Philip J. Thomas
Professor, Department of Physiology at UT Southwestern Medical Center at Dallas
Room ND12.124D6001 Forest Park, Dallas TX 75390-9040
Membrane Protein Function & Dysfunction
Studies in our laboratory focus on the structure, folding, and function of membrane proteins and their misfolding as a basis of human disease. ABC transporters, including the cystic fibrosis transmembrane conductance regulator (CFTR), have served as our favored models for most of these biophysical, molecular biological, and cell biological studies. The ABC transporter supergene family is the largest in many of the completely sequenced microbial genomes and includes medically relevant members, including ATP-driven drug efflux pumps and bacterial toxin transporters, in addition to CFTR. Mutations in CFTR (>1000 to date) cause the fatal recessive disorder cystic fibrosis (CF). Many of these mutations alter the ability of the CFTR to efficiently fold into a functional structure that can traffic to the plasma membrane. These misfolded proteins are recognized and degraded by the proteasome. More recent work has also implicated the proteasome in the metabolism of a-synuclein, a membrane-associated protein whose misfolding is a hallmark of Parkinson's disease. Other CF-causing mutations alter the coupling of ATP binding and hydrolysis to solute transport through the transmembrane pore. Understanding the molecular pathology of CF and Parkinson's Disease is providing insight into how primary sequence encodes the folding pattern of membrane proteins, how the energy of ATP hydrolysis is utilized by ABC transporters to effect movement of a solute across a membrane barrier, and the relationship of proteasomal activity to misfolding and cellular pathology.