About Our Research

Currently, we are interested in Alzheimer’s disease (AD) and cancer. In AD, we are studying the structural mechanisms of the generation of amyloid-β peptide (Aβ). We also study the interaction between glycan and tau, which facilitates the spread of tau pathology, neurofibrillary tangle (NFT, the other pathological hallmark of AD). In cancer, we are studying the structural mechanism of Hedgehog signaling and p53 interactions.

Our Projects

Project 1: AD Drug Discovery Targeting Aβ Production

The intramembrane proteolysis mechanism can result in the formation of Aβ protein, which is a molecule that can aggregate into fibril and plaques in the brain, a pathological hallmark of Alzheimer’s disease (AD). We are seeking inhibitors which can stop Aβ processing.

AD drug discovery targeting Aβ precursor protein (APP) processing

Project 2: The Transmission of Tau Protein and Related Tau-glycans Interactions

Microtubule associated protein tau is an intrinsically disordered protein (IDP) and aggregates to form neurofibrillary tangles (NFT) within neurons, a pathological hallmark of AD. Recent work has shown that heparan sulfate proteoglycan (HSPG) on neuronal surface binds tau aggregates or misfolded tau monomers, facilitating tau uptake and intracellular seeding of aggregation. The structural basis of tau-glycans interactions will reveal many unanswered questions about tau pathology and implicate new strategy for AD drug discovery.

The transmission of tau protein and related tau-glycans interactions

A. Prion like spread of tau | B. Primary sequence of tau | C. Chemical structure of glycans

Cellular uptake of tau

(*KEY* blue: nucleus of the cell, green: tau)

Project 3: Hedgehog Autoprocessing and Cancer

The Hedgehog (Hh) signaling pathway plays vital roles in development while its aberrant activity is linked to multiple cancers. We study mechanisms involved in Hedgehog autoprocessing to guide drug discovery for inhibiting autoprocessing in cancers.

Hedgehog autoprocessing

Highlighted Publications

EGCG Binds Intrinsically Disordered N-terminal Domain of p53 and Disrupts p53-MDM2 Interaction

Jing Zhao, Xiaorong Liu, Alan Blayney, Lauren Gandy, Chao Yang, Xinyue Liu, Yuanyuan Xiao, Michael S. Cosgrove, Sozanne R. Solmaz, Yingkai Zhang, David Ban, Stewart N. Loh, Jianhan Chen and Chunyu Wang (2021).

Nature Communications 12: 986 (2021)

Substrate interaction inhibits intramembrane proteolysis and amyloid production

61. Jing Zhao, Yuanyuan Xiao, Xinyue Liu, Marilia Barros, Yueming Li, Xuben Hou, Nikolaos Robakis, Jon Dordick, Yingkai Zhang, Iban Ubarretxena-Belandia and Chunyu Wang.

Chemical Communications. 56, 2578-2581 (2020)

Rare 3‐O‐sulfation of Heparan Sulfate Enhances Tau Interaction and Cellular Uptake

Jing Zhao, Yanan Zhu, Xuehong Song, Yuanyuan Xiao, Guowei Su, Xinyue Liu, Zhangjie Wang, Yongmei Xu, Jian Liu, David Eliezer, Trudy F. Ramlall, Guy Lippens, James Gibson, Fuming Zhang, Robert J. Linhardt, Lianchun Wang, Chunyu Wang (2019).

Angewandte Chemie. DOI: 10.1002/anie.201913029.

General Base Swap Preserves Activity and Expands Substrate Tolerance in Hedgehog Autoprocessing

Jing Zhao, Daniel A. Ciulla, Jian Xie, Andrew G. Wagner, Drew A. Castillo, Allison S. Zwarycz, Zhongqian Lin, Seth Beadle, José-Luis Giner, Zhong Li, Hongmin Li, Nilesh Banavali, Brian P. Callahan, Chunyu Wang (2019).

Journal of the American Chemical Society. DOI: 10.1021/jacs.9b08914

Familial Alzheimer's Mutations within APPTM Increase Abeta42 Production by Enhancing the Accesibility of the Epsilon-Cleavage Site

Wen Chen, Eric Gamache, David Rosenman, Jian Xie, Maria Lopez, Yueming Li, and Chunyu Wang (2014).

Nature Communications 4:3037. DOI: 10.1038/ncomms4037.

High Pressure NMR Reveals Conformational Perturbations Disease-Causing Mutations in Amyloid β-Peptide

David J. Rosenman, Nicolina Clemente, Muhammod Ali, Angel Garcia and Chunyu Wang (2018).

Chemical Communications, 54: 4609-4612. DOI: 10.1039/C8CC01674G.

Vitamin B12 Inhibits LRRK2 Kinase Activity and Prevents Deficits in LRRK2 Models of Parkinson's Disease Pathogenesis

Adam Schaffner, Xianting Li, Nina Pan, Keita Morohashi, Emmanouela Leandrou, Anna Memou, Hardy Rideout, Yacob Gomez-Llorente, Lianteng Zhi, Hui Zhang, Chen Yao, Shu G. Chen, Farinaz Afsari, Christopher J. Elliott, Nicolina Clemente, Chunyu Wang, Ming-Ming Zhou, Iban Ubarretxena-Belandia, and Zhenyu Yue (2019).

Cell Research, 29 (4): 313 DOI: 10.1038/s41422-019-0153-8.

Coupled Transmembrane Substrate Docking and Helical Unwinding in Intramembrane Proteolysis of Amyloid Precursor Protein

Nicolina Clemente, Alaa Abidine, Iban Ubarretxena-Belandia and Chunyu Wang (2018).

Scientific Reports, 8:12411 | DOI:10.1038/s41598-018-30015-6.

A Single Aspartate Coordinates Two Catalytic Steps in Hedgehog Autoprocessing.

Jian Xie, Timothy Owen, Ke Xia, Brian Callahan and Chunyu Wang (2016).

Journal of the American Chemical Society. 138: 10806-10809. DOI: 10.1021/jacs.6b06928.

Glycan Determinants of Heparin-Tau Interaction.

Jackie Zhao, Isabelle Huvent, Guy Lippens, David Eliezer, Anqiang Zhang, Quanhong Li, Peter Tessier, Robert J Linhardt, Fuming Zhang, and Chunyu Wang (2017).

Biophysical Journal. 112(5): 921-932.

Zinc Inhibits Hedgehog Autoprocessing: Linking Zinc Deficiency with Hedgehog Activation.

Jian Xie, Timothy Owen, Ke Xia, Ajay Vikram Singh, Emily Tou, Lingyun Li, Brigitte Arduini, Hongmin Li, Leo Q. Wan, Brian Callahan and Chunyu Wang (2015).

J. Biol. Chem. 289(118): 11591-11600. Top 5 most viewed article March-April 2015 on JBC website.

Intramolecular Disulfide Bond between Catalytic Cysteines in an Intein Precursor

Wen Chen, Lingyun Li, Zhenming Du, Jiajing Liu, Julie N. Reitter, Kenneth V. Mills, Robert J. Linhardt, and Chunyu Wang (2012).

Journal of the American Chemical Society. 134(5):2500-2503.

Structural and Mutational Studies of a Hyperthermophilic Intein from DNA Polymerase II of Pyrococcus abyssi

Zhenming Du, Jiajing Liu, Clayton D. Albracht, Alice Hsu, Wen Chen, Michelle D. Marieni, Kathryn M. Colelli, Jennie E. Williams, Julie N. Reitter, Kenneth V. Mills, Chunyu Wang (2011).

Journal of Biological Chemistry, 286: 38638-38648.
With a cover illustration of Nov. 4, 2011 issue of JBC

Lysine-specific Molecular Tweezers Are Broad-Spectrum Inhibitors of Assembly and Toxicity of Amyloid Proteins

Sinha, Sharmistha; Lopes, Dahabada; Du, Zhenming; $ Pang, Eric; Shanmugam, Akila; Lomakin, Aleksey; Talbiersky, Peter; Tennstaedt, Annette; McDaniel, Kirsten; Bakshi, Reena; Kuo, Pei-Yi; Ehrmann, Michael; Benedek, George; Loo, Joseph; Klärner, Frank-Gerrit; Schrader, Thomas; Wang, Chunyu; Bitan, Gal (2011).

Journal of the American Chemical Society 133(42): 16958-16969.

Deficiency of Cyclophilin D Attenuates Mitochondrial and Neuronal Perturbation, and Ameliorates Learning Memory in Alzheimer’s Disease

Du, H., Guo, L., Fang, F., Chen, D., Sosunov, A., McKhann, G., Yan, Y.*, Wang, C., Zhang, H., Molkentin, J.D., Gunn-Moore, F.J., Vonsattel, J.P., Arancio, O., Chen, J.X., Yan, S.D. (2008).

Nature Genetics 14: 1097-1105.

The Alzheimer's Peptides Aβ40 and 42 Adopt Distinct Conformations in Water: A Combined MD/NMR Study

Sgourakis, N., Yan, Y., McCallum, S., Wang, C. and Garcia, A.E. (2007).

Journal of Molecular Biology 368:1448-1457.

Aβ40 Protects Non-Toxic Aβ42 Monomers from Aggregation

Yan, Y. and Wang, C. (2007).

Journal of Molecular Biology 369:909-916.

Aβ42 is More Rigid than Aβ40 in the C-Terminus: Implications for Aβ Aggregation and Toxicity

Yan, Y. and Wang, C. (2006).

Journal of Molecular Biology 364: 853-862.

C.WANG