Structural basis for adhesion G protein-coupled receptor Gpr126 function

Katherine Leon, Rebecca L. Cunningham, Joshua A. Riback, Ezra Feldman, Jingxian Li, Tobin R. Sosnick, Minglei Zhao, Kelly R. Monk and Demet Araç ()
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Katherine Leon: The University of Chicago
Rebecca L. Cunningham: Washington University School of Medicine
Joshua A. Riback: The University of Chicago
Ezra Feldman: The University of Chicago
Jingxian Li: The University of Chicago
Tobin R. Sosnick: The University of Chicago
Minglei Zhao: The University of Chicago
Kelly R. Monk: Washington University School of Medicine
Demet Araç: The University of Chicago

Nature Communications, 2020, vol. 11, issue 1, 1-14

Abstract: 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 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 relevant insights for ECR-targeted drug design.

Date: 2020
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DOI: 10.1038/s41467-019-14040-1

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