| Structural highlights
5udi is a 2 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: | |
| Related: | 5udj, 5udk, 5udl |
| Gene: | IFIT1, G10P1, IFI56, IFNAI1, ISG56 (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]
Publication Abstract from PubMed
IFIT1 (IFN-induced protein with tetratricopeptide repeats-1) is an effector of the host innate immune antiviral response that prevents propagation of virus infection by selectively inhibiting translation of viral mRNA. It relies on its ability to compete with the translation initiation factor eIF4F to specifically recognize foreign capped mRNAs, while remaining inactive against host mRNAs marked by ribose 2'-O methylation at the first cap-proximal nucleotide (N1). We report here several crystal structures of RNA-bound human IFIT1, including a 1.6-A complex with capped RNA. IFIT1 forms a water-filled, positively charged RNA-binding tunnel with a separate hydrophobic extension that unexpectedly engages the cap in multiple conformations (syn and anti) giving rise to a relatively plastic and nonspecific mode of binding, in stark contrast to eIF4E. Cap-proximal nucleotides encircled by the tunnel provide affinity to compete with eIF4F while allowing IFIT1 to select against N1 methylated mRNA. Gel-shift binding assays confirm that N1 methylation interferes with IFIT1 binding, but in an RNA-dependent manner, whereas translation assays reveal that N1 methylation alone is not sufficient to prevent mRNA recognition at high IFIT1 concentrations. Structural and functional analysis show that 2'-O methylation at N2, another abundant mRNA modification, is also detrimental for RNA binding, thus revealing a potentially synergistic role for it in self- versus nonself-mRNA discernment. Finally, structure-guided mutational analysis confirms the importance of RNA binding for IFIT1 restriction of a human coronavirus mutant lacking viral N1 methylation. Our structural and biochemical analysis sheds new light on the molecular basis for IFIT1 translational inhibition of capped viral RNA.
Structure of human IFIT1 with capped RNA reveals adaptable mRNA binding and mechanisms for sensing N1 and N2 ribose 2'-O methylations.,Abbas YM, Laudenbach BT, Martinez-Montero S, Cencic R, Habjan M, Pichlmair A, Damha MJ, Pelletier J, Nagar B Proc Natl Acad Sci U S A. 2017 Mar 1. pii: 201612444. doi:, 10.1073/pnas.1612444114. PMID:28251928[5]
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
- ↑ Abbas YM, Laudenbach BT, Martinez-Montero S, Cencic R, Habjan M, Pichlmair A, Damha MJ, Pelletier J, Nagar B. Structure of human IFIT1 with capped RNA reveals adaptable mRNA binding and mechanisms for sensing N1 and N2 ribose 2'-O methylations. Proc Natl Acad Sci U S A. 2017 Mar 1. pii: 201612444. doi:, 10.1073/pnas.1612444114. PMID:28251928 doi:http://dx.doi.org/10.1073/pnas.1612444114
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