Ph.D. Institute of Biophysics, Chinese Academy of Sciences, Beijing, P. R. China, 1999
Emory University, Atlanta, GA, 2007
University of California at San Diego, La Jolla, CA, 2002
Accepting new M.S. students in fall of 2021: Yes
Accepting new Ph.D. students in fall of 2021: Yes
4340 Scott Hall
Structure and function of SET and MYND domain-containing (SMYD) proteins.
How the “marriage” between SET and MYND domains made SMYD proteins so special
SMYD proteins are a special class of protein lysine methyltransferases with an MYND domain inserted into a SET domain. Structurally, these two functional domains are intimately bundled, with a conserved architecture, being integrated into a single coherent module in SMYD proteins. The evolutionary history of SMYD proteins is dated back to more than 1 billion years ago at the beginning of multicellular life. They were found in the plant Arabidopsis thaliana, the yeast Saccharomyces cerevisiae, as well as Filastera, one of the closest unicellular relatives to animals. However, what selective pressure that has driven the “marriage” of the SET and MYND domains, and what specific function that has evolved at the time of this marriage, remain unclear. From the time when SMYD1, the founding member of the SMYD protein family, was identified as being required for cardiomyocyte differentiation, our understanding of SMYD protein structure and function has been steadily increasing. To date, we have known that not only are they involved in heart and skeletal muscle development, but also have diverse other roles in both normal biology and disease states, ranging from tumor cell proliferation, cancer stemness and dormancy, the immune response, to a very recent association with ciliogenesis via regulating microtubule dynamics.
While the scope of SMYD protein research has been broadened significantly over the past two decades, it is becoming increasingly clear to us that the more we learn about their multifunctionality and multispecificity, the more we realize that there are more yet to be discovered. With the thriving of functional genomics studies, new research ideas are emerging in uncharted areas, including but not limited to mitochondrial and nucleolar ribosome biogenesis, RNA biology in stress granules, intellectual disability, calcium-dependent signaling, as well as sperm chromatin remodeling at fertilization. The main goal of our research is to uncover new paradigms in SMYD protein research while further broadening our understanding of their functional diversity. As our knowledge develops and advances, we want to conclude that the marriage between the SET and MYND domains that made SMYD proteins so special is a ultimate rule governing their past, present and future.
(Complete list of published work can be found here)
1. Zhang, Y., Hayden, S., Spellmon N., Xue, W., Martin, K., Muzzarelli, K., Kovari, L. and Yang, Z. Sperm chromatin-condensing protamine enhances SMYD5 thermal stability. Biochem Biophys Res Commun, 550(1):1-7, doi: 10.1016/j.bbrc.2021.02.073 (2021).
2. Zhang, Y. and Yang, Z. Molecular Cloning and Purification of the Protein Lysine Methyltransferase SMYD2 and its Co-crystallization with a Target Peptide from Estrogen Receptor alpha. Methods in Molecular Biology, in press (2021).
3. Zhang, Y., Alshammari, E., Sobota, J. and Yang, Z. SMYD protein family as promising biomarkers for cancer diagnosis and prognosis. Genomic and Epigenomic Biomarkers of Toxicology and Disease, in press, Wiley (2021).
4. Alshammari, E., Zhang, Y., Sobota, J. and Yang, Z. Aberrant DNA methylation of tumor suppressor genes and oncogenes as cancer biomarkers. Genomic and Epigenomic Biomarkers of Toxicology and Disease, in press, Wiley (2021).
5. Sobota, J., Zhang, Y., Alshammari, E. and Yang, Z. Emerging Non-Invasive Molecular Biomarkers for Early Cancer Detection. Genomic and Epigenomic Biomarkers of Toxicology and Disease, in press, Wiley (2021).
6. Qin, Z, Ou, S., Xu, L., Sorensen, K., Zhang, Y., Yang, Z., Hu, W. and Chen, F. Design, synthesis of isothiocyanate-containing hybrid androgen receptor (AR) antagonist to downregulate AR and induce ferroptosis in GSH–deficient prostate cancer cells. Chemical Biology & Drug Design, doi: 10.1111/cbdd.13826 (2021).
7. Hou, Y., Sun, X., Gheinani, P., Guan, X., Sharma, S., Zhou, Y., Jin, C., Yang, Z., Naren, A., Yin, J., Denning, T., Gewirtz, A., Xie, Z. and Li, C. Methyltransferase SMYD5 Exaggerates IBD by Downregulating Mitochondrial Functions via Post-translational Control of PGC-1α Stability. bioRxiv, 2020.11.16.385765, doi: 10.1101/2020.11.16.385765 (2020).
8. Jiang, Y., Liu, L., Manning, M., Bonboom, M., Lotvola, A., Yang, Z. and Yang, Z. Structural analysis, virtual screening and molecular simulation to identify potential inhibitors targeting 2'-O- ribose methyltransferase of SARS-CoV-2 coronavirus. Journal of Biomolecular Structure & Dynamics, 1-16, doi: 10.1080/07391102.2020.1828172s (2020).
9. Chansuwan, W., Khamhae, M., Yang, Z. and Sirinupong, N. Hydrolase-treated royal jelly attenuates LPS-induced inflammation and IgE-antigen-mediated allergic reaction. Functional Foods In Health & Disease. DOI: 10.31989/ffhd.v10i3.694 (2020).
10. Jahanbakhsh, S., Dekhne, M., Kohan-Ghadr, H., Bai, D., Awonuga, A., Morris, R., Yang, Z. and Abu-Soud H. The inhibition of lactoperoxidase catalytic activity through mesna (2-mercaptoethane sodium sulfonate). Journal of Inorganic Biochemistry,12(203):110911. doi: 10.1016/j.jinorgbio.2019.110911 (2020).
11. Zhang, Y., Li, C. and Yang, Z. Is MYND Domain-Mediated Assembly of SMYD3 Complexes Involved in Calcium Dependent Signaling? Frontiers in Molecular Biosciences. 6:121. doi:10.3389/fmolb.2019.00121 (2019).
12. Buaduang, N., Chansuwan, W., Towatana, N. Yang, Z. and Sirinupong, N. Tilapia Protein Hydrolysate Enhances Transepithelial Calcium Transport in Caco2 cells. Functional Foods In Health & Disease. doi: 10.31989/ffhd.v9i10.651 (2019).
13. Hu, W., Xu, L., Chen, B., Ou, S., Muzzarelli, K., Hu, D., Li, Y., Yang, Z., Griend, D., Prins, G. and Qin, Z. Targeting prostate cancer cells with enzalutamide-HDAC inhibitor hybrid drug 2-75. Prostate, 79(10):1166-1179. doi:10.1002/pros.23832 (2019).
14. Mu Zhang, Chen Hu, Niko Moses, Joshua Haakenson, Shengyan Xiang, Daniel Quan, Bin Fang, Yang, Z., Wenlong Bai, Gerold Bepler, Guo-Min Li, and Xiaohong Zhang. HDAC6 regulates DNA damage response via deacetylating MLH1. Journal of Biological Chemistry, doi:10.1074/jbc.RA118.006374 (2019).
15. Muzzarelli, K. M., Kuiper, B. D., Spellmon, N., Brunzelle, J. S., Hackett, J., Amblard, F., Zhou, S., Liu, P., Kovari, I. A., Yang, Z., Schinazi, R. F. & Kovari, L. C. Structural and antiviral studies of the human norovirus GII.4 protease. Biochemistry, doi:10.1021/acs.biochem.8b01063 (2019).
16. Cornett, E. M., Dickson, B. M., Krajewski, K., Spellmon, N., Umstead, A., Vaughan, R. M., Shaw, K. M., Versluis, P. P., Cowles, M. W., Brunzelle, J., Yang, Z., Vega, I. E., Sun, Z. W. & Rothbart, S. B. A functional proteomics platform to reveal the sequence determinants of lysine methyltransferase substrate selectivity. Science advances, 4:eaav2623, doi:10.1126/sciadv.aav2623 (2018).
17. Munkanatta Godage, D. N. P., VanHecke, G. C., Samarasinghe, K. T. G., Feng, H. Z., Hiske, M., Holcomb, J., Yang, Z., Jin, J. P., Chung, C. S. & Ahn, Y. H. SMYD2 glutathionylation contributes to degradation of sarcomeric proteins. Nature communications, 9:4341, doi:10.1038/s41467-018-06786-x (2018).
18. Kuiper, B. D., Muzzarelli, K. M., Keusch, B. J., Holcomb, J., Amblard, F., Liu, P., Zhou, S., Kovari, I. A., Yang, Z., Schinazi, R. F. & Kovari, L. C. Expression, Purification and Characterization of a GII.4 Norovirus Protease from Minerva Virus. Infectious disorders drug targets, 18:224-232 (2018).
19. Holcomb, J., Doughan, M., Spellmon, N., Lewis, B., Perry, M., Zhang, Y., Nico, L., Wan, J., Chakravarthy, S., Shang, W., Miao, Q., Stemmler, T. and Yang, Z. SAXS analysis of a soluble cytosolic NgBR construct including extracellular and transmembrane domains. PLoS One, 13(1):e0191371 (2018).
20. Wu, J., Xiang, S., Zhang, M., Fang, B., Huang, H., Kwon, O., Zhao, Y., Yang, Z., Bai, W., Bepler, G. and Zhang, X. Histone deacetylase 6 (HDAC6) deacetylates extracellular signal-regulated kinase 1 (ERK1) and thereby stimulates ERK1 activity. Journal of Biological Chemistry, 293(6):1976-1993 (2018).
21. Dai, X., Thiagarajan, D., Fang, J., Shen, J., Annam, N., Jiang, H., Ju, D., Xie, Y., Zhang, K., Tseng, Y., Yang, Z., Rishi, A., Li, H., Yang, M. and Li, L. SM22α suppresses cytokine-induced inflammation and the transcription of NF-κB inducing kinase (Nik) by modulating SRF transcriptional activity in vascular smooth muscle cells. PLoS One, 12(12):e0190191 (2017).
22. Jeelanna, R., Jahanbakhsh, S., Kohan-Ghadr, H., Thakur, M., Khan, S., Aldhaheri, S., Yang, Z., Andreana, P., Morris, R. and Abu-Soud, H. Mesna (2-Mercaptoethane Sodium Sulfonate) Functions as a Regulator of Inflammation Through Myeloperoxidase. Free Radical Biology & Medicine, 110:54-62 (2017).
23. Kuiper, B., Slater, K., Spellmon, N., Holcomb, J., Medapureddy, P., Muzzarelli, K., Yang, Z., Ovadia, R, Amblard, F., Kovari, I., Schinazi, R., Kovari, L. Increased activity of unlinked Zika virus NS2B/NS3 protease compared to linked Zika virus protease. Biochem Biophys Res Commun, S0006-291X(17):30567-3, (2017).
24. 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).
25. 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).
26. Zaidan, A., Spellmon, N., Choudhary, V., Li, C. and Yang, Z. N-Lysine Methyltransferase SMYD. Encyclopedia of Signaling Molecules, Chapter 101729-1, Springer (2017).
27. 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).