allis CD, Cheng X and Bestor TH. DNMT3L connects unmethylated lysine 4 of histone H3 to de novo methylation of DNA. Nature, 448:714-7, (2007).

35. Horton, J.R., Zhang, X., Maunus, R., Yang, Z, Wilson, G.G., Roberts, R.J. and Cheng, X. DNA nicking by HinP1I endonuclease: bending, base flipping and minor groove expansion. Nucleic Acids Res, 34:939-48, (2006).

36. Yang, Z., Horton, J.R., Maunus, R., Wilson, G.G., Roberts, R.J. and Cheng, X. Structure of HinP1I endonuclease reveals a striking similarity to the monomeric restriction enzyme MspI. Nucleic Acids Res, 33:1892-901, (2005).

37. Yang, Z., Shipman, L., Zhang, M., Anton, B.P., Roberts, R. and Cheng, X. Structural Characterization and Comparative Phylogenetic Analysis of Escherichia coli HemK, a Protein (N5)-glutamine Methyltransferase. Journal Molecular Biology, 340:695-706, (2004).

38. Bestor, T., Bourc'his, D., Cheng, X., Qiu. C. and Yang, Z. Meiotic Catastrophe and Transponson Remanimation in DNMT3L-Deficient Male Germ Cells. Cold Spring Harbor Symposia on Quantitative Biology - COLD SPRING HARBOR SYMP, 69:1-1 (2004).

39. Sawada, K., Yang, Z., Zhang, X. and Cheng, X. Crystal Structure of Yeast Histone H3 K79 Methyltransferase Dot1p. Journal of Biological Chemistry, 279:43296-306, (2004).

40. Yang, Z., Horton, J.R., Zhou, L., Zhang, X.L., Dong, A., Zhang, X., Schlagman, S.L., Kossykh, V., Hattman, S. and Cheng, X. Structure of the Bacteriophage T4 DNA Adenine Methyltransferases. Nature Structural Biology, 10:849-855, (2003).

41. Zhang, X., Yang, Z., Khan, S.I., Horton, J.R., Tamaru, I., Selker, E.U. and Cheng, X. Structural Basis for the Product Specificity of Histone Lysine Methyltransferases. Molecular Cell, 12:177-185, (2003).

42. Yang, Z., Pandi, L. and Doolittle, R.F. Crystal Structure of Fragment Double-D from Cross-Linked Lamprey Fibrin Reveals Isopeptide Linkages Across an Unexpected D-D Interface. Biochemistry, 41:15610-15617, (2002).

43. Yang, Z., Spraggon, G., Pandi, L., Everse, E.J., Riley, M. and Doolittle, R.F. Crystal Strucure of Fragment D from Lampery Fibrinogen Complexed with Peptide Gly-His-Arg-Pro-Amide. Biochemistry, 41:10218-10224, (2002).

44. Doolittle, R.F., Yang, Z. and Mochalkin, I. Crystal Structure Studies on Fibrinogen and Fibrin. Annals of the New York Academy of Sciences, 936:31-43, (2001).

45. Yang, Z., Kollman, J.M., Pandi, L. and Doolittle, R.F. Crystal Structure of Native Chicken Fibrinogen at 2.7 Resolution. Biochemistry, 40:12515-12523, (2001).

46. Yang, Z., Mochalkin, I. and Doolittle, R.F. A Model of Fibrin Formation Based on Crystal Structures of Fibrinogen and Fibrin Fragments Complexed with Synthetic Peptides. Proc. Natl. Acad. Sci. USA, 97:14156-14161, (2000).

47. Yang, Z., Mochalkin, I., Veerapandian, I., Riley, M. and Doolittle, R.F. Crystal Structure of Native Chicken Fibrinogen at 5.5 Resolution. Proc. Natl. Acad. Sci. USA, 97:3907-3912, (2000).

48. Yang, Z., Ye, S., Jing, G., Gui, L. and Liang, D. Crystal Structure of an N-Terminal Fragment SNR141 of Staphylococcal Nuclease R Refined at 1.9 Angstrom Resolution. Progress in Natural Science, 9:617-622, (1999).