Ph.D., 1984, Harvard University
Structural basis of macro-molecular recognition at the cell surface
My laboratory is interested in the structure and function of molecules involved in cell surface recognition, particularly those mediating recognition in the immune system. Much of our work has focused upon homologs of class I MHC proteins, which function in many ways that are distinct from their immunological role in peptide presentation to T cells. The three dimensional structures of MHC molecules seem to be ideally suited for their function in antigen presentation in the cellular immune response. A large groove located between two a-helices accommodates short peptides, which are examined by T cell receptors that simultaneously contact the peptide and the MHC protein, rationalizing the dual recognition properties of T cell receptors. Although it might appear that the MHC fold evolved specifically for antigen presentation, a number of other proteins have adapted the same basic fold to perform widely different roles within and outside of the immune system. These include an immunoglobulin G receptor (FcRn), the protein mutated in the iron storage disease hereditary hemochromatosis (HFE), a protein that stimulates lipid catabolism (Zn-a2-glycoprotein; ZAG), and virally encoded class I MHC homologs (UL18 and m144 from human and murine cytomegalovirus). These molecules illustrate the versatility of the MHC fold and raise intriguing questions about the ancestral function of MHC-related proteins and the evolution of the adaptive immune response.
To study these proteins, we use a combined approach of x-ray crystallography to determine structures, molecular biological techniques to produce proteins for crystallization and to modify them, and biochemistry to study the properties of the proteins we make. In the FcRn and HFE systems, we are also using structural information to address cell biological issues involving intracellular receptor-ligand trafficking. In addition to the studies of MHC homologs, we are interested in using structure/function studies to understand bacterial pathogenesis and the innate immune response to bacterial infection. Our efforts in these areas involve the study of the Yersinia pseudotuberculosis protein invasin, the insect immune response protein hemolin, and the mammalian mannose receptor, inhibitory receptor/ligand interactions.
Last modified 2009-09-21 03:53 PM