STRUCTURE FUNCTION RELATIONSHIPS OF ACTIVIN AND ITS RECEPTORS

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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.