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This version published online on May 27, 2004
Molecular Endocrinology, doi:10.1210/me.2004-0036
A more recent version of this article appeared on August 1, 2004
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Submitted on January 29, 2004
Accepted on May 18, 2004

Modulation of ligand selectivity associated with activation of the transmembrane region of the human follitropin receptor

Lucia Montanelli, Joost J J Van Durme, Guillaume Smits, Marco Bonomi, Patrice Rodien, Eric J Devor, Kristin Moffat-Wilson, Leonardo Pardo, Gilbert Vassart, and Sabine Costagliola*

IRIBHM, Université Libre de Bruxelles, Campus Erasme, B-1070 Brussels, Belgium, Service de Génétique Médicale, Hôpital Erasme, B-1070 Brussels, Belgium, Department of Endocrinology, University of Pisa, Italy, Institute of Endocrine Sciences, University of Milan, Istituto Auxologico Italiano IRCCS, Italy, INSERM EMI U0018, Angers, France, Molecular Genetics and Bioinformatics, Integrated DNA Technologies, 1710 Commercial Park, Coralville, Iowa 52241, USA, Laboratori de Medicina Computacional, Unitat de Bioestadística and Institut de Neurociències, Universitat Autònoma de Barcelona, 08193 Bellaterra, Spain

* To whom correspondence should be addressed. E-mail: scostag{at}ulb.ac.be.

Recently, three naturally occurring mutations in the serpentine region of the FSH receptor (D567N and T449I/A) have been identified in three families with spontaneous ovarian hyperstimulation syndrome (OHSS). All mutant receptors displayed abnormally high sensitivity to hCG and, in addition, D567N and T449A displayed concomitant increase in sensitivity to thyrotropin 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 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 hCG. In the hFSHr, specificity would be exerted both by the ectodomain and the serpentine portion.
Key words: G-protein coupled receptors • glycoprotein hormone receptors • follitropin • molecular dynamics




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