title: Identification of the structural and functional determinants of the extracellular domain of the human follicle stimulating hormone receptor.
abstract: 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.
authors.affiliation: Division of Structural Biology, National Institute for Research in Reproductive Health (ICMR), Jehangir Merwanji Street, Parel, Mumbai 400 012, India.
authors.forename: P S
authors.initials: PS
authors.lastname: Kene
authors.forename: V C
authors.initials: VC
authors.lastname: Nalavadi
authors.forename: R R
authors.initials: RR
authors.lastname: Dighe
authors.forename: K S
authors.initials: KS
authors.lastname: Iyer
authors.forename: S D
authors.initials: SD
authors.lastname: Mahale
mesh_terms: D000595:Amino Acid Sequence; D001667:Binding, Competitive; D000242:Cyclic AMP / Q000096:biosynthesis; D005260:Female; D005640:Follicle Stimulating Hormone / Q000378:metabolism; D006801:Humans; D008969:Molecular Sequence Data; D011485:Protein Binding; D017434:Protein Structure, Tertiary / Q000502:physiology; D011869:Radioligand Assay / Q000379:methods; D011962:Receptors, FSH / Q000737:chemistry* / Q000235:genetics / Q000378:metabolism; D015398:Signal Transduction / Q000502:physiology*; D013329:Structure-Activity Relationship
chemical_list: D011962:Receptors, FSH; D005640:Follicle Stimulating Hormone; D000242:Cyclic AMP