title: A conserved Asn in TM7 of the thyrotropin receptor is a common requirement for activation by both mutations and its natural agonist.
abstract: The wide spectrum of naturally occurring mutations able to activate the thyrotropin (TSH) receptor provides a useful tool to approach the structure of the active state(s) of the glycoprotein hormone receptors. Here we show that the side-chain of the highly conserved N7.49 (Asn 674) in TM7 is mandatory for activation of the TSH receptor, not only by TSH, but also by a panel of eight natural and two artificial activating mutations. Basal activity levels of the mutants were significantly decreased by suppression of the side-chain of N7.49 (N7.49A double mutants). In addition, comparative effects of the N7.49A substitution on the ten mutants demonstrate that basal activity and agonist- or mutation-stimulated activity might involve different structural changes.
authors.affiliation: IRIBHN, Université Libre de Bruxelles, Campus Erasme, 808 route de Lennik, B-1070, Brussels, Belgium
authors.forename: Sylvie
authors.initials: S
authors.lastname: Claeysen
authors.forename: Cédric
authors.initials: C
authors.lastname: Govaerts
authors.forename: Anne
authors.initials: A
authors.lastname: Lefort
authors.forename: Jacqueline
authors.initials: J
authors.lastname: Van Sande
authors.forename: Sabine
authors.initials: S
authors.lastname: Costagliola
authors.forename: Leonardo
authors.initials: L
authors.lastname: Pardo
authors.forename: Gilbert
authors.initials: G
authors.lastname: Vassart
mesh_terms: D000818:Animals; D001216:Asparagine / Q000235:genetics / Q000378:metabolism*; D001665:Binding Sites; D019556:COS Cells; D002522:Chlorocebus aethiops; D000242:Cyclic AMP / Q000378:metabolism*; D008562:Membrane Glycoproteins / Q000737:chemistry / Q000235:genetics / Q000378:metabolism*; D016297:Mutagenesis, Site-Directed; D011487:Protein Conformation; D011989:Receptors, Thyrotropin / Q000737:chemistry / Q000235:genetics / Q000378:metabolism*; D013972:Thyrotropin / Q000378:metabolism*
chemical_list: D008562:Membrane Glycoproteins; D011989:Receptors, Thyrotropin; D001216:Asparagine; D013972:Thyrotropin; D000242:Cyclic AMP