| Structural highlights
Function
[AGRG6_DANRE] G-protein coupled receptor which is activated by type IV collagen, a major constituent of the basement membrane. Couples to G(i)-proteins as well as G(s)-proteins (PubMed:25118328). Essential for normal differentiation of promyelinating Schwann cells and for normal myelination of axons (PubMed:19745155). Plays also a role in inner ear development (PubMed:24067352).[UniProtKB:Q86SQ4][1] [2] [3] Plays an important role in heart development (PubMed:24082093). Necessary and sufficient for axon sorting by Schwann cells independently of the ADGRG6-CTF (PubMed:25695270).[4] [5]
Publication Abstract from PubMed
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.
Structural basis for adhesion G protein-coupled receptor Gpr126 function.,Leon K, Cunningham RL, Riback JA, Feldman E, Li J, Sosnick TR, Zhao M, Monk KR, Arac D Nat Commun. 2020 Jan 10;11(1):194. doi: 10.1038/s41467-019-14040-1. PMID:31924782[6]
From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine.
References
- ↑ Monk KR, Naylor SG, Glenn TD, Mercurio S, Perlin JR, Dominguez C, Moens CB, Talbot WS. A G protein-coupled receptor is essential for Schwann cells to initiate myelination. Science. 2009 Sep 11;325(5946):1402-5. doi: 10.1126/science.1173474. PMID:19745155 doi:http://dx.doi.org/10.1126/science.1173474
- ↑ Geng FS, Abbas L, Baxendale S, Holdsworth CJ, Swanson AG, Slanchev K, Hammerschmidt M, Topczewski J, Whitfield TT. Semicircular canal morphogenesis in the zebrafish inner ear requires the function of gpr126 (lauscher), an adhesion class G protein-coupled receptor gene. Development. 2013 Nov;140(21):4362-74. doi: 10.1242/dev.098061. Epub 2013 Sep 25. PMID:24067352 doi:http://dx.doi.org/10.1242/dev.098061
- ↑ Paavola KJ, Sidik H, Zuchero JB, Eckart M, Talbot WS. Type IV collagen is an activating ligand for the adhesion G protein-coupled receptor GPR126. Sci Signal. 2014 Aug 12;7(338):ra76. doi: 10.1126/scisignal.2005347. PMID:25118328 doi:http://dx.doi.org/10.1126/scisignal.2005347
- ↑ Patra C, van Amerongen MJ, Ghosh S, Ricciardi F, Sajjad A, Novoyatleva T, Mogha A, Monk KR, Muhlfeld C, Engel FB. Organ-specific function of adhesion G protein-coupled receptor GPR126 is domain-dependent. Proc Natl Acad Sci U S A. 2013 Oct 15;110(42):16898-903. doi:, 10.1073/pnas.1304837110. Epub 2013 Sep 30. PMID:24082093 doi:http://dx.doi.org/10.1073/pnas.1304837110
- ↑ Petersen SC, Luo R, Liebscher I, Giera S, Jeong SJ, Mogha A, Ghidinelli M, Feltri ML, Schoneberg T, Piao X, Monk KR. The adhesion GPCR GPR126 has distinct, domain-dependent functions in Schwann cell development mediated by interaction with laminin-211. Neuron. 2015 Feb 18;85(4):755-69. doi: 10.1016/j.neuron.2014.12.057. PMID:25695270 doi:http://dx.doi.org/10.1016/j.neuron.2014.12.057
- ↑ Leon K, Cunningham RL, Riback JA, Feldman E, Li J, Sosnick TR, Zhao M, Monk KR, Arac D. Structural basis for adhesion G protein-coupled receptor Gpr126 function. Nat Commun. 2020 Jan 10;11(1):194. doi: 10.1038/s41467-019-14040-1. PMID:31924782 doi:http://dx.doi.org/10.1038/s41467-019-14040-1
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