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

Author:

Hameedi Mikhail A.,T. Prates EricaORCID,Garvin Michael R.,Mathews Irimpan I.ORCID,Amos B. KirtleyORCID,Demerdash Omar,Bechthold Mark,Iyer Mamta,Rahighi Simin,Kneller Daniel W.ORCID,Kovalevsky AndreyORCID,Irle StephanORCID,Vuong Van-QuanORCID,Mitchell Julie C.ORCID,Labbe Audrey,Galanie Stephanie,Wakatsuki SoichiORCID,Jacobson DanielORCID

Abstract

AbstractIn 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.

Funder

U.S. Department of Energy

U.S. Department of Health & Human Services | NIH | National Institute on Aging

U.S. Department of Health & Human Services | NIH | National Institute of General Medical Sciences

Laboratory Directed Research and Development Program of Oak Ridge National Laboratory, LOIS 10074

Publisher

Springer Science and Business Media LLC

Subject

General Physics and Astronomy,General Biochemistry, Genetics and Molecular Biology,General Chemistry,Multidisciplinary

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