Multi-Alignment Comparison of Coronavirus Non-Structural Proteins Nsp13-16 with Ribosomal proteins and other DNA/RNA modifying Enzymes Suggested Their Roles in the Regulation of Host Protein Synthesis

2020 ◽  
Author(s):  
ASIT KUMAR CHAKRABORTY
Keyword(s):  
Protein Synthesis ◽  
Ribosomal Proteins ◽  
Dna Methyltransferase ◽  
Atp Synthesis ◽  
Host Protein ◽  
Structural Proteins ◽  
23S Rrna ◽  
Structural Protein ◽  
Viral Protein Synthesis ◽  
Host Protein Synthesis

Recently we proposed that Coronavirus Nsp2 protein is a RNA topoisomerase and Nsp16 is a 2'-O-Ribose Uridine Methyltransferase. BLAST search found that Nsp13 non-structural protein was a 2'-O-Ribose Guanosine Capping Methyltransferase although it has been implicated as RNA helicase. Search with 200 RNA/DNA binding-modifying proteins confirmed Nsp13 protein homology to ribosomal L6 and L9 proteins and Nsp2 protein to L1 protein and Nsp15 protein to S1 and S22 ribosomal proteins. Further, Nsp13 has some homology with Cfr 23S rRNA methyltransferase and RNaseT whereas Nsp15 had close relation to RecA recombinase and Dcm DNA methyltransferase. Similarly, Nsp14 had homology with Cfr 23S rRNA methyltransferase and Nsp16 2’-O-Ribose MTase had some similarity to UvrC exinuclease and RNase. These suggested that Nsp2, Nsp13, Nsp14, Nsp15 and nsp16 non-structural proteins may be recruited easily to mitoribosome making chimera ribosome to methylate the rRNA or change its topology favouring viral protein synthesis and inhibiting host protein synthesis. Such change in host protein synthesis in the mitochondria may cause a inhibition in oxidative phosphorylation and ATP synthesis causing quick coma or heart failure as seen in many Corona-infected patients. Thus, targeting those viral proteins with drugs, antisense, ribozyme and CRISPR-Cas6 may cure Corona-infected patients.

scholarly journals Cleavage of Poly(A)-Binding Protein by Coxsackievirus 2A Protease In Vitro and In Vivo: Another Mechanism for Host Protein Synthesis Shutoff?

1999 ◽  
Vol 73 (1) ◽  
pp. 709-717 ◽  
Author(s):  
Vaishali Kerekatte ◽  
Brett D. Keiper ◽  
Cornel Badorff ◽  
Aili Cai ◽  
Kirk U. Knowlton ◽  
...  
Keyword(s):  
Protein Synthesis ◽  
Translation Initiation ◽  
Viral Protein ◽  
Binding Protein ◽  
Host Protein ◽  
Viral Protein Synthesis ◽  
2A Protease ◽  
Host Protein Synthesis

ABSTRACT Infection of cells by picornaviruses of the rhinovirus, aphthovirus, and enterovirus groups results in the shutoff of host protein synthesis but allows viral protein synthesis to proceed. Although considerable evidence suggests that this shutoff is mediated by the cleavage of eukaryotic translation initiation factor eIF4G by sequence-specific viral proteases (2A protease in the case of coxsackievirus), several experimental observations are at variance with this view. Thus, the cleavage of other cellular proteins could contribute to the shutoff of host protein synthesis and stimulation of viral protein synthesis. Recent evidence indicates that the highly conserved 70-kDa cytoplasmic poly(A)-binding protein (PABP) participates directly in translation initiation. We have now found that PABP is also proteolytically cleaved during coxsackievirus infection of HeLa cells. The cleavage of PABP correlated better over time with the host translational shutoff and onset of viral protein synthesis than did the cleavage of eIF4G. In vitro experiments with purified rabbit PABP and recombinant human PABP as well as in vivo experiments withXenopus oocytes and recombinant Xenopus PABP demonstrate that the cleavage is catalyzed by 2A protease directly. N- and C-terminal sequencing indicates that cleavage occurs uniquely in human PABP at482VANTSTQTM↓GPRPAAAAAA500, separating the four N-terminal RNA recognition motifs (80%) from the C-terminal homodimerization domain (20%). The N-terminal cleavage product of PABP is less efficient than full-length PABP in restoring translation to a PABP-dependent rabbit reticulocyte lysate translation system. These results suggest that the cleavage of PABP may be another mechanism by which picornaviruses alter the rate and spectrum of protein synthesis.

scholarly journals Ribosomal Proteins Homologies and Methylation of Mitoribosome by Corona Virus Nsp9, Nsp10 and Previously Described Nsp13-16 Proteins Suggested Their Roles in the Inhibition of Host Protein Synthesis: Discovery of New Therapeutic Targets against Corona Virus Infections

2020 ◽  
Author(s):  
Asit Kumar Chakraborty
Keyword(s):  
Protein Synthesis ◽  
Ribosomal Protein ◽  
Ribosomal Proteins ◽  
Mitochondrial Protein ◽  
Atp Synthesis ◽  
Host Protein ◽  
Virus Infections ◽  
Corona Virus ◽  
Computer Based ◽  
Novel Drug

Multi-Alignment method coupled with phylogenetic analysis we disclosed the Nsp9 and Nsp10 non-structural proteins of Corona Virus as rRNA RlmH/K methyltransferases with similarities with bin recombinase and int-core integrase fold. Further, Nsp9 has similarities to S8 ribosomal protein and Nap10 has similarity to S10 ribosomal protein. Previously, we showed Nsp13, Nsp14, Nsp15 and Nsp16 are also different types of rRNA RlmE/N and Cfr-like methyltransferases-ribonuclease with RNA helicase domains. Two domains of Nsp13 astonishingly have similarities to ribosomal proteins L6 and L9. Taken together, Nsp9/10 and Nsp13-16 proteins could mimic host ribosome assembly and also could methylate rRNA of mitobibosome preventing mitochondrial protein synthesis and oxidative phosphorylation. Low ATP synthesis causes lowering blood pressure following coma but very ATP concentration (1-10nM) surely induces platelets aggregation through vWA, collagen and GpIIb/IIIa proteins followed by fibrin formation and blood clotting as recently have seen in the lung of many Corona virus infected patients. We have also postulated that two polyproteins itself resemble like 28S and 38S mitoribosome subunits and compete with rRNAs inhibiting the ribosome turnover and new protein synthesis due to their similarities with many ribosomal proteins. Such finding may be valuable in computer-based novel drug design against Corona virus.

scholarly journals Targeting Stem-loop 1 of the SARS-CoV-2 5’UTR to suppress viral translation and Nsp1 evasion

2021 ◽  
Author(s):  
Setu M. Vora ◽  
Pietro Fontana ◽  
Valerie Leger ◽  
Ying Zhang ◽  
Tian-Min Fu ◽  
...  
Keyword(s):  
Protein Synthesis ◽  
Nonstructural Protein ◽  
Host Protein ◽  
Locked Nucleic Acid ◽  
Viral Protein Synthesis ◽  
Stem Loop ◽  
Viral Translation ◽  
Nonstructural Protein 1 ◽  
Host Protein Synthesis

SARS-CoV-2 is a highly pathogenic virus that evades anti-viral immunity by interfering with host protein synthesis, mRNA stability, and protein trafficking. The SARS-CoV-2 nonstructural protein 1 (Nsp1) uses its C-terminal domain to block the mRNA entry channel of the 40S ribosome to inhibit host protein synthesis. However, how SARS-CoV-2 circumvents Nsp1-mediated suppression for viral protein synthesis and if the mechanism can be targeted therapeutically remain unclear. Here we show that N- and C-terminal domains of Nsp1 coordinate to drive a tuned ratio of viral to host translation, likely to maintain a certain level of host fitness while maximizing replication. We reveal that the SL1 region of the SARS-CoV-2 5’ UTR is necessary and sufficient to evade Nsp1-mediated translational suppression. Targeting SL1 with locked nucleic acid antisense oligonucleotides (ASOs) inhibits viral translation and makes SARS-CoV-2 5’ UTR vulnerable to Nsp1 suppression, hindering viral replication in vitro at a nanomolar concentration. Thus, SL1 allows Nsp1 to switch infected cells from host to SARS-CoV-2 translation, presenting a therapeutic target against COVID-19 that is conserved among immune-evasive variants. This unique strategy of unleashing a virus’ own virulence mechanism against itself could force a critical trade off between drug resistance and pathogenicity.

scholarly journals Inhibition of Host Protein Synthesis and Degradation of Cellular mRNAs During Infection by Influenza and Herpes Simplex Virus

1982 ◽  
Vol 2 (12) ◽  
pp. 1644-1648 ◽  
Author(s):  
S. C. Inglis
Keyword(s):  
Protein Synthesis ◽  
Blot Hybridization ◽  
Host Protein ◽  
Cell Protein ◽  
Cellular Genes ◽  
Cellular Mrnas ◽  
The Stability ◽  
Simplex Virus ◽  
Host Protein Synthesis ◽  
Synthesis And Degradation

Cloned DNA copies of two cellular genes were used to monitor, by blot hybridization, the stability of particular cell mRNAs after infection by influenza virus and herpesvirus. The results indicated that the inhibition of host cell protein synthesis that accompanied infection by each virus could be explained by a reduction in the amounts of cellular mRNAs in the cytoplasm, and they suggested that this decrease was due to virus-mediated mRNA degradation.

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