University of Pittsburgh Department of Cell Biology
  • Research

    Transmembrane proteins establish the specific environments of cellular compartments separated by membranes. The proper expression and function of these proteins are critical to establishing the correct environmental conditions of these cellular compartments. ATP-Binding Cassette (ABC) transporters comprise a large superfamily of multi-domain proteins that regulate a variety of processes across cellular membranes. Mutations within these proteins result in human disease, such as cystic fibrosis and hypercholesterolemia, and altered expression of these proteins contributes to drug resistance in cancer. These transporters facilitate the movement of a variety of substrates from single ions (CFTR), cholesterol (ABCG5, ABCG8) and small molecules (Pgp, MDR) to large bacterial proteins (Type I secretion). My research focuses on the structure and function of these ABC transporters and the proteins that regulate and control their activity. First, using bacterial ABC transport systems, structure-function and mechanistic studies can be accomplished to better understand the reaction cycles associated with substrate translocation. Specifically, the protease secreting ABC-transporter systems, implicated to play a role in the pathogenesis of E. coli and P. aeruginosa, will be utilized to study the structure and function of these secretory systems using biochemical and structural approaches.

    Second, using the eukaryotic transport systems (CFTR, ABCG5 and ABCG8), biochemical and cell biological approaches will be used to identify the cellular systems that monitor the structure and regulate the function of these proteins. Previous work has demonstrated that mutation to these proteins can cause improper folding and retention in the ER and/or destabilization of the protein at the plasma membrane. Using biochemical, cell biological and genetic approaches, the cellular systems that are associated with monitoring the structure of these transporter systems will be identified and characterized.

  • Publications

    1. Baker JM, Hudson RP, Kanelis V, Choy WY, Thibodeau PH, Thomas PJ, Forman-Kay JD. CFTR regulatory region interacts with NBD1 predominantly via multiple transient helices. Nat Struct Mol Biol. 2007 Aug;14(8):738-45.
    2. Thibodeau PH, Brautigam CA, Machius M, Thomas PJ. Side chain and backbone contributions of Phe508 to CFTR folding. Nat Struct Mol Biol. 2005 Jan;12(1):10-6.
    3. Dorwart M, Thibodeau P, Thomas P. Cystic fibrosis: recent structural insights. J Cyst Fibros. 2004 Aug;3 Suppl 2:91-4. Review.
    4. Lewis HA, Buchanan SG, Burley SK, Conners K, Dickey M, Dorwart M, Fowler R, Gao X, Guggino WB, Hendrickson WA, Hunt JF, Kearins MC, Lorimer D, Maloney PC, Post KW, Rajashankar KR, Rutter ME, Sauder JM, Shriver S, Thibodeau PH, Thomas PJ, Zhang M, Zhao X, Emtage S. Structure of nucleotide-binding domain 1 of the cystic fibrosis transmembrane conductance regulator. EMBO J. 2004 Jan 28;23(2):282-93.
    5. Zhang XM, Wang XT, Yue H, Leung SW, Thibodeau PH, Thomas PJ, Guggino SE. Organic solutes rescue the functional defect in delta F508 cystic fibrosis transmembrane conductance regulator. J Biol Chem. 2003 Dec 19;278(51):51232-42.
    6. Wigley WC, Corboy MJ, Cutler TD, Thibodeau PH, Oldan J, Lee MG, Rizo J, Hunt JF, Thomas PJ. A protein sequence that can encode native structure by disfavoring alternate conformations. Nat Struct Biol. 2002 May;9(5):381-8.


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