STRUCTURE FUNCTION RELATIONSHIPS OF ACTIVIN AND ITS RECEPTORS

激活素在生殖调控中起着关键作用。它还在不同的过程中控制细胞的生长和分化，如胚胎发生过程中的中胚层诱导、神经细胞存活、骨形成和伤口修复。本项目旨在描述激活素及其受体的结合表面。我们将使用定点突变来产生结合特性被破坏或改变的配体和受体突变体。此外，还将开发与野生型激活素与其受体和/或卵泡抑素结合竞争的激活素突变体，并测试它们对内源性激活素生物利用度的影响。骨形态发生蛋白-2与其I型受体可溶性胞外结合的结构 BIRA-ECD结构域(BriA-ECD)已经公布，该计划的项目II最近解决了BMP-7与激活素II型受体胞外结构域(ActRII-ECD)的复合体的结构。这些晶体结构将使人们能够使用氨基酸序列比较和计算机建模方法来预测对激活素：受体结合至关重要的残基。确定激活素与其受体结合界面的残基将有助于合理设计生物活性激活素类似物和小分子激活素激动剂或拮抗剂。这些试剂基于其模拟或阻断激活素作用的能力，包括其对生殖功能的影响，将具有治疗潜力。

Activin plays a critical role in the regulation of reproduction. It also controls cell growth and differentiation in diverse processes such as mesoderm induction during embryogenesis, nerve cell survival, bone formation and wound repair. This Project proposes to characterize the binding surfaces on activin and its receptors. We will employ site-directed mutagenesis to generate ligand and receptor mutants with disrupted or altered binding properties. In addition, activin mutants that compete with the binding of wild-type activin to its receptors and/or follistatin will be developed and tested for their effects on the bioavailability of endogenous activin. The structure of Bone Morphogenetic Protein 2 (BMP-2) bound to its type IA receptor soluble extracellular domain (BRIA-ECD) has been published and Project II of this Program has recently solved the structure of BMP-7 in complex with the activin type II receptor extracellular domain (ActRII-ECD). These crystal structures will enable the use of amino acid sequence comparisons and computer modeling approaches to predict residues critical for activin:receptor binding. Defining the residues constituting the binding interfaces between activin and its receptors will allow rational design of bioactive activin analogs and small molecule activin agonists or antagonists. These reagents will have therapeutic potential based on their ability to mimic or block activin actions including its effects on reproductive function.