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

Dev Cell. 2005 Oct;9(4):535-43. doi: 10.1016/j.devcel.2005.09.008.

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

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

Substances

  • Follistatin
  • Ligands
  • Multiprotein Complexes
  • Protein Isoforms
  • Receptors, Transforming Growth Factor beta
  • Transforming Growth Factor beta
  • activin A
  • Activins
  • Inhibin-beta Subunits
  • Protein-Serine-Threonine Kinases
  • Activin Receptors, Type I
  • Receptor, Transforming Growth Factor-beta Type I
  • Receptor, Transforming Growth Factor-beta Type II

Associated data

  • PDB/2B0U