Structural basis for the inhibition of activin signalling by follistatin.
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.
Harrington
Adrian E
AE
Department of Biochemistry, University of Cambridge, Cambridge, UK.
Morris-Triggs
Samantha A
SA
Ruotolo
Brandon T
BT
Robinson
Carol V
CV
Ohnuma
Shin-Ichi
S
Hyvönen
Marko
M
D030301:Activin Receptors, Type II / Q000378:metabolism*; D028341:Activins / Q000037:antagonists & inhibitors* / Q000235:genetics / Q000378:metabolism; D000595:Amino Acid Sequence; D000818:Animals; D001665:Binding Sites; D018360:Crystallography, X-Ray; D019281:Dimerization; D004622:Embryo, Mammalian / Q000166:cytology / Q000378:metabolism; D004625:Embryo, Nonmammalian; D038681:Follistatin / Q000737:chemistry* / Q000235:genetics / Q000378:metabolism; D006801:Humans; D028322:Inhibin-beta Subunits / Q000037:antagonists & inhibitors* / Q000235:genetics / Q000378:metabolism; D008024:Ligands; D008958:Models, Molecular; D008969:Molecular Sequence Data; D009154:Mutation / Q000235:genetics; D011485:Protein Binding; D017434:Protein Structure, Tertiary; D051381:Rats; D017386:Sequence Homology, Amino Acid; D015398:Signal Transduction; D016212:Transforming Growth Factor beta / Q000378:metabolism; D014982:Xenopus laevis
D038681:Follistatin; D008024:Ligands; D016212:Transforming Growth Factor beta; C422405:activin A; D028341:Activins; D028322:Inhibin-beta Subunits; D030301:Activin Receptors, Type II