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

Thomas B. Thompson, Thomas F. Lerch, Robert W. Cook, Teresa K. Woodruff, Theodore S. Jardetzky*

*Corresponding author for this work

Research output: Contribution to journalArticlepeer-review

191 Scopus citations

Abstract

TGF-β 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-β 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.

Original languageEnglish (US)
Pages (from-to)535-543
Number of pages9
JournalDevelopmental Cell
Volume9
Issue number4
DOIs
StatePublished - Oct 2005

ASJC Scopus subject areas

  • Molecular Biology
  • Biochemistry, Genetics and Molecular Biology(all)
  • Developmental Biology
  • Cell Biology

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