Director, 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
BS California Institute of Technology 1983; PhD Yale University 1989; Jane Coffin Childs Postdoctoral Fellow, Massachusetts Institute of Technology 1989-1990
403E LGRT Tower A
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.