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.
- 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
- Inefficient SRP interaction with a nascent chain triggers a mRNA quality control pathway.
- Karamyshev AL, Patrick AE, Karamysheva ZN, Griesemer DS, Hudson H, Tjon-Kon-Sang S, Nilsson I, Otto H, Liu Q, Rospert S, von Heijne G, Johnson AE, Thomas PJ Cell 2014 Jan 156 1-2 146-57
- Regulatory R region of the CFTR chloride channel is a dynamic integrator of phospho-dependent intra- and intermolecular interactions.
- Bozoky Z, Krzeminski M, Muhandiram R, Birtley JR, Al-Zahrani A, Thomas PJ, Frizzell RA, Ford RC, Forman-Kay JD Proc. Natl. Acad. Sci. U.S.A. 2013 Nov 110 47 E4427-36
- Defining the disease liability of variants in the cystic fibrosis transmembrane conductance regulator gene.
- Sosnay PR, Siklosi KR, Van Goor F, Kaniecki K, Yu H, Sharma N, Ramalho AS, Amaral MD, Dorfman R, Zielenski J, Masica DL, Karchin R, Millen L, Thomas PJ, Patrinos GP, Corey M, Lewis MH, Rommens JM, Castellani C, Penland CM, Cutting GR Nat. Genet. 2013 Oct 45 10 1160-7
- Requirements for efficient correction of ?F508 CFTR revealed by analyses of evolved sequences.
- Mendoza JL, Schmidt A, Li Q, Nuvaga E, Barrett T, Bridges RJ, Feranchak AP, Brautigam CA, Thomas PJ Cell 2012 Jan 148 1-2 164-74
- Development of CFTR Structure.
- Patrick AE, Thomas PJ Front Pharmacol 2012 3 162
- TDP-43 identified from a genome wide RNAi screen for SOD1 regulators.
- Somalinga BR, Day CE, Wei S, Roth MG, Thomas PJ PLoS ONE 2012 7 4 e35818
- Alteration of CFTR transmembrane span integration by disease-causing mutations.
- Patrick AE, Karamyshev AL, Millen L, Thomas PJ Mol. Biol. Cell 2011 Dec 22 23 4461-71
- A screen to identify cellular modulators of soluble levels of an amyotrophic lateral sclerosis (ALS)-causing mutant SOD1.
- Somalinga BR, Miller GA, Malik HT, Wigley WC, Thomas PJ J Biomol Screen 2011 Oct 16 9 974-85
- CFTR Folding Consortium: methods available for studies of CFTR folding and correction.
- Peters KW, Okiyoneda T, Balch WE, Braakman I, Brodsky JL, Guggino WB, Penland CM, Pollard HB, Sorscher EJ, Skach WR, Thomas PJ, Lukacs GL, Frizzell RA Methods Mol. Biol. 2011 742 335-53
- The primary folding defect and rescue of ?F508 CFTR emerge during translation of the mutant domain.
- Hoelen H, Kleizen B, Schmidt A, Richardson J, Charitou P, Thomas PJ, Braakman I PLoS ONE 2010 5 11 e15458
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