SARS-CoV-2 ORF8 can fold into human factor 1 catalytic domain binding site on complement C3b: Predict functional mimicry

  1. Jasdeep Singh
  2. Sudeshna Kar
  3. Seyed Ehtesham Hasnain
  4. Surajit Ganguly

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Abstract

Pathogens are often known to use host factor mimicry to take evolutionary advantage. As the function of the non-structural ORF8 protein of SARS-CoV-2 in the context of host-pathogen relationship is still obscure, we investigated its role in host factor mimicry using computational protein modelling techniques. Modest sequence similarity of ORF8 of SARS-CoV-2 with the substrate binding site within the C-terminus serine-protease catalytic domain of human complement factor 1 (F1; PDB ID: 2XRC), prompted us to verify their resemblance at the structural level. The modelled ORF8 protein was found to superimpose on the F1 fragment. Further, protein-protein interaction simulation confirmed ORF8 binding to C3b, an endogenous substrate of F1, via F1-interacting region on C3b. Docking results suggest ORF8 to occupy the binding groove adjacent to the conserved “arginine-serine” (RS) F1-mediated cleavage sites on C3b. Comparative H-bond interaction dynamics indicated ORF8/C3b binding to be of higher affinity than the F1/C3b interaction. Hence, ORF8 is predicted to inhibit C3b proteolysis by competing with F1 for C3b binding using molecular mimicry with a possibility of triggering unregulated complement activation. This could offer a mechanistic premise for the unrestrained complement activation observed in large number of SARS-CoV-2 infected patients.

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  1. Version published to 10.1101/2020.06.08.107011v2 on bioRxiv
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    SciScore for 10.1101/2020.06.08.107011: (What is this?)

    Please note, not all rigor criteria are appropriate for all manuscripts.

    Table 1: Rigor

    Institutional Review Board Statementnot detected.
    Randomizationnot detected.
    Blindingnot detected.
    Power Analysisnot detected.
    Sex as a biological variablenot detected.

    Table 2: Resources

    Software and Algorithms
    SentencesResources
    S1) was performed using I-TASSER (Iterative Threading ASSEmbly Refinement) with human complement factor 1 (F1; PDB id: 2xrc) as template.
    I-TASSER
    suggested: (I-TASSER, RRID:SCR_014627)
    Without assigning any prior binding site (unbiased), protein-protein dockings were performed employing Patchdock using clustering RMSD of 4.0 and subsequently top 20 resulting solutions were refined using Firedock (26 - 30).
    Patchdock
    suggested: (PatchDock, RRID:SCR_017589)
    Interaction analysis was carried out using PDBPisa (https://www.ebi.ac.uk/pdbe/pisa/).
    https://www.ebi.ac.uk/pdbe/pisa/
    suggested: (PISA, RRID:SCR_015749)
    Images were constructed using PyMol while data was analysed using standard gromacs tools.
    PyMol
    suggested: (PyMOL, RRID:SCR_000305)

    Results from OddPub: We did not detect open data. We also did not detect open code. Researchers are encouraged to share open data when possible (see Nature blog).

    Results from LimitationRecognizer: An explicit section about the limitations of the techniques employed in this study was not found. We encourage authors to address study limitations.

    Results from TrialIdentifier: No clinical trial numbers were referenced.

    Results from Barzooka: We did not find any issues relating to the usage of bar graphs.

    Results from JetFighter: We did not find any issues relating to colormaps.

    Results from rtransparent:
    • Thank you for including a conflict of interest statement. Authors are encouraged to include this statement when submitting to a journal.
    • No funding statement was detected.
    • No protocol registration statement was detected.

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  3. Version published to 10.1101/2020.06.08.107011v1 on bioRxiv