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Structural basis for the inhibition of activin signalling by follistatin
Author(s) -
Harrington Adrian E,
MorrisTriggs Samantha A,
Ruotolo Brandon T,
Robinson Carol V,
Ohnuma Shinichi,
Hyvönen Marko
Publication year - 2006
Publication title -
the embo journal
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 7.484
H-Index - 392
eISSN - 1460-2075
pISSN - 0261-4189
DOI - 10.1038/sj.emboj.7601000
Subject(s) - follistatin , acvr2b , activin type 2 receptors , biology , tgf beta signaling pathway , activin receptor , receptor , dimer , microbiology and biotechnology , protein structure , biophysics , biochemistry , chemistry , organic chemistry
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 Å 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‐β family fold. The structure provides a detailed description of the inhibitory mechanism and gives insights into interactions of follistatin with other TGF‐β family proteins.