Molecular Mechanism of RNA Recognition by Zinc-Finger Antiviral Protein

Luo, Xiaohua; Wang, Xinlu; Gao, Yina; Zhu, Jingpeng; Liu, Songqin; Gao, Guangxia; Gao, Pu

doi:10.1016/j.celrep.2019.11.116

Cited by 106 publications

(186 citation statements)

References 23 publications

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“…1B, 3, 6, 7). These observations contrast with predictions from recent structural studies that UpA could not be accommodated within the ZAP binding site as an alternative to CpG (22,23). The possible existence of an entirely separate UpA binding site on ZAP or associated protein was indeed experimentally supported by the observed absence of binding of alternative YpR dinucleotides ( Fig.…”

Section: Alternative Dinucleotides and Cpg Context And Attenuation / contrasting

confidence: 89%

“…RNA transcripts of an E7 viral cDNA with an UpA-high insert in the coding region showed a 1000-fold greater binding to ZAP compared to WT sequences, similar to that observed for a similarly constructed CpG-high viral RNA (1). While co-crystallisation of ZAP with CpG-high ligands (22,23) has recently provided information on the interaction of the zinc finger domains with CpG dinucleotides (and the stoichiometry of bases surrounding the motif), it is conceivable that UpA, as a similarly shaped pyrimidine (Y) -purine (R) dinucleotide might fit into the binding site. This degree of target flexibility would imply that other YpR dinucleotides (UpG and CpA) might be also recognised.…”

Section: Introductionsupporting

confidence: 62%

“…Both conclusions fail to match the experimental findings of the current study. It was further predicted that the identity of -2 base (G) was critical for recognition (22). The ZAP structure study was published after our experimental studies were concluded, although there was, in retrospect, no association between ZAP binding affinity (or replication attenuation) with numbers of GNCG motifs in the various constructs analysed in the current study (data not shown).…”

Section: Alternative Dinucleotides and Cpg Context And Attenuation / mentioning

confidence: 67%

“…These findings suggest that there may be specifically favoured bases around the CpG binding ZAP that promotes binding. It is indeed intriguing, although not commented on in the studies, that both currently published structures of RNA bound to ZAP have U residues 5' to CpG (23) or at both 5' and 3'U sites (22), perhaps selected from other candidates because of their propensity to co-crystallise with ZAP.…”

Section: Alternative Dinucleotides and Cpg Context And Attenuation / mentioning

confidence: 99%

“…From analysis of the topology and size constraints of the CpG binding site and immediate upstream and downstream bases (22,23) It was concluded that there should be no base constraints on the immediate 5' (-1) base to CpG and not to be part of the CpG binding site (23). Similarly, the topology of both 5' (-1) are 3' (+1) bases were considered to not impose any base constraints.…”

Section: Alternative Dinucleotides and Cpg Context And Attenuation / mentioning

confidence: 99%

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Association of zinc-finger antiviral protein (ZAP) binding to viral genomic RNA with attenuation of replication of echovirus 7

Goonawardane

Nguyen

Simmonds

2020

Preprint

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Previous studies have implicated both zinc finger antiviral protein (ZAP) and oligoadenylate synthetase 3 (OAS3)/RNASeL in the attenuation of RNA viruses with elevated CpG and UpA dinucleotides. Mechanisms and inter-relationships between these two pathways were investigated using an echovirus 7 (E7) replicon with compositionally modified sequences inserted into the 3'untranslated region. ZAP and OAS3 immunoprecipitation (IP) assays provided complementary data on dinucleotide composition effects on binding. Elevated frequencies of alternative pyrimidine/purine (CpA and UpG) and reversed (GpC and ApU) dinucleotides showed no attenuating effect nor specific binding to ZAP by IP. However, the bases 3' and 5' to CpG motifs influenced replication and ZAP binding; UCGU enhanced CpG-mediated attenuation and ZAP-binding while A residues shielded CpGs from ZAP recognition. Attenuating effects of elevated frequencies of UpA on replication occurred independently of CpG dinucleotides and bound non-competitively with CpGenriched RNA consistent with a separate recognition site from CpG. Remarkably, immunoprecipitation with OAS3 antibody reproduced the specific binding to CpG-and UpA-enriched RNA sequences. However, OAS3 and ZAP were coimmunoprecipitated in both ZAP and OAS3 IP, and colocalised with E7 and stress granules (SGs) by confocal microscopy analysis of infected cells. ZAP's association with larger cellular complexes may mediate the recruitment of OAS3/RNAseL, KHNYN and other RNA degradation pathways.Importance. We have recently discovered that the OAS3/RNAseL antiviral pathway is essential for restriction of CpG-and UpA-enriched viruses, in addition to the requirement for zinc finger antiviral protein (ZAP). The current study provides evidence for the specific dinucleotide and wider recognition contexts associated with virus recognition and attenuation. It further documents the association of ZAP and OAS3 and association with stress granules and a wider protein interactome that may mediate antiviral effects in different cellular compartments. The study provides a striking re-conceptualisation of the pathways associated with this aspect of antiviral defence.

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Section: Alternative Dinucleotides and Cpg Context And Attenuation / contrasting

confidence: 89%

Section: Introductionsupporting

confidence: 62%

Section: Alternative Dinucleotides and Cpg Context And Attenuation / mentioning

confidence: 67%

Section: Alternative Dinucleotides and Cpg Context And Attenuation / mentioning

confidence: 99%

Section: Alternative Dinucleotides and Cpg Context And Attenuation / mentioning

confidence: 99%

See 3 more Smart Citations

Association of zinc-finger antiviral protein (ZAP) binding to viral genomic RNA with attenuation of replication of echovirus 7

Goonawardane

Nguyen

Simmonds

2020

Preprint

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Codon usage bias of human papillomavirus type 33 and 58: A comprehensive analysis

Tan,

Xie,

Jiang

et al. 2024

J Basic Microbiol

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Cervical cancer is closely linked to specific strains of human papillomavirus (HPV), notably HPV‐33 and HPV‐58, which exhibit a significant prevalence among women in China. Nevertheless, the codon usage bias in HPV‐33 and HPV‐58 is not well comprehended. The objective of this research is to analyze the codon usage patterns HPV‐33 and HPV‐58, pinpoint the primary factors that influence codon preference. The overall preference for codon usage in two HPV genotypes is not significant. Both HPV genotypes exhibit a preference for codons that end with A/U. The GC3 content for HPV‐33 is 25.43% ± 0.35%, and for HPV‐58, it is 29.44% ± 0.57%. Out of the 26 favored codons in HPV‐33 and HPV‐58 (relative synonymous codon usage (RSCU) > 1), 25 conclude with A/U. Principal component analysis (PCA) shows a tight clustering of the entire genome sequences of HPV‐33 and HPV‐58, suggesting a similarity in their RSCU preferences. Moreover, an examination of dinucleotide abundance indicated that translation selection influenced the development of a distinctive dinucleotide usage pattern in HPV‐33 and HPV‐58. Additionally, a combined analysis involving an effective number of codons plot, parity rule 2, and neutrality analysis demonstrated that, for HPV‐33 and HPV‐58, the primary determinant influencing codon usage preference is natural selection. HPV‐33 and HPV‐58 exhibit a restricted set of favored codons in common with humans, potentially mitigating competition for translation resources. Our discoveries could provide valuable perspectives on the evolutionary patterns and codon usage preferences of HPV‐33 and HPV‐58 viruses, contributing to the development and application of relevant HPV subtype vaccines.

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Compositional biases in RNA viruses: Causes, consequences and applications

Gaunt

Digard

2021

WIREs RNA

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If each of the four nucleotides were represented equally in the genomes of viruses and the hosts they infect, each base would occur at a frequency of 25%. However, this is not observed in nature. Similarly, the order of nucleotides is not random (e.g., in the human genome, guanine follows cytosine at a frequency of ~0.0125, or a quarter the number of times predicted by random representation). Codon usage and codon order are also nonrandom. Furthermore, nucleotide and codon biases vary between species. Such biases have various drivers, including cellular proteins that recognize specific patterns in nucleic acids, that once triggered, induce mutations or invoke intrinsic or innate immune responses. In this review we examine the types of compositional biases identified in viral genomes and current understanding of the evolutionary mechanisms underpinning these trends. Finally, we consider the potential for large scale synonymous recoding strategies to engineer RNA virus vaccines, including those with pandemic potential, such as influenza A virus and Severe Acute Respiratory Syndrome Coronavirus Virus 2. This article is categorized under: RNA in Disease and Development > RNA in Disease RNA Evolution and Genomics > Computational Analyses of RNA RNA Interactions with Proteins and Other Molecules > Protein‐RNA Recognition

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Molecular Mechanism of RNA Recognition by Zinc-Finger Antiviral Protein

Abstract: Highlights d Structure of ZAP N-terminal domain in complex with a CGrich single-stranded RNA d CG dinucleotide acts as the essential element in ZAP target sequence d The optimal binding motif of ZAP is C(n 7)G(n)CG d ZAP can bind to multiple sites on an RNA molecule

Cited by 106 publications

References 23 publications

Association of zinc-finger antiviral protein (ZAP) binding to viral genomic RNA with attenuation of replication of echovirus 7

Association of zinc-finger antiviral protein (ZAP) binding to viral genomic RNA with attenuation of replication of echovirus 7

Codon usage bias of human papillomavirus type 33 and 58: A comprehensive analysis

Compositional biases in RNA viruses: Causes, consequences and applications

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