Faculty Photo Coming Soon.
Professor, The Ben May Department for Cancer Research
Affiliation: Professor, The Ben May Department for Cancer Research, Committee on Cancer Biology, Committee on Microbiology, Committee on Neurobiology, Committee on Cell Physiology
Structural basis of cell signal transduction and its application to human health
Ph.D., Univ. of Texas at Austin
B.S., National University of Taiwan
The research of my laboratory focuses on elucidating the molecular basis of cell communication. My current researches deal with the biology of bacterial adenylyl cyclase toxins, proteins that secreted by human bacterial pathogens. These toxins by themselves are not active till they enter into target cells and are associated with cellular proteins that serve as the activator. These adenylyl cyclase toxins become highly active and can then raise the intracellular cyclic AMP (cAMP) of its host cells to pathogenic levels. Cyclic AMP is a prototypic diffusible second messenger that controls diverse physiological responses. The unregulated increase of intracellular cAMP level can alter the functions of host cells to benefit the bacterial propagation.
One of such adenylyl cyclase toxins is edema factor (EF) secreted by Bacillus anthracis, the etiologic agent for anthrax. The other is CyaA secreted Bordetella pertussis that causes whooping cough. Both EF and CyaA bind the cellular calcium sensor, calmodulin, with high affinity. We have solved the x-ray structures of EF and CyaA as well as applied biochemical and biophysical analyses to address how calmodulin binds and activates EF and CyaA. We will continue these approaches to elucidate the principles in how protein-protein interaction leads to catalytic activation as well as how two proteins from two different organisms evolve to gain the desired biological activities. Many bacterial toxins, such as Botulinum toxin (BoTox) and Cholera toxin, have been developed as the experimental and therapeutic tools. We are currently exploring the therapeutic potential of adenylyl cyclase toxin in cancer treatment.
Adenylyl cyclase toxins have also been identified biochemically from Pseudomonas aeruginosa which is one of hospital-acquired pathogens that threatens the health of the immuno-compromised patients such as those with AIDS or cystic fibrosis (ExoY). Genomic sequences of Yersinia pestis (plague), Yersinia pseudotuberculosis (gastrointestinal syndromes), Vibrio Cholerae (massive diarrhea) reveal two novel members of adenylyl cyclase toxins. This suggests that adenylyl cyclase toxin may be used broadly by pathogenic bacteria to alter the host defense. We will apply biochemical, structural, and pharmacologic approaches to analyze the roles of these adenylyl cyclase toxins in bacterial pathogenesis.
The incident of bioterrorism-related anthrax in 2001 has moved the challenge against anthrax from an obscure agricultural problem to the center of biodefense. Given the ease of making antibiotic-resistant anthrax strains and unknown enemies, the best defense against anthrax is to build up a battery of possible antidotes against anthrax. We have developed several small molecular anti-anthrax toxin leads that can potently inhibit the action of anthrax toxins, EF and lethal factor. We will continue to discover and improve anti-anthrax toxin leads, which could then be further developed as the adjunct therapeutic against anthrax infection.
- Drum, C.L., Yan, S.-Z., Bard, J., Shen, Y.-Q., Lu, D., Soelaiman, S., Grabarek, Z., Bohm, A., and Tang, W.-J. (2002) Structural basis for the activation of anthrax adenylyl cyclase exotoxin by calmodulin, Nature 415:396-402.
- Shen, Y.-Q., Lee, Y.-S., Soelaiman, S., Bergson, P., Lu, D., Chen, A., Beckingham, K., Grabarek, Z., Mrksich, M., Tang, W.-J. (2002) Physiological calcium concentrations regulate calmodulin binding and catalysis of adenylyl cyclase exotoxins. EMBO J. 21: 6721-6732.
- Shen, Y.-Q., Zhukovskaya, N.L., Zimmer, M.I., Soelaiman, S., Wang, C.R., Gibbs, C.S., Tang, W.-J. (2004) Selective inhibition of anthrax edema factor by adefovir: a prototype for adjunctive therapy and probe of anthrax pathogenesis. Proc. Natl. Acad. Sci. USA 101:3242-3247.
- Lee, Y.-S., Bergson, P., He, W.-S., Mrksich, M., Tang, W.-J. (2004) Discovery of a small molecule that inhibits the interaction of anthrax edema factor with its cellular activator, calmodulin. Chem. & Biol. 11:1139-46.
- 5Shen, Y., Zhukovskaya, N.L., Guo, Q., Florián, J., and Tang, W.-J. (2005) Calcium-independent calmodulin binding and two-metal-ion catalytic mechanism of anthrax edema factor. EMBO J. 24:929-941.
- Guo, Q., Shen, Y., Lee, Y.-S., Gibbs, C.S., Mrksich, M., and Tang, W.-J. (2005) Structural basis for the interaction of adenylyl cyclase toxin of Bordetella pertussis with calmodulin. EMBO J. 24:3190-3201.
- Shen, Y., Joachimiak, A., Rosner, M.R., and Tang, W.-J. (2006) Structures of human insulin degrading enzyme reveal a new substrate recognition mechanism. Nature 443:870-874.
- Im, H., Manolopoulou, M., Malito, E., Shen, Y., Zhao, J., Neant-Fery, M., Sun, C.-Y., Meredith, S.C., Sisodia, S.S., Leissring, M., and Tang, W.-J. (2007) Structure of substrate-free human insulin degrading enzyme (IDE) and biophysical analysis of ATP-induced conformational switch of IDE. J. Biol. Chem. 282:25453-63.
- Malito, E., Hulse, R.E., and Tang, W.-J. (2008) Amyloid-β degrading cryptidase: insulin degrading enzyme, presequence peptidase, and neprilysin. CMLS 65:2574-85. (PMC2756532)
- Malito, E., Ralat, L.A. Manolopoulou, M., Tsay, J.L., Wadlington, N.L. and Tang, W.-J. (2008) Molecular Bases for the recognition of short peptide substrates and cysteine-directed modifications of human insulin-degrading enzyme. Biochemistry 47:12822-12834. (PMC2652632)
- Manolopoulou, M., Guo, Q., Malito, E. Schilling, A, and Tang, W.J. (2009) Molecular basis of catalytic chamber-assisted unfolding and cleavage of human insulin by human insulin degrading enzyme. J. Biol. Chem. 284:14177-88. (PMC2682866).
- Ralat, L.A., Ren, M., Schilling, A.B., and Tang, W.J. (2009) Protective role of CYS-178 against the inactivation and oligomerization of human insulin-degrading enzyme by oxidation and nitrosylation. J. Biol. Chem. 284:34005-18. (PMC2797171)
- Guo Q, Manolopoulou M, Bian Y, Schilling AB, Tang WJ. (2010) Molecular basis for the recognition and cleavages of IGF-II, TGF-α, and amylin by human insulin-degrading enzyme. J. Mol. Biol. 395:430-443. (PMC2813390)
- Ren, M., Guo, Q., Guo, L., Lenz, M., Qian, F., Koenen, R.R., Xu, H., Schilling, A.B., Weber, C., Ye, R.D., Dinner, A.R., and Tang, W.-J. (2010) Polymerization of MIP-1 chemokine (CCL-3 and CCL-4) and clearance of MIP-1 by insulin degrading enzyme. EMBO J. 29:3952-3966. (PMC3020635)
- Ralat, L.A., Guo, Q., Ren, M., Funke, T., Dickey, D.M., Potter, L.R., and Tang, W.-J. (2011) Insulin-degrading enzyme modulates the natriuretic peptide- mediated signaling response. J. Biol. Chem. 286:4670-4679. (PMC3039328)