Crystal structure and nucleotide selectivity of human IFIT5/ISG58

Feng, Feng; Yuan, Lingmin; Wang, Yao E.; Crowley, Catherine; Lv, Zhuo; Li, Jingjing; Liu, Yingfang; Cheng, Genhong; Zeng, Su; Liang, Huanhuan

doi:10.1038/cr.2013.80

Cited by 33 publications

(51 citation statements)

References 9 publications

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“…We built on recent high-resolution structures of human IFIT5 alone and with bound homopolymer 5′-ppp RNA oligonucleotides (16,18,19) by mutagenesis of numerous side chains brought together in a central cavity at the base of a wide cleft created by an atypical TPR Eddy topology of repeat packing (Fig. 1A, the eight tandem α helix TPRs are differentially colored and non-TPR elements are in gray).…”

Section: Ifit5 Sequencementioning

confidence: 99%

“…Studies of IFIT1 report its preferential binding to either 5′ triphosphate (ppp) RNA (15) or cap0 RNA (11,20) or optimally cap0 without guanosine N7-methylation (10). Reports of IFIT5 RNA binding specificity are likewise inconsistent: the protein has been described to bind RNA single-stranded 5′ ends with ppp and monophosphate (p) but not OH (16); ppp but not p, OH, or cap0 (18); ppp but not cap0 (10,20); or single-stranded 5′-p RNA and double-stranded DNA (19).…”

mentioning

confidence: 99%

“…Human IFIT1, IFIT2, and IFIT3 coassemble in cells into poorly characterized multimeric complexes that exclude IFIT5 (15, 16). Recombinant IFIT family proteins range from monomer to multimer, with crystal structures solved for a human IFIT2 homodimer (17), the human IFIT5 monomer (16,18,19), and an N-terminal fragment of human IFIT1 (18). Studies of IFIT1 report its preferential binding to either 5′ triphosphate (ppp) RNA (15) or cap0 RNA (11,20) or optimally cap0 without guanosine N7-methylation (10).…”

mentioning

confidence: 99%

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Broad and adaptable RNA structure recognition by the human interferon-induced tetratricopeptide repeat protein IFIT5

Katibah

Qin

Sidote

et al. 2014

Proc. Natl. Acad. Sci. U.S.A.

118

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Interferon (IFN) responses play key roles in cellular defense against pathogens. Highly expressed IFN-induced proteins with tetratricopeptide repeats (IFITs) are proposed to function as RNA binding proteins, but the RNA binding and discrimination specificities of IFIT proteins remain unclear. Here we show that human IFIT5 has comparable affinity for RNAs with diverse phosphate-containing 5′-ends, excluding the higher eukaryotic mRNA cap. Systematic mutagenesis revealed that sequence substitutions in IFIT5 can alternatively expand or introduce bias in protein binding to RNAs with 5′ monophosphate, triphosphate, cap0 (triphosphate-bridged N7-methylguanosine), or cap1 (cap0 with RNA 2′-O-methylation). We defined the breadth of cellular ligands for IFIT5 by using a thermostable group II intron reverse transcriptase for RNA sequencing. We show that IFIT5 binds precursor and processed tRNAs, as well as other RNA polymerase III transcripts. Our findings establish the RNA recognition specificity of the human innate immune response protein IFIT5.innate immunity | poly-U tailing | protein-RNA interaction | RNA post-transcriptional modifications | tRNA processing I nnate immune responses provide a front-line defense against pathogens. Unlike adaptive immune responses, innate immunity relies on general principles of discrimination between self and pathogen epitopes to trigger pathogen suppression (1). Pathogen-specific features that can provide this discrimination come under evolutionary selection to evade host detection, and in turn, host genes adapt new recognition specificities for pathogen signatures. Among the most clearly established targets of innate immune response recognition are nucleic acid structures not typical of the host cell, such as cytoplasmic double-stranded RNA (2). Detection of a pathogen nucleic acid signature robustly induces type I IFN, which activates a cascade of pathways for producing antiviral effectors (3).Cytoplasmic viral RNA synthesis occurs without cotranscriptional coupling to the 5′-capping machinery, which acts pervasively on host cell nuclear RNA polymerase II transcripts (4, 5). Eukaryotic mRNA 5′ ends are first modified by addition of a cap0 structure containing N7-methylated guanosine, which is joined to the first nucleotide (nt) of RNA by a 5′-5′ triphosphate linkage (7mGpppN). In higher eukaryotes including humans, cap0 is further modified by ribose 2′-O-methylation of at least 1 nt (7mGpppNm, cap1) and sometimes 2 nt (7mGpppNmpNm, cap2). Cap0 addition makes essential contributions to mRNA biogenesis and function in steps of mRNA splicing, translation, and protection from decay (4, 5). In contrast, the biological role of mRNA cap0 modification to cap1 and cap2 structures is largely enigmatic. Some viruses encode enzymes for 7mGpppN formation and, less frequently, the ribose 2′-O-methylation necessary to generate cap1 (6). Recent studies show that virally encoded cap 2′-O-methyltransferase activity can inhibit the innate immune response (7-11).The IFN-induced protein with tetratricop...

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Section: Ifit5 Sequencementioning

confidence: 99%

mentioning

confidence: 99%

mentioning

confidence: 99%

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Broad and adaptable RNA structure recognition by the human interferon-induced tetratricopeptide repeat protein IFIT5

Katibah

Qin

Sidote

et al. 2014

Proc. Natl. Acad. Sci. U.S.A.

118

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“…In humans, IFIT1, IFIT2, IFIT3, and IFIT5 as well as IFIT1B and IFIT1P1, a pseudogene, are expressed, while mouse expresses Ifit1, Ifit2, and Ifit3 along with Ifit1b, Ifit1c and Ifit3b, with the latter three genes largely uncharacterized [13]. Structures of a truncated form of IFIT1 [48], full length IFIT2 [49,50], IFIT5 [48,51], and IFIT5 bound to 5′ppp RNA [48] have been solved (Figure 3), which highlight some of the key properties that allow IFIT proteins to engage ssRNA in a 5′ end dependent manner [48,50]. Unlike RLRs, where the RNA recognition is carried out by multiple domains, different TPRs in IFIT proteins form the binding pocket.…”

Section: Ifit Proteins Differentiate 5′ Of Ssrna Rnamentioning

confidence: 99%

“…Specificity of the 5′ ssRNA has been explored biochemically, which support the notion that 2′O methylation is an important property for binding, recognition, and signaling by IFIT family of proteins [36,52]. Biochemical studies on the basis of the available structural date and molecular modeling lead to the dissection of the RNA binding site [52] and identified nucleotide preferences for some IFIT family proteins such as the AU preference for IFIT2 [49]. …”

Section: Ifit Proteins Differentiate 5′ Of Ssrna Rnamentioning

confidence: 99%

When your cap matters: structural insights into self vs non-self recognition of 5′ RNA by immunomodulatory host proteins

Leung

Amarasinghe

2016

Current Opinion in Structural Biology

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Cytosolic recognition of viral RNA is important for host innate immune responses. Differential recognition of self vs non-self RNA is a considerable challenge as the inability to differentiate may trigger aberrant immune responses. Recent work identified the composition of the RNA 5′, including the 5′ cap and its methylation state, as an important determinant of recognition by the host. Recent studies have advanced our understanding of the modified 5′ RNA recognition and viral antagonism of RNA receptors. Here, we will discuss RIG-I and IFIT proteins as examples of host proteins that detect dsRNA and ssRNA, respectively.

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Diversity and structural‐functional insights of alpha‐solenoid proteins

Arrías,

Osmanli,

Peralta

et al. 2024

Protein Science

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Alpha‐solenoids are a significant and diverse subset of structured tandem repeat proteins (STRPs) that are important in various domains of life. This review examines their structural and functional diversity and highlights their role in critical cellular processes such as signaling, apoptosis, and transcriptional regulation. Alpha‐solenoids can be classified into three geometric folds: low curvature, high curvature, and corkscrew, as well as eight subfolds: ankyrin repeats; Huntingtin, elongation factor 3, protein phosphatase 2A, and target of rapamycin; armadillo repeats; tetratricopeptide repeats; pentatricopeptide repeats; Pumilio repeats; transcription activator‐like; and Sel‐1 and Sel‐1‐like repeats. These subfolds represent distinct protein families with unique structural properties and functions, highlighting the versatility of alpha‐solenoids. The review also discusses their association with disease, highlighting their potential as therapeutic targets and their role in protein design. Advances in state‐of‐the‐art structure prediction methods provide new opportunities and challenges in the functional characterization and classification of this kind of fold, emphasizing the need for continued development of methods for their identification and proper data curation and deposition in the main databases.

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Crystal structure and nucleotide selectivity of human IFIT5/ISG58

Cited by 33 publications

References 9 publications

Broad and adaptable RNA structure recognition by the human interferon-induced tetratricopeptide repeat protein IFIT5

Broad and adaptable RNA structure recognition by the human interferon-induced tetratricopeptide repeat protein IFIT5

When your cap matters: structural insights into self vs non-self recognition of 5′ RNA by immunomodulatory host proteins

Diversity and structural‐functional insights of alpha‐solenoid proteins

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