个人简介

BS California Institute of Technology 1983; PhD Yale University 1989; Jane Coffin Childs Postdoctoral Fellow, Massachusetts Institute of Technology 1989-1990

研究领域

Biophysical Chemistry/Director of the Chemistry-Biology Interface Program (CBI)/Mechanisms of Membrane Proteins Involved in Signaling or Bioenergetics/Including Receptors and Transporters/Structural Biology of Membrane Proteins Using Solid-State NMR Spectroscopy

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.

近期论文

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Koshy, S.S., Li, X., Eyles, S.J., Weis, R.M. and Thompson, L.K. (2014) "Hydrogen Exchange Differences between Chemoreceptor Signaling Complexes Localize to Functionally Important Subdomains" Biochemistry Article ASAP. Briegel, A., Ladinsky, M.S., Oikonomou, C., Jones, C.,W. Harris, M.J., Fowler, D.J., Chang, Y.-W., Thompson, L.K., Armitage, J.,P. and Jensen, G.J. (2014) "Structure of bacterial cytoplasmic chemoreceptor arrays and implications for chemotactic signaling", eLife 3, e02151. Briegel, A., Wong, M., Hodges, H., Oikonomou, C., Piasta, K.N., Harris, M.J., Fowler, D.J., Thompson, L.K., Falke, J.J., Kiessling, L.L., and Jensen, G.J. (2014) "New insights into bacterial chemoreceptor array structure and assembly from electron cryotomography", Biochemistry 53, 1575-1585. Harris, M.J. and Thompson, L.K. (2014) "A Promising Prognosis for Solid State NMR of Functional Membrane Protein Complexes", invited chapter for Advances in Biological Solid-State NMR: Proteins and Membrane-Active Peptides, (F. Separovic and A. Naito, Eds.), RSC Publishing, 405-424. Mukherjee, S., Thompson, L.K., Godin, S., Schackwitz, W., Lipzen, A., Martin, J., and Blanchard, J.L. (2014) "Population level analysis of evolved mutations underlying improvements in plant hemicellulose and cellulose fermentation by Clostridium phytofermentans" PLOS ONE 9, e86731. Koshy, S.S., Eyles, S.J., Weis, R.M. and Thompson, L.K. (2013) "Hydrogen Exchange Mass Spectrometry of Functional Membrane-bound Chemotaxis Receptor Complexes", Biochemistry 52, 8833-8842. Karunanayake Mudiyanselage, A.P.K.K., Yang, M., Accomando, L.A.-R., Thompson, L.K., and Weis, R.M. (2013) "Membrane-association of a protein increases the rate, extent and specificity of chemical crosslinking" Biochemistry 52, 6127-6136. Sferdean, F.C, Weis, R.M. and Thompson, L.K. (2012) "Ligand Affinity and Kinase Activity are Independent of Bacterial Chemotaxis Receptor Concentration: Insight into Signaling Mechanisms", Biochemistry 51, 6920-6931. Fowler, D.J., Harris, M.J., and Thompson, L.K. (2012) "Heat management strategies for solid-state NMR of functional proteins", J. Mag. Res. 222, 112-118. Thompson, L. K. (2011) "Solid State NMR of Membrane Proteins: Moving Towards Greater Complexity", Annual Reports on NMR Spectroscopy 73, 127-158. Request reprint. Fowler, D. J., Khalifah, P. G., and Thompson, L. K. (2010) "Design and characterization of a calixarene inclusion compound for calibration of long-range carbon–fluorine distance measurements by solid-state NMR", J. Mag. Res. 207, 153-157. Fowler, D. J., Weis, R. M., and Thompson, L. K. (2010) "Kinase-active Signaling Complexes of Bacterial Chemoreceptors Do Not Contain Proposed Receptor-Receptor Contacts Observed in Crystal Structures", Biochemistry 49, 1425-1434. 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. Gallagher, G. J., Hong, M., and Thompson, L. K. (2004) "Solid-state NMR spin diffusion for measurement of membrane-bound peptide structure: Gramicidin A", Biochemistry 43, 7899-7906. Thompson, L. K. (2003) "Unraveling the secrets of Alzheimer's ß-amyloid fibrils", invited commentary for Proc. Nat. Acad. Sci USA 100, 383-385. Thompson, L. K. (2002) "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) "Site-directed solid-state NMR measurement of a ligand-induced conformational change in the serine bacterial chemoreceptor", Biochemistry 40, 1358-1366. Balazs, Y. S. & Thompson, L. K. (1999) "Practical methods for solid-state NMR distance measurements on large biomolecules: constant-time rotational resonance", J. Mag. Res. 139, 371-376. Kumashiro, K. K., Schmidt-Rohr, K., Murphy, O.J., III, Ouellette, K. L., Cramer, W. A., Thompson, L. K. (1998) "A Novel Tool for Probing Membrane Protein Structure: Solid-State NMR with Proton Spin Diffusion and X-Nucleus Detection", J. Am. Chem. Soc. 120, 5043-5051. Wang, J., Balazs, Y. S., & Thompson, L. K. (1997) "Solid-state REDOR NMR distance measurements at the ligand site of a bacterial chemotaxis membrane receptor", Biochemistry 36, 1699-1703. Parkhe, A. D., Seeley, S. K., Gardner, K., Thompson, L., & Lewis, R. V., (1997) "Structural Studies of Spider Silk Proteins in the Fiber", J. Molecular Recognition 10, 1-6. Seeley, S. K., Wittrock, G. K., Thompson, L. K., & Weis, R. M. (1996) "Oligomers of the Cytoplasmic Fragment from the Escherichia coli Aspartate Receptor Dissociate Through an Unfolded Transition State", Biochemistry 35, 16336-16345. Seeley, S. K., Weis, R. M., & Thompson, L. K. (1996) "The Cytoplasmic Fragment of the Aspartate Receptor Displays Globally Dynamic Behavior", Biochemistry 35, 5199-5206. Wang, J., Parkhe, A. D., Tirrell, D. A., & Thompson, L. K. (1996) "Crystalline Aggregates of the Repetitive Polypeptide {(AlaGly)3GluGly(GlyAla)3GluGly}10: Structure and Dynamics by 13C Magic Angle Spinning Nuclear Magnetic Resonance Spectroscopy", Macromolecules 29, 1548-1553. Herzfeld, J., Auger, M., Farrar, M. R., Lakshmi, K. V., McDermott, A. E., Raap, J., Thompson, L. K., van der Wielen, C. M., Lugtenburg, J., & Griffin, R. G. (1993) "Recent Solid State NMR Studies of Bacteriorhodopsin" in Frontiers of Photobiology (A. Shima et al., eds.), pp. 221-225, Elsevier Science Publishers B. V. Thompson, L. K., McDermott, A. E., Raap, J., van der Wielen, C. M., Brown, R. S., Lugtenburg, J., Herzfeld, J., & Griffin, R. G. (1992) "Rotational Resonance NMR Study of the Active Site Structure in Bacteriorhodopsin: Conformation of the Schiff Base Linkage", Biochemistry 31, 7931-7938. McDermott, A. E., Thompson, L. K., Winkel, C., Farrar, M. R., Pelletier, S., Lugtenburg, J., Herzfeld, J., & Griffin, R. G. (1991) "Mechanism of Proton Pumping in Bacteriorhodopsin by Solid State NMR: The Protonation State of Tyrosine in the Light-Adapted and M States", Biochemistry 30, 8366-8371. Buser, C. A., Thompson, L. K., Diner, B. A., and Brudvig, G. W. (1990) "Electron-Transfer Reactions in Mn-depleted Photosystem II" Biochemistry 29, 8977-8985. Thompson, L.K., Miller, A.-F., Buser, C.A., de Paula, J.C., and Brudvig, G.W. (1989) "Characterization of the Multiple Forms of Cytochrome b559 in Photosystem II", Biochemistry 28, 8048-8056. Thompson, L. K., Blaylock, R., Sturtevant, J. M., and Brudvig, G. W. (1989) "Molecular Basis of the Heat Denaturation of Photosystem II", Biochemistry 28, 6686-6695. Thompson, L.K., Miller, A.-F., de Paula, J.C., and Brudvig, G.W. (1988) "Electron Donation in Photosystem II" Israel J. Chem. 28, 121-128. Thompson, L.K. and Brudvig, G.W. (1988) "Cytochrome b559 May Function to Protect Photosystem II From Photoinhibition", Biochemistry 27, 6653-6658. Thompson, L. K., Sturtevant, J. M., and Brudvig, G. W. (1987) "Cytochrome b559 Plays a Structural Role in the Oxygen Evolving Complex of Photosystem II" in Progress in Photosynthesis Research, I (Biggins, J., Ed.) pp 609-612, Martinus Nijhoff Publishers, Dordrecht, The Netherlands. Thompson, L. K., Sturtevant, J. M., and Brudvig, G. W. (1986) "Differential Scanning Calorimetric Studies of Photosystem II: Evidence for a Structural Role for Cytochrome b559 in the Oxygen Evolving Complex", Biochemistry 25, 6161-6169.