Structural Studies of Inhibin/Activin Receptor Complexes

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Activin and Inhibin are members of an important superfamily of peptide hormones/growth factors that regulate many cellular growth and differentiation processes. Activin and inhibin play a central role in the reproductive systems of animals by regulation of FSH levels and spermatogenesis. The hormones are also implicated in folliculogenesis. The goal of this research is to better understand the interactions of TGF-beta signaling molecules and their receptors. This proposal focuses on how activin and inhibin interact with the extracellular domains of their signaling receptors RI and RII. Initial goals are to produce significant amounts of protein for use in crystallographic and biophysical studies. Complex formation will be tested and analyzed by gel filtration affinity chromatography, analytical ultracentrifugation, IAsys, and in vitro cellular assays. These methods will be useful in determining how complexes are formed along with their equilibrium and association/ dissociation rate constants. Complexes will be used in crystallization experiments in order to solve their three dimensional structures. Structure determination will be carried out at the Advanced Photon Source at Argonne National Laboratory. These experiments will lead to a better understanding of receptor signaling mechanisms within the TGF-beta superfamily.