The structure of the follistatin:activin complex reveals antagonism of both type I and type II receptor binding

This structural study, published by Theodore Jardetzky's group at Northwestern University, was a seminal work that resolved the follistatin:activin complex by X-ray crystallography at high resolution, elucidating the molecular mechanism by which follistatin antagonizes TGF-β/activin/myostatin signaling. The context was the therapeutic importance of the different isoforms — particularly FS-315, the primary serum form — as endogenous regulators of muscle growth, fertility, and oncogenesis.

The authors expressed recombinant follistatin and activin A, crystallized the complex, and solved the structure, demonstrating that two follistatin molecules wrap around one activin A molecule symmetrically, forming a 2:1 complex in which approximately one-third of the activin surface is buried at the interface with follistatin.

The most surprising finding was mechanistic: follistatin simultaneously blocks both activin receptor binding sites — the follistatin N-terminal domain occupies the type I receptor site, while the additional FS domains occupy the type II receptor site. The N-terminal domain in fact adopts a topology that mimics type I receptors, contradicting previous models that assumed only type II receptor blockade.

The study also clarified the differences between the FS-288, FS-303, and FS-315 isoforms: FS-315 (the form with C-terminal acidic extension) does not bind heparan sulfate and therefore remains in free circulation in serum, being the main systemic neutralizing form of activin and myostatin. In contrast, FS-288 binds tightly to cell surfaces.

This work was fundamental for the subsequent development of myostatin inhibitors based on follistatin (AAV-FS344/FS315 gene therapy in muscular dystrophies) and activin modulators in reproductive medicine and oncology, providing the structural basis for the rational design of these therapies.