Patrick Thibodeau, PhD
537 Bridgeside Point II
450 Technology Drive
Pittsburgh, PA 15219
My lab is interested in the fundamental principles of protein structure and dynamics. The acquisition of native protein structure and the dynamics associated with the native state are critical for proper protein biosynthesis and the regulation of protein function. Specifically, we are interested in transmembrane proteins and their roles in human physiology and pathogen virulence. The majority of this work is focused on understanding the roles of the ATP-Binding Cassette (ABC) transporter family of proteins in regulating normal physiology and the virulence of bacterial pathogens.
There are two main focuses of our current research:
First, we are interested in addressing structure-function and physiological questions related to mammalian ABC transporters. There are 48 known ABC transporters in the human genome. Among these, we are interested in understanding the functional and physiological roles of two: CFTR and ABCC6. Mutations in CFTR are responsible for cystic fibrosis, while mutations in ABCC6 are causative of ectopic mineralization disorders and are associated with premature heart disease. Our studies of these proteins are focused on elucidating the folding pathways that promote the formation of native state structure, identifying the mechanisms by which disease-causing mutations impact these pathways, and developing strategies that might be useful in correcting these defects.
Second, we are interested in the physical basis of Type I secretion in gram-negative bacteria and the role of the Type I exoproteins in bacterial virulence. Multiple human pathogens, including E. coli, P. aeruginosa, and B. pertussis utilize Type I secretion systems to export virulence factors and toxins. The secreted virulence factors range in size between 10 kDa to 1 MDa and alter host-pathogen interactions by facilitating adherence and modulating host responses to the pathogen. We are focused on understanding the structural and functional regulation of the serralysin proteases, the physical mechanisms associated with their secretion, and their impact on host tissues during bacterial infection. Specifically, we are interested in the roles of these proteases in modulating host-pathogen interactions in P. aeruginosa infection of the airway. These studies focus on the role of both native and non-native proteins structures, the regulation of protease activity, and the effects of these exoproteases on host physiology.
All of our studies rely on a combination of biochemical and biophysical approaches to evaluate protein structure and dynamics in vitro, including spectroscopy, X-ray crystallography, NMR, and functional biochemistry. These studies are complemented by cell culture and in vivo models, which rely on microscopy, biochemistry, and electrophysiological approaches to evaluate changes in protein structure and function in cellular environments.
Aiping Zheng, Research Associate