Dataset Information

Structure of Furin Protease Binding to SARS-CoV-2 Spike Glycoprotein and Implications for Potential Targets and Virulence.

ABSTRACT: The COVID-19 pandemic is an urgent global health emergency, and the presence of Furin site in the SARS-CoV-2 spike glycoprotein alters virulence and warrants further molecular, structural, and biophysical studies. Here we report the structure of Furin in complex with SARS-CoV-2 spike glycoprotein, demonstrating how Furin binds to the S1/S2 region of spike glycoprotein and eventually cleaves the viral protein using experimental functional studies, molecular dynamics, and docking. The structural studies underline the mechanism and mode of action of Furin, which is a key process in host cell entry and a hallmark of enhanced virulence. Our whole-exome sequencing analysis shows the genetic variants/alleles in Furin were found to alter the binding affinity for viral spike glycoprotein and could vary in infectivity in humans. Unravelling the mechanisms of Furin action, binding dynamics, and the genetic variants opens the growing arena of bona fide antibodies and development of potential therapeutics targeting the blockage of Furin cleavage.

SUBMITTER: Vankadari N

PROVIDER: S-EPMC7409919 | biostudies-literature | 2020 Aug

REPOSITORIES: biostudies-literature

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Structure of Furin Protease Binding to SARS-CoV-2 Spike Glycoprotein and Implications for Potential Targets and Virulence.

Vankadari Naveen N

The journal of physical chemistry letters 20200805 16

The COVID-19 pandemic is an urgent global health emergency, and the presence of Furin site in the SARS-CoV-2 spike glycoprotein alters virulence and warrants further molecular, structural, and biophysical studies. Here we report the structure of Furin in complex with SARS-CoV-2 spike glycoprotein, demonstrating how Furin binds to the S1/S2 region of spike glycoprotein and eventually cleaves the viral protein using experimental functional studies, molecular dynamics, and docking. The structural s ...[more]

PMID: 32787225

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Project description:The SARS-CoV-2 spike protein mediates attachment of the virus to host cell receptor and fusion between the virus and cell membrane. The S1 subunit of the spike glycoprotein (S1 protein) contains the angiotensin converting enzyme 2 (ACE2) receptor binding domain. The SARS-CoV-2 variants of concern contain mutations in the S1 subunit. The spike protein is the primary target of neutralizing antibodies generated following infection and constitutes the viral component of mRNA based COVID-19 vaccines. Therefore, in this work we assessed the effect of exposure (24 hours) of 10 nM SARS-CoV-2 recombinant S1 protein on physiologically relevant human bronchial (bro) and alveolar (alv) lung mucosa models cultured at air-liquid interface (ALI) (n=6/experimental group). Corresponding sham exposed samples served as control. The bro-ALI model was developed using primary bronchial epithelial cells and the alv-ALI model using representative type II pneumocytes. Exposure of S1 protein induced the surface expression of ACE2, toll like receptor (TLR) 2, and TLR4 in both bro-ALI and alv-ALI models. Transcript expression analysis identified 117 (bro-ALI) and 97 (alv-ALI) differentially regulated genes (p< 0.01). Pathway analysis revealed enriched terms as specific as COVID-19, interferon (IFN) signaling, influenza, Corona virus, anti-viral response in the bro-ALI. Secreted levels of Interleukin (IL) 4 and IL12 were significantly (p<0.05; non-parametric) increased whereas IL6 decreased in the bro-ALI. In case of alv-ALI, enriched terms involving p53, APRIL, tight junction, integrin kinase, IL1 signaling were identified. These terms are associated with lung fibrosis. Further, significantly (p<0.05; non-parametric) increased levels of secreted pro-inflammatory cytokines IFNγ, IL1ꞵ, IL2, IL4, IL6, IL8, IL10, IL12, IL13, and tumor necrosis factor alpha were detected in alv-ALI. Altered levels of these cytokines are also associated with lung fibrotic response. Taken together, we observed a typical anti-viral response in the bronchial model whereas a pro-fibrotic response in the alveolar model. Therefore the bro-ALI and alv-ALI models may serve as an easy and robust platform for assessing the pathogenicity of variants of concern at different lung regions.

Dataset Information

Structure of Furin Protease Binding to SARS-CoV-2 Spike Glycoprotein and Implications for Potential Targets and Virulence.

Publications

Structure of Furin Protease Binding to SARS-CoV-2 Spike Glycoprotein and Implications for Potential Targets and Virulence.

Similar Datasets

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