The research carried out in Dr. Thomas laboratory at UT Southwestern focuses 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 archaebacterial homologues serve as models for biophysical, molecular biological, and cell biological studies directed at understanding these processes. 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 and lipid pumps and bacterial toxin transporters, in addition to the CFTR channel. Mutations in cftr (>1,000 to date) cause the fatal recessive disorder cystic fibrosis (CF). Many of these mutations alter the ability of this membrane protein to efficiently fold into a functional structure. Others alter coupling of ATP to the transmembrane solute pore. Understanding these defects at a molecular level is providing insight into how primary sequence encodes the folding pattern of integral membrane proteins and how the energy of ATP hydrolysis is utilized to effect movement of a solute across a membrane barrier. In addition, the system is providing insight into the mechanisms that cells employ to recognize and process misfolded proteins.
|Undergraduate||Columbia University Central Office , Chemical Engineering|
|Graduate School||University of North Dakota-Main Campus (1988)|
- Mechanisms of membrane protein folding
- Molecular mechanisms for cellular quality control of misfolded proteins
- Protein misfolding and disease
- Structure and function of ATP dependent transporters, channels, and proteases
- The torsin-family AAA+ protein OOC-5 contains a critical disulfide adjacent to Sensor-II that couples redox state to nucleotide binding.
- Zhu L, Wrabl JO, Hayashi AP, Rose LS, Thomas PJ Mol Biol Cell August 2008 19(8) 3599-612
- Congenital chloride-losing diarrhea causing mutations in the STAS domain result in misfolding and mistrafficking of SLC26A3.
- Dorwart MR, Shcheynikov N, Baker JM, Forman-Kay JD, Muallem S, Thomas PJ J Biol Chem March 2008 283(13) 8711-22
- Solubilizing mutations used to crystallize one CFTR domain attenuate the trafficking and channel defects caused by the major cystic fibrosis mutation.
- Pissarra LS, Farinha CM, Xu Z, Schmidt A, Thibodeau PH, Cai Z, Thomas PJ, Sheppard DN, Amaral MD Chem Biol January 2008 15(1) 62-9
- Building an understanding of cystic fibrosis on the foundation of ABC transporter structures.
- Mendoza JL, Thomas PJ J Bioenerg Biomembr December 2007 39(5-6) 499-505
- CFTR regulatory region interacts with NBD1 predominantly via multiple transient helices.
- Baker JM, Hudson RP, Kanelis V, Choy WY, Thibodeau PH, Thomas PJ, Forman-Kay JD Nat Struct Mol Biol August 2007 14(8) 738-45
- A protein sequence that can encode native structure by disfavoring alternate conformations.
- Wigley WC, Corboy MJ, Cutler TD, Thibodeau PH, Oldan J, Lee MG, Rizo J, Hunt JF, Thomas PJ Nat Struct Biol May 2002 9(5) 381-8
- Cooperative, ATP-dependent association of the nucleotide binding cassettes during
- Moody JE, Millen L, Binns D, Hunt JF, Thomas PJ J Biol Chem April 2002 277 21111-4
- Aberrant CFTR-dependent HCO3- transport in mutations associated with cystic fibrosis.
- Choi JY, Muallem D, Kiselyov K, Lee MG, Thomas PJ, Muallem S Nature March 2001 410(6824) 94-7
- Protein solubility and folding monitored in vivo by structural complementation of a genetic marker protein.
- Wigley WC, Stidham RD, Smith NM, Hunt JF, Thomas PJ Nat Biotechnol February 2001 19(2) 131-6
- Dynamic association of proteasomal machinery with the centrosome.
- Wigley WC, Fabunmi RP, Lee MG, Marino CR, Muallem S, DeMartino GN, Thomas PJ J Cell Biol May 1999 145(3) 481-90
Honors & Awards
- Established Investigator Award
American Heart Association (1998)
- Bioenergetics Award
Biophysical Society (1991)
- Young Investigator’s Award
Johns Hopkins University School of Medicine (1991)
- Biophysical Society
- Scientific Advisor Cystic Fibrosis Foundation
- Scientific Advisory Board Reata Pharmaceuticals