| HOME | HELP | FEEDBACK | SUBSCRIPTIONS | ARCHIVE | SEARCH | TABLE OF CONTENTS |
Faculté de Médecine Paris Sud (B.K., S.G., C.A., E.M., N.d.R.), 94270 Le Kremlin Bicêtre; and Institut National de la Santé et de la Recherche Médicale Unité 584 (C.A., F.H., P.A.K., N.d.R.), Hormone Targets Faculté de Médecine Necker-Enfants Malades, 75015 Paris, France
Address all correspondence and requests for reprints to: Nicolas de Roux, Institut National de la Santé et de la Recherche Médicale, Unité 584, Hormone Targets, Faculté de Médecine Necker-Enfants Malades, 156 rue de Vaugirard, 75015 Paris, France. E-mail: deroux{at}necker.fr.
Several molecular models of glycoprotein hormone receptor activation have been proposed. It has been suggested that ligand binding to the ectodomain (ECD) leads to major changes in intramolecular interactions between the ECD and the transmembrane domain. We studied these intramolecular modifications by generating a recombinant LH/CG receptor (LHR) bearing an intramolecular cleavage site. We did this by inserting a furin site at position 316 in the hinge region of the ECD (LHR_Fur316). Affinity for human chorionic gonadotropin (hCG) and cAMP production upon hCG stimulation was identical to those of wild-type LHR. Western blot analysis showed that the LHR_Fur316 receptor was cleaved into two subunits linked by disulfide bridges. Chemical shedding of the ECD from the transmembrane domain did not increase basal adenylate cyclase activity, indicating that the first 294 residues did not act as an inverse agonist. The truncated LHR_316 was still activated by hCG but with an EC50 higher than that for the wild-type receptor. Zero length cross-linking was used to study intramolecular interactions between the two domains of LHR_Fur316. Cross-linking efficiency was similar for the basal and activated states, which indicated that the two domains interacted closely in the basal state, and this tight interaction persisted during activation. Our data suggest that activation of the LHR results from subtle modifications of intramolecular interactions between the two domains and low-affinity binding of hCG to the extracellular loops or residues preceding the first transmembrane segment.
This article has been cited by other articles:
 |
|
 |
|
  G. Kleinau, H. Jaeschke, S. Mueller, B. M. Raaka, S. Neumann, R. Paschke, and G. Krause Evidence for cooperative signal triggering at the extracellular loops of the TSH receptor FASEB J, August 1, 2008; 22(8): 2798 - 2808. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 P. Nurwakagari, A. Breit, C. Hess, H. Salman-Livny, D. Ben-Menahem, and T. Gudermann A conformational contribution of the luteinizing hormone-receptor ectodomain to receptor activation J. Mol. Endocrinol., February 1, 2007; 38(2): 259 - 275. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 M. Bonomi, M. Busnelli, L. Persani, G. Vassart, and S. Costagliola Structural Differences in the Hinge Region of the Glycoprotein Hormone Receptors: Evidence from the Sulfated Tyrosine Residues Mol. Endocrinol., December 1, 2006; 20(12): 3351 - 3363. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 S. Mueller, G. Kleinau, H. Jaeschke, S. Neumann, G. Krause, and R. Paschke Significance of Ectodomain Cysteine Boxes 2 and 3 for the Activation Mechanism of the Thyroid-stimulating Hormone Receptor J. Biol. Chem., October 20, 2006; 281(42): 31638 - 31646. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 S. Costagliola, E. Urizar, F. Mendive, and G. Vassart Specificity and promiscuity of gonadotropin receptors Reproduction, September 1, 2005; 130(3): 275 - 281. [Abstract] [Full Text] [PDF]
|
|
| HOME | HELP | FEEDBACK | SUBSCRIPTIONS | ARCHIVE | SEARCH | TABLE OF CONTENTS |
| Endocrinology | Endocrine Reviews | J. Clin. End. & Metab. |
| Molecular Endocrinology | Recent Prog. Horm. Res. | All Endocrine Journals |
