Abstract
Nonstructural protein 1 (nsp1) of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) is a 180-residue protein that blocks translation of host mRNAs in SARS-CoV-2-infected cells. Although it is known that SARS-CoV-2's own RNA evades nsp1's host translation shutoff, the molecular mechanism underlying the evasion was poorly understood. We performed an extended ensemble molecular dynamics simulation to investigate the mechanism of the viral RNA evasion. Simulation results suggested that the stem loop structure of the SARS-CoV-2 RNA 5'-untranslated region (SL1) binds to both nsp1's N-terminal globular region and intrinsically disordered region. The consistency of the results was assessed by modeling nsp1-40S ribosome structure based on reported nsp1 experiments, including the X-ray crystallographic structure analysis, the cryo-EM electron density map, and cross-linking experiments. The SL1 binding region predicted from the simulation was open to the solvent, yet the ribosome could interact with SL1. Cluster analysis of the binding mode and detailed analysis of the binding poses suggest residues Arg124, Lys47, Arg43, and Asn126 may be involved in the SL1 recognition mechanism, consistent with the existing mutational analysis.
Highlights
SARS-CoV-2 belongs to Betacoronaviridae, and is the causative pathogen of COVID-19
This blockade inhibits the formation of the 48S ribosome pre-initiation complex, which is essential for translation initiation. [3, 13] But while nsp1 shuts down host mRNA translation, it is known that the viral RNAs are translated even in the presence of the nsp1, and that they evade degradation. [2,3,4]
We modeled and simulated a complex comprised of SARS-CoV-2 nsp1 and the SARS-CoV-2 5’-untranslated region (5’-UTR)’s first stem loop using extended ensemble molecular simulations
Summary
SARS-CoV-2 (severe acute respiratory syndrome coronavirus 2) belongs to Betacoronaviridae, and is the causative pathogen of COVID-19. Nsp functions to suppress host gene expression [1,2,3,4,5,6] and induce host mRNA cleavage, [1, 2, 7,8,9] effectively blocking translation of host mRNAs. The translation shutoff hinders the host cell’s innate immune response including interferon-dependent signaling. [11,12,13] The structural analysis showed that two α-helices are formed in the C-terminal region (153–160, 166–179) of nsp and binds to the 40S ribosome. These helices block host translation by shutting the ribosomal tunnel used by the mRNA. This blockade inhibits the formation of the 48S ribosome pre-initiation complex, which is essential for translation initiation. [3, 13] But while nsp shuts down host mRNA translation, it is known that the viral RNAs are translated even in the presence of the nsp, and that they evade degradation. [2,3,4]
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