Chunyu Wang, M.D., Ph.D.
Rensselaer Polytechnic Institute
Chunyu Wang is a native of Shanghai, China. Originally he planned to become a physician and obtained his MD from the renowned Peking Union Medical College in 1996. In the same year, he decided to pursue research and joined Cornell University as a PhD student, specializing in solution NMR of proteins. After earning his PhD in 2000, he moved to Prof. Arthur G. Palmer’s lab at Columbia University as a postdoctoral associate to develop NMR methods for studying protein dynamics. In 2005, he started his own research group at Rensselaer Polytechnic Institute, focusing on NMR studies of proteins involved Alzheimer’s disease and intein-mediated protein auto processing.
Alzheimer’s disease research
We focus on the structural biology of Aβ and the structural mechanism of increased Aβ42/Aβ40 ratio in familial Alzheimer’s disease (FAD).
Structural mechanism of FAD mutations within the transmembrane domain of the amyloid β-protein precursor (APP-TM).
APP-TM is the substrate from which the enzyme γ-secretase generates Aβ. Several mutations within APP-TM can cause FAD but little is known about the mechanism by which they cause the disease. We are the first to compare the structure and dynamics of normal APP-TM with FAD mutants. We discovered that the FAD mutations V44M and V44A change the structure and dynamics of ε-site for γ-secretase cleavage, thereby favoring the production of Aβ42, the form of Aβ that is most closely associated with Alzheimer’s disease (AD) (Chen et al., Nat. Commun. 2014). This work has important implications for AD mechanism and suggests that ε-cleavage can be a target for drug discovery aimed at reducing Aβ production and the Aβ42/Aβ40 ratio. Future work plan to explore the interaction between APP-TM and γ-secretase at atomic resolution.
Nuclear magnetic resonance (NMR) and molecular dynamics (MD) simulation of Aβ monomer structure, dynamics and aggregation.
In collaboration with Angel Garcia at Rensselaer Polytechnic Institute, we combined MD simulation with NMR to characterize Aβ, which is an intrinsically disordered protein not amenable to conventional structural methods. We pioneered the validation of MD simulation with NMR data such as J-couplings and showed that Aβ40 and Aβ42 have different conformational ensembles, providing mechanistic insights to their different aggregation behavior. This 2007 paper has been already cited more than 200 times (Sgourakis et al., J. Mol. Biol. 2007) and was followed by a number of high-impact papers describing the conformational landscape of various Aβ species (e.g., Rosenman et al., J. Mol. Biol. 2013). Protein dynamics are crucial for function yet their role in the Aβ aggregation has been poorly understood. Using solution-state NMR, we demonstrated that Aβ40, Aβ42 and M35-oxidized Aβ42 have significant differences in backbone and side chain dynamics, mirroring the differences in their aggregation properties (Yan et al., J. Am. Chem. Soc. 2008). We also showed that Aβ40 could inhibit Aβ42 aggregation and therefore has a protective role in AD (Yan and Wang J. Mol. Biol. 2007). In addition, because several mutations within Aβ itself can cause FAD. We are investigating how these FAassociated mutations disrupt normal Aβ structure and dynamics, leading to enhanced Aβ toxicity.
Nuclear magnetic resonance (NMR) helps determine the binding site of CLR01 on Aβ.
Using isotopically labeled Aβ40 we measured changes in peak intensity and chemical shifts and showed that the main binding site of CLR01 is Lys16, whereas Lys28 and Arg5 are secondary binding sites. These data correlated with mass-spectrometry findings, providing additional confidence in the identification of the bindings sites.
S Sinha, DHJ Lopes, Z Du, ES Pang, A Shanmugam, A Lomakin, P Talbiersky, A Tennstaedt, K McDaniel, R Bakshi, P-Y Kuo, M Ehrmann, GB Benedek, JA Loo, F-G Klärner, T Schrader, C Wang, G Bitan (2011) Lysine-specific molecular tweezers are broad-spectrum inhibitor of aggregation and toxicity of amyloid proteins. Journal of the American Chemical Society, 133: 16958–16969.
Wen Chen, Eric Gamache, David Rosenman, Jian Xie, Maria Lopez, Yueming Li, and Chunyu Wang (2014). “Familial Alzheimer’s Mutations within APPTM Increase Aβ42 Production by Enhancing the Accessibility of the ε-Cleavage Site”. Nature Communications 4:3037 doi: 10.1038/ncomms4037.
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., McCallum, S.A., Wang, C. (2008). “M35 oxidation Causes Aβ40-like Changes in Structure and Dynamics in Aβ42” Journal of the American Chemical Society 130: 5394-5395.
Rosenman, D.J., Connors, C., Chen, W., Wang, C., Garcia, A.E., (2013). “Monomers Transiently Sample Oligomer and Fibril-like Configurations: Ensemble Characterization Using a Combined MD/NMR Approach” Journal of Molecular Biology 425(18): 3338-3359.
Yan, Y. and Wang, C. (2007) “Aβ40 Protects Non-Toxic Aβ42 Monomers from Aggregation”, Journal of Molecular Biology 369:909-916.