The Faculty


Structural basis of cell signal transduction and its application to human health


National Taiwan University, Taipei, Taiwan, B.S. Zoology 06/1982

Taiwanese Air Force, Taiwan, First Liertenant 08/1984

University of Texas, Austin, Austin, Texas, PhD Biological Sciences 06/1988

University of Texas Austin, Austin, Texas, Postdoctoral fellow Virology 08/1988

University of Texas Southwestern Medical School, Dallas, Texas, Postdoctoral fellow Pharmacology 06/1993

Awards and honors

1983 - 1984 University fellowship University of Texas, Austin

1995 - 1996 Young Investigator Cancer Research Foundation

1999 - 2002 Established Investigator American Heart Association

Research Summary

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.

Selected Papers

  1. Mancl JM, Suarez C, Liang WG, Kovar DR, Tang WJ. Pseudomonas aeruginosa exoenzyme Y directly bundles actin filaments. J Biol Chem. 2020 03 13; 295(11):3506-3517. 

    Li NS, Liang W, Piccirilli JA, Tang WJ. Reinvestigating the synthesis and efficacy of small benzimidazole derivatives as presequence protease enhancers. Eur J Med Chem. 2019 Dec 15; 184:111746. 

    Leroux F, Bosc D, Beghyn T, Hermant P, Warenghem S, Landry V, Pottiez V, Guillaume V, Charton J, Herledan A, Urata S, Liang W, Sheng L, Tang WJ, Deprez B, Deprez-Poulain R. Identification of ebselen as a potent inhibitor of insulin degrading enzyme by a drug repurposing screening. Eur J Med Chem. 2019 Oct 01; 179:557-566. 

    Farcasanu M, Wang AG, Uchanski T, Bailey LJ, Yue J, Chen Z, Wu X, Kossiakoff A, Tang WJ. Rapid Discovery and Characterization of Synthetic Neutralizing Antibodies against Anthrax Edema Toxin. Biochemistry. 2019 07 09; 58(27):2996-3004. 

    Lai R, Tang WJ, Li H. Catalytic Mechanism of Amyloid-ß Peptide Degradation by Insulin Degrading Enzyme: Insights from Quantum Mechanics and Molecular Mechanics Style Møller-Plesset Second Order Perturbation Theory Calculation. J Chem Inf Model. 2018 09 24; 58(9):1926-1934. 

    Zhang Z, Liang WG, Bailey LJ, Tan YZ, Wei H, Wang A, Farcasanu M, Woods VA, McCord LA, Lee D, Shang W, Deprez-Poulain R, Deprez B, Liu DR, Koide A, Koide S, Kossiakoff AA, Li S, Carragher B, Potter CS, Tang WJ. Ensemble cryoEM elucidates the mechanism of insulin capture and degradation by human insulin degrading enzyme. Elife. 2018 03 29; 7. 

    Bailey LJ, Sheehy KM, Dominik PK, Liang WG, Rui H, Clark M, Jaskolowski M, Kim Y, Deneka D, Tang WJ, Kossiakoff AA. Locking the Elbow: Improved Antibody Fab Fragments as Chaperones for Structure Determination. J Mol Biol. 2018 02 02; 430(3):337-347. 

    Sharma S, Galanina N, Guo A, Lee J, Kadri S, Van Slambrouck C, Long B, Wang W, Ming M, Furtado LV, Segal JP, Stock W, Venkataraman G, Tang WJ, Lu P, Wang YL. Identification of a structurally novel BTK mutation that drives ibrutinib resistance in CLL. Oncotarget. 2016 Oct 18; 7(42):68833-68841. 

    Yue J, Zhang Y, Liang WG, Gou X, Lee P, Liu H, Lyu W, Tang WJ, Chen SY, Yang F, Liang H, Wu X. In vivo epidermal migration requires focal adhesion targeting of ACF7. Nat Commun. 2016 05 24; 7:11692. 

    Liang WG, Triandafillou CG, Huang TY, Zulueta MM, Banerjee S, Dinner AR, Hung SC, Tang WJ. Structural basis for oligomerization and glycosaminoglycan binding of CCL5 and CCL3. Proc Natl Acad Sci U S A. 2016 May 03; 113(18):5000-5. 

    Tang WJ. Targeting Insulin-Degrading Enzyme to Treat Type 2 Diabetes Mellitus. Trends Endocrinol Metab. 2016 Jan; 27(1):24-34. 

    Deprez-Poulain R, Hennuyer N, Bosc D, Liang WG, Enée E, Marechal X, Charton J, Totobenazara J, Berte G, Jahklal J, Verdelet T, Dumont J, Dassonneville S, Woitrain E, Gauriot M, Paquet C, Duplan I, Hermant P, Cantrelle FX, Sevin E, Culot M, Landry V, Herledan A, Piveteau C, Lippens G, Leroux F, Tang WJ, van Endert P, Staels B, Deprez B. Catalytic site inhibition of insulin-degrading enzyme by a small molecule induces glucose intolerance in mice. Nat Commun. 2015 Sep 23; 6:8250. 

    Lübker C, Dove S, Tang WJ, Urbauer RJ, Moskovitz J, Urbauer JL, Seifert R. Different Roles of N-Terminal and C-Terminal Domains in Calmodulin for Activation of Bacillus anthracis Edema Factor. Toxins (Basel). 2015 Jul 13; 7(7):2598-614.

    Liang WG, Ren M, Zhao F, Tang WJ. Structures of human CCL18, CCL3, and CCL4 reveal molecular determinants for quaternary structures and sensitivity to insulin-degrading enzyme. J Mol Biol. 2015 Mar 27; 427(6 Pt B):1345-1358. 

BPHYS Student

NIck Bayhi