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Title: Structural basis for adhesion G protein-coupled receptor Gpr126 function

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.

Authors:
 [1];  [2];  [1];  [1];  [1];  [1];  [1];  [3]; ORCiD logo [1]
  1. Univ. of Chicago, IL (United States)
  2. Washington Univ. School of Medicine, St. Louis, MO (United States)
  3. Washington Univ. School of Medicine, St. Louis, MO (United States); Oregon Health & Science Univ., Portland, OR (United States)
Publication Date:
Research Org.:
Argonne National Lab. (ANL), Argonne, IL (United States)
Sponsoring Org.:
USDOE Office of Science (SC); National Institutes of Health (NIH); National Science Foundation Graduate Research Fellowship
OSTI Identifier:
1591910
Grant/Contract Number:  
AC02-06CH11357; 9 P41 GM103622-18; R01-GM120322; R01-NS079445; T32GM007183; DGE-1745038
Resource Type:
Accepted Manuscript
Journal Name:
Nature Communications
Additional Journal Information:
Journal Volume: 11; Journal Issue: 1; Journal ID: ISSN 2041-1723
Publisher:
Nature Publishing Group
Country of Publication:
United States
Language:
ENGLISH
Subject:
59 BASIC BIOLOGICAL SCIENCES; alternative splicing; G protein-coupled receptors; peripheral nervous system; X-ray crystallography

Citation Formats

Leon, Katherine, Cunningham, Rebecca L., Riback, Joshua A., Feldman, Ezra, Li, Jingxian, Sosnick, Tobin R., Zhao, Minglei, Monk, Kelly R., and Araç, Demet. Structural basis for adhesion G protein-coupled receptor Gpr126 function. United States: N. p., 2020. Web. doi:10.1038/s41467-019-14040-1.
Leon, Katherine, Cunningham, Rebecca L., Riback, Joshua A., Feldman, Ezra, Li, Jingxian, Sosnick, Tobin R., Zhao, Minglei, Monk, Kelly R., & Araç, Demet. Structural basis for adhesion G protein-coupled receptor Gpr126 function. United States. doi:https://doi.org/10.1038/s41467-019-14040-1
Leon, Katherine, Cunningham, Rebecca L., Riback, Joshua A., Feldman, Ezra, Li, Jingxian, Sosnick, Tobin R., Zhao, Minglei, Monk, Kelly R., and Araç, Demet. Fri . "Structural basis for adhesion G protein-coupled receptor Gpr126 function". United States. doi:https://doi.org/10.1038/s41467-019-14040-1. https://www.osti.gov/servlets/purl/1591910.
@article{osti_1591910,
title = {Structural basis for adhesion G protein-coupled receptor Gpr126 function},
author = {Leon, Katherine and Cunningham, Rebecca L. and Riback, Joshua A. and Feldman, Ezra and Li, Jingxian and Sosnick, Tobin R. and Zhao, Minglei and Monk, Kelly R. and Araç, Demet},
abstractNote = {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.},
doi = {10.1038/s41467-019-14040-1},
journal = {Nature Communications},
number = 1,
volume = 11,
place = {United States},
year = {2020},
month = {1}
}

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