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EMBO J. 2006 Mar 8;25(5):1035-45. Epub 2006 Feb 16.

Structural basis for the inhibition of activin signalling by follistatin.

Author information

1
Department of Biochemistry, University of Cambridge, Cambridge, UK.

Abstract

The secreted, multidomain protein follistatin binds activins with high affinity, inhibiting their receptor interaction. We have dissected follistatin's domain structure and shown that the minimal activin-inhibiting fragment of follistatin is comprised of the first and second Fs domains (Fs12). This protein can bind to activin dimer and form a stable complex containing two Fs12 molecules and one activin dimer. We have solved crystal structures of activin A alone and its complex with Fs12 fragment to 2 A resolution. The complex structure shows how Fs12 molecules wrap around the back of the 'wings' of activin, blocking the type II receptor-binding site on activin A. Arginine 192 in Fs2 is a key residue in this interaction, inserting itself in between activin's fingers. Complex formation imposes a novel orientation for the EGF- and Kazal-like subdomains in the Fs2 domain and activin A shows further variation from the canonical TGF-beta family fold. The structure provides a detailed description of the inhibitory mechanism and gives insights into interactions of follistatin with other TGF-beta family proteins.

PMID:
16482217
PMCID:
PMC1409725
DOI:
10.1038/sj.emboj.7601000
[Indexed for MEDLINE]
Free PMC Article

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