Follistatin

Follistatin (FST) is a regulator of TGFβ family signaling and acts by selectively binding to TGFβ family ligands and preventing ligand binding to the receptor complex. Follistatin has the ability to suppress the follicle stimulating hormone (FSH). Follistatin is first described as a follicle-stimulating hormone inhibiting substance present in ovarian follicular fluid. Follistatin binds activin A and myostatin with low nanomolar (nM) affinity, completely surrounds the ligand occluding all of the receptor binding sites and binds to the ligand^[1][2]. Follistatin is a 32-35-kDa glycoprotein composed of four domains including an N-terminal domain (ND) followed by three follistatin domains (FSD1, FSD2, and FSD3). C-terminal splicing of follistatin can occur to generate various isoforms including FS288 and FS315. Follistatin neutralizes the TGFβ ligands, myostatin and activin A, by forming a nearly irreversible non-signaling complex by surrounding the ligand and preventing interaction with TGFβ receptors. In humans, the gene encoding follistatin is located on chromosome 5q11.2. The follistatin protein contains a TGF-β binding site where activins, bone morphonegic proteins (BMPs) and growth differentiation factors (GDFs) are bound with high affinity and thereby neutralised. The ligand binding site for follistatin overlaps with the type I and type II receptor binding sites for these ligands. Follistatin also contains a heparin binding site where proteoglycans in the extracellular matrix can bind, and therefore follistatin is believed to bind the extracellular matrix. There are two major isoforms of FST, FST288, which is anchored to the cell surface by interactions with heparin sulfate proteoglycans, and FST315, which is the predominant form found in circulation. The two isoforms arise from alternative splicing; the 315 isoform includes a 27 amino acid acidic C-terminal tail, which follistatin 288 does not have. The acidic tail on follistatin 315 neutralises the heparin binding site, thereby inhibiting the binding of follistatin 315 to the extracellular matrix^[1][2][3].

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