LEUKOCYTE ROLLING INTERACTIONS IN VASCULAR SHEAR FLOW

细胞与其他细胞或细胞基质的黏附在许多生物过程中是至关重要的。尤其是白细胞，对免疫系统至关重要。有几个黏附分子家族，其中整合素是最通用的。由于它们的大小和复杂性，与其他黏附分子家族相比，可用的结构信息很少。这项建议旨在确定一个整合素分子(β2整合素或“易”整合素)的晶体结构，或通过确定其亚单位和片段的结构来剖析一个整合素。作为上一次授权期的延续，我们还将确定ICAM-1(或ICAM-3或ICAM-5)的整个胞外部分的结构，以及由β2整合素与配体形成的结合域的复合体，如ICAM-1、ICAM-2或ICAM-3的片段。我们希望最终从结构的角度帮助解开与这些黏附分子相关的“内向外”和“外向内”信号传递的机制。这对于了解黏附如何在各种组织中对刺激做出反应是极其重要的。最后，我们还将从其他细胞表面蛋白的胞外部分，如Nidogen，甚至一些含有与整合素中发现的非常相似的β-螺旋体的细菌蛋白的胞外部分，进行β-螺旋体结构域(整合素中关键的配体结合域)的结构分析。我们想要探索β-螺旋桨结构域作为一个重要模块的进化试验，该模块用于各种细胞识别过程中的蛋白质-蛋白质相互作用。

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.