SARS-CoV-2 Entry Protein TMPRSS2 and Its Homologue, TMPRSS4 Adopts Structural Fold Similar to Blood Coagulation and Complement Pathway Related Proteins

  1. Vijaykumar Yogesh Muley
  2. Amit Singh
  3. Karl Gruber
  4. Alfredo Varela-Echavarría

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Abstract

The severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) utilizes TMPRSS2 receptor to enter target human cells and subsequently causes coronavirus disease 19 (COVID-19). TMPRSS2 belongs to the type II serine proteases of subfamily TMPRSS, which is characterized by the presence of the serine-protease domain. TMPRSS4 is another TMPRSS member, which has a domain architecture similar to TMPRSS2. TMPRSS2 and TMPRSS4 have been shown to be involved in SARS-CoV-2 infection. However, their normal physiological roles have not been explored in detail. In this study, we analyzed the amino acid sequences and predicted 3D structures of TMPRSS2 and TMPRSS4 to understand their functional aspects at the protein domain level. Our results suggest that these proteins are likely to have common functions based on their conserved domain organization. Furthermore, we show that the predicted 3D structure of their serine protease domain has significant similarity to that of plasminogen which dissolves blood clot, and of other blood coagulation related proteins. Additionally, molecular docking analyses of inhibitors of four blood coagulation and anticoagulation factors show the same high specificity to TMPRSS2 and TMPRSS4 3D structures. Hence, our observations are consistent with the blood coagulopathy observed in COVID-19 patients and their predicted functions based on the sequence and structural analyses offer avenues to understand better and explore therapeutic approaches for this disease.

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    SciScore for 10.1101/2021.04.26.441280: (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: Protein sequences of TMPRSS2 and TMPRSS4 from humans and their mouse orthologs were obtained from the UniProt database (Bateman et al., 2017).
    UniProt
    suggested: (UniProtKB, RRID:SCR_004426)
    Protein domains were identified using the scanProsite tool from the ProSite database (Castro et al., 2006; Sigrist et al., 2009).
    ProSite
    suggested: (PROSITE, RRID:SCR_003457)
    Multiple sequence alignment of human and mouse proteins was constructed using the MAFFT plugin of JalView program, and visualized using the latter (Katoh et al., 2018; Waterhouse et al., 2009).
    MAFFT
    suggested: (MAFFT, RRID:SCR_011811)
    JalView
    suggested: (Jalview, RRID:SCR_006459)
    The predicted structures belonging to this region were then uploaded to the CATH web server to obtain the structural domain hits from available crystal structures (Dawson et al., 2017).
    CATH
    suggested: None
    Then, the 3D protein structure corresponding to this region was compared with the template structures identified by Phyre2 and top 20 structural homologs obtained from HHPred search, together containing 36 unique structures.
    HHPred
    suggested: (HHpred, RRID:SCR_010276)
    Protein 3D structure analysis: We computed the root mean square deviation (RMSD) between the backbone structure of the protease domain alone, the SRCR domain alone and both domains of TMPRSS2 and TMPRSS4 with the above-mentioned 36 PDB structures using the align module in PyMOL, with maximum iteration cycles of 20 and BLOSUM62 as a scoring matrix (Schrödinger, LLC, 2015).
    PyMOL
    suggested: (PyMOL, RRID:SCR_000305)
    The target protein structures were preprocessed to remove the bad contacts using the wizard integrated into Maestro.
    Maestro
    suggested: (Maestro, RRID:SCR_016748)

    Results from OddPub: Thank you for sharing your data.

    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.
    • 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.

    Results from scite Reference Check: We found no unreliable references.

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  2. Version published to 10.1101/2021.04.26.441280 on bioRxiv