Structure Study of Angiopoietins and the Tie2 Receptor

描述(申请人提供)：血管生成是一个复杂的细胞过程，涉及原始血管的分支、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着核心作用。血管生成素是一种分泌分子，通过内皮特异性Tie2受体发出信号。这是一个独特的受体酪氨酸激酶信号系统，不同的血管生成素配体虽然高度同源，但可能以上下文依赖的方式发挥激动剂或拮抗剂的作用。要详细了解血管生成素-Tie信号的机制及其在血管生成过程中的作用，需要对Angiopoietins和Tie受体及其相互作用进行全面的结构和生物物理分析。这一建议的具体目标包括：1)至少两个血管生成素家族成员的配体结合域的结构分析；2)Tie2的配体结合域以及相关孤儿受体Tie1的等价区的结构分析；3)受体识别和形成Angiopoietin-Tie2复合体的结构分析；4)血管生成素-Tie相互作用和受体激活的生化特征。

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.