STRUCTURE FUNCTION RELATIONSHIPS OF ACTIVIN AND ITS RECEPTORS

激活素在生殖调节中起着关键作用。它还在多种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。本项目拟对激活素及其受体的结合表面进行表征。我们将采用定点诱变来产生具有破坏或改变结合特性的配体和受体突变体。此外，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，并测试其对内源性激活素生物利用度的影响。骨形态发生蛋白2 （BMP-2）的结构与其可溶性IA型受体结合

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.