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Structural and functional characterization of NEMO cleavage by SARS-CoV-2 3CLpro

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  • Mikhail A. Hameedi

    (SLAC National Accelerator Laboratory, Stanford Synchrotron Radiation Lightsource, Structural Molecular Biology
    SLAC National Accelerator Laboratory, Stanford Synchrotron Radiation Lightsource, Biosciences
    Stanford University
    National Virtual Biotechnology Laboratory, US Department of Energy)

  • Erica T. Prates

    (National Virtual Biotechnology Laboratory, US Department of Energy
    Oak Ridge National Laboratory)

  • Michael R. Garvin

    (National Virtual Biotechnology Laboratory, US Department of Energy
    Oak Ridge National Laboratory)

  • Irimpan I. Mathews

    (SLAC National Accelerator Laboratory, Stanford Synchrotron Radiation Lightsource, Structural Molecular Biology)

  • B. Kirtley Amos

    (University of Kentucky)

  • Omar Demerdash

    (National Virtual Biotechnology Laboratory, US Department of Energy
    Oak Ridge National Laboratory)

  • Mark Bechthold

    (Stanford University)

  • Mamta Iyer

    (Chapman University School of Pharmacy)

  • Simin Rahighi

    (Chapman University School of Pharmacy)

  • Daniel W. Kneller

    (National Virtual Biotechnology Laboratory, US Department of Energy
    Oak Ridge National Laboratory)

  • Andrey Kovalevsky

    (National Virtual Biotechnology Laboratory, US Department of Energy
    Oak Ridge National Laboratory)

  • Stephan Irle

    (Oak Ridge National Laboratory)

  • Van-Quan Vuong

    (University of Tennessee Knoxville)

  • Julie C. Mitchell

    (National Virtual Biotechnology Laboratory, US Department of Energy
    Oak Ridge National Laboratory)

  • Audrey Labbe

    (National Virtual Biotechnology Laboratory, US Department of Energy
    Oak Ridge National Laboratory)

  • Stephanie Galanie

    (National Virtual Biotechnology Laboratory, US Department of Energy
    Oak Ridge National Laboratory
    Merck & Co., Inc.)

  • Soichi Wakatsuki

    (SLAC National Accelerator Laboratory, Stanford Synchrotron Radiation Lightsource, Structural Molecular Biology
    SLAC National Accelerator Laboratory, Stanford Synchrotron Radiation Lightsource, Biosciences
    Stanford University
    National Virtual Biotechnology Laboratory, US Department of Energy)

  • Daniel Jacobson

    (National Virtual Biotechnology Laboratory, US Department of Energy
    Oak Ridge National Laboratory)

Abstract

In addition to its essential role in viral polyprotein processing, the SARS-CoV-2 3C-like protease (3CLpro) can cleave human immune signaling proteins, like NF-κB Essential Modulator (NEMO) and deregulate the host immune response. Here, in vitro assays show that SARS-CoV-2 3CLpro cleaves NEMO with fine-tuned efficiency. Analysis of the 2.50 Å resolution crystal structure of 3CLpro C145S bound to NEMO226–234 reveals subsites that tolerate a range of viral and host substrates through main chain hydrogen bonds while also enforcing specificity using side chain hydrogen bonds and hydrophobic contacts. Machine learning- and physics-based computational methods predict that variation in key binding residues of 3CLpro-NEMO helps explain the high fitness of SARS-CoV-2 in humans. We posit that cleavage of NEMO is an important piece of information to be accounted for, in the pathology of COVID-19.

Suggested Citation

  • Mikhail A. Hameedi & Erica T. Prates & Michael R. Garvin & Irimpan I. Mathews & B. Kirtley Amos & Omar Demerdash & Mark Bechthold & Mamta Iyer & Simin Rahighi & Daniel W. Kneller & Andrey Kovalevsky &, 2022. "Structural and functional characterization of NEMO cleavage by SARS-CoV-2 3CLpro," Nature Communications, Nature, vol. 13(1), pages 1-15, December.
    • Handle: RePEc:nat:natcom:v:13:y:2022:i:1:d:10.1038_s41467-022-32922-9
    DOI: 10.1038/s41467-022-32922-9
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    References listed on IDEAS

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    1. Jaeyong Lee & Liam J. Worrall & Marija Vuckovic & Federico I. Rosell & Francesco Gentile & Anh-Tien Ton & Nathanael A. Caveney & Fuqiang Ban & Artem Cherkasov & Mark Paetzel & Natalie C. J. Strynadka, 2020. "Crystallographic structure of wild-type SARS-CoV-2 main protease acyl-enzyme intermediate with physiological C-terminal autoprocessing site," Nature Communications, Nature, vol. 11(1), pages 1-9, December.
    2. Eduardo Levy Yeyati & Federico Filippini., 2021. "Social and Economic Impact of COVID-19," Department of Economics Working Papers wp_gob_2021_09, Universidad Torcuato Di Tella.
    3. Daniel W. Kneller & Gwyndalyn Phillips & Hugh M. O’Neill & Robert Jedrzejczak & Lucy Stols & Paul Langan & Andrzej Joachimiak & Leighton Coates & Andrey Kovalevsky, 2020. "Structural plasticity of SARS-CoV-2 3CL Mpro active site cavity revealed by room temperature X-ray crystallography," Nature Communications, Nature, vol. 11(1), pages 1-6, December.
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