1s4y

Protein Summary

Activins are members of the TGF-beta superfamily. Originally discovered for their ability to induce RSH expression, activins were subsequently shown to regulate cell differentiation and proliferation, reproduction, wound healing and the inflammatory response in a variety of tissues (1). Disregulation of TGF-beta signaling has been implicated in a number of cancers, as well as degenerative and vascular diseases (1). Consequently, the mechanisms of ligand-receptor interactions in this superfamily have been the focus of intense study.

The activin dimer (A, B or AB) is generated via intra-subunit disulfide bond formation involving six conserved cysteine residues folding into a unique cystine knot structure (Fig. 1). Following disulfide formation, proteolytic cleavage removes almost 300 residues from the homo-dimeric precursor to generate the mature activin. Binding of dimeric activin to type II receptor results in activation of the type I receptor and subsequent phosphorylation of Smad proteins, leading to downstream propagation of signaling.





Figure 1. Cystine knot motif in human activin A (pdb id: 1s4y). Six overlapping cysteines (Cys11-Cys81, Cys40-Cys113, Cys44-Cys115) stabilize the adjacent beta sheets. An additional disulfide (Cys4-Cys12), not part of the knot, is formed at the N-terminus.

Previous structures of activin bound to activin receptor IIb extra-cellular domains (ActRIIb ECDs) have revealed drastic differences between the two ligand subunits (2, 3). The structure of the almost complete ECD of ActRIIb from mouse in complex with human activin A (4), reveals a third orientation of the ligand with respect to the receptor (Fig. 2), supporting the hypothesis that the activin dimer can adopt multiple orientations, some of which disrupt binding to the type I receptor interface while still retaining binding to intact type II receptor interfaces. The different orientations of the activin dimer, extended ("wings spread") or compact ("wings closed"), could thus account for the observed differences in affinity of activin for type I and type II receptors.





Figure 2. The activin dimer can adopt a range of orientations. Left, activin (in blue) bound to two ActRIIb ECDs (in magenta) shows the activin dimer (pdb id: 1nys) in a compact ("wings closed") orientation. The helix constituting part of the type I receptor binding interface is disordered in this complex. Right, activin (in green) bound to two ActRIIb ECDs (in yellow) (pdb id: 1s4y) shows the activin dimer in a more extended ("wings spread") orientation. Both the helix and much of the dimer interface forming the type I receptor binding interface remain intact.

Increasing evidence suggests that ligand-mediated assembly of TGF-beta receptors is independent of direct receptor-receptor interactions (3, 4). Cooperativity could be achieved by diffusion and stoichiometry constraints within biological membranes, with distinct receptor spacings immobilizing activin in a type I-binding competent orientation (4).

Ligand Summary

activin A dimer