Communication among leukocyte and between leukocytes and endothelium are essential in the development of an efficient immune response to antigenic challenge and in host defense against pathogens. The integrins are a family of cell surface heterodimers that play essential roles in multiple immune functions. The beta 2 integrins consist of the common beta 2 subunit (CD18) associated with one of four alpha subunits. Beta 2 integrins mediate dynamic actively-regulated adhesion to ligands on endothelium, other cell types and pathogens. The proposal outlines studies seeking an understanding of integrin-ligand interactions and how they are regulated by signaling processes initiated from inside the cell. Two types of domains, an extracellular A-domain of about 200 amino acids and an intracellular CD18 cytoplasmic domain play critical roles respectively in metal-dependent protein ligand binding and in receptor affinity modulation. The PI and his colleagues have solved the crystal structure of the CD11b A-domain and identified a potential ligand binding site. Studies of the CD18 cytoplasmic domain identified critical serine- /threonines which were postulated to be sites of protein phosphorylation. This application proposes to: (1) derive the crystal structure of the CD11a A-domain, and (2) define its ligand binding regions, and (3) elucidate the nature and function of cytoplasmic CD18-binding proteins. Biochemical, structural, cellular and molecular biology techniques will be used. These studies will help understand not only the fundamental properties of regulated adhesion via the integrins, but also will help design non-antibody based receptor antagonists that could be life-saving in integrin-mediated ischemia reperfusion-injury syndromes.
| Xiong, J P; Stehle, T; Diefenbach, B et al. (2001) Crystal structure of the extracellular segment of integrin alpha Vbeta3. Science 294:339-45 |
| Xiong, J P; Li, R; Essafi, M et al. (2000) An isoleucine-based allosteric switch controls affinity and shape shifting in integrin CD11b A-domain. J Biol Chem 275:38762-7 |
