title: A tethered agonist within the ectodomain activates the adhesion G protein-coupled receptors GPR126 and GPR133.
abstract: Adhesion G protein-coupled receptors (aGPCRs) comprise the second largest yet least studied class of the GPCR superfamily. aGPCRs are involved in many developmental processes and immune and synaptic functions, but the mode of their signal transduction is unclear. Here, we show that a short peptide sequence (termed the Stachel sequence) within the ectodomain of two aGPCRs (GPR126 and GPR133) functions as a tethered agonist. Upon structural changes within the receptor ectodomain, this intramolecular agonist is exposed to the seven-transmembrane helix domain, which triggers G protein activation. Our studies show high specificity of a given Stachel sequence for its receptor. Finally, the function of Gpr126 is abrogated in zebrafish with a mutated Stachel sequence, and signaling is restored in hypomorphic gpr126 zebrafish mutants upon exogenous Stachel peptide application. These findings illuminate a mode of aGPCR activation and may prompt the development of specific ligands for this currently untargeted GPCR family.
authors.affiliation: Institute of Biochemistry, Medical Faculty, University of Leipzig, 04103 Leipzig, Germany; Novo Nordisk Center for Basic Metabolic Research, Department of Biomedical Sciences, University of Copenhagen, 2200 Copenhagen, Denmark. Electronic address: liebscher@medizin.uni-leipzig.de.
authors.forename: Ines
authors.initials: I
authors.lastname: Liebscher
authors.affiliation: Institute of Biochemistry, Medical Faculty, University of Leipzig, 04103 Leipzig, Germany.
authors.forename: Julia
authors.initials: J
authors.lastname: Schön
authors.affiliation: Department of Developmental Biology, Washington University School of Medicine, St. Louis, MO 63110, USA.
authors.forename: Sarah C
authors.initials: SC
authors.lastname: Petersen
authors.affiliation: Institute of Biochemistry, Medical Faculty, University of Leipzig, 04103 Leipzig, Germany.
authors.forename: Liane
authors.initials: L
authors.lastname: Fischer
authors.affiliation: Institute of Biochemistry, Medical Faculty, University of Leipzig, 04103 Leipzig, Germany; Department of Developmental Biology, Washington University School of Medicine, St. Louis, MO 63110, USA.
authors.forename: Nina
authors.initials: N
authors.lastname: Auerbach
authors.affiliation: Institute of Biochemistry, Medical Faculty, University of Leipzig, 04103 Leipzig, Germany.
authors.forename: Lilian Marie
authors.initials: LM
authors.lastname: Demberg
authors.affiliation: Department of Developmental Biology, Washington University School of Medicine, St. Louis, MO 63110, USA.
authors.forename: Amit
authors.initials: A
authors.lastname: Mogha
authors.affiliation: Institute of Biochemistry, Medical Faculty, University of Leipzig, 04103 Leipzig, Germany.
authors.forename: Maxi
authors.initials: M
authors.lastname: Cöster
authors.affiliation: Institute of Biochemistry, Medical Faculty, University of Leipzig, 04103 Leipzig, Germany.
authors.forename: Kay-Uwe
authors.initials: KU
authors.lastname: Simon
authors.affiliation: Core Unit Peptide Technologies, Medical Faculty, University of Leipzig, 04103 Leipzig, Germany.
authors.forename: Sven
authors.initials: S
authors.lastname: Rothemund
authors.affiliation: Department of Developmental Biology, Washington University School of Medicine, St. Louis, MO 63110, USA.
authors.forename: Kelly R
authors.initials: KR
authors.lastname: Monk
authors.affiliation: Institute of Biochemistry, Medical Faculty, University of Leipzig, 04103 Leipzig, Germany. Electronic address: schoberg@medizin.uni-leipzig.de.
authors.forename: Torsten
authors.initials: T
authors.lastname: Schöneberg
mesh_terms: D000595:Amino Acid Sequence; D000818:Animals; D001665:Binding Sites; D019556:COS Cells; D002522:Chlorocebus aethiops; D006801:Humans; D008969:Molecular Sequence Data; D009842:Oligopeptides / Q000737:chemistry / Q000494:pharmacology*; D011485:Protein Binding; D043562:Receptors, G-Protein-Coupled / Q000819:agonists* / Q000737:chemistry / Q000378:metabolism; D015027:Zebrafish
chemical_list: C547021:ADGRD1 protein, human; C488660:ADGRG6 protein, human; D009842:Oligopeptides; D043562:Receptors, G-Protein-Coupled