Structures of an ActRIIB:activin A complex reveal a novel binding mode for TGF-beta ligand:receptor interactions

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Abstract
The TGF‐β 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‐β ligands that regulate cellular differentiation, proliferation, activation and apoptosis. Activins signal through complexes formed with type I and type II serine/threonine kinase receptors. We have solved the crystal structure of activin A bound to the extracellular domain of a type II receptor, ActRIIB, revealing the details of this interaction. ActRIIB binds to the outer edges of the activin finger regions, with the two receptors juxtaposed in close proximity, in a mode that differs from TGF‐β3 binding to type II receptors. The dimeric activin A structure differs from other known TGF‐β ligand structures, adopting a compact folded‐back conformation. The crystal structure of the complex is consistent with recruitment of two type I receptors into a close packed arrangement at the cell surface and suggests that diversity in the conformational arrangements of TGF‐β ligand dimers could influence cellular signaling processes.