| Structural highlights
Function
[MXRA8_MOUSE] Transmembrane protein which can modulate activity of various signaling pathways, probably via binding to integrin ITGAV:ITGB3 (PubMed:18366072, PubMed:22492581, PubMed:29702220). Mediates heterophilic cell-cell interactions in vitro (PubMed:18366072). Inhibits osteoclastogenesis downstream of TNFSF11/RANKL and CSF1, where it may function by attenuating signaling via integrin ITGB3 and MAP kinase p38 (PubMed:22492581). Plays a role in cartilage formation where it promotes proliferation and maturation of growth plate chondrocytes (PubMed:29702220). Stimulates formation of primary cilia in chondrocytes (PubMed:29702220). 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 (PubMed:29702220). Plays a role in angiogenesis where it suppresses migration of endothelial cells and also promotes their apoptosis (By similarity). Inhibits VEGF-induced activation of AKT and p38 MAP kinase in endothelial cells (By similarity). Also inhibits VTN (vitronectin)-mediated integrin ITGAV:ITGB3 signaling and activation of PTK2/FAK (By similarity). May play a role in the maturation and maintenance of the blood-brain barrier (PubMed:14603461).[UniProtKB:Q9BRK3][1] [2] [3] [4]
Publication Abstract from PubMed
Mxra8 is a receptor for multiple arthritogenic alphaviruses that cause debilitating acute and chronic musculoskeletal disease in humans. Herein, we present a 2.2 A resolution X-ray crystal structure of Mxra8 and 4 to 5 A resolution cryo-electron microscopy reconstructions of Mxra8 bound to chikungunya (CHIKV) virus-like particles and infectious virus. The Mxra8 ectodomain contains two strand-swapped Ig-like domains oriented in a unique disulfide-linked head-to-head arrangement. Mxra8 binds by wedging into a cleft created by two adjacent CHIKV E2-E1 heterodimers in one trimeric spike and engaging a neighboring spike. Two binding modes are observed with the fully mature VLP, with one Mxra8 binding with unique contacts. Only the high-affinity binding mode was observed in the complex with infectious CHIKV, as viral maturation and E3 occupancy appear to influence receptor binding-site usage. Our studies provide insight into how Mxra8 binds CHIKV and creates a path for developing alphavirus entry inhibitors.
Cryo-EM Structure of Chikungunya Virus in Complex with the Mxra8 Receptor.,Basore K, Kim AS, Nelson CA, Zhang R, Smith BK, Uranga C, Vang L, Cheng M, Gross ML, Smith J, Diamond MS, Fremont DH Cell. 2019 May 6. pii: S0092-8674(19)30392-7. doi: 10.1016/j.cell.2019.04.006. PMID:31080061[5]
From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine.
References
- ↑ Yonezawa T, Ohtsuka A, Yoshitaka T, Hirano S, Nomoto H, Yamamoto K, Ninomiya Y. Limitrin, a novel immunoglobulin superfamily protein localized to glia limitans formed by astrocyte endfeet. Glia. 2003 Dec;44(3):190-204. PMID:14603461 doi:http://dx.doi.org/10.1002/glia.10279
- ↑ Jung YK, Jin JS, Jeong JH, Kim HN, Park NR, Choi JY. DICAM, a novel dual immunoglobulin domain containing cell adhesion molecule interacts with alphavbeta3 integrin. J Cell Physiol. 2008 Sep;216(3):603-14. doi: 10.1002/jcp.21438. PMID:18366072 doi:http://dx.doi.org/10.1002/jcp.21438
- ↑ 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 S, Park HR, Lee EJ, Jang JA, Han MS, Kim GW, Jeong JH, Choi JY, Beier F, Jung YK. Dicam promotes proliferation and maturation of chondrocyte through Indian hedgehog signaling in primary cilia. Osteoarthritis Cartilage. 2018 Jul;26(7):945-953. doi:, 10.1016/j.joca.2018.04.008. Epub 2018 Apr 25. PMID:29702220 doi:http://dx.doi.org/10.1016/j.joca.2018.04.008
- ↑ Basore K, Kim AS, Nelson CA, Zhang R, Smith BK, Uranga C, Vang L, Cheng M, Gross ML, Smith J, Diamond MS, Fremont DH. Cryo-EM Structure of Chikungunya Virus in Complex with the Mxra8 Receptor. Cell. 2019 May 6. pii: S0092-8674(19)30392-7. doi: 10.1016/j.cell.2019.04.006. PMID:31080061 doi:http://dx.doi.org/10.1016/j.cell.2019.04.006
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