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.
MeSH terms
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Activin Receptors, Type I / metabolism*
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Activins / chemistry*
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Activins / genetics
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Activins / metabolism
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Amino Acid Sequence
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Animals
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Binding Sites
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Cricetinae
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Crystallography, X-Ray
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Follistatin / chemistry*
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Follistatin / genetics
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Follistatin / metabolism
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Inhibin-beta Subunits / chemistry*
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Inhibin-beta Subunits / genetics
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Inhibin-beta Subunits / metabolism
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Ligands
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Models, Molecular
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Molecular Sequence Data
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Multiprotein Complexes
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Protein Binding
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Protein Isoforms / chemistry
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Protein Isoforms / genetics
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Protein Isoforms / metabolism
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Protein Serine-Threonine Kinases
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Protein Structure, Tertiary*
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Receptor, Transforming Growth Factor-beta Type I
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Receptor, Transforming Growth Factor-beta Type II
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Receptors, Transforming Growth Factor beta / metabolism*
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Sequence Alignment
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Transforming Growth Factor beta / metabolism
Substances
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Follistatin
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Ligands
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Multiprotein Complexes
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Protein Isoforms
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Receptors, Transforming Growth Factor beta
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Transforming Growth Factor beta
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activin A
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Activins
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Inhibin-beta Subunits
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Protein Serine-Threonine Kinases
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Activin Receptors, Type I
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Receptor, Transforming Growth Factor-beta Type I
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Receptor, Transforming Growth Factor-beta Type II