W0042

Crystal Structures of an ActRIIB: Activin A Complex Reveal a Novel Binding Mode for TGF-beta Ligand:Receptor Interactions. Thomas B. Thompson, Teresa K. Woodruff, Theodore S. Jardetzky, BMBCB, Northwestern Univ., 2205 Tech Dr., Evanston, IL 60208

The TGF-_ superfamily of ligands and receptors stimulate cellular events in diverse processes ranging from cell fate specification in development to immune suppression. Activins define a major subgroup of TGF-_ ligands, acting as morphogens in early Xenopus development and as regulators of the menstrual cycle in humans, signaling through complexes formed with type I and type II serine/threonine kinase receptors. We have solved the crystal structure of activin bound to the extracellular domain of a type II receptor, ActRIIB, revealing the details of this interaction. The dimeric activin structure differs from other known TGF-_ ligand structures, adopting a compact folded-back conformation. ActRIIB binds to the outer edges of the activin finger regions, with the two receptors juxtaposed in close proximity. The crystal structure of the complex is consistent with recruitment of two type I receptors into a close packed arrangement at the cell surface, suggesting that signaling diversity in the TGF-_ superfamily could be linked to distinct conformational arrangements of ligand:receptor complexes.