| Structural highlights
Function
[MXRA8_HUMAN] Transmembrane protein which can modulate activity of various signaling pathways, probably via binding to integrin ITGAV:ITGB3 (PubMed:22492581, PubMed:23386276). Mediates heterophilic cell-cell interactions in vitro (By similarity). Inhibits osteoclastogenesis downstream of TNFSF11/RANKL and CSF1, where it may function by attenuating signaling via integrin ITGB3 and MAP kinase p38 (By similarity). Plays a role in cartilage formation where it promotes proliferation and maturation of growth plate chondrocytes (By similarity). Stimulates formation of primary cilia in chondrocytes (By similarity). Enhances expression of genes involved in the hedgehog signaling pathway in chondrocytes, including the hedgehog signaling molecule IHH; may also promote signaling via the PTHLH/PTHrP pathway (By similarity). Plays a role in angiogenesis where it suppresses migration of endothelial cells and also promotes their apoptosis (PubMed:23386276). Inhibits VEGF-induced activation of AKT and p38 MAP kinase in endothelial cells (PubMed:23386276). Also inhibits VTN (vitronectin)-mediated integrin ITGAV:ITGB3 signaling and activation of PTK2/FAK (PubMed:23386276). May play a role in the maturation and maintenance of the blood-brain barrier (By similarity).[UniProtKB:Q9DBV4][1] [2] (Microbial infection) Contributes to arthritogenic alphavirus pathogenesis and acts as a receptor for these viruses.[3]
Publication Abstract from PubMed
Arthritogenic alphaviruses, such as Chikungunya virus (CHIKV), cause severe and debilitating rheumatic diseases worldwide, resulting in severe morbidity and economic costs. Recently, MXRA8 was reported as an entry receptor. Here, we present the crystal structures of the mouse MXRA8, human MXRA8 in complex with the CHIKV E protein, and the cryo-electron microscopy structure of human MXRA8 and CHIKV virus-like particle. MXRA8 has two Ig-like domains with unique structural topologies. This receptor binds in the "canyon" between two protomers of the E spike on the surface of the virion. The atomic details at the interface between the two binding entities reveal that both the two domains and the hinge region of MXRA8 are involved in interaction with CHIKV E1-E2 residues from two protomers. Notably, the stalk region of MXRA8 is critical for CHIKV virus entry. This finding provides important information regarding the development of therapeutic countermeasures against those arthritogenic alphaviruses.
Molecular Basis of Arthritogenic Alphavirus Receptor MXRA8 Binding to Chikungunya Virus Envelope Protein.,Song H, Zhao Z, Chai Y, Jin X, Li C, Yuan F, Liu S, Gao Z, Wang H, Song J, Vazquez L, Zhang Y, Tan S, Morel CM, Yan J, Shi Y, Qi J, Gao F, Gao GF Cell. 2019 Jun 13;177(7):1714-1724.e12. doi: 10.1016/j.cell.2019.04.008. Epub, 2019 May 9. PMID:31080063[4]
From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine.
References
- ↑ Jung YK, Han SW, Kim GW, Jeong JH, Kim HJ, Choi JY. DICAM inhibits osteoclast differentiation through attenuation of the integrin alphaVbeta3 pathway. J Bone Miner Res. 2012 Sep;27(9):2024-34. doi: 10.1002/jbmr.1632. PMID:22492581 doi:http://dx.doi.org/10.1002/jbmr.1632
- ↑ Han SW, Jung YK, Lee EJ, Park HR, Kim GW, Jeong JH, Han MS, Choi JY. DICAM inhibits angiogenesis via suppression of AKT and p38 MAP kinase signalling. Cardiovasc Res. 2013 Apr 1;98(1):73-82. doi: 10.1093/cvr/cvt019. Epub 2013 Feb 4. PMID:23386276 doi:http://dx.doi.org/10.1093/cvr/cvt019
- ↑ Zhang R, Kim AS, Fox JM, Nair S, Basore K, Klimstra WB, Rimkunas R, Fong RH, Lin H, Poddar S, Crowe JE Jr, Doranz BJ, Fremont DH, Diamond MS. Mxra8 is a receptor for multiple arthritogenic alphaviruses. Nature. 2018 May;557(7706):570-574. doi: 10.1038/s41586-018-0121-3. Epub 2018 May, 16. PMID:29769725 doi:http://dx.doi.org/10.1038/s41586-018-0121-3
- ↑ Song H, Zhao Z, Chai Y, Jin X, Li C, Yuan F, Liu S, Gao Z, Wang H, Song J, Vazquez L, Zhang Y, Tan S, Morel CM, Yan J, Shi Y, Qi J, Gao F, Gao GF. Molecular Basis of Arthritogenic Alphavirus Receptor MXRA8 Binding to Chikungunya Virus Envelope Protein. Cell. 2019 Jun 13;177(7):1714-1724.e12. doi: 10.1016/j.cell.2019.04.008. Epub, 2019 May 9. PMID:31080063 doi:http://dx.doi.org/10.1016/j.cell.2019.04.008
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