Glycoprotein hormone receptors: determinants in leucine-rich repeats responsible for ligand specificity.
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.
Smits
Guillaume
G
IRIBHM, Université Libre de Bruxelles, Campus Erasme, 808 route de Lennik, B-1070 Brussels, Belgium.
Campillo
Mercedes
M
Govaerts
Cédric
C
Janssens
Véronique
V
Richter
Christine
C
Vassart
Gilbert
G
Pardo
Leonardo
L
Costagliola
Sabine
S
D019943:Amino Acid Substitution; D000818:Animals; D019556:COS Cells; D006801:Humans; D007700:Kinetics; D007930:Leucine / Q000737:chemistry; D008024:Ligands; D008958:Models, Molecular; D016297:Mutagenesis, Site-Directed; D017434:Protein Structure, Tertiary; D011962:Receptors, FSH / Q000737:chemistry / Q000235:genetics / Q000378:metabolism; D011974:Receptors, LH / Q000737:chemistry / Q000235:genetics / Q000378:metabolism; D018013:Receptors, Neuropeptide / Q000737:chemistry* / Q000235:genetics / Q000378:metabolism*; D011989:Receptors, Thyrotropin / Q000737:chemistry / Q000235:genetics / Q000378:metabolism; D011994:Recombinant Proteins / Q000737:chemistry / Q000235:genetics / Q000378:metabolism; D020449:Repetitive Sequences, Amino Acid; D055672:Static Electricity; D013816:Thermodynamics
D008024:Ligands; D011962:Receptors, FSH; D011974:Receptors, LH; D018013:Receptors, Neuropeptide; D011989:Receptors, Thyrotropin; D011994:Recombinant Proteins; D007930:Leucine