Inhibin A and B negatively regulate the production and secretion of follicle stimulating hormone (FSH) from the anterior pituitary, control ovarian follicle development and steroidogenesis, and act as tumor suppressors in the gonads. Inhibins regulate these reproductive events by forming high affinity complexes with betaglycan and activin or bone morphogenetic protein type II receptors. In this study, the binding site of inhibin A for betaglycan was characterised using inhibin A mutant proteins. An epitope for high affinity betaglycan binding was detected spanning the outer convex surface of the inhibin a-subunit. Homology modeling indicates that key a-subunit residues (Y50, V108, T111, S112, F118, K119 and Y120) form a contiguous epitope in this region of the molecule. Disruption of betaglycan binding by the simultaneous substitution of T111, S112 and Y120 to alanine yielded an inhibin A variant that was unable to suppress activin-induced FSH release by rat pituitary cells in culture. Together these results indicate that a high affinity interaction between betaglycan and residues V108-Y120 of the inhibin a-subunit mediate inhibin A s biological activity.
|Pages (from-to)||16743 - 16751|
|Number of pages||9|
|Journal||Journal of Biological Chemistry|
|Publication status||Published - 2008|