Identification of follicle-stimulating hormone-selective beta-strands in the N-terminal hormone-binding exodomain of human gonadotropin receptors.
Glycoprotein hormone receptors contain large N-terminal extracellular domains (ECDs) that distinguish these receptors from most other G protein-coupled receptors. Each glycoprotein hormone receptor ECD consists of a curved leucine-rich repeat domain flanked by N- and C-terminal cysteine-rich regions. Selectivity of the different glycoprotein hormone receptors for their cognate hormones is exclusively determined by their ECDs and, in particular, their leucine-rich repeat domain. To identify human (h)FSH-selective determinants we used a gain-of-function mutagenesis strategy in which beta-strands of the hLH receptor (hLH-R) were substituted with their hFSH receptor (hFSH-R) counterparts. Introduction of hFSH-R beta-strand 1 into hLH-R conferred responsiveness to hFSH, whereas hLH-R mutants harboring one of the other hFSH-R beta-strands displayed none or very limited sensitivity to hFSH. However, combined substitution of hFSH-R beta-strand 1 and some of the other hFSH-R beta-strands further increased the sensitivity of the mutant hLH-R to hFSH. The apparent contribution of multiple hFSH-R beta-strands in providing a selective hormone binding interface corresponds well with their position in relation to hFSH as recently determined in the crystal structure of hFSH in complex with part of the hFSH-R ECD.
Department of Endocrinology, Utrecht University, The Netherlands.
Henry F
HF
Vischer
Joke C M
JC
Granneman
Jan
J
Bogerd
D000595:Amino Acid Sequence; D002478:Cells, Cultured; D006063:Chorionic Gonadotropin / Q000494:pharmacology; D005110:Extracellular Space; D005640:Follicle Stimulating Hormone / Q000378:metabolism*; D006062:Gonadotropins / Q000494:pharmacology; D006801:Humans; D007986:Luteinizing Hormone / Q000494:pharmacology; D008958:Models, Molecular; D008969:Molecular Sequence Data; D016297:Mutagenesis, Site-Directed; D050506:Mutant Chimeric Proteins / Q000378:metabolism; D011485:Protein Binding; D017433:Protein Structure, Secondary; D017434:Protein Structure, Tertiary; D011967:Receptors, Gonadotropin / Q000737:chemistry* / Q000378:metabolism*; D011974:Receptors, LH / Q000235:genetics / Q000378:metabolism; D017386:Sequence Homology, Amino Acid; D040681:Structural Homology, Protein; D013379:Substrate Specificity; D014162:Transfection
D006063:Chorionic Gonadotropin; D006062:Gonadotropins; D050506:Mutant Chimeric Proteins; D011967:Receptors, Gonadotropin; D011974:Receptors, LH; D007986:Luteinizing Hormone; D005640:Follicle Stimulating Hormone