Wei-Jen Tang

Research Summary


cAMP-Mediated Signal Transduction, Anthrax Pathogenesis

Overview

The research of my laboratory focuses on elucidating the structural and molecular basis of the interaction of protein with their partner proteins or ligand/drug. One current research direction is to address the structure and function of human insulin degrading enzyme (IDE) as well as the therapeutic potential of this enzyme. IDE is a zinc metalloprotease and it is involved in the clearance of insulin and amyloid β, peptides involved in the progression of diabetes and Alzheimer's disease, respectively. IDE has unusual substrate selectivity that represents unique properties in protein-protein interaction. We solved structures of human IDE in complex with four substrates (insulin B chain, amyloid-b (1-40) (Aβ), amylin, and glucagon) to elucidate the molecular basis of this unique substrate selectivity. Our structure model also provides a valuable tool in starting the exploration of IDE-based therapeutics in controlling cerebral Aβ accumulation and blood sugar levels. Future directions in studying IDE in my lab include the elucidation of the molecular basis in the regulation of IDE catalysis, the discovery of small molecule IDE activator and inhibitor leads, and the protein engineering of IDE to make an IDE-based therapeutic for Alzheimer's disease.

The other research direction deals with the biology of bacterial toxins secreted by human bacterial pathogens. One toxin family that we have studied is adenylyl cyclase toxins which 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 to raise the intracellular cyclic AMP (cAMP) of its host cells to pathogenic levels. The unregulated increase of intracellular cAMP level can alter the functions of host cells to benefit the bacterial propagation. We have studied two adenylyl cyclase toxins, edema factor (EF) secreted by bacteria that cause anthrax and CyaA, which is secreted bacteria that cause 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 also are exploring the therapeutic potential of adenylyl cyclase toxins in human diseases as well.

The incident of bioterrorism-related anthrax in 2001 has moved the challenge against anthrax from an obscure agricultural problem to the center of bio-defense. Giving 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.


Spring 2009 News - Class of 2008 students identified Wei-jen Tang as one of the instructors and mentors who had been most influential during the course of their University of Chicago education.