Glycoprotein hormone receptors: Determinants in leucine-rich repeats responsible for ligand specificity

Guillaume Smits, Mercedes Campillo, Cédric Govaerts, Veronique Janssens, Christine Richter, Gilbert Vassart, Leonardo Pardo, Sabine Costagliola

Research output: Contribution to journalArticleResearchpeer-review

159 Citations (Scopus)

Abstract

Glycoprotein hormone receptors [thyrotropin (TSHr), luteinizing hormone/chorionic gonadotropin (LH/CGr), follicle stimulating hormone (FSHr)] are rhodopsin-like G protein-coupled receptors with a large extracellular N-terminal portion responsible for hormone recognition and binding. In structural models, this ectodomain is composed of two cysteine clusters flanking nine leucine-rich repeats (LRRs). The LRRs form a succession of β-strands and α-helices organized into a horseshoe-shaped structure. It has been proposed that glycoprotein hormones interact with residues of the β-strands making the concave surface of the horseshoe. Gain-of-function homology scanning of the β-strands of glycoprotein hormone receptors allowed identification of the critical residues responsible for the specificity towards human chorionic gonadotropin (hCG). Substitution of eight or two residues of the LH/CGr into the TSHr or FSHr, respectively, resulted in constructs displaying almost the same affinity and sensitivity for hCG as wild-type LH/CGr. Molecular dynamics simulations and additional site-directed mutagenesis provided a structural rationale for the evolution of binding specificity in this duplicated gene family.
Original languageEnglish
Pages (from-to)2692-2703
JournalEMBO Journal
Volume22
DOIs
Publication statusPublished - 2 Jun 2003

Keywords

  • Duplicated genes
  • G-protein coupled receptors
  • Glycoprotein hormone receptors
  • Leucine-rich repeats
  • Molecular dynamics

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