| Structural highlights
6c6k is a 6 chain structure with sequence from Human. Full crystallographic information is available from OCA. For a guided tour on the structure components use FirstGlance.
| | Ligands: | |
| NonStd Res: | |
| Gene: | IFIT1, G10P1, IFI56, IFNAI1, ISG56 (HUMAN), IFIT3, CIG-49, IFI60, IFIT4, ISG60 (HUMAN) |
| Resources: | FirstGlance, OCA, PDBe, RCSB, PDBsum, ProSAT |
Function
[IFIT1_HUMAN] Interferon-induced antiviral RNA-binding protein that specifically binds single-stranded RNA bearing a 5'-triphosphate group (PPP-RNA), thereby acting as a sensor of viral single-stranded RNAs and inhibiting expression of viral messenger RNAs. Single-stranded PPP-RNAs, which lack 2'-O-methylation of the 5' cap and bear a 5'-triphosphate group instead, are specific from viruses, providing a molecular signature to distinguish between self and non-self mRNAs by the host during viral infection. Directly binds PPP-RNA in a non-sequence-specific manner. Viruses evolved several ways to evade this restriction system such as encoding their own 2'-O-methylase for their mRNAs or by stealing host cap containing the 2'-O-methylation (cap snatching mechanism). Exhibits antiviral activity against several viruses including human papilloma and hepatitis C viruses.[1] [2] [3] [4] [IFIT3_HUMAN] IFN-induced antiviral protein which acts as an inhibitor of cellular as well as viral processes, cell migration, proliferation, signaling, and viral replication. Enhances MAVS-mediated host antiviral responses by serving as an adapter bridging TBK1 to MAVS which leads to the activation of TBK1 and phosphorylation of IRF3 and phosphorylated IRF3 translocates into nucleus to promote antiviral gene transcription. Exihibits an antiproliferative activity via the up-regulation of cell cycle negative regulators CDKN1A/p21 and CDKN1B/p27. Normally, CDKN1B/p27 turnover is regulated by COPS5, which binds CDKN1B/p27 in the nucleus and exports it to the cytoplasm for ubiquitin-dependent degradation. IFIT3 sequesters COPS5 in the cytoplasm, thereby increasing nuclear CDKN1B/p27 protein levels. Upregulates CDKN1A/p21 by downregulating MYC, a repressor of CDKN1A/p21. Can negatively regulate the apoptotic effects of IFIT2.[5] [6] [7] [8] [9]
Publication Abstract from PubMed
Although interferon-induced proteins with tetratricopeptide repeats (IFIT proteins) inhibit infection of many viruses by recognizing their RNA, the regulatory mechanisms involved remain unclear. Here we report a crystal structure of cap 0 (m(7)GpppN) RNA bound to human IFIT1 in complex with the C-terminal domain of human IFIT3. Structural, biochemical, and genetic studies suggest that IFIT3 binding to IFIT1 has dual regulatory functions: (1) extending the half-life of IFIT1 and thereby increasing its steady-state amounts in cells; and (2) allosterically regulating the IFIT1 RNA-binding channel, thereby enhancing the specificity of recognition for cap 0 but not cap 1 (m(7)GpppNm) or 5'-ppp RNA. Mouse Ifit3 lacks this key C-terminal domain and does not bind mouse Ifit1. The IFIT3 interaction with IFIT1 is important for restricting infection of viruses lacking 2'-O methylation in their RNA cap structures. Our experiments establish differences in the regulation of IFIT1 orthologs and define targets for modulation of human IFIT protein activity.
Human IFIT3 Modulates IFIT1 RNA Binding Specificity and Protein Stability.,Johnson B, VanBlargan LA, Xu W, White JP, Shan C, Shi PY, Zhang R, Adhikari J, Gross ML, Leung DW, Diamond MS, Amarasinghe GK Immunity. 2018 Mar 20;48(3):487-499.e5. doi: 10.1016/j.immuni.2018.01.014. Epub, 2018 Mar 8. PMID:29525521[10]
From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine.
References
- ↑ Terenzi F, Saikia P, Sen GC. Interferon-inducible protein, P56, inhibits HPV DNA replication by binding to the viral protein E1. EMBO J. 2008 Dec 17;27(24):3311-21. doi: 10.1038/emboj.2008.241. Epub 2008 Nov, 13. PMID:19008854 doi:http://dx.doi.org/10.1038/emboj.2008.241
- ↑ Li Y, Li C, Xue P, Zhong B, Mao AP, Ran Y, Chen H, Wang YY, Yang F, Shu HB. ISG56 is a negative-feedback regulator of virus-triggered signaling and cellular antiviral response. Proc Natl Acad Sci U S A. 2009 May 12;106(19):7945-50. doi:, 10.1073/pnas.0900818106. Epub 2009 Apr 28. PMID:19416887 doi:http://dx.doi.org/10.1073/pnas.0900818106
- ↑ Raychoudhuri A, Shrivastava S, Steele R, Kim H, Ray R, Ray RB. ISG56 and IFITM1 proteins inhibit hepatitis C virus replication. J Virol. 2011 Dec;85(24):12881-9. doi: 10.1128/JVI.05633-11. Epub 2011 Oct 5. PMID:21976647 doi:http://dx.doi.org/10.1128/JVI.05633-11
- ↑ Abbas YM, Pichlmair A, Gorna MW, Superti-Furga G, Nagar B. Structural basis for viral 5'-PPP-RNA recognition by human IFIT proteins. Nature. 2013 Jan 13. doi: 10.1038/nature11783. PMID:23334420 doi:http://dx.doi.org/10.1038/nature11783
- ↑ Xiao S, Li D, Zhu HQ, Song MG, Pan XR, Jia PM, Peng LL, Dou AX, Chen GQ, Chen SJ, Chen Z, Tong JH. RIG-G as a key mediator of the antiproliferative activity of interferon-related pathways through enhancing p21 and p27 proteins. Proc Natl Acad Sci U S A. 2006 Oct 31;103(44):16448-53. doi:, 10.1073/pnas.0607830103. Epub 2006 Oct 18. PMID:17050680 doi:http://dx.doi.org/10.1073/pnas.0607830103
- ↑ Schmeisser H, Mejido J, Balinsky CA, Morrow AN, Clark CR, Zhao T, Zoon KC. Identification of alpha interferon-induced genes associated with antiviral activity in Daudi cells and characterization of IFIT3 as a novel antiviral gene. J Virol. 2010 Oct;84(20):10671-80. doi: 10.1128/JVI.00818-10. Epub 2010 Aug 4. PMID:20686046 doi:http://dx.doi.org/10.1128/JVI.00818-10
- ↑ Stawowczyk M, Van Scoy S, Kumar KP, Reich NC. The interferon stimulated gene 54 promotes apoptosis. J Biol Chem. 2011 Mar 4;286(9):7257-66. doi: 10.1074/jbc.M110.207068. Epub 2010, Dec 29. PMID:21190939 doi:http://dx.doi.org/10.1074/jbc.M110.207068
- ↑ Pichlmair A, Lassnig C, Eberle CA, Gorna MW, Baumann CL, Burkard TR, Burckstummer T, Stefanovic A, Krieger S, Bennett KL, Rulicke T, Weber F, Colinge J, Muller M, Superti-Furga G. IFIT1 is an antiviral protein that recognizes 5'-triphosphate RNA. Nat Immunol. 2011 Jun 5;12(7):624-30. doi: 10.1038/ni.2048. PMID:21642987 doi:http://dx.doi.org/10.1038/ni.2048
- ↑ Liu XY, Chen W, Wei B, Shan YF, Wang C. IFN-induced TPR protein IFIT3 potentiates antiviral signaling by bridging MAVS and TBK1. J Immunol. 2011 Sep 1;187(5):2559-68. doi: 10.4049/jimmunol.1100963. Epub 2011, Aug 3. PMID:21813773 doi:http://dx.doi.org/10.4049/jimmunol.1100963
- ↑ Johnson B, VanBlargan LA, Xu W, White JP, Shan C, Shi PY, Zhang R, Adhikari J, Gross ML, Leung DW, Diamond MS, Amarasinghe GK. Human IFIT3 Modulates IFIT1 RNA Binding Specificity and Protein Stability. Immunity. 2018 Mar 20;48(3):487-499.e5. doi: 10.1016/j.immuni.2018.01.014. Epub, 2018 Mar 8. PMID:29525521 doi:http://dx.doi.org/10.1016/j.immuni.2018.01.014
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