Multi-Alignment Comparison of Coronavirus Non-Structural Proteins Nsp13- Nsp16 with Ribosomal Proteins and other DNA/RNA Modifying Enzymes Suggested their Roles in the Regulation of Host Protein Synthesis

Chakraborty, A. K.; Bengal, India Technology-West

doi:10.46619/ijcmi.2020.1024

Cited by 10 publications

(5 citation statements)

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“…The ORF1ab generates sixteen functional peptides proteolytically: Nsp1(1-180aa), Nsp2(181-818aa), Nsp3(819-2763aa), Nsp4(2764-3263aa), Nsp5(3264-3569aa), Nsp6(3570-3859aa), Nsp7(3860-3942aa), Nsp8(3943-4140aa), Nsp9(4141-4253aa), Nsp10(4265-4392aa), Nsp11(4393-4400aa), Nsp12(4401-5324aa), Nsp13(5325-5925aa), Nsp14(5926-6462aa), Nsp15(6453-6798aa) and Nsp16(6799-7096aa) (10). The functions of the most sixteen enzymes were reported: Trans-activator (nsp1), RNA topoisomerase (nsp2), two proteases (nsp3 and nsp5), RNA-dependent RNA polymerase (nsp12), RNA helicase and capping methyltransferase (nsp13), nucleases (nsp14 and nsp15) and methyl transferases (nsp16) and accessory proteins (nsp7, nsp8, nsp9 and nsp10) (11)(12)(13)(14)(15)(16)(17)(18). The ORF1ab protein was reported as 7096 − 7092 AAs in different variants.…”

Section: Introductionmentioning

confidence: 99%

Higher Omicron JN.1 Coronavirus Transmission due to Unique 17MPLF Spike Insertion compensating 24LPP, 69HV, 145Y, 211N and 483V deletions in the spike

CHAKRABORTY

2024

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The COVID-19 Spike protein 24LPP, 69HV, 143VYY, 156FR, 212L deletions, 215EPE and 249RWMD insertions were very well characterized. Changes in spike likely select RBD in a favorable 3-D structure to interact with ACE-2 receptor of human cells for coronavirus entry. Our goal is to characterize the newly spreading JN.1 subvariant and related omicron coronaviruses. BLASTP search found a 17MPLF four amino acid insertion in omicron BA.2.86 subvariant and its precedent JN.1 subvariant which had unique L452S (L455 in Wuhan) spike mutation. The JN.1 variant also contained 2375SGF deletion in ORF1ab, 24LPP, 69HV, 145Y, 211N (208N in BA.2) and 483V (480V in BA.2) deletions in the spike, 31ERS deletion in N-protein and 26nt deletion in 3’-UTR (NC_045512.2). Many unique JN.1 spike mutations (242N = H249N, 261D = A268D, 352T = K360T, 400K = R407K, 442H = P449H, 449W = L456W, 474K = N485K, 480K = A488K and 566V = A574V) might be also important. The BLASTN search with insertion oligo found over 3895 JN.1 related sequences in the NCBI Database and were well distributed in America and Europe but more monopartite JN.1 sequences deposited from Europe. Although, JN.1 acquired the 69HV deletion lately but did not generated from BA.4 or BA.5 lineages and it was solely generated from BA.2.86 variant. Swiss-Model detected a wing structure with basic amino acid in the middle of tripartite spike of JN.1 and important ACE-2 first interacting surface amino acids were changed. The small M protein of JN.1 had D3H, A63T and A104V mutations but Swiss Model showed no gross change in 3-D structure. Further, four JN.1 specific ORF1ab polyprotein mutations were detected: T170I mutation in nsp1 as well as D1600N, K1973R mutations in nsp3 protease and R3821K mutation in nsp6. Astonishingly, after a long journey of XBB.1.5.1 to XBB.1.5.100 subvariants spread, a sudden five amino acids deletion (176EGKEG and180EGKQG in Wuhan) in the spike of XBB.1.5.103 subvariant was found. The ORF8 immune-regulatory protein expression was abolished in all XBB.1 subvariants including XBB.1.5.103 and XBB.1.16.23 as expected due to termination codon mutations (AAA = TAA, CAA = TAA, GGA = TGA). But such ORF8 gene mutation (GGA = TGA) was also found in ongoing dominated JD.1.1, FL.1.5.1, HV.1 and EG.5.1.1 subvariants, derived from XBB.1 lineage. The FL.1.5.1 variant also has 82GHV deletion instead 82GHVMV in the nsp1 protein as well as a 27nt deletion (27887 5’-aac gaa cat gaa att tct tgt ttt ctt-3’) in the ORF7a gene. Partial or no expression of nsp1, ORF7a and ORF8 regulatory proteins cause coronavirus more immune deficient and less pathogenic. The spread of JN.1 has sent an alarm among health officials worldwide. It is worthwhile to see if JN.1 coronavirus goes nsp1 or OR7a deletion and ORF8 termination codon mutation with time lowering pathogenicity.

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Section: Introductionmentioning

confidence: 99%

Higher Omicron JN.1 Coronavirus Transmission due to Unique 17MPLF Spike Insertion compensating 24LPP, 69HV, 145Y, 211N and 483V deletions in the spike

CHAKRABORTY

2024

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“…The most unique property of coronavirus is ORf1ab polyprotein (7096aa) that proteolytically is cleaved into sixteen polypeptides including important enzymes like RNA polymerase and proteases. We clearly demonstrated through multi-alignment approach that nsp2 was an RNA topoisomerase that was a target for vaccine and drug development (4) and nsp13 was a mRNA Capping Methyltranaferase (5) and nsp16 was a Uridine 2'-OH RlmE methyltransferase (6). Due to mutation, deletion and insertion coronavirus spread and its death potential was changed time to time generating many Variant Of Concern (VOC) (7,8).…”

Section: Introductionmentioning

confidence: 99%

The G36S, M147I, G265S, T568I, N852S new mutations in the Spike of Omicron JN.1 subvariants: New subvariants JN.1.1 to JN.1.5 nomenclature and oligonucleotides design for JN.1 subvariants detection

CHAKRABORTY

2024

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The JN.1 omicron coronavirus spread is havoc. Recently, few old people were died following JN.1 infections with co-morbidity. We are tracking the new mutation profiles of JN.1, JN.2 and JN.3 coronaviruses in the database to predict the newer mutations in the spike that could be important for virus entry in the lung cells. The SARS-CoV-2 sequences deposited on 12th January, 2024 by Opentrons P and Howard D were analyzed in a pilot scale. The new spike mutations in the JN.1 variants were found as: G36S (accession no. PP115250), M147I (accession no. PP116273), T568I (accession no. PP115301) and N852S (PP106538). The role of such mutations located outside the RBD region of spike was not known but NH2-terminal deletions (24LPP, 69HV, 143VYY) and insertions (17MPLF, 147RWMD) were allowed in different omicron variants. BLASTP search with G36S-peptide produced six identical sequences deposited by four independent US investigators with spike 17MPLF insertion and L452S mutation but new T568I (OR941013) and N852S (PP106538) spike mutations were found. BLASTP search with T568I-peptide gave 25 identical sequences deposited by eight independent US investigators demonstrating T568I mutation in the spike was authentic. Multi-alignment of those spike detected T568I mutation but PP030032 sequence had no 17MPLF insertion and PP051563 sequence had no L452S mutation being pre-JN.1 lineages. Similarly, M147I-peptide produced seven 100% similarity sequences. But the sequences OR082643, OR985352 and OR833719 had no L452S mutation and PP029920 had no 17MPLF insertion being pre-JN.1 variants whereas PP077772, PP016544 and OR976328 appeared authentic JN.1 and G265S spike mutation in PP106544 was new. The new mutations detected in the ORF1ab polyprotein nsp3 protein were: E1559K and T1998A mutations (accession no. PP116246) and S2500F mutation (accession no. PP116233). Thus, characterized JN.1 RefSeq sequences with L452S mutation plus other new mutation in the spike were given JN.1.1 to JN.1.5 subvariants nomenclature and variant specific oligonucleotides were made for their detection after WGS. However, selection with JN.1-S-L452S-oligo and JN.123-S-MPLF-oligo must be done first and then other oligonucleotides will be used to select JN.1.1. to JN.1.5 subvariants. The T568I mutation spread suggested such spike interacted with ACE-2 receptor better similar to N501Y and D614G mutated spike whereas both dominant mutations were also appeared in JN.1.

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“…The nsp6, nsp7, nsp8, nsp9 and nsp10 were small accessory proteins involved in RNA polymerase replication complex (Slanina, H., et al, 2021;Biswal, M et al, 2021). The nsp14 and nsp15 are ribonucleases (Chakraborty, 2020b) and nsp16 is 2'-O methyltransferase (Chakraborty, 2020c) and nsp13 is RNA helicase and may have capping methyl transferase activity (Chakraborty & Chanda, 2021). The ORF3a, ORF6, ORF7a/7b, ORF8 and ORF10 small proteins also coded from 3' end of the genome and have roles in regulating cellular genes (Hachim et In USA, Wuhan-D614G mutant rst peak between March-August, 2020, Alpha (B.1.1.7) 2nd peak with spike 69 HV deletion immune-escape mutant between January-June, 2021 followed by 3rd peak of Delta (B.1.617.2, AY.X) with spike 157 FR deletion mutant between June to December, 2021.…”

Section: Introductionmentioning

confidence: 99%

Highly infectious, less pathogenic and antibody resistant Omicron XBB.1, XBB.1.5 and XBB.1.5.1-XBB.1.5.39 subvariant Coronaviruses do not produce ORF8 protein due to 8th codon GGA=TGA Termination Codon Mutation

Chakraborty

2023

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RNA viruses are very mutation prone. We recently reported SARS-CoV-2 ORF8 gene CAA = TAA and AAA = TAA Termination Codon Mutations in B.1.1.7 variants with no production of viable ORF8 protein. We described here another GGA = TGA termination codon in the 8th codon of ORF8 gene located exclusively in XBB.1 (XBB.1.16 and XBB.1.22) and XBB.1.5 subvariants (XBB.1.5.1 to XBB.1.5.39) but not in XBB.2 variant or Alpha, Beta, Gamma, Delta and Omicron BA.1, BA.2, BA.4, BA.5, BF.7 and BQ.1 subvariants. However, G > T mutation at 27915 also created an alternate ATG codon but the protein product was short due to preceding TAG and TGA termination codons. The originally located following ATG codons were there but in alternate reading frames and ultimately no ORF8 protein was formed in XBB.1.5 subvariants which were spreading highly now over BA.2.75, BA.4.6, BA.5.2.1, BF.7 and BQ.1.1 subvariants. This is a vivid example of three termination codon mutations in the coronavirus ORF8 protein which was implicated as target for many human proteins regulating interferon production, chromosome instability, antibody production, pathogenicity and virus clearance. The 30nt deletion in the 3’-UTR, including 24LPP, and 145Y deletions in Spike protein as well as N-protein 31ERS and ORF1ab polyprotein 3675SGF deletions made XBB.1.5 Omicron coronavirus weak and less pathogenic so that WHO declared coronaviruses as non-emergency pathogen.

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Multi-Alignment Comparison of Coronavirus Non-Structural Proteins Nsp13- Nsp16 with Ribosomal Proteins and other DNA/RNA Modifying Enzymes Suggested their Roles in the Regulation of Host Protein Synthesis

Abstract: Recently, we published Coronavirus Nsp16 protein is a RlmE 2'-O-Ribose Uridine Methyl transferase implicated in 21S rRNA methylation of mitoribosome inhibiting host protein synthesis which might cause the inhibition of oxidation

Cited by 10 publications

References 50 publications

Higher Omicron JN.1 Coronavirus Transmission due to Unique 17MPLF Spike Insertion compensating 24LPP, 69HV, 145Y, 211N and 483V deletions in the spike

Higher Omicron JN.1 Coronavirus Transmission due to Unique 17MPLF Spike Insertion compensating 24LPP, 69HV, 145Y, 211N and 483V deletions in the spike

The G36S, M147I, G265S, T568I, N852S new mutations in the Spike of Omicron JN.1 subvariants: New subvariants JN.1.1 to JN.1.5 nomenclature and oligonucleotides design for JN.1 subvariants detection

Highly infectious, less pathogenic and antibody resistant Omicron XBB.1, XBB.1.5 and XBB.1.5.1-XBB.1.5.39 subvariant Coronaviruses do not produce ORF8 protein due to 8th codon GGA=TGA Termination Codon Mutation

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