The Structure of the Follistatin:Activin Complex Reveals Antagonism of Both Type I and Type II Receptor Binding

Abstract

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.

Inhibin α-Subunit N Terminus Interacts with Activin Type IB Receptor to Disrupt Activin Signaling

“…Materials-Purified human activin A, inhibin A, the extracellular domain of mouse ALK4 (ALK4-ECD), ActRIIB (ActRIIB-ECD), and mouse follistatin 288 (Fst 288) were produced by our laboratory (35,36). The CHO-Flp-in cell line and pcDNA5 plasmid used for cloning and establishment of isogenic stable cell lines were purchased from Invitrogen (Carlsbad, CA).…”

von Willebrand Factor Type C Domain-containing Proteins Regulate Bone Morphogenetic Protein Signaling through Different Recognition Mechanisms

“…the residues determining binding affinity and specificity) are still poorly understood. In follistatin-activin complex, two follistatin monomers surround the dimeric ligand and bury the binding sites for type I and type II receptors (15,16). Mutational analysis revealed that only residues at the type II receptor-binding surface of activin are critical for high affinity follistatin binding, and the interaction surfaces of activin for type II receptors and follistatin are overlapping but not identical (17).…”

A Smad-binding Element in Intron 1 Participates in Activin-dependent Regulation of the Follistatin Gene

“…They also bind and inactivate myostatin and some bone morphogenetic proteins with varying degrees of affinity (14). Structural studies of the follistatin-activin complex have elucidated the basis for this interaction and provided clues about the determinants of follistatin binding to other ligands (15,16). The follistatin gene comprising 6 exons produces two alternatively spliced mRNA transcripts and the corresponding proteins of 315 or 288 amino acids (FS315 or FS288) (17, 18).…”