The molecular mechanisms that a cell uses to monitor and relay information about its environment to its interior are not well understood. Cell surface receptors are the gateways through which this information is relayed. The activation of receptor molecules embedded in the cell's membrane is fundamental to virtually every vital physiological function. Better knowledge of these mechanisms may lead to development of new disease treatments, using detailed structures of receptors complexed with their ligands as templates for engineering novel drugs.
K. Christopher Garcia is studying the structure and function of cell surface receptor recognition and activation in biological systems directly implicated in human health and disease. The receptor systems he studies are at the interface between immunity, neurobiology, and microbial pathogenesis. He focuses on "shared" receptors, which can recognize and bind to several different molecules, or ligands, often eliciting unique responses. Although this is a common phenomenon in biological signaling, until recently, researchers puzzled over how a single molecule could recognize so many different binding partners.
While others puzzled, Garcia pursued the question with extraordinary tenacity, bringing to bear his broad knowledge of many areas of science. Uniting structural studies of these receptors with biochemical and biophysical experiments, Garcia has identified new paradigms for recognition and activation of a variety of receptors that play critical roles in autoimmunity (T cell receptor and peptide-MHC), cancer (gp130 and cytokine receptors), neural growth and repair (p75 neurotrophin and Nogo receptors), and blood pressure regulation (ANP receptor).
Each of these receptors acts in a unique way. For example, the T cell receptor interacts with antigenic peptide and MHC in a manner representing the convergence of 400 million years of coevolution by our cellular immune system. Garcia and his colleagues determined the structure of the first complete TCR and its complex with peptide-MHC. Subsequent biophysical studies have shown that activation of the TCR is achieved through a complex combination of conformational change and kinetic discrimination. However, the precise molecular basis of TCR recognition and activation, as well as other lineages of immune receptors, remains a long-term challenge for the Garcia lab.
Another receptor binding paradigm elucidated by the Garcia lab is that of gp130—a growth factor receptor that is frequently aberrantly activated in disorders of the blood, such as leukemia. Its components cluster together in a precise temporal and geometric sequence, like pieces of a jigsaw puzzle, to assemble a receptor signaling complex. In contrast to the positive cooperativity exhibited by gp130 during signaling, the p75 neurotrophin receptor appears to induce a conformational change in its ligand, nerve growth factor, in order to prevent assembly of a higher order signaling complex. And the ANP receptor, which is crucial to the body's response to high blood pressure, is activated by a large conformational change that does not require the assembly of multiple components.
Garcia's long-term goal is to probe these systems more deeply, working to examine entire receptor molecules before and after activation, loaded with their full complements of extracellular ligands and intracellular adapter molecules. Understanding the many ways in which the relatively simple act of ligand binding prompts conformational change and ultimately activates receptors should help researchers design drugs targeting receptors whose functions affect human disease.