Opposite contribution of two ligand-selective determinants in the N-terminal hormone-binding exodomain of human gonadotropin receptors.
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 beta-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 beta-strands in conferring hCG/ hLH responsiveness to this mutant hFSH-R. Human LH-R beta-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 beta-strand 6, rather than the introduction of its corresponding hLH-R beta-strand, appeared to allow the interaction of hCG/ hLH with the hFSH-R. Hence, hFSH-R beta-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 beta-strands 3 and 6, respectively.[1]References
- Opposite contribution of two ligand-selective determinants in the N-terminal hormone-binding exodomain of human gonadotropin receptors. Vischer, H.F., Granneman, J.C., Bogerd, J. Mol. Endocrinol. (2003) [Pubmed]
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