The structure of the follistatin:activin complex reveals antagonism of both type I and type II receptor binding

TGF-beta ligands stimulate diverse cellular differentiation and growth responses by signaling through type I and II receptors. Ligand antagonists, such as Follistatin, block signaling and are essential regulators of physiological responses. Here we report the structure of Activin A, a TGF-beta ligand, bound to the high-affinity antagonist Follistatin. Two Follistatin molecules encircle activin, neutralizing the ligand by burying one-third of its residues and its receptor binding sites. Previous studies have suggested that type I receptor binding would not be blocked by Follistatin, but the crystal structure reveals that the Follistatin N-terminal domain has an unexpected fold that mimics a universal type I receptor motif and occupies this receptor binding site. The formation of follistatin:BMP:type I receptor complexes can be explained by the stoichiometric and geometric arrangement of the activin:follistatin complex. The mode of ligand binding by Follistatin has important implications for its ability to neutralize homo- and heterodimeric ligands of this growth factor family.