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Modulation of Ligand Selectivity Associated with Activation of the Transmembrane Region of the Human Follitropin Receptor

Institut de Recherche Interdisciplinaire en Biologie Humaine et Moléculaire, Université Libre de Bruxelles (L.M., J.J.J.V.D., G.S., M.B., G.V., S.C.), Campus Erasme, B-1070 Brussels, Belgium; Service de Génétique Médicale (G.S., G.V.), Hôpital Erasme, B-1070 Brussels, Belgium; Department of Endocrinology (L.M.), University of Pisa, 54126 Pisa, Italy; Institute of Endocrine Sciences (M.B.), University of Milan, Istituto Auxologico Italiano Istituto di Ricovero e Cura a Carattere Scientifico, Milan 20145, Italy; Institut National de la Santé et de la Recherche Médicale Equipe Mixte U0018 (P.R.), Angers 49035, France; Molecular Genetics and Bioinformatics (E.J.D., K.M.-W.), Integrated DNA Technologies, Coralville, Iowa 52241; and Laboratori de Medicina Computacional (L.P.), Unitat de Bioestadística and Institut de Neurociències, Universitat Autònoma de Barcelona, 08193 Bellaterra, Spain

Address all correspondence and requests for reprints to: Dr. Sabine Costagliola, IRIBHM, Université Libre de Bruxelles, Campus Erasme, Route de Lennik 808, B-1070 Brussels. E-mail: scostag{at}ulb.ac.be.

Recently, three naturally occurring mutations in the serpentine region of the FSH receptor (FSHr) (D567N and T449I/A) have been identified in three families with spontaneous ovarian hyperstimulation syndrome (OHSS). All mutant receptors displayed abnormally high sensitivity to human chorionic gonadotropin and, in addition, D567N and T449A displayed concomitant increase in sensitivity to TSH and detectable constitutive activity. In the present study, we have used a combination of site-directed mutagenesis experiments and molecular modeling to explore the mechanisms responsible for the phenotype of the three OHSS FSHr mutants. Our results suggest that all mutations lead to weakening of interhelical locks between transmembrane helix (TM)-VI and TM-III, or TM-VI and TM-VII, which contributes to maintaining the receptor in the inactive state. They also indicate that broadening of the functional specificity of the mutant FSHr constructs is correlated to their increase in constitutive activity. This relation between basal activity and functional specificity is a characteristic of the FSHr, which is not shared by the other glycoprotein hormone receptors. It leads to the interesting suggestion that different pathways have been followed during primate evolution to avoid promiscuous stimulation of the TSHr and FSHr by human chorionic gonadotropin. In the hFSHr, specificity would be exerted both by the ectodomain and the serpentine portion.

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