High affinity binding of SARS-CoV-2 spike protein enhances ACE2 carboxypeptidase activity

  1. Jinghua Lu
  2. Peter D. Sun

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Abstract

A novel coronavirus (SARS-CoV-2) has emerged to a global pandemic and caused significant damages to public health. Human angiotensin-converting enzyme 2(ACE2) was identified as the entry receptor for SARS-CoV-2. As a carboxypeptidase, ACE2 cleaves many biological substrates besides Ang II to control vasodilatation and permeability. Given the nanomolar high affinity between ACE2 and SARS-CoV-2 spike protein, we wonder how this interaction would affect the enzymatic activity of ACE2. Surprisingly, SARS-CoV-2 trimeric spike protein increased ACE2 proteolytic activity ~3-10 fold when fluorogenic caspase-1 substrate and Bradykinin-analog peptides were used to characterize ACE2 activity. In addition, the enhancement was mediated by ACE2 binding of RBD domain of SARS-CoV-2 spike. These results highlighted the altered activity of ACE2 during SARS-CoV-2 infection and would shed new lights on the pathogenesis of COVID-19 and its complications for better treatments.

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  1. ScreenIT

    SciScore for 10.1101/2020.07.01.182659: (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
    Initial velocities were plotted versus substrate concentration and fit to the Mechaelis-Menten equation v=Vmax[S]/(Km +[S]) using GraphPad Prism software.
    GraphPad Prism
    suggested: (GraphPad Prism, RRID:SCR_002798)

    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:
    However, a limitation of our study is that we could not systemically measure the levels of various ACE2 substrates and their cleaved products in COVID-19 patients currently, but we would propose that the ratios between vasodilators and vasoconstrictors would change during SARS-CoV-2 infection due to the high affinity interaction between ACE2 and SARS-CoV-2 spike protein and subsequently altered ACE2 enzymatic activity and substrate selectivity. Compared to previous outbreaks of SARS-CoV and MERS, SARS-CoV-2 is more contagious and clinical symptoms of COVID-19 are more variable4. In addition to the accumulation of fluid in the lung, a considerable fraction of critically ill COVID-19 patients developed deep venous thrombosis or pulmonary embolism5. These clinical observations share a common prognostic feature that pointed to the cardiovascular system. Vasodilation, vasoconstriction, and permeability are the essential components of the cardiovascular system, which are regulated by the crosstalk of many hormones and biological active peptides. Among them, renin-angiotensin system and kinin-kellikrein system have major effects upon the cardiovascular systems14, 17. Importantly, ACE2 catalyzes the conversion of these regulatory peptides in these systems to maintain the homeostatic state. Among the biological active substrates, ACE2 cleaves Ang II (DRVYIHP↓F), Apelin-13(QRPRLSHKGPMP↓F), and dynorphin A 1-13(YGGFLRRIRPKL↓K) with high proteolytic efficiency (Km <10uM and kcat/Km >1×10...

    Results from TrialIdentifier: No clinical trial numbers were referenced.

    Results from Barzooka: We found bar graphs of continuous data. We recommend replacing bar graphs with more informative graphics, as many different datasets can lead to the same bar graph. The actual data may suggest different conclusions from the summary statistics. For more information, please see Weissgerber et al (2015).

    Results from JetFighter: Please consider improving the rainbow (“jet”) colormap(s) used on pages 26 and 22. At least one figure is not accessible to readers with colorblindness and/or is not true to the data, i.e. not perceptually uniform.

    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 10.1101/2020.07.01.182659 on bioRxiv