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  • The EMBO Journal (2003) 22, 2692 - 2703
  • doi:10.1093/emboj/cdg260

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

Guillaume Smits1,2, Mercedes Campillo3, Cédric Govaerts1,4, Véronique Janssens1, Christine Richter1, Gilbert Vassart1,2, Leonardo Pardo3 and Sabine Costagliola1

  1. IRIBHM, Université Libre de Bruxelles, Campus Erasme, 808 route de Lennik, B-1070 Brussels, Belgium
  2. Service de Génétique Médicale, Hôpital Erasme, B-1070 Brussels, Belgium
  3. Laboratori de Medicina Computacional, Unitat de Bioestadística, Facultat de Medicina, Universitat Autònoma de Barcelona, 08193 Bellaterra, Spain
  4. Present address: Cellular and Molecular Pharmacalogy Department, University of California, San Francisco, CA 94143-2240, USA

Correspondence to:

Gilbert Vassart, E-mail: gvassart@ulb.ac.be

Received 20 January 2003; Accepted 1 April 2003; Revised 12 March 2003

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 beta-strands and alpha-helices organized into a horseshoe-shaped structure. It has been proposed that glycoprotein hormones interact with residues of the beta-strands making the concave surface of the horseshoe. Gain-of-function homology scanning of the beta-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.

  • Keywords:

    • duplicated genes,
    • glycoprotein hormone receptors,
    • G-protein coupled receptors,
    • leucine-rich repeats,
    • molecular dynamics