Developmental Cell
Volume 9, Issue 4, October 2005, Pages 535-543
Journal home page for Developmental Cell

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

https://doi.org/10.1016/j.devcel.2005.09.008Get rights and content
Under an Elsevier user license
open archive

Summary

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.

Cited by (0)

4

Present address: Department of Molecular Genetics, Biochemistry, and Microbiology, University of Cincinnati, 231 Albert Sabin Way, Cincinnati, Ohio 45267.