Interaction of Follicle‐Stimulating Hormone (FSH) Receptor Binding Inhibitor‐8: A Novel FSH‐Binding Inhibitor, with FSH and its Receptor

Abstract

Follicle-stimulating hormone (FSH) receptor binding inhibitor (FRBI-8) is a novel octapeptide purified from human ovarian follicular fluid. In vitro, it inhibits the binding of FSH to granulosa cells and in vivo, it induces atresia in developing follicles in rodents. This peptide, when administered to marmosets and bonnet monkeys, altered the circulating progesterone levels. This study was carried out to elucidate structure of the FRBI-8 and understand its mechanism of inhibiting interaction of FSH to its receptors. Homology modeling predicted that the FRBI-8 adopts a turn and random coil. This is further confirmed by circular dichroism and NMR. Docking studies of the FRBI-8 with reported FSH-FSHR hormone binding (FSHR(HB)) domain complex using ZDOCK algorithm revealed that the FRBI-8 binds to FSHbetaL2-FSHR(HB) binding interface which is otherwise known to be crucial for activation of signal transduction cascade. FRBI-8 analogs were designed by replacing the acidic amino acid residues at positions 2, 5 and 6 with Ala, individually. Docking studies revealed that D6A mutant (FRBI-8(D6A)) had a higher binding affinity than the native FRBI-8. In vitro radioreceptor assay with FRBI-8(D6A) showed 50% lower IC(50) compared with the FRBI-8, confirming the in silico observations. Thus, the study reveals that both FRBI-8 and FRBI-8(D6A) interfered with the binding of FSH to its receptor.

FSHR and LHR Expression and Signaling as Well as Maturation and Apoptosis of Cumulus-Oocyte Complexes Following Treatment with FSH Receptor Binding Inhibitor in Sheep

“…These results indicate that FSH induced sheep oocyte maturation [17]. However, FSH-receptor binding inhibitor (FRBI), as an FSH antagonist, influenced the efficacy of FSH by blocking the binding of FSH to FSHR in the presence of FSH [8, 10]. In vivo administration of FRBI resulted in the suppression of ovulation and induced follicular atresia and apoptosis of mice [7, 21] and further impaired the proliferation of granulosa cells.…”

“…In vivo administration of FRBI resulted in the suppression of ovulation and induced follicular atresia and apoptosis of mice [7, 21] and further impaired the proliferation of granulosa cells. Therefore, FRBI interfered with FSH-FSHR interaction leading to a blockage of FSH action [3]. Currently, little information has been recorded about FRBI effects on follicular development and reproduction functions in human and animals [2, 13].…”

“…FSH activates multiple signaling pathways to regulate genes necessary for follicular maturation [2]. FSH acts via cognate FSH receptor (FSHR) existed on the granulosa cells of ovary follicles [3]. FSHR is an important mediator in human and animals’ reproduction [4].…”

“…After rat granulosa cells were treated with FRBI in the presence or absence of FSH, progesterone (P) secretion was inhibited in a dose-dependent manner [10]. FRBI blocked the binding of FSH to FSHR, and altered FSH action at the receptor level [3, 9].…”

“…FRBI blocked the binding of FSH to FSHR, and altered FSH action at the receptor level [3, 9]. Currently, little information has been recorded about FRBI effects on follicular development and reproduction functions in human and animals [2].…”