Structural Studies on Integrin-Mediated Cell-Cell Adhesion

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This proposal entitled "Structure and interaction of IgSF and integrin families" is a continuation of my previous works supported by the NIH grant HL48675. During the past funding period we have successfully carried out structural studies on ICAM-1, integrin aLp2,aiIBp3 and their interactions. In the next budget period, we will extend our structural studies to other ICAM family members (ICAM-3, -4 and -5) and their interactions with two leukocyte-specific p2 integrins, the aLp2 and OM^, in order to investigate ICAM/p2 docking mechanism in general, their specificities, and how various ICAMs/p2 interactions specialize in different p2-associated biological settings. We will make efforts to decipher the IgSF/integrin interaction interface at high resolution, to obtain ternary complex structure of ICAM-1 with I domains from both aLp2 and OMP2. We will collaborate with Dr. Shimaoka to carry out structural investigation on monoclonal antibodies that selectively bind high-affinity aL I domain, which should be of medical importance. We will collaborate with Dr. Springer in structural studies on non-I-domain-containing integrins <x4p7 and/or 04^1 on leukocyte interacting with their endothelial receptors MAdCAM-1 and/or VCAM-1. These are key to understand the adhesion .mechanism of leukocyte integrins in vascular biology. We have also started the study on another leukocyte-specific integrin aEp? and its interaction with E-cadherin on epithelium to investigate E-cadherin's distinct integrin-binding mechanism. We hope through these studies to compare different leukocyte integrin-binding mechanisms and explore the specificity issue in leukocyte integrin-mediated cell-cell adhesion in the context of immunological significances and potential medical applications.