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Structural Differences in the Hinge Region of the Glycoprotein Hormone Receptors: Evidence from the Sulfated Tyrosine Residues

Institut de Recherche Interdisciplinaire en Biologie Humaine et Moléculaire, Université Libre de Bruxelles (M.Bo., G.V., S.C.), and Service de Génétique Médicale (G.V.), Hôpital Erasme, B-1070 Brussels, Belgium; Department of Medical Sciences (M.Bo., M.Bu., L.P.), University of Milan, and Laboratory of Endocrinological Research, Istituto Auxologico Italiano Istituto di Ricovero e Cura a Carattere Scientifico (IRCCS), 20095 Cusano Milanino and Fondazione IRCCS Ospedale Maggiore di Milano, Mangiagalli e Regina Elena, 20100 Milan, Italy

Address all correspondence and requests for reprints to: Marco Bonomi, Laboratory of Endocrinological Research, Istituto Auxologico Italiano Istituto di Ricovero e Cura a Carattere Scientifico (IRCCS), Via Zucchi 18, I-20095 Cusano Milanino-Milan, Italy. E-mail: dmbonomi{at}tin.it.

Tyrosine sulfation is a late posttranslational modification of proteins that takes place in the Golgi network. In the past few years, this process has been identified as an important modulator of protein-protein interactions. Sulfated tyrosine residues have recently been identified in the C-terminal, so-called hinge region of the ectodomain of glycoprotein hormone receptors [TSH, LH/chorionic gonadotropin (CG), and FSH receptors] and were shown to play an important role in the interaction with their natural ligands. The position of two sulfated tyrosine residues in a Y-D/E-Y motif appears perfectly conserved in the alignment of TSH and LH receptors from different species, and site-directed mutagenesis experiments demonstrated that sulfation of the first residue of this motif was responsible for the functional effect on hormone binding. In contrast, the corresponding motif is not conserved in the FSH receptor, in which the first tyrosine residue is missing: the Y-D/E-Y motif is replaced by F³³³DY³³⁵. We extend here our previous observation that, in this case, it is sulfation of the second sole tyrosine residue in the motif that is functionally important. An LH/CG receptor harboring an F³³¹DY³³³ motif (i.e. displaying decreased sensitivity to human CG) was used as a backbone in which short portions of the FSH receptor were substituted. Segments from the FSH receptor capable of restoring sensitivity to human CG were identified by transfection of the chimeras in COS-7 cells. These experiments identified key amino acid residues in the hinge region of the FSH receptor associated with the functional role of the second sulfated tyrosine residue in a Y-D/E-Y motif, allowing for efficient hormone binding. The experiments represent strong evidence that structural differences in the hinge regions of FSH and LH/CG receptors play a significant role in hormone-receptor-specific recognition.

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