LEUKOCYTE ROLLING INTERACTIONS IN VASCULAR SHEAR FLOW

细胞与其他细胞或细胞基质的粘附在许多生物过程中是至关重要的。白细胞对免疫系统尤其重要。有几个粘附分子家族，其中整合素是最通用的。由于它们的大尺寸和复杂性，与其他粘附分子家族相比，很少有结构信息可用。本提案旨在确定一个整合素分子（β 2整合素或“简单”整合素）的晶体结构，或通过确定其亚基和片段的结构来解剖一个整合素。作为上一个授权期的延续，我们还将确定ICAM-1（或ICAM-3或ICAM-5）的整个细胞外部分的结构，以及β 2-整合素与配体（如ICAM-1、ICAM-2或ICAM-3的片段）的结合域复合物。我们希望最终从结构的角度帮助解开与这些粘附分子相关的“由内而外”和“由外而内”的信号传导机制。这对于理解粘连是如何在各种组织中响应刺激而调节的非常重要。最后，我们还将从其他细胞表面蛋白质的细胞外部分进行β -螺旋桨结构域（整合素中关键的配体结合结构域）的结构分析，例如氮气原，甚至一些含有与整合素中发现的非常相似的β -螺旋桨的细菌蛋白质。我们想探索β -螺旋桨结构域的进化试验，作为在各种细胞识别过程中蛋白质-蛋白质相互作用中使用的重要模块。

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.