Principal Research Interests
Membrane proteins are key players in the essential cellular processes of energy and signal
transduction. Our laboratory is interested in understanding the molecular mechanisms of such processes: How does a membrane receptor transmit a signal across the membrane? How does a transporter use the energy of ATP hydrolysis to drive transport across the membrane? Such molecules and processes are of both fundamental and medical interest.
 The transmembrane receptors of bacterial chemotaxis bind specific attractant molecules and transmit this information across the membrane to direct the swimming of the bacterium. Both receptor conformational changes and receptor clusters are known to be important in the signaling mechanism. As with most membrane proteins, the traditional tools of structural biology have not been able to provide structures of the intact receptor to measure and follow the ligand-induced conformational changes. We have used a powerful site-directed distance measurement strategy to measure helix-helix distances in the periplasmic domain of the intact serine receptor that are consistent in magnitude with a proposed ligand-induced piston mechanism. Additional distance measurements are in progress to test structural models of the receptor clusters. Companion biochemical experiments are testing the role of receptor clustering in the signaling mechanism. In collaboration with Robert Weis’ lab, we are applying a number of biochemical and biophysical approaches to receptor arrays to provide a molecular picture of how a protein transmits a signal across a membrane.
ABC transporters are a large family of proteins that use the energy of ATP hydrolysis to drive transport of molecules into or out of the cell. Recent crystal structures of these proteins are providing new insights into proposed alternating access mechanisms of transport. We have initiated a new project to establish correlations between activity changes and structural changes, with the goal of understanding how ATP hydrolysis is coupled to the conformational changes that transport the substrate across the membrane.
Our overall strategy is to combine biophysical experiments including emerging solid-state NMR methods with biochemical approaches to probe the structure and mechanism of membrane proteins. Membrane proteins are both tremendously important (as pharmaceutical targets for example) and poorly understood, making this an area rich in opportunities for exciting research.
Representative Publications
Kovacs, F. A., Gallagher, G. J., Fowler, D. J., and Thompson, L. K. (2007) “A practical guide for solid-state NMR distance measurements in proteins”, Concepts in Magnetic Resonance 30A, 21-39.
"Solid-state NMR spin diffusion for measurement
of membrane-bound peptide structure: Gramicidin A ", Biochemistry
43 , 7899-7906. Gallagher, G. J., Hong, M., and Thompson,
L. K. (2004)
"Unraveling
the secrets of Alzheimer's ß-amyloid fibrils ",
invited commentary for Proc. Nat. Acad. Sci USA
100, 383-385. Thompson,
L. K. (2003)
"Solid-state
NMR studies of the structure and mechanisms of proteins ", Current Opinion in
Structural Biology 12,
661-669. Isaac, B., Gallagher, G. J., Balazs, Y. S., & Thompson,
L. K., (2002)
"Site-directed
rotational resonance solid-state NMR distance measurements
probe structure and mechanism in the transmembrane domain
of the serine bacterial chemoreceptor ",
Biochemistry 41 , 3025-3036. Murphy, O. J., III, Yi, X., Weis,
R. M., & Thompson,
L. K. (2001)
"Hydrogen
exchange reveals a stable and expandable core within the
aspartate receptor cytoplasmic domain ",
J. Biol. Chem. 276 , 43262-43269. Murphy, O. J., III, Kovacs,
F. A., Sicard, E., & Thompson,
L. K. (2001)
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