A Tethered Agonist within the Ectodomain Activates the Adhesion G Protein-Coupled Receptors GPR126 and GPR133

A Tethered Agonist within the Ectodomain Activates the Adhesion G Protein-Coupled Receptors GPR126 and GPR133

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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 s...

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Main Authors: Ines Liebscher, Julia Schön, Sarah C. Petersen, Liane Fischer, Nina Auerbach, Lilian Marie Demberg, Amit Mogha, Maxi Cöster, Kay-Uwe Simon, Sven Rothemund, Kelly R. Monk, Torsten Schöneberg
Format: Article
Language:English
Published: Elsevier 2014-12-01
Series:Cell Reports
Online Access:http://www.sciencedirect.com/science/article/pii/S221112471401002X
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spelling doaj-3f3477fcd9df49e4bfc98d591c8d863e2020-11-25T00:20:06ZengElsevierCell Reports2211-12472014-12-01962018202610.1016/j.celrep.2014.11.036A Tethered Agonist within the Ectodomain Activates the Adhesion G Protein-Coupled Receptors GPR126 and GPR133Ines Liebscher0Julia Schön1Sarah C. Petersen2Liane Fischer3Nina Auerbach4Lilian Marie Demberg5Amit Mogha6Maxi Cöster7Kay-Uwe Simon8Sven Rothemund9Kelly R. Monk10Torsten Schöneberg11Institute of Biochemistry, Medical Faculty, University of Leipzig, 04103 Leipzig, GermanyInstitute of Biochemistry, Medical Faculty, University of Leipzig, 04103 Leipzig, GermanyDepartment of Developmental Biology, Washington University School of Medicine, St. Louis, MO 63110, USAInstitute of Biochemistry, Medical Faculty, University of Leipzig, 04103 Leipzig, GermanyInstitute of Biochemistry, Medical Faculty, University of Leipzig, 04103 Leipzig, GermanyInstitute of Biochemistry, Medical Faculty, University of Leipzig, 04103 Leipzig, GermanyDepartment of Developmental Biology, Washington University School of Medicine, St. Louis, MO 63110, USAInstitute of Biochemistry, Medical Faculty, University of Leipzig, 04103 Leipzig, GermanyInstitute of Biochemistry, Medical Faculty, University of Leipzig, 04103 Leipzig, GermanyCore Unit Peptide Technologies, Medical Faculty, University of Leipzig, 04103 Leipzig, GermanyDepartment of Developmental Biology, Washington University School of Medicine, St. Louis, MO 63110, USAInstitute of Biochemistry, Medical Faculty, University of Leipzig, 04103 Leipzig, GermanyAdhesion 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.http://www.sciencedirect.com/science/article/pii/S221112471401002X
collection DOAJ
language English
format Article
sources DOAJ
author Ines Liebscher
Julia Schön
Sarah C. Petersen
Liane Fischer
Nina Auerbach
Lilian Marie Demberg
Amit Mogha
Maxi Cöster
Kay-Uwe Simon
Sven Rothemund
Kelly R. Monk
Torsten Schöneberg
spellingShingle Ines Liebscher
Julia Schön
Sarah C. Petersen
Liane Fischer
Nina Auerbach
Lilian Marie Demberg
Amit Mogha
Maxi Cöster
Kay-Uwe Simon
Sven Rothemund
Kelly R. Monk
Torsten Schöneberg
A Tethered Agonist within the Ectodomain Activates the Adhesion G Protein-Coupled Receptors GPR126 and GPR133
Cell Reports
author_facet Ines Liebscher
Julia Schön
Sarah C. Petersen
Liane Fischer
Nina Auerbach
Lilian Marie Demberg
Amit Mogha
Maxi Cöster
Kay-Uwe Simon
Sven Rothemund
Kelly R. Monk
Torsten Schöneberg
author_sort Ines Liebscher
title A Tethered Agonist within the Ectodomain Activates the Adhesion G Protein-Coupled Receptors GPR126 and GPR133
title_short A Tethered Agonist within the Ectodomain Activates the Adhesion G Protein-Coupled Receptors GPR126 and GPR133
title_full A Tethered Agonist within the Ectodomain Activates the Adhesion G Protein-Coupled Receptors GPR126 and GPR133
title_fullStr A Tethered Agonist within the Ectodomain Activates the Adhesion G Protein-Coupled Receptors GPR126 and GPR133
title_full_unstemmed A Tethered Agonist within the Ectodomain Activates the Adhesion G Protein-Coupled Receptors GPR126 and GPR133
title_sort tethered agonist within the ectodomain activates the adhesion g protein-coupled receptors gpr126 and gpr133
publisher Elsevier
series Cell Reports
issn 2211-1247
publishDate 2014-12-01
description 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.
url http://www.sciencedirect.com/science/article/pii/S221112471401002X
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