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bioRxiv · 10.1101/805515

Structural basis for adhesion G protein-coupled receptor Gpr126 function

Leon, K.·Cunningham, R.·Riback, J.·Feldman, E.·Li, J.·Sosnick, T.·Zhao, M.·Monk, K.·Arac, D.
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Abstract

Many drugs target the extracellular regions (ECRs) of cell-surface receptors. The large and alternatively-spliced ECRs of adhesion G protein-coupled receptors (aGPCRs) have key functions in diverse biological processes including neurodevelopment, embryogenesis, and tumorigenesis. However, their structures and mechanisms of action remain unclear, hampering drug development. The aGPCR Gpr126/Adgrg6 regulates Schwann cell myelination, ear canal formation, and heart development; and GPR126 mutations cause myelination defects in human. Here, we determine the structure of the complete zebrafish Gpr126 ECR and reveal five domains including a previously-unknown domain. Strikingly, the Gpr126 ECR adopts a closed conformation that is stabilized by an alternatively spliced linker and a conserved calcium-binding site. Alternative splicing regulates ECR conformation and receptor signaling, while mutagenesis of the newly-characterized calcium-binding site abolishes Gpr126 function in vivo. These results demonstrate that Gpr126 ECR utilizes a multi-faceted dynamic approach to regulate receptor function and provide novel insights into ECR-targeted drug design.

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Leon, K., Cunningham, R., Riback, J., Feldman, E., Li, J., Sosnick, T., Zhao, M., Monk, K., Arac, D.. 2019-10-17. Structural basis for adhesion G protein-coupled receptor Gpr126 function. https://doi.org/10.1101/805515

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