Structure Study of Angiopoietins and the Tie2 Receptor

描述（由申请人提供）：血管生成是一个复杂的细胞过程，涉及原始血管分支、扩张和成熟为复杂的微血管系统。血管生成素/Tie受体-配体系统在这些事件中起核心作用。血管生成素是通过内皮特异性Tie 2受体发出信号的分泌分子。这是一种独特的受体酪氨酸激酶信号传导系统，因为不同的血管生成素配体，尽管高度同源，但可以以环境依赖性方式作为激动剂或拮抗剂起作用。详细了解血管生成素-Tie信号传导的机制及其在血管生成过程中的功能需要对血管生成素和Tie受体以及它们的相互作用进行全面的结构和生物物理分析。该提案的具体目标包括：i）至少两个血管生成素家族成员的配体结合结构域的结构分析，ii）Tie 2的配体结合结构域以及相关孤儿受体Tie 1的等同区域的结构分析，iii）受体识别的结构分析和血管生成素-Tie 2复合物的形成，和iv）血管生成素-Tie 2复合物的生物化学表征。Tie相互作用和受体激活。

DESCRIPTION (provided by applicant): Angiogenesis is a complex cellular process involving the branching, expansion, and maturation of primordial blood vessels into a complex microvasculature. The Angiopoietin/Tie receptor-ligand system plays a central role in these events. The Angiopoietins are secreted molecules that signal through the endothelial specific Tie2 receptor. This is a unique receptor tyrosine kinase signaling system in that distinct Angiopoietin ligands, although highly homologous, may function as agonist or antagonist in a context dependent manner. A detailed understanding of the mechanisms of Angiopoietin-Tie signaling and their function during angiogenesis requires comprehensive structural and biophysical analysis of both the Angiopoietins and the Tie receptors as well as of their interactions. The specific goals of this proposal include: i) structural analysis of the ligand binding domain of at least two Angiopoietin family members, ii) structural analysis of the ligand-binding domain of Tie2 as well as of the equivalent region of the related orphan receptor Tie1, iii) structural analysis of receptor recognition and formation of an Angiopoietin-Tie2 complex and iv) biochemical characterization of Angiopoietin-Tie interactions and receptor activation.