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

Hameedi, Mikhail A.; T. Prates, Erica; Garvin, Michael R.; Mathews, Irimpan I.; Amos, B. Kirtley; Demerdash, Omar; Bechthold, Mark; Iyer, Mamta; Rahighi, Simin; Kneller, Daniel W.; Kovalevsky, Andrey; Irle, Stephan; Vuong, Van-Quan; Mitchell, Julie C.; Labbe, Audrey; Galanie, Stephanie; Wakatsuki, Soichi; Jacobson, Daniel

doi:10.1038/s41467-022-32922-9

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

Journal Article · Thu Sep 08 00:00:00 UTC 2022 · Nature Communications

DOI: https://doi.org/10.1038/s41467-022-32922-9 · OSTI ID:1886096

Hameedi, Mikhail A.;

; Garvin, Michael R.;

;

; Demerdash, Omar; Bechthold, Mark; Iyer, Mamta; Rahighi, Simin;

;

; Labbe, Audrey; Galanie, Stephanie;

;

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 NEMO _226–234 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.

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Research Organization:: Oak Ridge National Laboratory (ORNL), Oak Ridge, TN (United States)

Sponsoring Organization:: National Institutes of Health (NIH); USDOE; USDOE Office of Science (SC), Basic Energy Sciences (BES)

Grant/Contract Number:: AC02-76SF00515; AC05-00OR22725

OSTI ID:: 1886096

Journal Information:: Nature Communications, Journal Name: Nature Communications Journal Issue: 1 Vol. 13; ISSN 2041-1723

Publisher:: Nature Publishing GroupCopyright Statement

Country of Publication:: United Kingdom

Language:: English

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