Regulation of the Dimerization and Activity of SARS-CoV-2 Main Protease through Reversible Glutathionylation of Cysteine 300
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Abstract
SARS-CoV-2 encodes main protease (M pro ), an attractive target for therapeutic interventions. We show M pro is susceptible to glutathionylation leading to inhibition of dimerization and activity. Activity of glutathionylated M pro could be restored with reducing agents or glutaredoxin. Analytical studies demonstrated that glutathionylated M pro primarily exists as a monomer and that a single modification with glutathione is sufficient to block dimerization and loss of activity. Proteolytic digestions of M pro revealed Cys300 as a primary target of glutathionylation, and experiments using a C300S M pro mutant revealed that Cys300 is required for inhibition of activity upon M pro glutathionylation. These findings indicate that M pro dimerization and activity can be regulated through reversible glutathionylation of Cys300 and provides a novel target for the development of agents to block Mpro dimerization and activity. This feature of M pro may have relevance to human disease and the pathophysiology of SARS-CoV-2 in bats, which develop oxidative stress during flight.
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SciScore for 10.1101/2021.04.09.439169: (What is this?)
Please note, not all rigor criteria are appropriate for all manuscripts.
Table 1: Rigor
Institutional Review Board Statement not detected. Randomization not detected. Blinding not detected. Power Analysis not detected. Sex as a biological variable not detected. Table 2: Resources
Software and Algorithms Sentences Resources The cultures were grown in Terrific Broth media supplemented with ampicillin (Quality Biological, Gaithersburg, MD). Quality Biologicalsuggested: NoneThe mass of the protein was determined by protein deconvolution using Agilent’s Mass Hunter software. Agilent’s Mass Huntersuggested: NoneMasssuggested: NoneThe mass determination for peptides was done by deconvolution (resolved isotope) using Agilent Mass Hunter software (Agilent). Agilent Mass Huntersuggested: NoneResults from OddPub…
SciScore for 10.1101/2021.04.09.439169: (What is this?)
Please note, not all rigor criteria are appropriate for all manuscripts.
Table 1: Rigor
Institutional Review Board Statement not detected. Randomization not detected. Blinding not detected. Power Analysis not detected. Sex as a biological variable not detected. Table 2: Resources
Software and Algorithms Sentences Resources The cultures were grown in Terrific Broth media supplemented with ampicillin (Quality Biological, Gaithersburg, MD). Quality Biologicalsuggested: NoneThe mass of the protein was determined by protein deconvolution using Agilent’s Mass Hunter software. Agilent’s Mass Huntersuggested: NoneMasssuggested: NoneThe mass determination for peptides was done by deconvolution (resolved isotope) using Agilent Mass Hunter software (Agilent). Agilent Mass Huntersuggested: NoneResults 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.
- 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.
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