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PS Kene, VC Nalavadi, RR Dighe, KS Iyer, and SD Mahale

The extracellular domain (ECD) of the human follicle-stimulating hormone receptor (hFSHR) is believed to be the major determinant of hormone selectivity. Different discrete, discontinuous regions on the ECD of the hFSHR have been suggested to be crucial for hormone binding. However, the role of the ECD in signal transduction is not well understood. This study provides some insight into these aspects of the structure-function relationship of the ECD of hFSHR. Ten peptides were selected from the ECD on the basis of their ability to be surface oriented, synthesized by the solid-phase method using fluorenylmethyloxycarbonyl chemistry, purified and characterized. They were further studied for their ability to modulate both human follicle-stimulating hormone (hFSH)-FSHR binding and cAMP generation. Competitive inhibition studies showed that, of all the peptides studied, peptides 285-300 and 297-310 hFSHR were able to inhibit hFSH binding to FSHR. Both peptides function as weak competitive inhibitors of hFSH-FSHR binding. Peptides 285-300 hFSHR, 216-235 hFSHR, 184-195 hFSHR, 79-89 hFSHR and 15-31 hFSHR were observed to inhibit FSH-induced cAMP production. In summary, this study suggests that discrete, functional domains of the ECD have a role in hormone binding and signal transduction. Region 285-300 has been identified as a novel region crucial for both FSH binding and cAMP generation.

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DD Jagtap, SD Mahale, AK Mishra, TD Nandedkar, and KS Iyer

An in-depth study of the L2beta long-loop region of human chorionic gonadotrophin (hCG), earlier identified to be a conformational bioneutralization epitope and receptor-binding site of the hormone, was carried out. The linear 38-57 hCGbeta peptide and the corresponding cyclic disulphide peptide were synthesized and antipeptide antibodies developed. Binding studies with antibodies to the linear peptide, and with hCGbeta, hCG and human LH suggest that part of the region is buried at the alpha/beta interface and part exposed in hCG. Observation of the surface exposure of residues 47-53 from the crystal structure of hCG was confirmed by epitope mapping studies of the region. The region is not unique to hCG as a majority of the antibodies to both the linear and cyclic peptides did not exhibit the required specificity. Competitive inhibition studies with the linear and cyclic peptides failed to show inhibition of radiolabelled hCG binding to its receptors. However, both the antipeptide antibodies were able to bioneutralize the hormone in an in vivo assay. Taken together, these results seem to indicate that the L2beta long-loop region is not a receptor-binding site of hCG but spatially close to it.