Frontiers in Cell and Developmental Biology (Jun 2022)

The N Terminus of Adhesion G Protein–Coupled Receptor GPR126/ADGRG6 as Allosteric Force Integrator

  • Jakob Mitgau,
  • Julius Franke,
  • Camilla Schinner,
  • Gabriele Stephan,
  • Sandra Berndt,
  • Dimitris G. Placantonakis,
  • Hermann Kalwa,
  • Volker Spindler,
  • Caroline Wilde,
  • Ines Liebscher

DOI
https://doi.org/10.3389/fcell.2022.873278
Journal volume & issue
Vol. 10

Abstract

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The adhesion G protein–coupled receptor (aGPCR) GPR126/ADGRG6 plays an important role in several physiological functions, such as myelination or peripheral nerve repair. This renders the receptor an attractive pharmacological target. GPR126 is a mechano-sensor that translates the binding of extracellular matrix (ECM) molecules to its N terminus into a metabotropic intracellular signal. To date, the structural requirements and the character of the forces needed for this ECM-mediated receptor activation are largely unknown. In this study, we provide this information by combining classic second-messenger detection with single-cell atomic force microscopy. We established a monoclonal antibody targeting the N terminus to stimulate GPR126 and compared it to the activation through its known ECM ligands, collagen IV and laminin 211. As each ligand uses a distinct mode of action, the N terminus can be regarded as an allosteric module that can fine-tune receptor activation in a context-specific manner.

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