Genetic variants in TMPRSS2 and Structure of SARS-CoV-2 spike glycoprotein and TMPRSS2 complex

  1. Ravikanth Vishnubhotla
  2. Naveen Vankadari
  3. Vijayasarathy Ketavarapu
  4. Ramars Amanchy
  5. Steffie Avanthi
  6. Govardhan Bale
  7. Duvvur Nageshwar Reddy
  8. Mitnala Sasikala

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Abstract

SARS-CoV-2, a highly transmittable pathogen has infected over 3.8 million people around the globe. The spike glycoprotein of SARS-CoV-2 engages host ACE2 for adhesion, TMPRSS2 for activation and entry. With the aid of whole-exome sequencing, we report a variant rs12329760 in TMPRSS2 gene and its mutant V160M, which might impede viral entry. Furthermore, we identified TMPRSS2 cleavage sites in S2 domain of spike glycoprotein and report the structure of TMPRSS2 in complex with spike glycoprotein. We also report the structures of protease inhibitors in complex with TMPRSS2, which could hamper the interaction with spike protein. These findings advance our understanding on the role of TMPRSS2 and in the development of potential therapeutics.

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  1. ScreenIT

    SciScore for 10.1101/2020.06.30.179663: (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
    Functionally relevant variants were identified using Polyphen and SIFT scores.
    Polyphen
    suggested: None
    SIFT
    suggested: (SIFT, RRID:SCR_012813)
    Structural modelling of TMPRSS2 and SARS-CoV-2 spike glycoprotein trimer: To better understand the structure of TMPRSS2, including the position and organization of the catalytic site for substrate processing, we modelled the monomer structure of human TMPRSS2 employing SWISS-MODEL and I-TASSER.
    I-TASSER
    suggested: (I-TASSER, RRID:SCR_014627)
    Ensured the residues occupied Ramachandran favored positions using Coot (www.mrc-imb.cam.uk/).
    Coot
    suggested: (Coot, RRID:SCR_014222)
    The final model of complex structure of activated SARS-CoV-2 spike glycoprotein homotrimer and TMPRSS2 was visualized in PyMol.
    PyMol
    suggested: (PyMOL, RRID:SCR_000305)
    Further jelly body refinement was done in the CCP4 program suite35 and then Coot (www.mrc-imb.cam.uk/) to ensure appropriate docking and no steric hindrance clashes in the side chain residues.
    CCP4
    suggested: (CCP4, RRID:SCR_007255)

    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: We detected the following sentences addressing limitations in the study:
    Limitation of this study is that we have not shown the association of V160M variant with infectivity in COVID-19 patients and instability of the protein is shown by in silico approaches. Further studies are needed in COVID-19 patients to explore the association and functional assays to gain mechanical insights on the role of the variant. As in other human diseases, the incidence, severity, progression and therapeutic response have a genetic predisposition, susceptibility to COVID-19 may also have a predisposition. Although age, sex and comorbidities are shown to associate with varied incidence and severity of the disease, host genetic predisposition has not been explored. This study reports for the first time host factor genetics, molecular structure of TMPRSS2 and its cleavage sites on S2 subunit of spike glycoprotein. It is interesting to note that a significant proportion are variant carriers in India with lesser incidence of COVID-19 as compared to other ethnicities including USA and European countries that have a lower variant carriers with higher incidence. While we report the importance of host genetic factors for the first time, COVID-19 host genetics initiative (https://www.covid19hg.org/) reiterate the need to study the role of human genome in explaining COVID-19 severity and susceptibility.

    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.
    • Thank you for including a funding statement. Authors are encouraged to include this statement when submitting to a journal.
    • No protocol registration statement was detected.

    About SciScore

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  2. Version published to 10.1101/2020.06.30.179663v1 on bioRxiv