Activation of the cAMP pathway by the TSH receptor involves switching of the ectodomain from a tethered inverse agonist to an agonist

Molecular Endocrinology
Virginie Vlaeminck-GuillemS Costagliola

Abstract

Several lines of evidence indicate that constraining intramolecular interactions between transmembrane domains are required to maintain G protein-coupled receptors in an inactive conformation in the absence of agonist. For the glycoprotein hormone receptors, which harbor a long amino-terminal ectodomain responsible for hormone binding, it has been suggested that the ectodomain could contribute to these negative constraints. To test this hypothesis, we expressed at the surface of COS-7 cells mutants of the TSH receptor in which variable portions of the amino-terminal ectodomain are replaced by a 19-residue tag from bovine rhodopsin. Whereas none of the rhodopsin-tagged truncated mutants could be activated by saturating concentrations of TSH, the constructs with the shortest amino-terminal extension displayed increased constitutive activity toward the cAMP pathway, when compared with the wild-type holoreceptor. The shortest truncated construct was strongly activated by the introduction of mutations in transmembrane segment VI (D633A), or in the third intracellular loop (A623I) of the receptor. The magnitude of the stimulation was similar to that observed when the same mutations were introduced in the intact wild-type receptor. On...Continue Reading

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Citations

Jul 14, 2009·Proceedings of the National Academy of Sciences of the United States of America·Susanne NeumannMarvin C Gershengorn
Feb 6, 2010·Proceedings of the National Academy of Sciences of the United States of America·Gilbert Vassart
Apr 29, 2011·The Journal of Biological Chemistry·Gunnar KleinauGerd Krause
Oct 12, 2010·Thyroid : Official Journal of the American Thyroid Association·Eijun NishiharaBasil Rapoport
Jul 18, 2002·The Journal of Clinical Investigation·Terry DaviesRauf Latif
Dec 5, 2002·The Journal of Clinical Investigation·Takao AndoTerry F Davies
Aug 3, 2005·The Journal of Clinical Investigation·Terry F DaviesRauf Latif
Mar 5, 2009·PloS One·Olga ValverdeCatherine Ledent
Jan 5, 2008·European Journal of Pediatrics·Sema AkcurinSabine Costagliola
Apr 3, 2008·FASEB Journal : Official Publication of the Federation of American Societies for Experimental Biology·Gunnar KleinauGerd Krause
Apr 29, 2011·Reviews in Endocrine & Metabolic Disorders·Alfredo Ulloa-AguirreEric Reiter
Dec 5, 2003·Molecular Genetics and Metabolism·D A Chistiakov
Apr 3, 2004·Molecular Genetics and Metabolism·Bjarne Knudsen, Nadir R Farid
Jul 3, 2010·Autoimmunity Reviews·Klaus ZöphelMatthias Schott
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Jul 13, 2018·Minerva ginecologica·Francesco De Pascali, Eric Reiter

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