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 β-strands. Hence, hormone selectivity of each GpHR for its cognate ligand is defined by amino acid sequence divergence in these β-strands between different GpHRs. To identify the molecular determinants that allow promiscuous activation of the cfFSHR by cfLH, β-strands were systematically exchanged between the cfFSHR and the human FSHR. Both gain-of-function and loss-of-function mutational approaches revealed that β-strand 2 of the cfFSHR contains determinants that contribute to the receptor’s responsiveness to cfLH.