Studies in our laboratory focus on the folding, structure, and function of integral membrane proteins and their misfolding as the basis of human disease. The cystic fibrosis conductance regulator (CFTR) and microbial homologues have served as our favored models for the bulk of these biophysical, molecular biological, and cell biological studies. These proteins are members of the ABC transporter supergene family of ATP-dependent active transporters and channels. This supergene family is the largest in many of the completely sequenced microbial genomes and includes many medically relevant members, including ATP-driven drug efflux pumps and bacterial toxin transporters, in addition to CFTR. Mutations in cftr (>900 to date) cause the fatal recessive disorder cystic fibrosis (CF). Many of these mutations alter the ability of the membrane protein to efficiently fold into a functional structure. Others alter the mechano chemistry of the transport gating cycle. Understanding these defects at a molecular level is providing insight into how primary sequence encodes the folding pattern of integral membrane proteins, how cellular systems cope with the aberrant protein, and how the energy of ATP hydrolysis is utilized to effect movement of a solute across a membrane barrier.
RESEARCH INTERESTS
Mechanisms of membrane protein folding
Protein misfolding and disease
Molecular mechanisms for cellular quality control of misfolded proteins
Structure and function of ATP dependent transporters, channels, and proteases
RECENT PUBLICATIONS
Thibodeau PH, Brautigam CA, Machius M, Thomas PJ, "Side chain and backbone contributions of Phe508 to CFTR folding." Nat Struct Mol Biol, 12(1):10-6, January 2005
Liu CW, Giasson BI, Lewis KA, Lee VM, Demartino GN, Thomas PJ, "A precipitating role for truncated alpha-synuclein and the proteasome in alpha-synuclein aggregation: implications for pathogenesis of Parkinson disease." J Biol Chem, 280(24):22670-8, June 2005
Liu CW, Li X, Thompson D, Wooding K, Chang TL, Tang Z, Yu H, Thomas PJ,, "ATP binding and ATP hydrolysis play distinct roles in the function of 26S" Mol Cell, 24:39-50, October 2006
Liu CW, Corboy MJ, DeMartino GN, Thomas PJ, "Endoproteolytic activity of the proteasome" Science, 299:408-11, January 2003
Baker JM, Hudson RP, Kanelis V, Choy WY, Thibodeau PH, Thomas PJ, Forman-Kay, "CFTR regulatory region interacts with NBD1 predominantly via multiple transient" Nat Struct Mol Biol, 14:738-45, August 2007
SIGNIFICANT PUBLICATIONS
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, 9(5):381-8, May 2002
Choi JY, Muallem D, Kiselyov K, Lee MG, Thomas PJ, Muallem S, "Aberrant CFTR-dependent HCO3- transport in mutations associated with cystic fibrosis." Nature, 410(6824):94-7, March 2001
Wigley WC, Stidham RD, Smith NM, Hunt JF, Thomas PJ, "Protein solubility and folding monitored in vivo by structural complementation of a genetic marker protein." Nat Biotechnol, 19(2):131-6, February 2001
Wigley WC, Fabunmi RP, Lee MG, Marino CR, Muallem S, DeMartino GN, Thomas PJ, "Dynamic association of proteasomal machinery with the centrosome." J Cell Biol, 145(3):481-90, May 1999
Moody JE, Millen L, Binns D, Hunt JF, Thomas PJ, "Cooperative, ATP-dependent association of the nucleotide binding cassettes during" J Biol Chem, 277:21111-4, April 2002
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