Opposite contribution of two ligand-selective determinants in the N-terminal hormone-binding exodomain of human gonadotropin receptors

Henry F Vischer, Joke C M Granneman, Jan Bogerd

Research output: Contribution to JournalArticleAcademicpeer-review


The nine leucine-rich repeat-containing exodomains of the human FSH receptor (hFSH-R) and the human LH/chorionic gonadotropin receptor (hLH-R) harbor molecular determinants that allow the mutually exclusive binding of human FSH (hFSH) and human LH (hLH)/human chorionic gonadotropin (hCG) when these hormones are present in physiological concentrations. Previously, we have shown that the beta-strands of hLH-R leucine-rich repeats 3 and 6 can confer full hCG/hLH responsiveness and binding when simultaneously introduced into a hFSH-R background without affecting the receptor's responsiveness to hFSH. In the present study, we have determined the nature of contribution of each of these two beta-strands in conferring hCG/hLH responsiveness to this mutant hFSH-R. Human LH-R beta-strand 3 appeared to function as a positive hCG/hLH determinant by increasing the hCG/hLH responsiveness of the hFSH-R. In contrast, mutagenesis of hFSH-R beta-strand 6, rather than the introduction of its corresponding hLH-R beta-strand, appeared to allow the interaction of hCG/hLH with the hFSH-R. Hence, hFSH-R beta-strand 6 functions as a negative determinant and, as such, restrains binding of hCG/hLH to the hFSH-R. Detailed mutagenic analysis revealed that the ability of the hFSH-R to interact with hCG/hLH depends primarily on the identity of two amino acids (Asn104, a positive LH-R determinant, and Lys179 a negative FSH-R determinant) that are situated on the C-terminal ends of beta-strands 3 and 6, respectively.

Original languageEnglish
Pages (from-to)1972-81
Number of pages10
JournalMolecular Endocrinology
Issue number10
Publication statusPublished - Oct 2003


  • Amino Acid Sequence
  • Cells, Cultured
  • Chorionic Gonadotropin
  • Cyclic AMP-Dependent Protein Kinases
  • Enzyme-Linked Immunosorbent Assay
  • Follicle Stimulating Hormone
  • Humans
  • Leucine
  • Ligands
  • Luteinizing Hormone
  • Molecular Sequence Data
  • Mutagenesis, Site-Directed
  • Protein Binding
  • Protein Conformation
  • Protein Structure, Secondary
  • Protein Structure, Tertiary
  • Receptors, FSH
  • Receptors, LH
  • Repetitive Sequences, Nucleic Acid
  • Structure-Activity Relationship
  • Transfection
  • Journal Article


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