Ligand selectivity of gonadotropin receptors. Role of the beta-strands of extracellular leucine-rich repeats 3 and 6 of the human luteinizing hormone receptor

Henry F Vischer, Joke C M Granneman, Michiel J Noordam, Sietse Mosselman, Jan Bogerd

Research output: Contribution to JournalArticleAcademicpeer-review

Abstract

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.

Original languageEnglish
Pages (from-to)15505-13
Number of pages9
JournalJournal of Biological Chemistry
Volume278
Issue number18
DOIs
Publication statusPublished - 2 May 2003

Keywords

  • Amino Acid Sequence
  • Chorionic Gonadotropin
  • Follicle Stimulating Hormone
  • Humans
  • Leucine
  • Ligands
  • Luteinizing Hormone
  • Molecular Sequence Data
  • Protein Structure, Secondary
  • Receptors, LH
  • Repetitive Sequences, Amino Acid
  • Journal Article

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