title: The Activation Mechanism of Glycoprotein Hormone Receptors with Implications in the Cause and Therapy of Endocrine Diseases.
abstract: Glycoprotein hormones (GPHs) are the main regulators of the pituitary-thyroid and pituitary-gonadal axes. Selective interaction between GPHs and their cognate G protein-coupled receptors ensure specificity in GPH signaling. The mechanisms of how these hormones activate glycoprotein hormone receptors (GPHRs) or how mutations and autoantibodies can alter receptor function were unclear. Based on the hypothesis that GPHRs contain an internal agonist, we systematically screened peptide libraries derived from the ectodomain for agonistic activity on the receptors. We show that a peptide (p10) derived from a conserved sequence in the C-terminal part of the extracellular N terminus can activate all GPHRs in vitro and in GPHR-expressing tissues. Inactivating mutations in this conserved region or in p10 can inhibit activation of the thyroid-stimulating hormone receptor by autoantibodies. Our data suggest an activation mechanism where, upon extracellular ligand binding, this intramolecular agonist isomerizes and induces structural changes in the 7-transmembrane helix domain, triggering G protein activation. This mechanism can explain the pathophysiology of activating autoantibodies and several mutations causing endocrine dysfunctions such as Graves disease and hypo- and hyperthyroidism. Our findings highlight an evolutionarily conserved activation mechanism of GPHRs and will further promote the development of specific ligands useful to treat Graves disease and other dysfunctions of GPHRs.
authors.affiliation: From the Institute of Biochemistry.
authors.forename: Antje
authors.initials: A
authors.lastname: Brüser
authors.affiliation: From the Institute of Biochemistry.
authors.forename: Angela
authors.initials: A
authors.lastname: Schulz
authors.affiliation: Core Unit Peptide Technologies, and.
authors.forename: Sven
authors.initials: S
authors.lastname: Rothemund
authors.affiliation: Institute of Anatomy, Medical Faculty, University of Leipzig, 04103 Leipzig.
authors.forename: Albert
authors.initials: A
authors.lastname: Ricken
authors.affiliation: the Institute of Pharmacology and Toxicology & Bio-Imaging Center/Rudolf Virchow Center, University of Würzburg, 97078 Würzburg, and.
authors.forename: Davide
authors.initials: D
authors.lastname: Calebiro
authors.affiliation: Institute of Experimental Pediatric Endocrinology, Charité-Universitätsmedizin Berlin, 13353 Berlin, Germany.
authors.forename: Gunnar
authors.initials: G
authors.lastname: Kleinau
authors.affiliation: From the Institute of Biochemistry, schoberg@medizin.uni-leipzig.de.
authors.forename: Torsten
authors.initials: T
authors.lastname: Schöneberg
mesh_terms: D000595:Amino Acid Sequence; D000818:Animals; D000906:Antibodies / Q000494:pharmacology; D019556:COS Cells; D002522:Chlorocebus aethiops; D000242:Cyclic AMP / Q000378:metabolism; D004700:Endocrine System Diseases / Q000235:genetics* / Q000628:therapy*; D006023:Glycoproteins / Q000378:metabolism*; D006801:Humans; D008810:Mice, Inbred C57BL; D008958:Models, Molecular; D008969:Molecular Sequence Data; D016296:Mutagenesis / Q000235:genetics; D050505:Mutant Proteins / Q000378:metabolism; D009154:Mutation / Q000235:genetics; D010455:Peptides / Q000737:chemistry / Q000494:pharmacology; D017434:Protein Structure, Tertiary; D011956:Receptors, Cell Surface / Q000819:agonists / Q000378:metabolism*; D040681:Structural Homology, Protein; D013329:Structure-Activity Relationship; D013961:Thyroid Gland / Q000378:metabolism
chemical_list: D000906:Antibodies; D006023:Glycoproteins; D050505:Mutant Proteins; D010455:Peptides; D011956:Receptors, Cell Surface; D000242:Cyclic AMP
keywords: G protein-coupled receptor (GPCR); follicle-stimulating hormone (FSH); hormone receptor; luteinizing hormone; signal transduction; signaling; thyroid; thyroid-stimulating hormone