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 2019: Yes
Accepting new Ph.D. students in fall of 2019: Yes
4340 Scott Hall
Dr. Yang's research involves the structure and function of epigenetics and mitochondrial epigenetics regulators.
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. SMYD protein family has been considered as a promising drug target because of its disease association and crucial roles in disease pathogenesis.
Our main research interest is the structure and function of SMYD proteins in oxidative stress response, DNA damage repair, inflammation activation, protein trafficking, cell proliferation, and calcium signaling. We are aiming to dissect the epigenetic and non-epigenetic roles of SMYD proteins and how the fluctuation in their methylome is dynamically correlated with precise pattern of spatial and temporal gene expression. We want to gain a systems biology view of SMYD methylation networks and their dynamical changes in response to stress and biological stimuli. Ultimately, we want to determine what factors control substrate specificity and promiscuity and how conformational heterogeneity is translated into functional diversity.
1. Structural Biology of SMYD Proteins
In the past few years, we have determined several crystal structures of SMYD proteins using X-ray crystallography. Our success relies on a SUMO-tag protein purification system which is designed to increase recombinant protein expression and solubility. It also relies on our automated protein purification workflow that combines ion-exchange, affinity and size exclusion chromatography in a modular configuration aimed for high-yield and high-purity protein production. Our success also relies on a comprehensive collection of both sparsely-formulated and target-oriented crystallization conditions to maximize the coverage of crystallization search space. It also relies on guaranteed access to the brightest X-ray beams provided by LS-CAT synchrotron that allows us to determine X-ray structures to the highest resolution possible as well as the ability to work with difficult samples.
We published the first structure study of SMYD protein family (SMYD1). The structure of this unique class of protein lysine methyltransferases is bilobal with two lobes separated by a deep cleft. The substrate binding site is located at the bottom of the deep cleft, which connects to the cofactor binding site through the narrow target lysine access channel. The significance of this work is highlighted by the fact that SMYD1 is a key epigenetic regulator in heart development essential for the formation of a functional heart in an animal model system. The high resolution structure of SMYD1 active site provides a real prospect for structure-based discovery of heart regenerative medicine.
We are recognized for significant contribution to structural biology of SMYD protein family. In addition to SMYD1, we also solved and published one SMYD3 structure and nine SMYD2 structures. These additional structure studies have provided us new mechanistic insights into the regulation of substrate specificity and promiscuity. The broad substrate specificity of SMYD2 is achieved by distinct peptide binding modes and the intrinsic dynamics of peptide ligands. The substrate binding of SMYD proteins might also be regulated by autoinhibition via the conformational change of the C-terminal domain (CTD). However, the identification of the secondary peptide binding site (SBS) in SMYD2 adds another layer of complexity to regulation. We proposed two independent models for the secondary binding site regulating PARP1 binding to the substrate binding site. One is allosteric effect in which binding of a PARP1 peptide to the secondary binding site changes the structure or dynamics of the substrate binding site. The other is the secondary binding site guiding PARP1 to the substrate binding site.
The structural biology of SMYD proteins is still not completely unveiled. Currently no structure has been determined for SMYD4 and SMYD5. However, determining their structures is of particular interest because there are several unique structural features in these proteins that have clear functional implications. SMYD4 contains additional TPR repeats which can specifically interact with the very C-terminal tail of heat shock protein 90 (HSP90). SMYD5 does not have the conserved C-terminal domain (CTD) which is replaced by a highly negatively charged poly-E tract. We hypothesize that solving the structure of SMYD4 TPR repeats in complex with Hsp90 C-terminal tail will provide the structural basis for lysosome-dependent, chaperone-assisted selective autophagy. Consequently, this will shed light on the role of SMYD4 in Miller-Dieker syndrome, a congenital disease characterized by smooth brain and severe intellectual disability. SMYD4 and several lysosomal proteins are frequently deleted in Miller-Dieker patients and associated with disease severity. For SMYD5, we hypothesize that solving its structure will reveal a novel substrate recognition mode that involves the poly-E tract. Alternatively, the poly-E tract might be a DNA-structure mimics which interacts with Ku80 involved in DNA double stranded breaks repair via non-homologous end joining.
2. Molecular Cell Biology of SMYD Proteins in Signaling, Epigenetics, Endosomal Trafficking, and DNA Damage Repair
SMYD3 is an oncogene whose expression is abnormally elevated in over 15 types of cancers including breast cancer, prostate cancer, pancreatic cancer, and lung cancer. We propose that SMYD3 adopts an integrated model that combines signaling and epigenetic pathways to contribute to tumor cell proliferation and growth. In cytosol, SMYD3 will assemble a signaling complex with the G-protein coupled receptor VANGL1, phospholipase PLC3, Ca2+/calmodulin-dependent protein kinase CaMKII, and phosphatase PP3 inhibitor RCNA3. The formation of this complex will facilitate cellular calcium signaling and regulate NFAT-dependent inflammatory response, angiogenesis, or development and metastasis of tumors. SMYD3 will also assemble a nuclear epigenetic complex on the chromatin with the histone H3K4 methyltransferase MLL5, histone H3K9 demethylase KDM3B, and heat shock protein 90. These proteins will work together to define an active transcription state of SMYD3 target genes by depositing the active methyl marks onto H3K4 and removing the repressive methyl marks from H3K9. SMYD3 will be central to the formation of the locus-specific complexes due to its unique sequence specific DNA binding activity.
For SMYD2, we are interested in determining the role of the secondary binding site (SBS) in membrane trafficking and retrograde and anterograde vesicle transport to and from Golgi. The secondary binding site is not only novel to SMYD2 but also to the entire class of protein lysine methyltransferases for which no additional peptide binding site has been characterized. We plan to use the quantitative mass spectrometry-based proteomic approach SILAC (stable isotope labeling with amino acids) to objectively identify what endogenous proteins bind to the secondary binding site. Our hypothesis is that binding to the secondary binding site regulates SMYD2 substrate selectivity which is required for endosomal trafficking in cholesterol metabolism and homeostasis. The most significant phenotypes of SMYD2 knockout mice are increased circulating LDL and HDL cholesterol levels. Through comprehensive correlation analysis of SMYD2 interactome, methylome and transcriptome, we found that SMYD2 methylates and interacts with proteins that are enriched for lipid metabolism and microtubule-dependent endocytosis such as AP2A2, a component of the adaptor protein complex 2 (AP2) that is involved in clathrin-dependent endocytosis and SNX8, which is involved in intracellular protein transport from early endosomes to the trans-Golgi network. We will investigate LDL receptor recycling and cholesterol homeostasis using a FRAP (fluorescence recovery after photoconversion)-based method using human hepatic cell models with the CRISPR/Cas9 SMYD2 knockout and SMYD2 secondary binding site mutant knockin. If the secondary binding site is required for normal LDL receptor trafficking and internalization as well as normal cholesterol uptake from LDL, this will effectively link SMYD2 to a range of cardiovascular conditions since an elevated LDL cholesterol level is a major independent risk factor for atherosclerosis and heart diseases. Consistently, genome-wide association studies identified SMYD2 as a new disease-specific risk locus for abdominal aortic aneurysm, and abnormal SMYD2 promoter DNA methylation is associated with this deadly disease.
For SMYD5, we are interested in determining its role in DNA double stranded breaks repair in response to oxidative stress. The first hypothesis we tested was that SMYD5 was a mitochondrial protein involved in mtDNA maintenance and degradation. However, the subcellular localization of SMYD5 was mostly restricted to the nucleus in both fractionation procedures and fluorescence microscopy with GFP fusion or Myc-tag immunofluorescence. Similar results were observed for various cell culture models including the human bone osteosarcoma cell line U2OS, human embryonic kidney cells HEK293T, and mouse macrophage RAW 264.7 cell line regardless of LPS (lipopolysaccharide) stimulation. We found that the putative mitochondrial targeting signal of SMYD5 is actually a novel nuclear localization signal. Upon H2O2 treatment the interaction of SMYD5 with the exclusively nuclear protein Ku80 is significantly enhanced in immunoprecipitation of U2OS cell lysates. Our hypothesis is that the poly-E tract of SMYD5 regulates Ku80-mediated DNA double stranded breaks repair through DNA mimicry. The interaction between SMYD5 and Ku80 under oxidative stress will be mediated by two phosphorylation sites and one O-GlcNAcylation site immediately upstream of the poly-E tract. However, to gain further mechanistic insights into SMYD5 function, we are also interested in identifying new SMYD5 methylation targets. One approach we used is substrate screening using Lysine Oriented Peptide Libraries that contain nearly 50 million peptides. CHD1, a DNA helicase involved in chromatin remodeling, DNA double stranded breaks repair, and genomic stability was identified as a potential substrate using SMYD5 substrate selectivity profile derived from the screen. There is an apparent functional link between CHD1 and SMYD5 as SMYD5 is also involved in genomic stability and DNA double stranded breaks repair.
3. Systems Biology of SMYD2 Methylation Networks
SMYD2 is a SET and MYND domain-containing protein that catalyzes protein lysine methylation. SMYD2 is overexpressed in several cancers including gastric cancers, ESCC, pediatric leukemia, hepatocellular carcinoma, and breast cancers. SMYD2 contributes to drug resistance after genotoxic therapies in pancreatic ductal carcinoma. While the biology of SMYD2 is still poorly understood, it has been assumed that SMYD2 exerts its function through methylation of downstream targets. Indeed, the protein lysine methyltransferase activity of SMYD2 is required for cancer cell growth and proliferation. However, it is challenging to study the molecular mechanisms of SMYD2 activity because it has a broad substrate specificity. Over 10 substrates have been individually identified in targeted studies and hundreds more found in proteomic studies. A recent protein array study showed that SMYD2 has over 250 potential substrates. These targets are involved in transcriptional regulation, chromatin structure, cellular signaling, rRNA processing, protein synthesis, cell cycle regulation, cell proliferation, and inflammation. This indicates considerable complexity in SMYD2 biology which may involve multiple pathways to drive cancer development. We plan to develop a systems biology view of SMYD2 methylation networks in breast cancers. Our hypothesis is that SMYD2 drives distinct methylation networks that contribute to phenotypic differences between the subtypes of breast cancers. We will construct an updatable mathematical gene regulatory network model that integrates with available SMYD2 genomic, proteomic and methylomic data sets. The network will be built using Bayesian network analysis that will enable the capture of a rich and multidimensional view of SMYD2 biology that will yield probabilistic dependences for all regulator-gene pairs. The resulting model will be used to infer genome-wide SMYD2 methylation signatures and identify functional modules or pathways that control phenotypic differences among breast cancer. This integrated view will make it possible to better understand the relative importance of each SMYD2 target in the network, the complex interplay of its targets in the system, and how the architecture of the system constrains the behavior of its constituents.
4. Computational Biology and Conformational Dynamics
Protein dynamics and correlated domain motion are fundamental in mediating substrate recognition and allostery. However, the dynamical nature of SMYD proteins still remains poorly understood. Using molecular dynamics simulation and small angle X-ray scattering, we revealed that SMYD proteins can undergo both large scale conformational change and vibrational correlated localized motion. SMYD2 exhibits a negative correlated inter-lobe motion, while SMYD3 can undergo a spontaneous conformational transition from the closed state to an open state. In both proteins, the strongest pattern of motion extracted by principle component analysis is a correlated twisting motion of the C-lobe with respect to the N-lobe. Such a motion defining two distinct populations of conformational substates and causing an open-closed motion between the lobes, directly regulates the accessibility to the substrate binding site. In dynamical network, the communication between the communities in the N- and C-lobes is mediated by a lobe-bridging β hairpin. The majority of the central nodes that forms the optimal allosteric paths for the correlated dynamics is located within this β hairpin. There might be mutual effects between substrate binding and protein dynamics since this β hairpin constitutes an essential part of the substrate binding cleft. Molecular dynamics simulation was done using the scalable NAMD package. Principle component analysis and statistical analysis of molecular dynamics simulation trajectories were done with R. Small-angel X-ray scattering data was collected at APS BioCAT beamline.
5. Structure-based Drug Design and Biochemistry
The core of our drug discovery workflow integrates high-throughput virtual screening, knowledge-based molecular modeling, biochemical/cellular testing, structure determination, and structure-activity relationship (SAR) analysis. We perform in silico virtual screening using molecular docking against over 25 million commercially available compounds from ZINC database. We use both generic and target-specific binding assays for quantitative assessment of drug binding affinity. Generic assays may include isothermal titration calorimetry (ITC) which measures the binding via heat change, or thermal shift assay which is based on the binding-induced change in thermal stability. For target-specific binding assays, we usually design competitive fluorescence polarization (FP)-based binding assays for throughput and sensitivity. We use enzyme kinetic studies to yield information regarding the mechanism of inhibition, i.e., competitive, noncompetitive, or uncompetitive. We use various cell culture models to evaluate compound permeability and toxicity as well as their inhibition efficacy against specific cellular functions or pathways. Finally, we use a powerful empirical approach, the field-based 3D-QSAR to incorporate our experimental data into computational modeling process to provide suggestion for compound optimization and a biological activity-based scoring system.
This workflow has proven effective in our drug discovery efforts for SMYD proteins as well as in multiple collaborative drug development projects. We developed the inhibitors targeting SMYD3 active site with high selectivity over other SMYD proteins to prevent skeletal muscle wasting. We also developed the inhibitors against SMYD2 secondary binding site for selective inhibition of a subset of SMYD2 substrates that have exhibited promising inhibitory activity on cell proliferation of triple negative breast cancer cells. In one of our collaborative drug development projects, we developed the compounds that can act as a pharmacological chaperone to rescue misfolded CFTR mutants and promote CFTR maturation. We also developed several protein-protein interaction inhibitors aimed for breaking the Nek7-dependent inflammasome assembly during the macrophage-mediated immune response, and breaking the interaction between NHERF2 and LPA2 to enhance CFTR channel activity in cystic fibrosis.
In addition to structure-based drug design, we also perform experimental compound screening aimed for drug repurposing using high-throughput capable biochemical assays. In our laboratory, we have 97 FDA-approved cancer drugs, 127 naturally occurring products, 879 cancer-sensitive compounds, and 727 clinically-tested small molecules. Using this library, we seek to redevelop existing or “old” drugs for use in new medical conditions. This strategy has successfully been used in one of our drug development projects to target epigenetic interactions that are essential for breast cancer cell metastasis. One such target is the interaction between the Tudor domain of GASC1 and trimethylated histone H3K4. Using an intrinsic tryptophan fluorescence assay, we identified one compound from the library that can disrupt this interaction. Because this compound is highly drug-like with well-established safety profiles, it might well be appropriate for direct human use as well as for an immediate conduct of clinical trials.
1.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. The Prostate, in revision (2019).
2. 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).
3. 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).
4. 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).
5. 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).
6. 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).
7. 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).
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11. 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).
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19. 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).
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24. 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).
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28. 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).
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32. 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).
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50. 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).
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