Structural Studies on Integrin-Mediated Cell-Cell Adhesion

这篇题为“IgSF和整合素家族的结构和相互作用”的提案是我以前工作的延续 由NIH资助HL 48675支持。在过去的一段时间里，我们成功地进行了结构性的 ICAM-1、整合素aLp 2、aiIBp 3及其相互作用的研究。在下一个预算期间，我们将扩大我们的结构性 研究其他ICAM家族成员（ICAM-3，-4和-5）及其与两种白细胞特异性p2 为了研究ICAM/β 2对接机制，一般来说，它们的特异性，以及它们是如何与整合素α Lp 2和OMP 2结合的， 各种ICAMs/p2相互作用在不同的p2相关的生物环境中专门化。我们将努力 以高分辨率破译IgSF/整联蛋白相互作用界面，以获得ICAM-1的三元复合物结构， 来自aLp 2和OMP 2的I结构域。我们将与岛冈博士合作， 选择性结合高亲和性aL I结构域的单克隆抗体，其应该具有医学重要性。我们将 与Springer博士合作，对白细胞上不含I结构域的整合素<x4 p7和/或04^1进行结构研究 与其内皮受体MAdCAM-1和/或VCAM-1相互作用。这些是理解粘附力的关键 白细胞整合素在血管生物学中的作用机制。我们还开始了另一种白细胞特异性 整合素aEp？及其与上皮细胞上的E-cadherin的相互作用，以研究E-cadherin的独特整合素结合 机制我们希望通过这些研究来比较不同的白细胞整合素结合机制，探讨 白细胞整合素介导的细胞-细胞粘附的免疫学意义的特异性问题 以及潜在的医疗应用。

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.