Three-finger toxin fold for the extracellular ligand-binding domain of thetype II activin receptor serine kinase.

The transforming growth factor beta (TGF beta) superfamily of cytokines eli cit diverse biological responses by interacting with two distinct, but stru cturally related transmembrane receptor serine kinases (type I and type II) . The binding of these dimeric ligands to the type II receptor is the first event in transmembrane signaling for this family. Here we report the 1.5 A ngstrom resolution crystal structure of the extracellular ligand-binding do main of the type IT activin receptor (ActRII-ECD), which reveals a fold sim ilar to that of a class of toxins known as three-finger toxins. This fold i s primarily dictated by disulfide bonds formed by eight conserved cysteines , with a characteristic spacing, and thus is likely to be shared by most of the type I and II receptors for the TGF beta family. Sequence comparison w ith an evolutionarily distant activin binding-protein identifies several co nserved residues, including two hydrophobic clusters that may form binding surfaces for activin and the type I receptor.