Ligand selectivity of gonadotropin receptors. Role of the beta-strands of extracellular leucine-rich repeats 3 and 6 of the human luteinizing hormone receptor.
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.
Vischer
Henry F
HF
Department of Endocrinology, Utrecht University, Padualaan 8, 3584 CH Utrecht, The Netherlands.
Granneman
Joke C M
JC
Noordam
Michiel J
MJ
Mosselman
Sietse
S
Bogerd
Jan
J
D000595:Amino Acid Sequence; D006063:Chorionic Gonadotropin / Q000378:metabolism; D005640:Follicle Stimulating Hormone / Q000378:metabolism; D006801:Humans; D007930:Leucine; D008024:Ligands; D007986:Luteinizing Hormone / Q000378:metabolism; D008969:Molecular Sequence Data; D017433:Protein Structure, Secondary; D011974:Receptors, LH / Q000737:chemistry*; D020449:Repetitive Sequences, Amino Acid
D006063:Chorionic Gonadotropin; D008024:Ligands; D011974:Receptors, LH; D007986:Luteinizing Hormone; D005640:Follicle Stimulating Hormone; D007930:Leucine