Abstract
The difference in hormone selectivity between the human follicle-stimulating hormone receptor (hFSH-R) and human luteinizing hormone/chorionic gonadotropin receptor (hLH-R) is determined by their approximately 350 amino acid-long N-terminal receptor exodomains that allow the mutually exclusive binding of human follicle-stimulating hormone (hFSH) and human luteinizing hormone (hLH) when these hormones are present in physiological concentrations. The exodomains of each of these receptors consist of a nine-leucine-rich repeat-containing subdomain (LRR subdomain) flanked by N- and C-terminal cysteine-rich subdomains. Chimeric receptors, in which the structural subdomains of the hFSH-R exodomain were substituted with those of the hLH-R, showed a similar high responsiveness to human chorionic gonadotropin (hCG) and hLH as long as they harbored the LRR subdomain of the hLH-R. In addition, these chimeric receptors showed no responsiveness to hFSH. The LRR subdomains of the gonadotropin receptor exodomains are predicted to adopt a horseshoe-like conformation, of which the hormone-binding concave surface is composed of nine parallel beta-strands. Receptors in which individual beta-strands of the hFSH-R were replaced with the corresponding hLH-R sequences revealed that hCG and hLH selectivity is predominantly determined by hLH-R beta-strands 3 and 6. A mutant receptor in which the hFSH-R beta-strands 3 and 6 were substituted simultaneously with their hLH-R counterparts displayed a responsiveness to hCG and hLH similar to that of the wild type hLH-R. Responsiveness to hFSH was not affected by most beta-strand substitutions, suggesting the involvement of multiple low-impact determinants for this hormone.
Highlights
The difference in hormone selectivity between the human follicle-stimulating hormone receptor and human luteinizing hormone/chorionic gonadotropin receptor is determined by their ϳ350 amino acid-long N-terminal receptor exodomains that allow the mutually exclusive binding of human folliclestimulating hormone and human luteinizing hormone when these hormones are present in physiological concentrations
Taking advantage of the current knowledge of the structural conformation of the exodomain of glycoprotein hormone receptor (GpHR), we examined in more detail the contribution of the NCR, LRR, and CCR subdomains of the human luteinizing hormone (LH)-R exodomain in conferring human chorionic gonadotropin and/or human LH selectivity when placed in the context of a human Follicle-stimulating hormone (FSH)-R background
These chimeric receptors were functionally similar to wild type human luteinizing hormone/chorionic gonadotropin receptor (hLH-R) (Fig. 2, C and D, and Table I) in their responsiveness to human folliclestimulating hormone (hFSH), as well as to human chorionic gonadotropin (hCG) and human luteinizing hormone (hLH)
Summary
The difference in hormone selectivity between the human follicle-stimulating hormone receptor (hFSH-R) and human luteinizing hormone/chorionic gonadotropin receptor (hLH-R) is determined by their ϳ350 amino acid-long N-terminal receptor exodomains that allow the mutually exclusive binding of human folliclestimulating hormone (hFSH) and human luteinizing hormone (hLH) when these hormones are present in physiological concentrations. In which the structural subdomains of the hFSH-R exodomain were substituted with those of the hLH-R, showed a similar high responsiveness to human chorionic gonadotropin (hCG) and hLH as long as they harbored the LRR subdomain of the hLH-R. These chimeric receptors showed no responsiveness to hFSH. The coordinated interplay between the complementary and specific actions of FSH and LH(/CG) is required to guarantee successful reproduction The interaction between these gonadotropins and their respective receptors is highly specific, and there is virtually no cross-reactivity between hormones and heterologous receptors (i.e. high receptor selectivity) except for LH and CG, which both act on the LH-R [2, 3]. Each of the LRR -strands is composed of a highly conserved X1X2LX3LX4X5 motif (Fig. 1), in
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