LxxIxE-like Motif in Spike Protein of SARS-CoV-2 that is Known to Recruit the Host PP2A-B56 Phosphatase Mimics Artepillin C, an Immunomodulator, of Brazilian Green Propolis

  1. Halim Maaroufi

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Abstract

SARS-CoV-2 is highly contagious and can cause acute respiratory distress syndrome (ARDS) and multiple organ failure that are largely attributed to the cytokine storm. The surface coronavirus spike (S) glycoprotein is considered as a key factor in host specificity because it mediates infection by receptor-recognition and membrane fusion. Here, the analysis of SARS-CoV-2 S protein revealed two B56-binding LxxIxE-like motifs in S1 and S2 subunits that could recruit the host protein phosphatase 2A (PP2A). The motif in S1 subunit is absent in SARS-CoV and MERS-CoV. Phosphatases and kinases are major players in the regulation of pro-inflammatory responses during pathogenic infections. Moreover, studies have shown that viruses target PP2A in order to manipulate host’s antiviral responses. Recent researches have indicated that SARS-CoV-2 is involved in sustained host inflammation. Therefore, by controlling acute inflammation, it is possible to eliminate its dangerous effects on the host. Among efforts to fight COVID-19, the interaction between LxxIxE-like motif and the PP2A-B56-binding pocket could be a target for the discovery and/or development of a bioactive ligand inhibitor for therapeutic purposes. Indeed, a small molecule called Artepillin C (ArtC), a main compound in Brazilian honeybee green propolis, mimics the side chains of LxxLxE motif. Importantly, ArtC is known, among other effects, to have anti-inflammatory activity that makes it an excellent candidate for future clinical trials in COVID-19 patients.

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  1. ScreenIT

    SciScore for 10.1101/2020.04.01.020941: (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
    Sequence analysis: To search probable short linear motifs (SLiMs), SARS-CoV-2 spike protein sequence was scanned with the eukaryotic linear motif (ELM) resource (http://elm.eu.org/).
    http://elm.eu.org/
    suggested: (Eukaryotic Linear Motif, RRID:SCR_003085)
    3D modeling and molecular docking: 3D structure of Artepillin C (ArtC) was obtained from PubChem database: https://pubchem.ncbi.nlm.nih.gov/compound/5472440#section=3D-Conformer.
    PubChem
    suggested: (PubChem, RRID:SCR_004284)
    The docking of the two peptides into B56 regulatory subunit of PPA2 (PDBid: 5SWF_A) was performed with the software AutoDock vina
    AutoDock
    suggested: (AutoDock, RRID:SCR_012746)
    The electrostatic potential surface of the B56 subunit was realized with PyMOL software (http://pymol.org/).
    PyMOL
    suggested: (PyMOL, RRID:SCR_000305)
    Phylogeny: To establish the phylogenetic relationships between spike S protein of SARS-CoV-2 and representative betacoronaviruses, amino acid residues sequences were aligned with Clustal omega (Sievers et al., 2011) and a phylogenetic tree was constructed with MrBayes (Huelsenbeck and Ronquist, 2001)
    MrBayes
    suggested: (MrBayes, RRID:SCR_012067)

    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.

    About SciScore

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  2. Version published to 10.1101/2020.04.01.020941v2 on bioRxiv
  3. Version published to 10.1101/2020.04.01.020941v1 on bioRxiv