6ort | pdb_00006ort
Crystal Structure of Bos taurus Mxra8 Ectodomain
Structural highlights
FunctionMXRA8_BOVIN Transmembrane protein which can modulate activity of various signaling pathways, probably via binding to integrin ITGAV:ITGB3. Mediates heterophilic cell-cell interactions in vitro. Inhibits osteoclastogenesis downstream of TNFSF11/RANKL and CSF1, where it may function by attenuating signaling via integrin ITGB3 and MAP kinase p38. Plays a role in cartilage formation where it promotes proliferation and maturation of growth plate chondrocytes. Stimulates formation of primary cilia in chondrocytes. 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. Plays a role in angiogenesis where it suppresses migration of endothelial cells and also promotes their apoptosis. Inhibits VEGF-induced activation of AKT and p38 MAP kinase in endothelial cells. Also inhibits VTN (vitronectin)-mediated integrin ITGAV:ITGB3 signaling and activation of PTK2/FAK. May play a role in the maturation and maintenance of the blood-brain barrier.[UniProtKB:Q9BRK3][UniProtKB:Q9DBV4] Publication Abstract from PubMedAlphaviruses are emerging, mosquito-transmitted RNA viruses with poorly understood cellular tropism and species selectivity. Mxra8 is a receptor for multiple alphaviruses including chikungunya virus (CHIKV). We discovered that while expression of mouse, rat, chimpanzee, dog, horse, goat, sheep, and human Mxra8 enables alphavirus infection in cell culture, cattle Mxra8 does not. Cattle Mxra8 encodes a 15-amino acid insertion in its ectodomain that prevents Mxra8 binding to CHIKV. Identical insertions are present in zebu, yak, and the extinct auroch. As other Bovinae lineages contain related Mxra8 sequences, this insertion likely occurred at least 5 million years ago. Removing the Mxra8 insertion in Bovinae enhances alphavirus binding and infection, while introducing the insertion into mouse Mxra8 blocks CHIKV binding, prevents infection by multiple alphaviruses in cells, and mitigates CHIKV-induced pathogenesis in mice. Our studies on how this insertion provides resistance to CHIKV infection could facilitate countermeasures that disrupt Mxra8 interactions with alphaviruses. An Evolutionary Insertion in the Mxra8 Receptor-Binding Site Confers Resistance to Alphavirus Infection and Pathogenesis.,Kim AS, Zimmerman O, Fox JM, Nelson CA, Basore K, Zhang R, Durnell L, Desai C, Bullock C, Deem SL, Oppenheimer J, Shapiro B, Wang T, Cherry S, Coyne CB, Handley SA, Landis MJ, Fremont DH, Diamond MS Cell Host Microbe. 2020 Feb 18. pii: S1931-3128(20)30047-0. doi:, 10.1016/j.chom.2020.01.008. PMID:32075743[1] From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine. References
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