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Opposite Contribution of Two Ligand-Selective Determinants in the N-Terminal Hormone-Binding Exodomain of Human Gonadotropin Receptors

Department of Endocrinology, Utrecht University, 3584 CH Utrecht, The Netherlands

Address all correspondence and requests for reprints to: Jan Bogerd, Utrecht University, Department of Endocrinology, Padualaan 8, 3584 CH Utrecht, The Netherlands. E-mail: J.Bogerd{at}bio.uu.nl.

The nine leucine-rich repeat-containing exodomains of the human FSH receptor (hFSH-R) and the human LH/chorionic gonadotropin receptor (hLH-R) harbor molecular determinants that allow the mutually exclusive binding of human FSH (hFSH) and human LH (hLH)/human chorionic gonadotropin (hCG) when these hormones are present in physiological concentrations. Previously, we have shown that the ß-strands of hLH-R leucine-rich repeats 3 and 6 can confer full hCG/hLH responsiveness and binding when simultaneously introduced into a hFSH-R background without affecting the receptor’s responsiveness to hFSH. In the present study, we have determined the nature of contribution of each of these two ß-strands in conferring hCG/hLH responsiveness to this mutant hFSH-R. Human LH-R ß-strand 3 appeared to function as a positive hCG/hLH determinant by increasing the hCG/hLH responsiveness of the hFSH-R. In contrast, mutagenesis of hFSH-R ß-strand 6, rather than the introduction of its corresponding hLH-R ß-strand, appeared to allow the interaction of hCG/hLH with the hFSH-R. Hence, hFSH-R ß-strand 6 functions as a negative determinant and, as such, restrains binding of hCG/hLH to the hFSH-R. Detailed mutagenic analysis revealed that the ability of the hFSH-R to interact with hCG/hLH depends primarily on the identity of two amino acids (Asn¹⁰⁴, a positive LH-R determinant, and Lys¹⁷⁹ a negative FSH-R determinant) that are situated on the C-terminal ends of ß-strands 3 and 6, respectively.

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