Associate Professor of Biology
Director, Biochemistry & Biophysics Graduate Program
Joint appointment in Chemistry and Chemical Biology
Education and Training
B.S. Beijing University, 1991
M.D. Peking Union Medical College, 1996
Ph.D. Department of Biochemistry and Molecular Genetics, Cornell University, Mentor: Dr. Linda K. Nicholson, 2000
Postdoctoral Training, Department of Biochemistry and Molecular Biophysics, Columbia University, Mentor: Dr. Arthur G. Palmer, 2001-2004
Tel: (518) 276-3497
Fax: (518) 276-2344
Office: Biotech Center Rm. 2229
Rensselaer Polytechnic Institute
110 8th Street
Troy, NY 12180
Alzheimer’s disease, Aβ, protein aggregation, mechanism and applications of protein splicing, protein recognition, protein dynamics, membrane proteins, NMR spectroscopy.
My research focuses on protein structure and dynamics in Alzheimer’s disease and protein splicing.
Alzheimer’s disease (AD) is the most common type of dementia, characterized by progressive and irreversible memory loss. Annual cost for AD mounts to $604 billion globally, representing 1% of world GDP! A small peptide, called amyloid β-peptide (Aβ), is the major component of amyloid plaque, a pathological hallmark of AD. Evidence from human genetics, biochemistry and mouse models strongly suggests a causative role for Ab in AD. In order to understand the disease mechanism and to search for AD therapeutics, we are studying the structural biology of Aβ:
- Dynamics of Ab and Ab aggregation with nuclear magnetic resonance (NMR) and molecular dynamics (MD). Aβ aggregates to form neurotoxic oligomers and fibrils, which is a critical step in AD pathogenesis. In a series of four papers, we have demonstrated that protein dynamics play a crucial role in Ab aggregation. A few mutations with Ab peptide can cause a hereditary form of AD. We are investigating how these mutations disrupts normal Ab structure and dynamics, leading to enhanced Ab toxicity.
- Mechanism of Ab toxicity. The interaction of Aβ with normal proteins underlies the mechanism of Aβ toxicity, which disrupts neural networks and eventually leads to memory failure. We have been pursuing the structural studies of Aβ interactions with proteins such as ABAD (Aβ-binding Alcohol Dehydrogenase), CypD (cyclophilin D) and RAGE (Receptors for Advanced Glycation Product). The high-resolution structural information obtained will be the basis of rational drug design for AD.
- Protective roles of Ab40 in Alzheimer’s disease. Enhancing the protective mechanism in AD is an overlooked direction in AD drug discovery. Recently, we have demonstrated a critical, protective function for a specific type of Ab, the 40 amino acid residue Ab40. Currently we are exploring the mechanism of such a protective effect and the possible application of Aβ40 to the prevention and treatment of AD.
- Structural basis of AD-causing mutations in Ab precursor protein. Ab is generated from a precursor protein amyloid precursor protein (APP). We are solving the solution NMR structure of a crucial part of APP responsible for Ab generation, the transmembrane domain of amyloid precursor protein (APPTM). Twelve mutations within APPTM can cause AD. The structural and dynamic differences between WT and mutant APPTM will provide insights into the pathogenesis and management of AD.
Protein splicing is a fascinating, self-catalyzed reaction occurring in some proteins. An intervening protein sequence, intein, catalyzes its own removal from a precursor protein with the concomitant ligation of the flanking sequences. Protein splicing has been hailed as “Nature’s gift to protein chemist” and has found wide spread applications in biomedical research. Although the basic steps of protein splicing are well-known, the catalytic mechanisms of intein splicing are still poorly understood. There are three thrusts in this research:
- Testing the pKa shift hypothesis. The pKa value measures the acidity of a functional group in an enzyme. We have discovered that the pKa value of a highly conserved histidine changes during intein catalysis and have proposed a new mechanism for protein splicing. This hypothesis is supported by evidence from numerous experiments and we are validating the generality of the pKa shift mechanism in more inteins.
- Testing the dynamic activation hypothesis. Inteins from organisms living at high temperature (thermophiles) splice only at high temperature. This temperature dependence of splicing is likely due to the activation of protein motions critical for catalysis. Solution NMR is one of the most powerful methods for studying protein dynamics. We have recently characterized the dynamics of an intein at atomic details and we will continue to characterize the dynamics of a hyperthermophilic intein.
- Application of intein inhibitors to treating tuberculosis. The survival of Mycobacteria tuberculosis (Mtu), the organism that causes TB, relies on intein mediated protein splicing, while the metabolism of human cell doesn’t require protein splicing. Thus inhibitors of protein splicing may develop into a novel class of anti-TB drugs with minimal side effects on human cells. We are studying existing intein inhibitors and developing new inhibitors, using NMR, directed evolution and structural modeling.
Yan, Y. and Wang, C. (2006) “Aβ42 is More Rigid than Aβ40 in the C-Terminus: Implications for Aβ Aggregation and Toxicity”, Journal of Molecular Biology 364: 853-862.
Yan, Y., Liu, Y., Sorci, M., Belfort, G., Lustbader J.W., Yan, S.D. and Wang, C. (2007) “Surface Plasmon Resonance and Nuclear Magnetic Resonance Studies of ABAD-Aβ Interaction” Biochemistry 46: 1724-1731.
Sgourakis, N., Yan, Y., McCallum, S., Wang, C. and Garcia, A.E. (2007) “The Alzheimer's peptides Aβ40 and 42 adopt distinct conformations in water: A combined MD / NMR study” Journal of Molecular Biology 368:1448-1457.
Yan, Y. and Wang, C. (2007) “Aβ40 protects non-toxic Aβ42 monomers from aggregation” Journal of Molecular Biology 369:909-916.
Yan, Y., McCallum, S.A., Wang, C. (2008). M35 oxidation Causes Aβ40-like Changes in Structure and Dynamics in Aβ42. Journal of the American Chemical Society. Published online April 1, 2008.
Heng Du, Lan Guo, Fang Fang, Doris Chen, Alexander Sosunov, Guy McKhann, Yilin Yan, Chunyu Wang, Hong Zhang, Jeffery D Molkentin, Frank J. Gunn-Moore, Jean Paul Vonsattel, Ottavio Arancio, John Xi Chen, Shi Du Yan (2008). Deficiency of Cyclophilin D attenuates mitochondrial and neuronal perturbation, and ameliorates learning memory in Alzheimer’s disease. Nature Genetics. 14(10): 1097-1105.
Alexey V. Gribenko, Mayank M. Patel, Jiajing Liu, Scott A. McCallum, Chunyu Wang, George I. Makhatadze (2009). “Rational Stabilization of Enzymes by Computational Redesign of Surface Charge-Charge Interactions.” Proceedings of the National Academy of Science. 106(8): 2601-2606.
Zhenming Du, Philip T. Shemella, Yangzhong Liu, Scott A. McCallum, Brian Pereira, Saroj K. Nayak, Georges Belfort, Marlene Belfort and Chunyu Wang (2009). “Highly Conserved Histidine Plays a Dual Catalytic Role in Protein Splicing: a pKa Shift Mechanism”, Journal of the American Chemical Society, Published online July 24 2009.
Du, Z., Liu, Y., Ban, D., Lopez, M., Belfort, M. and Wang, C. (2010). “Backbone Dynamics and Global Effects of an Activity Enhancing Mutation in Minimized Mtu RecA Inteins”, Journal of Molecular Biology 400: 755-767.
Du, Z., Zheng, Y., Patterson, M., Liu, Y. and Wang, C. (2011) “pKa Coupling at Intein Active Site: Implications for Coordination Mechanism of Protein Splicing with a Conserved Aspartate”, Journal of the American Chemical Society 133:10275-10282.
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) “Lysine-specific molecular tweezers are broad-spectrum inhibitors of assembly and toxicity of amyloid proteins”, Journal of the American Chemical Society 133(42): 16958-16969.
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). “Structural and Mutational Studies of a Hyperthermophilic Intein from DNA Polymerase II of Pyrococcus abyssi”, Journal of Biological Chemistry, 286: 38638-38648. With a cover illustration of Nov. 4, 2011 issue of JBC.
Zhenming Du, Jiajing Liu,
Julie N. Reitter, Kenneth V. Mills,
Robert J. Linhardt, and Chunyu Wang
(2012). “Intramolecular Disulfide Bond between Catalytic Cysteines in an Intein Precursor” Journal of the American Chemical Society.