Structural and functional characterization of NEMO cleavage by SARS-CoV-2 3CLpro.
Mikhail Ali HameediErica T PratesMichael R GarvinIrimpan MathewsB Kirtley AmosOmar DemerdashMark BechtholdMamta IyerSimin RahighiDaniel W KnellerAndrey Y KovalevskyStephan IrleVan-Quan VuongJulie C MitchellAudrey LabbeStephanie GalanieSoichi WakatsukiDaniel A JacobsonPublished in: bioRxiv : the preprint server for biology (2021)
In addition to its essential role in viral polyprotein processing, the SARS-CoV-2 3C-like (3CLpro) protease 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 2.14 Å resolution crystal structure of 3CLpro C145S bound to NEMO 226-235 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.
Keyphrases
- sars cov
- respiratory syndrome coronavirus
- machine learning
- immune response
- endothelial cells
- dna binding
- physical activity
- oxidative stress
- toll like receptor
- healthcare
- deep learning
- transcription factor
- dendritic cells
- pi k akt
- lps induced
- inflammatory response
- cell proliferation
- nuclear factor
- single cell
- binding protein
- structural basis