Identification of a luteinizing hormone-selective determinant in the exodomain of a follicle-stimulating hormone receptor.
Mammalian glycoprotein hormone receptors (GpHRs) display a stringent selectivity for their cognate hormones. In contrast, the follicle-stimulating hormone receptor of the African catfish (cfFSHR) is promiscuously activated by catfish luteinizing hormone (cfLH). Glycoprotein hormones bind to the concave site of the cusp-shaped N-terminal GpHR exodomain, which is formed by 9-10 parallel beta-strands. Hence, hormone selectivity of each GpHR for its cognate ligand is defined by amino acid sequence divergence in these beta-strands between different GpHRs. To identify the molecular determinants that allow promiscuous activation of the cfFSHR by cfLH, beta-strands were systematically exchanged between the cfFSHR and the human FSHR. Both gain-of-function and loss-of-function mutational approaches revealed that beta-strand 2 of the cfFSHR contains determinants that contribute to the receptor's responsiveness to cfLH.
Vischer
Henry F
HF
Division Endocrinology & Metabolism, Department of Biology, Faculty of Science, Utrecht University, Padualaan 8, 3584 CH Utrecht, The Netherlands.
Granneman
Joke C M
JC
Koelink
Pim J
PJ
Marques
Rute B
RB
Bogerd
Jan
J
D000595:Amino Acid Sequence; D000818:Animals; D002397:Catfishes / Q000502:physiology*; D002460:Cell Line; D000242:Cyclic AMP / Q000096:biosynthesis; D017362:Cyclic AMP Response Element-Binding Protein / Q000378:metabolism; D004252:DNA Mutational Analysis; D018076:DNA, Complementary / Q000096:biosynthesis / Q000235:genetics; D004797:Enzyme-Linked Immunosorbent Assay; D006801:Humans; D008024:Ligands; D007986:Luteinizing Hormone / Q000235:genetics*; D008969:Molecular Sequence Data; D011956:Receptors, Cell Surface / Q000096:biosynthesis / Q000235:genetics; D011962:Receptors, FSH / Q000235:genetics*
D017362:Cyclic AMP Response Element-Binding Protein; D018076:DNA, Complementary; D008024:Ligands; D011956:Receptors, Cell Surface; D011962:Receptors, FSH; D007986:Luteinizing Hormone; D000242:Cyclic AMP