A molecular dissection of the glycoprotein hormone receptors

  • Gilbert Vassart
  • Leonardo Pardo
  • Sabine Costagliola
Part of the Research and Perspectives in Endocrine Interactions book series (RPEI)


In glycoprotein hormone receptors, a subfamily of rhodopsin-like G protein-coupled receptors, the recognition and activation steps are carried out by separate domains of the proteins. Specificity of recognition of the hormones [thyrotropin (TSH), lutropin (LH), human chorionic gonadotropin (hCG), follitropin (FSH)] involves leucine-rich repeats (LRR) present in an aminoterminal ectodomain and can be associated with a limited number of residues at key positions of the LRRs. The mechanism by which binding of the hormones results in activation is proposed to involve switching of the ectodomain from a tethered inverse agonist to a full agonist of the serpentine, rhodopsin-like portion of the receptor. Unexpectedly, the picture is complicated by the observation that promiscuous activation of one of the receptors (FSHr) by hCG or TSH can result from activating mutations affecting the serpentine portion of the receptors.


Molecular Electrostatic Potential Luteinizing Hormone Receptor Thyrotropin Receptor Thyroid Adenoma Molecular Dissection 
These keywords were added by machine and not by the authors. This process is experimental and the keywords may be updated as the learning algorithm improves.


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  1. Ando T, Latif R, Pritsker A, Moran T, Nagayama Y, Davies TF (2002) A monoclonal thyroid-stimulating antibody, J Clin Invest 110:1667–1674PubMedCrossRefGoogle Scholar
  2. Ascoli M, Fanelli F, Segaloff DL (2002), The lutropin/choriogonadotropin receptor, a 2002 perspective. Endocr Rev 23:141–174PubMedCrossRefGoogle Scholar
  3. Ballesteros JA, Jensen AD, Liapakis G, Rasmussen SG, Shi L, Gether U, Javitch JA (2001) Activation of the beta 2-adrenergic receptor involves disruption of anionic lock between the cytoplasmic ends of transmembrane segments 3 and 6. J Biol Chem 276:29171–29177PubMedCrossRefGoogle Scholar
  4. Bhowmick N, Huang J, Puett D, Isaacs NW, Lapthorn AJ (1996) Determination of residues important in hormone binding to the extracellular domain of the luteinizing hormone/chorionic gonadotropin receptor by site-directed mutagenesis and modeling. Mol Endocrinol 10:1147–1159PubMedCrossRefGoogle Scholar
  5. Braun T, Schofield PR, Sprengel R (1991) Amino-terminal leucine-rich repeats in gonadotropin receptors determine hormone selectivity. EMBO J 10:1885–1890PubMedGoogle Scholar
  6. Claeysen S, Govaerts C, Lefort A, Van Sande J, Costagliola S, Pardo L, Vassart G (2002) A conserved Asn in TM7 of the TSH receptor is a common requirement for activation by both mutations and its natural agonist. FEBS Lett 517:195–200PubMedCrossRefGoogle Scholar
  7. Cornelis S, Uttenweiler-Joseph S, Panneels V, Vassart G, Costagliola S (2001) Purification and characterization of a soluble bioactive amino-terminal extracellular domain of the human thyrotropin receptor. Biochemistry 40:9860–9869PubMedCrossRefGoogle Scholar
  8. Costagliola S, Franssen JD, Bonomi M, Urizar E, Willnich M, Bergmann A, Vassart G (2002a) Generation of a mouse monoclonal TSH receptor antibody with stimulating activity. Biochem.Biophys Res Commun 299:891–896PubMedCrossRefGoogle Scholar
  9. Costagliola S, Panneels V, Bonomi M, Koch J, Many MC, Smits G, Vassart G (2002b) Tyrosine sulfation is required for agonist recognition by glycoprotein hormone receptors EMBO J 21:504–513PubMedCrossRefGoogle Scholar
  10. Delvigne A, Rozenberg S (2002) Epidemiology and prevention of ovarian hyperstimulation syndrome (OHSS): a review. Human ReprodUpdate. 8:559–577Google Scholar
  11. Dias JA, Zhang Y, Liu X (1994) Receptor binding and functional properties of chimeric human follitropin prepared by an exchange between a small hydrophilic intercysteine loop of human follitropin and human lutropin. J Biol Chem 269:25289–25294PubMedGoogle Scholar
  12. Dias JA, Van Roey P (2001) Structural biology of human follitropin and its receptor. Arch Med Res 32:510–519PubMedCrossRefGoogle Scholar
  13. Dong J, Ye P, Schade AJ, Gao S, Romo GM, Turner NT, McIntire LV, Lopez JA (2001) Tyrosine sulfation of glycoprotein I(b)alpha. Role of electrostatic interactions in von Willebrand factor binding. J Biol Chem. 276:16690–16694PubMedCrossRefGoogle Scholar
  14. Duprez L, Parma J, Van Sande J, Allegeier A, Leclère J, Schvartz C, Delisle MJ, Decoulx M, Orgiazzi J, Dumont JE, Vassart G (1994) Germline mutations in the thyrotropin receptor gene cause non autoimmune autosomal dominant hyperthyroidism. Nature Genet 7:396–401PubMedCrossRefGoogle Scholar
  15. Duprez L, Parma J, Costagliola S, Hermans J, Van Sande J, Dumont JE, Vassart G (1997) Constitutive activation of the TSH receptor by spontaneous mutations affecting the N-terminal extracellular domain. FEBS Lett 409:469–474PubMedCrossRefGoogle Scholar
  16. Fox KM, Dias JA, Van Roey P (2001) Three-dimensional structure of human follicle-stimulating hormone. Mol Endocrinol 15:378–389PubMedCrossRefGoogle Scholar
  17. Fritze O, Filipek S, Kuksa V, Palczewski K, Hofmann KP, Ernst OP (2003) Role of the conserved NPxxY(x)5,6F motif in the rhodopsin ground state and during activation. Proc Natl Acad Sci U.S A 100:2290–2295PubMedCrossRefGoogle Scholar
  18. Govaerts C, Lefort A, Costagliola S, Wodak SJ, Ballesteros JA, Van Sande J, Pardo L, Vassart G (2001) A conserved ASN in TM7 is a on/off switch in the activation of the TSH receptor. J Biol Chem 2001 276:22991–9PubMedCrossRefGoogle Scholar
  19. Gross B, Misrahi M, Sar S, Milgrom E (1991) Composite structure of the human thyrotropin receptor gene. Biochem Biophys Res Commun 177:679–687PubMedCrossRefGoogle Scholar
  20. Grossmann M, Weintraub BD, Szkudlinski MW (1997) Novel insights into the molecular mechanisms of human thyrotropin action: structural, physiological, and therapeutic implications for the glycoprotein hormone family. Endocr Rev 18:476–501PubMedCrossRefGoogle Scholar
  21. Ho SC, Van Sande J, Lefort A, Vassart G, Costagliola S (2001) Effects of mutations involving the highly conserved S281HCC motif in the extracellular domain of the thyrotropin (TSH) receptor on TSH binding and constitutive activity. Endocrinology 142:2760–2767PubMedCrossRefGoogle Scholar
  22. Ji I, Lee C, Song Y, Conn PM, Ji TH (2002) Cis-and trans-activation of hormone receptors: the LH receptor. Mol Endocrinol 16:1299–1308PubMedCrossRefGoogle Scholar
  23. Jiang X, Dreano M, Buckler DR, Cheng S, Ythier A, Wu H, Hendrickson WA, el Tayar N (1995) Structural predictions for the ligand-binding region of glycoprotein hormone receptors and the nature of hormone-receptor interactions. Structure 3:1341–1353PubMedCrossRefGoogle Scholar
  24. Kajava AV, Vassart G, Wodak SJ (1995) Modeling of the three-dimensional structure of proteins with the typical leucine-rich repeats. Structure 3:867–877PubMedCrossRefGoogle Scholar
  25. Kobe B, Deisenhofer J (1993) Crystal structure of porcine ribonuclease inhibitor, a protein with leucine-rich repeats. Nature 366:751–756PubMedCrossRefGoogle Scholar
  26. Kobe B, Kajava AV (2001) The leucine-rich repeat as a protein recognition motif. Curr Opin Structn Biol 11:725–732CrossRefGoogle Scholar
  27. Kopp P, Muirhead S, Jourdain N, Gu WX, Jameson JL, Rodd C (1997) Congenital hyperthyroidism caused by a solitary toxic adenoma harboring a novel somatic mutation (serine281->isoleucine) in the extracellular domain of the thyrotropin receptor. J Clin Invest 100:1634–1639PubMedCrossRefGoogle Scholar
  28. Kudo M, Osuga Y, Kobilka BK, Hsueh AJ (1996) Transmembrane regions V and VI of the human luteinizing hormone receptor are required for constitutive activation by a mutation in the third intracellular loop. J Biol Chem 271:22470–22478PubMedCrossRefGoogle Scholar
  29. Lapthorn AJ, Harris DC, Littlejohn A, Lustbader JW, Canfield RE, Machin KJ, Morgan FJ, Isaacs NW (1994) Crystal structure of human chorionic gonadotropin, Nature 369:455–461PubMedCrossRefGoogle Scholar
  30. Lee C, Ji I, Ryu K, Song Y, Conn PM, Ji TH (2002) Two defective heterozygous luteinizing hormone receptors can rescue hormone action. J Biol Chem 277:15795–15800PubMedCrossRefGoogle Scholar
  31. Lin Z, Shenker A, Pearlstein R (1997) A model of the lutropin/choriogonadotropin receptor: insights into the structural and functional effects of constitutively activating mutations. Protein Eng 10:501–510PubMedCrossRefGoogle Scholar
  32. Moyle WR, Campbell RK, Myers RV, Bernard MP, Han Y, Wang X (1994) Co-evolution of ligand-receptor pairs. Nature 368:251–255PubMedCrossRefGoogle Scholar
  33. Nagayama Y, Russo D, Chazenbalk GD, Wadsworth HL, Rapoport B (1990) Extracellular domain chimeras of the TSH and LH/CG receptors reveal the mid-region (amino acids 171–260) to play a vital role in high affinity TSH binding, Biochem Biophys Res Commun 173:1150–1156PubMedCrossRefGoogle Scholar
  34. Nakabayashi K, Kudo M, Kobilka B, Hsueh AJ (2000) Activation of the luteinizing hormone receptor following substitution of Ser-277 with selective hydrophobic residues in the ectodomain hinge region. J Biol Chem 275:30264–30271PubMedCrossRefGoogle Scholar
  35. Neumann S, Krause G, Chey S, Paschke R (2001) A free carboxylate oxygen in the side chain of position 674 in transmembrane domain 7 is necessary for TSH receptor activation. Mol Endocrinol 15:1294–1305PubMedCrossRefGoogle Scholar
  36. Nishi S, Nakabayashi K, Kobilka B, Hsueh AJ (2002) The ectodomain of the luteinizing hormone receptor interacts with exoloop 2 to constrain the transmembrane region: studies using chimeric human and fly receptors. J Biol Chem 277:3958–3964PubMedCrossRefGoogle Scholar
  37. Nothacker HP, Grimmelikhuijzen CJ (1993) Molecular cloning of a novel, putative G protein-coupled receptor from sea anemones structurally related to members of the FSH, TSH, LH/CG receptor family from mammals. Biochem Biophys Res Commun 197:1062–1069PubMedCrossRefGoogle Scholar
  38. Okada T, Fujiyoshi Y, Silow M, Navarro J, Landau EM, Shichida Y (2002) Functional role of internal water molecules in rhodopsin revealed by X-ray crystallography. Proc Natl Acad Sci USA 99:5982–5987PubMedCrossRefGoogle Scholar
  39. Palczewski K, Kumasaka T, Hori T, Behnke CA, Motoshima H, Fox BA, Le T, I, Teller DC, Okada T, Stenkamp RE, Yamamoto M, Miyano M (2000) Crystal structure of rhodopsin: A G protein-coupled receptor. Science 289:739–745PubMedCrossRefGoogle Scholar
  40. Parma J, Duprez L, Van Sande J, Cochaux P, Gervy C, Mockel J, Dumont JE, Vassart G (1993) Somatic mutations in the thyrotropin receptor gene cause hyperfunctioning thyroid adenomas. Nature 365:649–651PubMedCrossRefGoogle Scholar
  41. Parma J, Van Sande J, Swillens S, Tonacchera M, Dumont JE, Vassart G (1995) Somatic mutations causing constitutive activity of the TSH receptor are the major cause of hyperfunctional thyroid adenomas: identification of additional mutations activating both the cAMP and inisitolphosphate-Ca++ cascades. Mol Endocrinol 9:725–733PubMedCrossRefGoogle Scholar
  42. Parma J, Duprez L, Van Sande J, Hermans J, Van Vliet G, Costagliola S, Rodien P, Dumont JE, Vassart G (1997) Diversity and prevalence of somatic mutations in the TSH receptor and Gs alpha genes as a cause of toxic thyroid adenomas. J Clin Endocrinol Metab 82:2695–2701PubMedCrossRefGoogle Scholar
  43. Refetoff S, Dumont JE, Vassart G (2001) Thyroid disorders. In: Scriver CR, Beaudet AL, Sly WS, Valle eds. The metabolic and molecular bases of inherited diseases. McGraw-Hill, New York, pp 4029–4076Google Scholar
  44. Remy JJ, Nespoulous C, Grosclaude J, Grebert D, Couture L, Pajot E, Salesse R (2001) Purification and structural analysis of a soluble human chorionogonadotropin hormone-receptor complex. J Biol Chem 276:1681–1687PubMedGoogle Scholar
  45. Ridge KD, Abdulaev NG, Sousa M, Palczewski K (2003) Phototransduction: crystal clear. Trends Biochem Sci 28:479–487PubMedCrossRefGoogle Scholar
  46. Rodien P, Bremont C, Sanson ML, Parma J, Van Sande J, Costagliola S, Luton JP, Vassart G, Duprez L (1998) Familial gestational hyperthyroidism caused by a mutant thyrotropin receptor hypersensitive to human chorionic gonadotropin. New Engl J Med 339:1823–1826PubMedCrossRefGoogle Scholar
  47. Sanders J, Jeffreys J, Depraetere H, Richards T, Evans M, Kiddie A, Brereton K, Groenen M, Oda Y, Rees Smith B (2002) Thyroid stimulating monoclonal antibodies. Thyroid. 12:1043–50PubMedCrossRefGoogle Scholar
  48. Schmidt A, MacColl R, Lindau-Shepard B, Buckler DR, Dias JA (2001) Hormone-induced conformational change of the purified soluble hormone binding domain of follitropin receptor complexed with single chain follitropin. J Biol Chem 276:23373–23381PubMedCrossRefGoogle Scholar
  49. Sealfon SC, Chi L, Ebersole BJ, Rodic V, Zhang D, Ballesteros JA, Weinstein H (1995) Related contribution of specific helix 2 and 7 residues to conformational activation of the serotonin 5-HT2A receptor. J Biol Chem 270:16683–16688PubMedCrossRefGoogle Scholar
  50. Shenker A (2002) Activatingmutations of the lutropin choriogonadotropin receptor in precocious puberty. Receptors Channels 8:3–18PubMedCrossRefGoogle Scholar
  51. Smits G, Govaerts C, Nubourgh I, Pardo L, Vassart G, Costagliola S (2002) Lysine 183 and glutamic acid 157 of the thyrotropin receptor: two interacting residues with a key role in determining specificity towards TSH and hCG. Mol Endocrinol 16:722–35PubMedCrossRefGoogle Scholar
  52. Smits G, Campillo M, Govaerts C, Janssens V, Richter C, Vassart G, Pardo L, Costagliola S (2003a) Glycoprotein hormone receptors: determinants in leucine-rich repeats responsible for ligand specificity. EMBO J 22:2692–2703PubMedCrossRefGoogle Scholar
  53. Smits G, Olatunbosun O, Delbaere A, Pierson R, Vassart G, Costagliola S (2003b) Ovarian hyperstimulation syndrome due to a mutation in the follicle-stimulating hormone receptor. New Engl J Med 349:760–766PubMedCrossRefGoogle Scholar
  54. Szkudlinski MW, Fremont V, Ronin C, Weintraub BD (2002) Thyroid-stimulating hormone and thyroid-stimulating hormone receptor structure-function relationships. Physiol Rev 82:473–502PubMedGoogle Scholar
  55. Urizar E, Montanelli L, Loy T, Bonomi M, Swillens S, Gales C, Bouvier M, Smits G, Vassart G, Costagliola S (2005) Glycoprotein hormone receptors: link between receptor homodimerization and negative cooperativity 1, EMBO J 24:1954–1964PubMedCrossRefGoogle Scholar
  56. Van Sande J, Massart C, Costagliola S, Alleier A, Cetani F, Vassart G, Dumont JE (1996) Specific activation of the thyrotropin receptor by trypsin. Mol Cell Endocrinol 119:161–168PubMedCrossRefGoogle Scholar
  57. Vasseur C, Rodien P, Beau I, Desroches A, Gerard C, de Poncheville L, Chaplot S, Savagner F, Croue A, Mathieu E, Lahlou N, Descamps P, Misrahi M (2003) A chorionic gonadotropin-sensitive mutation in the follicle-stimulating hormone receptor as a cause of familial gestational spontaneous ovarian hyperstimulation syndrome. New Engl J Med 349:753–759PubMedCrossRefGoogle Scholar
  58. Vlaeminck V, Ho SC, Rodien P, Vassart G, Costagliola S (2002) Activation of the cAMP pathway by the TSH receptor involves switching of the ectodomain from a tethered inverse agonist to an agonist. Mol Endocrinol 16:736–746CrossRefGoogle Scholar
  59. Wu H, Lustbader JW, Liu Y, Canfield RE, Hendrickson WA (1994) Structure of human chorionic gonadotropin at 2.6 A resolution from MAD analysis of the selenomethionyl protein. Structure 2:545–558PubMedCrossRefGoogle Scholar
  60. Zhang M, Tong KP, Fremont V, Chen J, Narayan P, Puett D, Weintraub BD, Szkudlinski MW (2000) The extracellular domain suppresses constitutive activity of the transmembrane domain of the human TSH receptor: implications for hormone-receptor interaction and antagonist design. Endocrinology 141:3514–3517PubMedCrossRefGoogle Scholar
  61. Zhou W, Flanagan C, Ballesteros JA, Konvicka K, Davidson JS, Weinstein H, Millar RP, Sealfon SC (1994) A reciprocal mutation supports helix 2 and helix 7 proximity in the gonadotropin-releasing hormone receptor. Mol Pharmacol 45:165–170PubMedGoogle Scholar

Copyright information

© Springer-Verlag Berlin Heidelberg 2006

Authors and Affiliations

  • Gilbert Vassart
    • 1
    • 2
  • Leonardo Pardo
    • 3
  • Sabine Costagliola
    • 1
  1. 1.IRIBHMUniversité Libre de BruxellesBrusselsBelgium
  2. 2.Service de Génétique MédicaleHôpital ErasmeBrusselsBelgium
  3. 3.Laboratori de Medicina Computacional, Unitat de Bioestadística, Facultat de MedicinaUniversitat Autònoma de BarcelonaBellaterraSpain

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