PUBLICATION
Structural basis for adhesion G protein-coupled receptor Gpr126 function
- Authors
- Leon, K., Cunningham, R.L., Riback, J.A., Feldman, E., Li, J., Sosnick, T.R., Zhao, M., Monk, K.R., Araç, D.
- ID
- ZDB-PUB-200112-4
- Date
- 2020
- Source
- Nature communications 11: 194 (Journal)
- Registered Authors
- Monk, Kelly
- Keywords
- none
- MeSH Terms
-
- Alternative Splicing
- Animals
- Binding Sites
- Crystallography, X-Ray
- Drug Design
- Gene Expression Regulation, Developmental
- HEK293 Cells
- Humans
- Models, Molecular
- Protein Conformation
- Protein Domains
- Receptors, G-Protein-Coupled/chemistry*
- Receptors, G-Protein-Coupled/genetics*
- Receptors, G-Protein-Coupled/metabolism*
- Schwann Cells/metabolism
- Zebrafish/genetics
- Zebrafish/metabolism
- Zebrafish Proteins/chemistry*
- Zebrafish Proteins/genetics*
- Zebrafish Proteins/metabolism*
- PubMed
- 31924782 Full text @ Nat. Commun.
Citation
Leon, K., Cunningham, R.L., Riback, J.A., Feldman, E., Li, J., Sosnick, T.R., Zhao, M., Monk, K.R., Araç, D. (2020) Structural basis for adhesion G protein-coupled receptor Gpr126 function. Nature communications. 11:194.
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.
Genes / Markers
Expression
Phenotype
Mutations / Transgenics
Human Disease / Model
Sequence Targeting Reagents
Fish
Orthology
Engineered Foreign Genes
Mapping