Three-dimensional Structure of proteins involved in cell-cell and cell-matrix interaction and signaling.

Living cells constantly monitor and respond to their environment by detecting interactions between cell-surface receptors and their ligands. Many such interactions are highly regulated, and in different contexts may or may not occur or may lead to different outcomes. We are interested in the molecular mechanisms by which specific signals are received and transmitted by cell-surface receptors, and how the behavior of these receptors or their ligands is modulated in response to different environments. The principal method we use to study these interactions is x-ray crystallography. By determining the atomic structures of receptors and their ligands we hope to provide a molecular basis for understanding the behavior of these molecules in living systems.

We are currently pursuing studies in two systems. We have recently determined the crystal structures of a ligand-binding fragment of the (alpha)L(beta)2 (LFA-1, CD11a/CD18) integrin in conditions permissive and nonpermissive for ligand-binding. These structures have suggested a molecular basis for the variable affinity of this receptor for ligand. We are now pursuing studies of (alpha)L(beta)2 ligands and (alpha)L(beta)2-ligand complexes to further define the nature of these interactions. In collaboration with the laboratory of Phil Beachy, we have also recently determined the crystal structure of the N-terminal signaling domain of sonic hedgehog (Shh-N). This domain is responsible for inducing the formation of new structures in neighboring tissues at several times during embryonic development. The crystal structure of Shh-N revealed an unexpected feature that has led to new hypotheses concerning the mechanism of shh-N action. These hypotheses are currently being tested in biochemical and biological systems.