Research Summary
The ability to capture, process, and decode information from the environment is a fundamental property of all forms of life. Receptors in the plasma membrane of cells are one of the main channels through which information in the form of chemical, mechanical, or electrical signals is translated into the biochemical language of the cells.
A key design principle of many membrane receptors is that sensing is energetically passive, and no external energy is required. That is, the energetics of ligand binding is converted to a local conformational change and into the output signal. A major goal of our research is to the mechanism of this allosteric process in G protein-coupled receptors (GPCRs). We study the flow of information, from a single protein level to the cell level, to try to understand the molecular nature of biological information processing. Such knowledge is fundamental for developing new therapeutics, as well as designing synthetic receptors and sensors. We are doing so by using highly interdisciplinary analyses involving cutting edge single-molecule FRET, quantitative live-cell microscopy, protein engineering and proteomic approaches that draw from physics, chemistry, cell biology and synthetic biology. Interested? Get in touch with us!
For many large multidomain GPCRs, how local ligand-induced conformational changes propagate during the activation process, and how ligands tune the functional outcome of receptors by modifying their structure and dynamics, are poorly understood. Towards this goal we developed novel site-specific fluorescent labeling approaches which allowed us to visualize the propagation of conformational changes during the activation and modulation of class C GPCRs through single-molecule fluorescence resonance energy transfer (smFRET) and in vivo FRET imaging (in press).
Conformational rearrangement during activation of a metabotropic glutamate receptor.
Other questions that we think about: What are the design principles of receptors? How does evolution work to expand a receptor family? What are the roles of unstructured regions of receptors in their physiological functions?
