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

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, Stephan Irle, Vuong Van-Quan, Julie C. Mitchell, Audrey Labbe, Stephanie Galanie, Soichi Wakatsuki () and Daniel Jacobson ()
Additional contact information
Mikhail A. Hameedi: SLAC National Accelerator Laboratory, Stanford Synchrotron Radiation Lightsource, Structural Molecular Biology
Erica T. Prates: National Virtual Biotechnology Laboratory, US Department of Energy
Michael R. Garvin: National Virtual Biotechnology Laboratory, US Department of Energy
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
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
Andrey Kovalevsky: National Virtual Biotechnology Laboratory, US Department of Energy
Stephan Irle: Oak Ridge National Laboratory
Vuong Van-Quan: University of Tennessee Knoxville
Julie C. Mitchell: National Virtual Biotechnology Laboratory, US Department of Energy
Audrey Labbe: National Virtual Biotechnology Laboratory, US Department of Energy
Stephanie Galanie: National Virtual Biotechnology Laboratory, US Department of Energy
Soichi Wakatsuki: SLAC National Accelerator Laboratory, Stanford Synchrotron Radiation Lightsource, Structural Molecular Biology
Daniel Jacobson: National Virtual Biotechnology Laboratory, US Department of Energy

Nature Communications, 2022, vol. 13, issue 1, 1-15

Abstract: 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.

Date: 2022
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DOI: 10.1038/s41467-022-32922-9

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