PDBsum entry 2arv

Hormone/growth factor

PDB id: 2arv

Contents

Protein chains

116 a.a.

106 a.a.

Ligands

SO4 ×4

GOL ×3

1PG

Waters ×54

References listed in PDB file

Key reference

Title

Structural basis for the inhibition of activin signalling by follistatin.

Authors

A.E.Harrington, S.A.Morris-Triggs, B.T.Ruotolo, C.V.Robinson, S.Ohnuma, M.Hyvönen.

Ref.

EMBO J, 2006, 25, 1035-1045. [DOI no: 10.1038/sj.emboj.7601000]

PubMed id

16482217

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.

Figure 3.
Figure 3 Overall architecture of the activin–Fs12 complex. (A) View down the two-fold axis of symmetry showing the two follistatin fragments binding to the back of the activin A fingers. Activin protomers are coloured red and orange, the interchain disulphide is shown in yellow. Follistatin domains Fs1 and Fs2 are coloured blue and green, respectively. (B) A perpendicular view of the complex showing the closed conformation of activin and Fs12 fragments wrapping along the activin A, shown as a surface model.

Figure 6.
Figure 6 Interaction surface between activin and Fs12 and ActRIIB. Comparison of activin binding by Fs12 and the extracellular domain of the type II activin receptor (Greenwald et al, 2004; PDB:1s4y). Activin protomers are shown as molecular surfaces (orange and red), and the two Fs12 molecules (A, blue Fs1 and green Fs2) and two type II receptor domains (B, blue and green) are shown as ribbon diagrams. The activin surface is coloured dark grey over atoms that are closer than 4 Å from the interacting protein. Water molecules sandwiched between the two proteins are shown as light blue spheres. Both complexes are shown in the same orientation for the orange activin A protomer.

The above figures are reprinted by permission from Macmillan Publishers Ltd: EMBO J (2006, 25, 1035-1045) copyright 2006.