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.
Modulation of ligand selectivity associated with activation of the transmembrane region of the human follitropin receptor / L. Montanelli, J. Van Durme, G. Smits, M. Bonomi, P. Rodien, E. Devor, K. Moffat-Wilson, L. Pardo, G. Vassart, S. Costagliola. - In: MOLECULAR ENDOCRINOLOGY. - ISSN 0888-8809. - 18:8(2004 Aug 18), pp. 2061-2073.
|Titolo:||Modulation of ligand selectivity associated with activation of the transmembrane region of the human follitropin receptor|
|Settore Scientifico Disciplinare:||Settore MED/13 - Endocrinologia|
Settore MED/40 - Ginecologia e Ostetricia
Settore BIO/11 - Biologia Molecolare
Settore BIO/14 - Farmacologia
|Data di pubblicazione:||18-ago-2004|
|Digital Object Identifier (DOI):||http://dx.doi.org/10.1210/me.2004-0036|
|Appare nelle tipologie:||01 - Articolo su periodico|