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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.

SUBMITTER: Liebscher I 

PROVIDER: S-EPMC4277498 | biostudies-literature | 2014 Dec

REPOSITORIES: biostudies-literature

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A tethered agonist within the ectodomain activates the adhesion G protein-coupled receptors GPR126 and GPR133.

Liebscher Ines I   Schön Julia J   Petersen Sarah C SC   Fischer Liane L   Auerbach Nina N   Demberg Lilian Marie LM   Mogha Amit A   Cöster Maxi M   Simon Kay-Uwe KU   Rothemund Sven S   Monk Kelly R KR   Schöneberg Torsten T  

Cell reports 20141218 6

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 intramolecul  ...[more]

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