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| | <StructureSection load='6e5u' size='340' side='right'caption='[[6e5u]], [[Resolution|resolution]] 3.80Å' scene=''> | | <StructureSection load='6e5u' size='340' side='right'caption='[[6e5u]], [[Resolution|resolution]] 3.80Å' scene=''> |
| | == Structural highlights == | | == Structural highlights == |
| - | <table><tr><td colspan='2'>[[6e5u]] is a 16 chain structure with sequence from [http://en.wikipedia.org/wiki/9infa 9infa] and [http://en.wikipedia.org/wiki/Human Human]. Full crystallographic information is available from [http://oca.weizmann.ac.il/oca-bin/ocashort?id=6E5U OCA]. For a <b>guided tour on the structure components</b> use [http://oca.weizmann.ac.il/oca-docs/fgij/fg.htm?mol=6E5U FirstGlance]. <br> | + | <table><tr><td colspan='2'>[[6e5u]] is a 16 chain structure with sequence from [https://en.wikipedia.org/wiki/Homo_sapiens Homo sapiens] and [https://en.wikipedia.org/wiki/Influenza_A_virus Influenza A virus]. Full crystallographic information is available from [http://oca.weizmann.ac.il/oca-bin/ocashort?id=6E5U OCA]. For a <b>guided tour on the structure components</b> use [https://proteopedia.org/fgij/fg.htm?mol=6E5U FirstGlance]. <br> |
| - | </td></tr><tr id='gene'><td class="sblockLbl"><b>[[Gene|Gene:]]</b></td><td class="sblockDat">NXF1, TAP ([http://www.ncbi.nlm.nih.gov/Taxonomy/Browser/wwwtax.cgi?mode=Info&srchmode=5&id=9606 HUMAN]), NXT1 ([http://www.ncbi.nlm.nih.gov/Taxonomy/Browser/wwwtax.cgi?mode=Info&srchmode=5&id=9606 HUMAN]), NS1, NS ([http://www.ncbi.nlm.nih.gov/Taxonomy/Browser/wwwtax.cgi?mode=Info&srchmode=5&id=11320 9INFA])</td></tr> | + | </td></tr><tr id='method'><td class="sblockLbl"><b>[[Empirical_models|Method:]]</b></td><td class="sblockDat" id="methodDat">X-ray diffraction, [[Resolution|Resolution]] 3.8Å</td></tr> |
| - | <tr id='resources'><td class="sblockLbl"><b>Resources:</b></td><td class="sblockDat"><span class='plainlinks'>[http://oca.weizmann.ac.il/oca-docs/fgij/fg.htm?mol=6e5u FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=6e5u OCA], [http://pdbe.org/6e5u PDBe], [http://www.rcsb.org/pdb/explore.do?structureId=6e5u RCSB], [http://www.ebi.ac.uk/pdbsum/6e5u PDBsum], [http://prosat.h-its.org/prosat/prosatexe?pdbcode=6e5u ProSAT]</span></td></tr> | + | <tr id='resources'><td class="sblockLbl"><b>Resources:</b></td><td class="sblockDat"><span class='plainlinks'>[https://proteopedia.org/fgij/fg.htm?mol=6e5u FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=6e5u OCA], [https://pdbe.org/6e5u PDBe], [https://www.rcsb.org/pdb/explore.do?structureId=6e5u RCSB], [https://www.ebi.ac.uk/pdbsum/6e5u PDBsum], [https://prosat.h-its.org/prosat/prosatexe?pdbcode=6e5u ProSAT]</span></td></tr> |
| | </table> | | </table> |
| | == Function == | | == Function == |
| - | [[http://www.uniprot.org/uniprot/I7CAR2_9INFA I7CAR2_9INFA]] Inhibits post-transcriptional processing of cellular pre-mRNA, by binding and inhibiting two cellular proteins that are required for the 3'-end processing of cellular pre-mRNAs: the 30 kDa cleavage and polyadenylation specificity factor/CPSF4 and the poly(A)-binding protein 2/PABPN1. In turn, unprocessed 3' end pre-mRNAs accumulate in the host nucleus and are no longer exported to the cytoplasm. Cellular protein synthesis is thereby shut off very early after virus infection. Viral protein synthesis is not affected by the inhibition of the cellular 3' end processing machinery because the poly(A) tails of viral mRNAs are produced by the viral polymerase through a stuttering mechanism.[RuleBase:RU362113][SAAS:SAAS01036581] Prevents the establishment of the cellular antiviral state by inhibiting TRIM25-mediated DDX58 ubiquitination, which normally triggers the antiviral transduction signal that leads to the activation of type I IFN genes by transcription factors IRF3 and IRF7. Prevents human EIF2AK2/PKR activation, either by binding double-strand RNA, or by interacting directly with EIF2AK2/PKR. This function may be important at the very beginning of the infection, when NS1 is mainly present in the cytoplasm. Also binds poly(A) and U6 snRNA.[RuleBase:RU362113][SAAS:SAAS01036591] [[http://www.uniprot.org/uniprot/NXF1_HUMAN NXF1_HUMAN]] Involved in the nuclear export of mRNA species bearing retroviral constitutive transport elements (CTE) and in the export of mRNA from the nucleus to the cytoplasm. The NXF1-NXT1 heterodimer is involved in the export of HSP70 mRNA in conjunction with ALYREF/THOC4 and THOC5.<ref>PMID:9660949</ref> <ref>PMID:19165146</ref> [[http://www.uniprot.org/uniprot/NXT1_HUMAN NXT1_HUMAN]] Stimulator of protein export for NES-containing proteins. Also plays a role in the nuclear export of U1 snRNA, tRNA, and mRNA. The NXF1-NXT1 heterodimer is involved in the export of HSP70 mRNA in conjunction with ALYREF/THOC4 and THOC5.<ref>PMID:10567585</ref> <ref>PMID:10848583</ref> <ref>PMID:11259602</ref> <ref>PMID:19165146</ref> | + | [https://www.uniprot.org/uniprot/NXF1_HUMAN NXF1_HUMAN] Involved in the nuclear export of mRNA species bearing retroviral constitutive transport elements (CTE) and in the export of mRNA from the nucleus to the cytoplasm. The NXF1-NXT1 heterodimer is involved in the export of HSP70 mRNA in conjunction with ALYREF/THOC4 and THOC5.<ref>PMID:9660949</ref> <ref>PMID:19165146</ref> |
| | <div style="background-color:#fffaf0;"> | | <div style="background-color:#fffaf0;"> |
| | == Publication Abstract from PubMed == | | == Publication Abstract from PubMed == |
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| | </div> | | </div> |
| | <div class="pdbe-citations 6e5u" style="background-color:#fffaf0;"></div> | | <div class="pdbe-citations 6e5u" style="background-color:#fffaf0;"></div> |
| | + | |
| | + | ==See Also== |
| | + | *[[Nonstructural protein 3D structures|Nonstructural protein 3D structures]] |
| | == References == | | == References == |
| | <references/> | | <references/> |
| | __TOC__ | | __TOC__ |
| | </StructureSection> | | </StructureSection> |
| - | [[Category: Human]] | + | [[Category: Homo sapiens]] |
| | + | [[Category: Influenza A virus]] |
| | [[Category: Large Structures]] | | [[Category: Large Structures]] |
| - | [[Category: Ren, Y]] | + | [[Category: Ren Y]] |
| - | [[Category: Xie, Y]] | + | [[Category: Xie Y]] |
| - | [[Category: Mrna nuclear export]]
| + | |
| - | [[Category: Rna binding protein]]
| + | |
| Structural highlights
Function
NXF1_HUMAN Involved in the nuclear export of mRNA species bearing retroviral constitutive transport elements (CTE) and in the export of mRNA from the nucleus to the cytoplasm. The NXF1-NXT1 heterodimer is involved in the export of HSP70 mRNA in conjunction with ALYREF/THOC4 and THOC5.[1] [2]
Publication Abstract from PubMed
Influenza viruses antagonize key immune defence mechanisms via the virulence factor non-structural protein 1 (NS1). A key mechanism of virulence by NS1 is blocking nuclear export of host messenger RNAs, including those encoding immune factors(1-3); however, the direct cellular target of NS1 and the mechanism of host mRNA export inhibition are not known. Here, we identify the target of NS1 as the mRNA export receptor complex, nuclear RNA export factor 1-nuclear transport factor 2-related export protein 1 (NXF1-NXT1), which is the principal receptor mediating docking and translocation of mRNAs through the nuclear pore complex via interactions with nucleoporins(4,5). We determined the crystal structure of NS1 in complex with NXF1-NXT1 at 3.8 A resolution. The structure reveals that NS1 prevents binding of NXF1-NXT1 to nucleoporins, thereby inhibiting mRNA export through the nuclear pore complex into the cytoplasm for translation. We demonstrate that a mutant influenza virus deficient in binding NXF1-NXT1 does not block host mRNA export and is attenuated. This attenuation is marked by the release of mRNAs encoding immune factors from the nucleus. In sum, our study uncovers the molecular basis of a major nuclear function of influenza NS1 protein that causes potent blockage of host gene expression and contributes to inhibition of host immunity.
Structural basis for influenza virus NS1 protein block of mRNA nuclear export.,Zhang K, Xie Y, Munoz-Moreno R, Wang J, Zhang L, Esparza M, Garcia-Sastre A, Fontoura BMA, Ren Y Nat Microbiol. 2019 Oct;4(10):1671-1679. doi: 10.1038/s41564-019-0482-x. Epub, 2019 Jul 1. PMID:31263181[3]
From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine.
See Also
References
- ↑ Gruter P, Tabernero C, von Kobbe C, Schmitt C, Saavedra C, Bachi A, Wilm M, Felber BK, Izaurralde E. TAP, the human homolog of Mex67p, mediates CTE-dependent RNA export from the nucleus. Mol Cell. 1998 Apr;1(5):649-59. PMID:9660949
- ↑ Katahira J, Inoue H, Hurt E, Yoneda Y. Adaptor Aly and co-adaptor Thoc5 function in the Tap-p15-mediated nuclear export of HSP70 mRNA. EMBO J. 2009 Mar 4;28(5):556-67. doi: 10.1038/emboj.2009.5. Epub 2009 Jan 22. PMID:19165146 doi:10.1038/emboj.2009.5
- ↑ Zhang K, Xie Y, Munoz-Moreno R, Wang J, Zhang L, Esparza M, Garcia-Sastre A, Fontoura BMA, Ren Y. Structural basis for influenza virus NS1 protein block of mRNA nuclear export. Nat Microbiol. 2019 Oct;4(10):1671-1679. doi: 10.1038/s41564-019-0482-x. Epub, 2019 Jul 1. PMID:31263181 doi:http://dx.doi.org/10.1038/s41564-019-0482-x
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