The Functional Consequences of the Novel Ribosomal Pausing Site in SARS-CoV-2 Spike Glycoprotein RNA

Postnikova, Olga A.; Uppal, Sheetal; Huang, Weiliang; Kane, Maureen A.; Villasmil, Rafael; Rogozin, Igor B.; Poliakov, Eugenia; Redmond, T. Michael

doi:10.3390/ijms22126490

Cited by 13 publications

(25 citation statements)

References 66 publications

(94 reference statements)

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“…Making the S protein resistant to the enzymatic processing is critical for the rVSV assembly and enhances virus production. The novel ribosomal pausing site, CGGCGG (RR) ( 36 ) was not present in our codon-optimized sequence (AGGAGA) or the R682G mutant (GGGAGA).…”

Section: Discussionmentioning

confidence: 99%

Furin and TMPRSS2 Resistant Spike Induces Robust Humoral and Cellular Immunity Against SARS-CoV-2 Lethal Infection

et al. 2022

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An effective COVID-19 vaccine against broad SARS-CoV-2 variants is still an unmet need. In the study, the vesicular stomatitis virus (VSV)-based vector was used to express the SARS-CoV-2 Spike protein to identify better vaccine designs. The replication-competent of the recombinant VSV-spike virus with C-terminal 19 amino acid truncation (SΔ19 Rep) was generated. A single dose of SΔ19 Rep intranasal vaccination is sufficient to induce protective immunity against SARS-CoV-2 infection in hamsters. All the clones isolated from the SΔ19 Rep virus contained R682G mutation located at the Furin cleavage site. An additional S813Y mutation close to the TMPRSS2 cleavage site was identified in some clones. The enzymatic processing of S protein was blocked by these mutations. The vaccination of the R682G-S813Y virus produced a high antibody response against S protein and a robust S protein-specific CD8+ T cell response. The vaccinated animals were protected from the lethal SARS-CoV-2 (delta variant) challenge. The S antigen with resistance to enzymatic processes by Furin and TMPRSS2 will provide better immunogenicity for vaccine design.

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Section: Discussionmentioning

confidence: 99%

Furin and TMPRSS2 Resistant Spike Induces Robust Humoral and Cellular Immunity Against SARS-CoV-2 Lethal Infection

et al. 2022

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“…It has been shown that artificial deletions in the S1/S2 site produce attenuated virus variants [152]. In fact, an insertion in position 681-684 can alter the viral function [153], suggesting that P681 may be under intense selective pressure.…”

Section: P681 Residuementioning

confidence: 99%

The Development of SARS-CoV-2 Variants: The Gene Makes the Disease

Perez-Gomez

2021

JDB

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A novel coronavirus (SARS-CoV-2) emerged towards the end of 2019 that caused a severe respiratory disease in humans called COVID-19. It led to a pandemic with a high rate of morbidity and mortality that is ongoing and threatening humankind. Most of the mutations occurring in SARS-CoV-2 are synonymous or deleterious, but a few of them produce improved viral functions. The first known mutation associated with higher transmissibility, D614G, was detected in early 2020. Since then, the virus has evolved; new mutations have occurred, and many variants have been described. Depending on the genes affected and the location of the mutations, they could provide altered infectivity, transmissibility, or immune escape. To date, mutations that cause variations in the SARS-CoV-2 spike protein have been among the most studied because of the protein’s role in the initial virus–cell contact and because it is the most variable region in the virus genome. Some concerning mutations associated with an impact on viral fitness have been described in the Spike protein, such as D614G, N501Y, E484K, K417N/T, L452R, and P681R, among others. To understand the impact of the infectivity and antigenicity of the virus, the mutation landscape of SARS-CoV-2 has been under constant global scrutiny. The virus variants are defined according to their origin, their genetic profile (some characteristic mutations prevalent in the lineage), and the severity of the disease they produce, which determines the level of concern. If they increase fitness, new variants can outcompete others in the population. The Alpha variant was more transmissible than previous versions and quickly spread globally. The Beta and Gamma variants accumulated mutations that partially escape the immune defenses and affect the effectiveness of vaccines. Nowadays, the Delta variant, identified around March 2021, has spread and displaced the other variants, becoming the most concerning of all lineages that have emerged. The Delta variant has a particular genetic profile, bearing unique mutations, such as T478K in the spike protein and M203R in the nucleocapsid. This review summarizes the current knowledge of the different mutations that have appeared in SARS-CoV-2, mainly on the spike protein. It analyzes their impact on the protein function and, subsequently, on the level of concern of different variants and their importance in the ongoing pandemic.

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“…The slippery sequence (UUUAAAC) and a downstream hairpin-type pseudoknot help express proteins by causing a deformation of the reading frames ( Bakhshandeh et al., 2021 ). Recently, it has been shown that the -PRRA- insertion sequence thought to be a translational pause site may be involved in the occurrence of stop codons ( Postnikova et al., 2021 ). It has also been demonstrated that codon usage bias, which plays an important role in efficient RNA translation, determines programmed ribosomal frameshifting and ribosome pausing ( Postnikova et al., 2021 ).…”

Section: The Genome Structure General Characteristics Of Sars-cov-2mentioning

confidence: 99%

“…Recently, it has been shown that the -PRRA- insertion sequence thought to be a translational pause site may be involved in the occurrence of stop codons ( Postnikova et al., 2021 ). It has also been demonstrated that codon usage bias, which plays an important role in efficient RNA translation, determines programmed ribosomal frameshifting and ribosome pausing ( Postnikova et al., 2021 ). Insertion of the furin site may be associated with the enhanced infectivity of SARS-CoV-2.…”

Section: The Genome Structure General Characteristics Of Sars-cov-2mentioning

confidence: 99%

“…This overlapping translation pausing is also strong evidence for the punctuated mode of evolution ( Gould, 1994 ; Heasley et al., 2021 ). Furthermore, there are two variants (-HRRA- and -LRRA-), whose functional mechanism is not yet clear, that have recently been identified ( Postnikova et al., 2021 ). Some believe that the -HRRA- probably impact infection and pathogenesis of the virus ( Plante et al., 2021 ).…”

Section: The Genome Structure General Characteristics Of Sars-cov-2mentioning

confidence: 99%

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SARS-CoV-2 and Emerging Variants: Unmasking Structure, Function, Infection, and Immune Escape Mechanisms

Jia

Tian

et al. 2022

Front. Cell. Infect. Microbiol.

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As of April 1, 2022, over 468 million COVID-19 cases and over 6 million deaths have been confirmed globally. Unlike the common coronavirus, SARS-CoV-2 has highly contagious and attracted a high level of concern worldwide. Through the analysis of SARS-CoV-2 structural, non-structural, and accessory proteins, we can gain a deeper understanding of structure-function relationships, viral infection mechanisms, and viable strategies for antiviral therapy. Angiotensin-converting enzyme 2 (ACE2) is the first widely acknowledged SARS-CoV-2 receptor, but researches have shown that there are additional co-receptors that can facilitate the entry of SARS-CoV-2 to infect humans. We have performed an in-depth review of published papers, searching for co-receptors or other auxiliary membrane proteins that enhance viral infection, and analyzing pertinent pathogenic mechanisms. The genome, and especially the spike gene, undergoes mutations at an abnormally high frequency during virus replication and/or when it is transmitted from one individual to another. We summarized the main mutant strains currently circulating global, and elaborated the structural feature for increased infectivity and immune evasion of variants. Meanwhile, the principal purpose of the review is to update information on the COVID-19 outbreak. Many countries have novel findings on the early stage of the epidemic, and accruing evidence has rewritten the timeline of the outbreak, triggering new thinking about the origin and spread of COVID-19. It is anticipated that this can provide further insights for future research and global epidemic prevention and control.

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The Functional Consequences of the Novel Ribosomal Pausing Site in SARS-CoV-2 Spike Glycoprotein RNA

Cited by 13 publications

References 66 publications

Furin and TMPRSS2 Resistant Spike Induces Robust Humoral and Cellular Immunity Against SARS-CoV-2 Lethal Infection

Furin and TMPRSS2 Resistant Spike Induces Robust Humoral and Cellular Immunity Against SARS-CoV-2 Lethal Infection

The Development of SARS-CoV-2 Variants: The Gene Makes the Disease

SARS-CoV-2 and Emerging Variants: Unmasking Structure, Function, Infection, and Immune Escape Mechanisms

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