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