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.
Thompson
Thomas B
TB
Department of Biochemistry, Northwestern University, Evanston, Illinois 60208, USA.
Lerch
Thomas F
TF
Cook
Robert W
RW
Woodruff
Teresa K
TK
Jardetzky
Theodore S
TS
D030201:Activin Receptors, Type I / Q000378:metabolism*; D028341:Activins / Q000737:chemistry* / Q000235:genetics / Q000378:metabolism; D000595:Amino Acid Sequence; D000818:Animals; D001665:Binding Sites; D006224:Cricetinae; D018360:Crystallography, X-Ray; D038681:Follistatin / Q000737:chemistry* / Q000235:genetics / Q000378:metabolism; D028322:Inhibin-beta Subunits / Q000737:chemistry* / Q000235:genetics / Q000378:metabolism; D008024:Ligands; D008958:Models, Molecular; D008969:Molecular Sequence Data; D046912:Multiprotein Complexes; D011485:Protein Binding; D020033:Protein Isoforms / Q000737:chemistry / Q000235:genetics / Q000378:metabolism; D017346:Protein Serine-Threonine Kinases; D017434:Protein Structure, Tertiary; D000077293:Receptor, Transforming Growth Factor-beta Type I; D000077294:Receptor, Transforming Growth Factor-beta Type II; D018125:Receptors, Transforming Growth Factor beta / Q000378:metabolism*; D016415:Sequence Alignment; D016212:Transforming Growth Factor beta / Q000378:metabolism
D038681:Follistatin; D008024:Ligands; D046912:Multiprotein Complexes; D020033:Protein Isoforms; D018125:Receptors, Transforming Growth Factor beta; D016212:Transforming Growth Factor beta; C422405:activin A; D028341:Activins; D028322:Inhibin-beta Subunits; D017346:Protein Serine-Threonine Kinases; D030201:Activin Receptors, Type I; D000077293:Receptor, Transforming Growth Factor-beta Type I; D000077294:Receptor, Transforming Growth Factor-beta Type II