Adhesion of cells to other cells or to the cellular matrix is crucial in many biological processes. Leukocyte, in particular, is vital for the immune system. There are several adhesion molecule families, of which integrins are the most versatile. Because of their large size and complexity, there is little structural information available, compared to other adhesion molecule families. This proposal aims to determine the crystal structures of one integrin molecule (beta2 integrins or an """"""""easy"""""""" integrins), or dissect one integrin by determining structures of its subunits and fragments. As a continuation from the previous grant period, we will also determine the structure of the whole extracellular portion of ICAM-1 (or ICAM-3 or ICAM-5) as well as a complex of binding domain from beta2- integrin with ligand such as fragment of ICAM-1, ICAM-2 or ICAM-3. We would like to eventually help unravel the mechanism of """"""""inside-out"""""""" and """"""""outside-in"""""""" signaling associated with these adhesion molecules from the structural point of view. This is extremely important for understanding how the adhesion is regulated in response to stimuli in various tissues. Finally we will also carry out structure analyses of the beta-propeller domain (the critical ligand-binding domain in integrin) from the extracellular portion of other cell surface proteins, such as nidogen, and even some bacterial proteins that contain beta-propellers very similar to those found in integrins. We would like to explore the evolutionary trial of the beta-propeller domain as an important module used in protein-protein interactions in various cell recognition processes.
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