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

Abstract

The TGF-β superfamily of ligands and receptors stimulate cellular events in diverse processes ranging from cell late 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.