Philip Thomas, PhD

Professor
Endowed Title: Ruth S. Harrell Professorship in Medical Research
Physiology
Graduate Program: Integrative Biology
Molecular Biophysics

Contact Information

UT Southwestern Medical Center
5323 Harry Hines Boulevard
Dallas, Texas 75390

Office Phone: 214-645-6000

philip.thomas@utsouthwestern.edu

Biography

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.

Education

Graduate SchoolUniversity of North Dakota-Main Campus (1988)

Research Interests

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

Publications

Featured
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

Featured
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

Featured
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

Featured
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

Featured
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

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

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

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

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)

Professional Associations/Affiliations

American Society for Biochemistry and Molecular Biology

Biophysical Society

Scientific Advisor Cystic Fibrosis Foundation

Scientific Advisory Board Reata Pharmaceuticals

Scientific Advisory Board, Dystonia Medical Research Foundation (1999-present)