Structural insights into the mechanism of RNA recognition by the N-terminal RNA-binding domain of the SARS-CoV-2 nucleocapsid phosphoprotein

Khan, Abbas; Khan, Muhammad Tahir; Saleem, Shoaib; Junaid, Muhammad; Ali, Arif; Ali, Syed Shujait; Khan, Mazhar; Wei, Dong‐Qing

doi:10.1016/j.csbj.2020.08.006

Cited by 85 publications

(91 citation statements)

References 45 publications

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“…S3, Table S3 ) and highlights, as previously reported (16), a group of cellular kinases associated with N protein. The viral nucleocapsid has been shown to be phosphorylated and phosphorylation is suggested to be important for its function (19, 20). This highlights cellular kinase inhibitors as drugs with possible activity against SARS-CoV-2.…”

Section: Resultsmentioning

confidence: 99%

The proximal proteome of 17 SARS-CoV-2 proteins links to disrupted antiviral signaling and host translation

Meyers

Ramanathan

Shanderson

et al. 2021

Preprint

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Viral proteins localize within subcellular compartments to subvert host machinery and 25 promote pathogenesis. To study SARS-CoV-2 biology, we generated an atlas of 2422 26 human proteins vicinal to 17 SARS-CoV-2 viral proteins using proximity proteomics. This 27 identified viral proteins at specific intracellular locations, such as association of accessary 28 proteins with intracellular membranes, and projected SARS-CoV-2 impacts on innate 29 immune signaling, ER-Golgi transport, and protein translation. It identified viral protein 30 adjacency to specific host proteins whose regulatory variants are linked to COVID-19 31 severity, including the TRIM4 interferon signaling regulator which was found proximal to 32 the SARS-CoV-2 M protein. Viral NSP1 protein adjacency to the EIF3 complex was 33 associated with inhibited host protein translation whereas ORF6 localization with MAVS 34 was associated with inhibited RIG-I 2CARD-mediated IFNB1 promoter activation. 35 Quantitative proteomics identified candidate host targets for the NSP5 protease, with 36 specific functional cleavage sequences in host proteins CWC22 and FANCD2. This data 37 resource identifies host factors proximal to viral proteins in living human cells and 38 nominates pathogenic mechanisms employed by SARS-CoV-2.

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Section: Resultsmentioning

confidence: 99%

The proximal proteome of 17 SARS-CoV-2 proteins links to disrupted antiviral signaling and host translation

Meyers

Ramanathan

Shanderson

et al. 2021

Preprint

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“…The N protein is highly abundant in the viruses. Its function involves entering the host cells, binding to the viral RNA genome and forms the ribonucleoprotein core to facilitate its replication and process the virus particle assembly and release 27 . Previous reports showed that the N protein from SARS-CoV and MERS-CoV were highly inflammatory nature to promote the expression of inflammatory cytokines, chemokines, prothrombinase and were able to induce acute lung inflammation in mouse model [28][29][30] .…”

Section: Discussionmentioning

confidence: 99%

Direct activation of endothelial cells by SARS-CoV-2 nucleocapsid protein is blocked by Simvastatin

Qian

Lei

Patel

et al. 2021

Preprint

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Emerging evidence suggests that endothelial activation plays a central role in the pathogenesis of acute respiratory distress syndrome (ARDS) and multi-organ failure in patients with COVID-19. However, the molecular mechanisms underlying endothelial activation in COVID-19 patients remain unclear. In this study, the SARS-CoV-2 viral proteins that potently activate human endothelial cells were screened to elucidate the molecular mechanisms involved with endothelial activation. It was found that nucleocapsid protein (NP) of SARS-CoV-2 significantly activated human endothelial cells through TLR2/NF-κB and MAPK signaling pathways. Moreover, by screening a natural microbial compound library containing 154 natural compounds, simvastatin was identified as a potent inhibitor of NP-induced endothelial activation. Remarkablely, though the protein sequences of N proteins from coronaviruses are highly conserved, only NP from SARS-CoV-2 induced endothelial activation. The NPs from other coronaviruses such as SARS-CoV, MERS-CoV, HUB1-CoV and influenza virus H1N1 did not affect endothelial activation. These findings are well consistent with the results from clinical investigations showing broad endotheliitis and organ injury in severe COVID-19 patients. In conclusion, the study provides insights on SARS-CoV-2-induced vasculopathy and coagulopathy, and suggests that simvastatin, an FDA-approved lipid-lowering drug, may benefit to prevent the pathogenesis and improve the outcome of COVID-19 patients.

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“…The coronavirus N protein is an important viral structural protein, which plays an important role in promoting of genome packaging, RNA chaperoning, intracellular protein transport, DNA degradation, interference in host translation, and restricting host immune responses [ 8 ]. It is reported that coronavirus N protein may help tether the genome to replicase-transcriptase complex (RTC), and package the encapsidated genome into virions by binding nsp3 protein which is also an antagonist of interferon and viral encoded repressor (VSR) of RNA interference (RNAi) that further benefits the viral replication [ 9 ].…”

Section: Introductionmentioning

confidence: 99%

Identification and functional analysis of the SARS-COV-2 nucleocapsid protein

Gao

Liu

et al. 2021

BMC Microbiol

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Background A severe form of pneumonia, named coronavirus disease 2019 (COVID-19) by the World Health Organization is widespread on the whole world. The severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) was proved to be the main agent of COVID-19. In the present study, we conducted an in depth analysis of the SARS-COV-2 nucleocapsid to identify potential targets that may allow identification of therapeutic targets. Methods The SARS-COV-2 N protein subcellular localization and physicochemical property was analyzed by PSORT II Prediction and ProtParam tool. Then SOPMA tool and swiss-model was applied to analyze the structure of N protein. Next, the biological function was explored by mass spectrometry analysis and flow cytometry. At last, its potential phosphorylation sites were analyzed by NetPhos3.1 Server and PROVEAN PROTEIN. Results SARS-COV-2 N protein composed of 419 aa, is a 45.6 kDa positively charged unstable hydrophobic protein. It has 91 and 49% similarity to SARS-CoV and MERS-CoV and is predicted to be predominantly a nuclear protein. It mainly contains random coil (55.13%) of which the tertiary structure was further determined with high reliability (95.76%). Cells transfected with SARS-COV-2 N protein usually show a G1/S phase block company with an increased expression of TUBA1C, TUBB6. At last, our analysis of SARS-COV-2 N protein predicted a total number of 12 phosphorylated sites and 9 potential protein kinases which would significantly affect SARS-COV-2 N protein function. Conclusion In this study, we report the physicochemical properties, subcellular localization, and biological function of SARS-COV-2 N protein. The 12 phosphorylated sites and 9 potential protein kinase sites in SARS-COV-2 N protein may serve as promising targets for drug discovery and development for of a recombinant virus vaccine.

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Structural insights into the mechanism of RNA recognition by the N-terminal RNA-binding domain of the SARS-CoV-2 nucleocapsid phosphoprotein

Abstract: Graphical abstract

Cited by 85 publications

References 45 publications

The proximal proteome of 17 SARS-CoV-2 proteins links to disrupted antiviral signaling and host translation

The proximal proteome of 17 SARS-CoV-2 proteins links to disrupted antiviral signaling and host translation

Direct activation of endothelial cells by SARS-CoV-2 nucleocapsid protein is blocked by Simvastatin

Identification and functional analysis of the SARS-COV-2 nucleocapsid protein

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