Conformational Dynamics in the Interaction of SARS-CoV-2 Papain-like Protease with Human Interferon-Stimulated Gene 15 Protein

Leite, Wellington; Weiss, Kevin L.; Phillips, G.N.; Qiu, Zhang; Qian, Shuo; Tsutakawa, Susan E.; Coates, Leighton; O’Neill, Hugh

doi:10.1021/acs.jpclett.1c00831

Cited by 18 publications

(15 citation statements)

References 32 publications

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“…This is in contrast to SARS PLpro, which exhibits greatest specificity for K48-linked ubiquitin chains. Structures of ISG15-bound SARS-CoV-2 PLpro have informed mutagenesis experiments, suggesting the mechanism of ISG15 specificity [ 90 , 91 , 92 ]. ISG15-conjugation is a key regulator of viral signaling; therefore, this likely represents a strategy to dampen immune responses ( Figure 2 ).…”

Section: Ubiquitylation Isgylation and Their Roles In Human Antiviral...mentioning

confidence: 99%

Targeting the Ubiquitylation and ISGylation Machinery for the Treatment of COVID-19

et al. 2022

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Ubiquitylation and ISGylation are protein post-translational modifications (PTMs) and two of the main events involved in the activation of pattern recognition receptor (PRRs) signals allowing the host defense response to viruses. As with similar viruses, SARS-CoV-2, the virus causing COVID-19, hijacks these pathways by removing ubiquitin and/or ISG15 from proteins using a protease called PLpro, but also by interacting with enzymes involved in ubiquitin/ISG15 machinery. These enable viral replication and avoidance of the host immune system. In this review, we highlight potential points of therapeutic intervention in ubiquitin/ISG15 pathways involved in key host–pathogen interactions, such as PLpro, USP18, TRIM25, CYLD, A20, and others that could be targeted for the treatment of COVID-19, and which may prove effective in combatting current and future vaccine-resistant variants of the disease.

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Section: Ubiquitylation Isgylation and Their Roles In Human Antiviral...mentioning

confidence: 99%

Targeting the Ubiquitylation and ISGylation Machinery for the Treatment of COVID-19

et al. 2022

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“…ISG15 encodes a ubiquitin-like protein, which is described to have several biological functions including antiviral activity during viral infections [29] . The gene MX1 mentioned above has a similar antiviral effect.…”

Section: Discussionmentioning

confidence: 99%

Analysis of differentially expressed genes between paroxysmal and persistent atrial fibrillation

Ning

Wang

et al. 2022

Preprint

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Background This study aims to analyze the differentially expressed long noncoding RNAs and messenger RNAs (DELncRNAs and DEmRNAs) in patients with paroxysmal and persistent atrial fibrillation and explore the novel AF-related molecular mechanisms.Methods Two target datasets about paroxysmal and persistent atrial fibrillation patients (GSE75092 and GSE113013) were downloaded and further analyzed from the Gene Expression Omnibus database by R software. Upregulated and downregulated differentially expressed genes (DEGs) and the co-expressed differentially expressed genes (co-DEGs) of the two datasets were identified, of which enrichment analyses and protein-protein interaction network construction were performed. Results A total of 127 DELncRNAs and 321 DEmRNAs were screened in GSE75092; a total of 46 DELncRNAs and 64 DEmRNAs were screened in GSE113013. 8 co-DEGs were further identified in the overlap between the two datasets on Venn Diagram, which comprises 3 LncRNA and 5 mRNA. GO and KEGG analysis were successfully performed on the DEGs and co-DEGs mentioned above and the protein-protein interaction network of DEGs was constructed.Conclusions Multiple DEGs were found in patients with either paroxysmal or persistent atrial fibrillation and their functions were mainly enriched in metabolism and inflammation-related signaling pathways. The antiviral defense mechanism of PAF is an interesting difference we found.

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“…It agrees well with the recent experimental studies. 33 These in-depth analyses would fill the critical gap of understanding how PLpro of the CoV family interacts with hISG15, leading to specificity in SCoV2. This study may help in designing drugs targeting PLpro of SARS-CoV-2 that can suppress the COVID-19 infection and promote antiviral immunity.…”

Section: Discussionmentioning

confidence: 99%

“… 30 − 32 However, it is important to consider the full-length hISG15 since both domains of hISG15 interact with PLpro. 33 …”

Section: Introductionmentioning

confidence: 99%

“…Relative to ubiquitin, ISG15 has low cross-species conservation, ranging from 58% to as low as 35% in mammals . Overall, CoVs-PLpro has been reported with robust deubiquitinating activities. , However, few studies have unveiled its importance in deISGylating activities. , The crystal structures of PLpro with the C-domain of ISG15 have been reported for all major coronavirues. − However, it is important to consider the full-length hISG15 since both domains of hISG15 interact with PLpro …”

Section: Introductionmentioning

confidence: 99%

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Unraveling the Molecular Mechanism of Recognition of Human Interferon-Stimulated Gene Product 15 by Coronavirus Papain-Like Proteases: A Multiscale Simulation Study

Roy

Jonniya

Poddar

et al. 2021

J. Chem. Inf. Model.

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The papain-like protease (PLpro) of the coronavirus (CoV) family plays an essential role in processing the viral polyprotein and immune evasion. Additional proteolytic activities of PLpro include deubiquitination and deISGylation, which can reverse the post-translational modification of cellular proteins conjugated with ubiquitin or (Ub) or Ub-like interferon-stimulated gene product 15 (ISG15). These activities regulate innate immune responses against viral infection. Thus, PLpro is a potential antiviral target. Here, we have described the structural and energetic basis of recognition of PLpro by the human ISG15 protein (hISG15) using atomistic molecular dynamics simulation across the CoV family, i.e., MERS-CoV (MCoV), SARS-CoV (SCoV), and SARS-CoV-2 (SCoV2). The cumulative simulation length for all trajectories was 32.0 μs. In the absence of the complete crystal structure of complexes, protein−protein docking was used. A mutation (R167E) was introduced across all three PLpro to study the effect of mutation on the protein−protein binding. Our study reveals that the apo-ISG15 protein remains closed while it adopts an open conformation when bound to PLpro, although the degree of openness varies across the CoV family. The binding free energy analysis suggests that hISG15 binds more strongly with SCoV2-PLpro compared to SCoV or MCoV. The intermolecular electrostatic interaction drives the hISG15-PLpro complexation. Our study showed that SCoV or MCoV-PLpro binds more strongly with the C-domain of hISG15, while SCoV2-PLpro binds more favorably the N-domain of hISG15. Overall, our study explains the molecular basis of differential deISGylating activities of PLpro among the CoV family and the specificity of SCoV2-PLpro toward hISG15.

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Conformational Dynamics in the Interaction of SARS-CoV-2 Papain-like Protease with Human Interferon-Stimulated Gene 15 Protein

Cited by 18 publications

References 32 publications

Targeting the Ubiquitylation and ISGylation Machinery for the Treatment of COVID-19

Targeting the Ubiquitylation and ISGylation Machinery for the Treatment of COVID-19

Analysis of differentially expressed genes between paroxysmal and persistent atrial fibrillation

Unraveling the Molecular Mechanism of Recognition of Human Interferon-Stimulated Gene Product 15 by Coronavirus Papain-Like Proteases: A Multiscale Simulation Study

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