Adrian E Harrington, Samantha A Morris-Triggs, Brandon T Ruotolo, Carol V Robinson, Shin-ichi Ohnuma, Marko Hyvönen. Structural basis for the inhibition of activin signalling by follistatin EMBO J 25, 1035-1045 (2006)
PDB code: 2ARP , 2ARV
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-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.
|Activin-follistatin FS12 complex||Activin-AR2B complex|
|Movie 1. Complex of activin with Follistatin FS12. Activin is coloured red and orange, and follistatin blue (Fs1 domain) and green (Fs2 domain). At the end of the movie, the interfacial residues are coloured on the surface in colour that corresponds to the interacting molecules, and interfacial waters are shown as light blue spheres.||Movie 2. Complex of activin with extracellular domain of activin type IIB receptor (PDB:...). Activin is coloured red and orange, andthe type AR2B domains in blue and green. At the end of the movie, the interfacial residues are coloured on the surface in colour that corresponds to the interacting molecules, and interfacial waters are shown as light blue spheres.|