SARS-CoV-2 Encodes a PPxY Late Domain Motif Known to Enhance Budding and Spread in Enveloped RNA Viruses

  1. Halim Maaroufi

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Abstract

The current COVID-19 ( Co rona vi rus D isease-20 19 ) pandemic is affecting the health and/or socioeconomic welfare of almost everyone in the world. Finding vaccines and therapeutics is therefore urgent, but elucidation of the molecular mechanisms that allow some viruses to cross host species boundaries, becoming a threat to human health, must also be given close attention. Here, analysis of all proteins of SARS-CoV-2 revealed a unique PPxY Late (L) domain motif, 25 PPAY 28 , in a spike (S) protein inside a predicted hot disordered loop subject to phosphorylation and binding. PPxY motifs in enveloped RNA viruses are known to recruit Nedd4 E3 ubiquitin ligases and ultimately the ESCRT complex to enhance virus budding and release, resulting in higher viral loads, hence facilitating new infections. Interestingly, proteins of SARS-CoV-1 do not feature PPxY motifs, which could explain why SARS-CoV-2 is more contagious than SARS-CoV-1. Should an experimental assessment of this hypothesis show that the PPxY motif plays the same role in SARS-CoV-2 as it does in other enveloped RNA viruses, this motif will become a promising target for the development of novel host-oriented antiviral therapeutics for preventing S proteins from recruiting Nedd4 E3 ubiquitin ligase partners.

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    SciScore for 10.1101/2020.04.20.052217: (What is this?)

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

    Table 1: Rigor

    NIH rigor criteria are not applicable to paper type.

    Table 2: Resources

    Software and Algorithms
    SentencesResources
    Sequence analysis: To search probable short linear motifs (SLiMs), SARS-CoV-2 spike protein sequence was scanned using the eukaryotic linear motif (ELM) resource (http://elm.eu.org/).
    http://elm.eu.org/
    suggested: (Eukaryotic Linear Motif, RRID:SCR_003085)
    Phylogeny: Amino acid sequences of different spike (S) proteins, namely those of SARS-CoV-2 (accession: YP_009724390.1), SARS-CoV-1 (P59594.1), bat_coronavirus_RaTG13 (QHR63300.2), pangolin_PCoV_GX-P5L (QIA48632.1), pangolin_PCoV_GX-P1E (QIA48623.1), bat_CoVZC45_CoV (AVP78031.1) and bat_Rs4874_CoV (ATO98205.1), were aligned using the T-coffee software (Rius et al., 2011).
    T-coffee
    suggested: (T-Coffee, RRID:SCR_011818)
    The phylogenetic tree was constructed using MrBayes (Huelsenbeck and Ronquist, 2001) with the following parameters: Likelihood model (Number of substitution types: 6(GTR); Substitution model: Poisson; Rates variation across sites: Invariable + gamma); Markov Chain Monte Carlo parameters (number of generations: 100 000; Sample a tree every: 1000 generations) and Discard first 500 trees sampled (burnin).
    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.

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  2. Version published to 10.1101/2020.04.20.052217 on bioRxiv