Follistatin Forms a Stable Complex With Inhibin A That Does Not Interfere With Activin A Antagonism

Area of Science:

• Endocrinology
• Molecular Biology
• Protein Biochemistry

Background:

• Inhibins are TGF-β family proteins suppressing FSH secretion by antagonizing activins.
• Follistatin also antagonizes activins by binding their common beta-chain.
• The interaction between inhibin A and follistatin remains incompletely understood.

Purpose of the Study:

• To characterize the inhibin A:follistatin 288 complex.
• To determine if this complex impacts inhibin A's antagonism of activin A.
• To elucidate the structural and functional consequences of follistatin binding to inhibin A.

Main Methods:

• Isolation and stoichiometric analysis of the inhibin A:follistatin 288 complex.
• Small-angle X-ray scattering (SAXS) and modeling for structural determination.
• Binding assays (surface plasmon resonance) and cell-based reporter assays (luciferase) to assess functional interactions and receptor binding.

Main Results:

• Inhibin A and follistatin 288 form a 1:1 complex, unlike the 1:2 ratio seen with activin homodimers.
• SAXS and modeling revealed inhibin A binds follistatin via the shared beta-chain, leaving the alpha-chain accessible.
• The inhibin A:follistatin complex dissociates upon binding activin receptor type IIb, enabling antagonism of activin signaling.
• Heparin binding affinity was reduced in the inhibin A:follistatin complex compared to follistatin alone.

Conclusions:

• Follistatin binding to inhibin A does not impede its ability to antagonize activin signaling.
• The inhibin A:follistatin complex effectively dissociates to allow receptor interaction and inhibition of activin signaling.
• This interaction maintains the suppressive effect of inhibin A on follicle-stimulating hormone (FSH) secretion.