Variations in Orf3a protein of SARS-CoV-2 alter its structure and function

Azad, Gajendra Kumar; Khan, Parimal Kumar

doi:10.1016/j.bbrep.2021.100933

Cited by 43 publications

(39 citation statements)

References 28 publications

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“…These mutant residues may help the SARS-CoV-2 variants in eliciting a distinct immune response from the wild type SARS-CoV-2. Several previous studies evidently support the findings with similar observations using the immunoinformatic approaches [32-34]. Hence, our study provides some insights in understanding the Nsp13 epitopes which could regulate host immune responses against SARS-CoV-2.…”

Section: Discussionsupporting

confidence: 89%

Identification and characterization of novel mutants of Nsp13 protein among Indian SARS-CoV-2 isolates

Kumari

Kumar

et al. 2021

Preprint

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SARS-CoV-2, the causative agent of COVID-19 has mutated rapidly which enabled them to adapt and evade the immune system of the host. Emerging SARS-CoV-2 variants with crucial mutations pose a global challenge in context of therapeutic drugs and vaccines being developed globally. There are currently no specific therapeutics or vaccines available to combat SARS-CoV-2 devastation. In view of this, the current study aimed to identify and characterize the mutations found in the Nsp13 of SARS-CoV-2 in Indian isolates. Non-structural protein, Nsp13 protein sequences from Indian isolates were analyzed by comparing with the first reported Severe acute respiratory syndrome Corona Virus-2 (SARS-CoV-2) protein sequence from Wuhan, China. Out of 825 Nsp13 protein sequences, a total of 38 mutations were observed among Indian isolates. Our data show that mutations in Nsp13 at various positions (H164Y, A237T, T214I, C309Y, S236I, P419S, V305E, G54S, H290Y, P53S, A308Y, and A308Y) have a significant impact on the protein's stability and flexibility. Also, the impact of Nsp13 mutations on the protein function were predicted based on PROVEAN score that includes 15 mutants as neutral and 23 mutants as deleterious effect. Furthermore, B-cell epitopes contributed by Nsp13 were identified using various predictive immunoinformatic tools. Immunological Parameters of Nsp13 such as antigenicity, allergenicity and toxicity were evaluated to predict the potential B-cell epitopes. The predicted peptide sequences were correlated with the observed mutants. Our predicted data showed that there are seven high rank linear epitopes as well as 18 discontinuous B-cell epitopes based on immunoinformatic tools. Moreover, it was observed that out of total 38 identified mutations among Indian SARS-CoV-2 Nsp13 protein, four mutant residues at position 142 (E142), 245 (H245), 247 (V247) and 419 (P419) are localised in the predicted B cell epitopic region. Altogether, the results of the present in-silico study might help to understand the impact of the identified mutations in Nsp13 protein on its stability, flexibility and function.

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Section: Discussionsupporting

confidence: 89%

Identification and characterization of novel mutants of Nsp13 protein among Indian SARS-CoV-2 isolates

Kumari

Kumar

et al. 2021

Preprint

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“…We underline as close to our p.(Val256Ilefs*3) mutation, the G254R was found to result in decreased intensity of specific epitopes (17). In addition, literature reported as within the ORF3a epitope, corresponding to peptide 4 (249-257), only three mutant residues are present (17). Our deletion is the first reported in this domain and we can speculate that the final effect can be similar to that of the G254R.…”

Section: Discussionsupporting

confidence: 76%

“…Among these mutations, the variant G251V is consistently highly frequent and has been isolated all over the world: very surprisingly, all these variants are absent in our sequenced viral genome. We underline as close to our p.(Val256Ilefs*3) mutation, the G254R was found to result in decreased intensity of specific epitopes (17). In addition, literature reported as within the ORF3a epitope, corresponding to peptide 4 (249-257), only three mutant residues are present (17).…”

Section: Discussionsupporting

confidence: 69%

Case Report: Discovery a Novel SARS-CoV-2 Variant in a Six-Months Long-Term Swab Positive Female Suffering From Non-Hodgkin Lymphoma

et al. 2021

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BackgroundWe report the case of a woman with non-Hodgkin lymphoma who remained positive on the molecular assay for SARS-CoV-2 for six months: she has never experienced a severe form of COVID-19 although in absence of seroconversion.MethodsThe whole SARS-CoV-2 genome analysis was performed by the CleanPlex SARS-CoV-2 Research and Surveillance NGS Panel (PARAGON GENOMICS, Hayward, USA).ResultsWe found twenty-two mutations in SARS-CoV-2 genome and a novel deleterious ORF3a frameshift c.766_769del corresponding to a unique and novel lineage. The region affected by this frameshift variant is reported as being important in determining SARS-CoV-2 immunogenicity. Patient’s immunophenotype showed the absence of B lymphocytes and significantly reduced T-cell count. Only after the treatment with hyperimmune plasma she finally became negative on the swab.ConclusionsOur findings could be helpful in the management of patients with immunodeficiency, particularly when novel variants, potentially altering the virus immune response, are present.

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“…ORF3a is the largest among all accessory proteins encoded by SARS-CoV-2, with 275 aa residues in length, sharing 72,7% protein identity with the SARS-CoV ORF3a ( Figure 1 ) ( 14 , 15 ). Structurally, this protein is a viroporin, an integral membrane protein able to function as an ion channel that may promote virus release ( 16 ) and it is required for maximal replication and virulence ( 17 ). ORF3a protein possess a cysteine-rich domain, a tyrosine-based sorting motif (YXXΦ) and a diacidic EXD motif, all of them involved in the cellular distribution of the cell, internalization of proteins into different subcellular compartments or in pathogenesis and immune evasion ( 18 , 19 ).…”

Section: Accessory Proteins Of Sars-cov-2mentioning

confidence: 99%

SARS-CoV-2 Accessory Proteins in Viral Pathogenesis: Knowns and Unknowns

et al. 2021

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There are still many unanswered questions concerning viral SARS-CoV-2 pathogenesis in COVID-19. Accessory proteins in SARS-CoV-2 consist of eleven viral proteins whose roles during infection are still not completely understood. Here, a review on the current knowledge of SARS-CoV-2 accessory proteins is summarized updating new research that could be critical in understanding SARS-CoV-2 interaction with the host. Some accessory proteins such as ORF3b, ORF6, ORF7a and ORF8 have been shown to be important IFN-I antagonists inducing an impairment in the host immune response. In addition, ORF3a is involved in apoptosis whereas others like ORF9b and ORF9c interact with cellular organelles leading to suppression of the antiviral response in infected cells. However, possible roles of ORF7b and ORF10 are still awaiting to be described. Also, ORF3d has been reassigned. Relevant information on the knowns and the unknowns in these proteins is analyzed, which could be crucial for further understanding of SARS-CoV-2 pathogenesis and to design strategies counteracting their actions evading immune responses in COVID-19.

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Variations in Orf3a protein of SARS-CoV-2 alter its structure and function

Cited by 43 publications

References 28 publications

Identification and characterization of novel mutants of Nsp13 protein among Indian SARS-CoV-2 isolates

Identification and characterization of novel mutants of Nsp13 protein among Indian SARS-CoV-2 isolates

Case Report: Discovery a Novel SARS-CoV-2 Variant in a Six-Months Long-Term Swab Positive Female Suffering From Non-Hodgkin Lymphoma

SARS-CoV-2 Accessory Proteins in Viral Pathogenesis: Knowns and Unknowns

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