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Sterically confined rearrangements of SARS-CoV-2 Spike protein control cell invasion

Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) is highly contagious, and transmission involves a series of processes that may be targeted by vaccines and therapeutics. During transmission, host cell invasion is controlled by a large-scale (200–300 Å) conformational change of the Spike...

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Autores principales: Dodero-Rojas, Esteban, Onuchic, Jose N, Whitford, Paul Charles
Formato: Online Artículo Texto
Lenguaje:English
Publicado: eLife Sciences Publications, Ltd 2021
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC8456623/
https://www.ncbi.nlm.nih.gov/pubmed/34463614
http://dx.doi.org/10.7554/eLife.70362
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author Dodero-Rojas, Esteban
Onuchic, Jose N
Whitford, Paul Charles
author_facet Dodero-Rojas, Esteban
Onuchic, Jose N
Whitford, Paul Charles
author_sort Dodero-Rojas, Esteban
collection PubMed
description Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) is highly contagious, and transmission involves a series of processes that may be targeted by vaccines and therapeutics. During transmission, host cell invasion is controlled by a large-scale (200–300 Å) conformational change of the Spike protein. This conformational rearrangement leads to membrane fusion, which creates transmembrane pores through which the viral genome is passed to the host. During Spike-protein-mediated fusion, the fusion peptides must be released from the core of the protein and associate with the host membrane. While infection relies on this transition between the prefusion and postfusion conformations, there has yet to be a biophysical characterization reported for this rearrangement. That is, structures are available for the endpoints, though the intermediate conformational processes have not been described. Interestingly, the Spike protein possesses many post-translational modifications, in the form of branched glycans that flank the surface of the assembly. With the current lack of data on the pre-to-post transition, the precise role of glycans during cell invasion has also remained unclear. To provide an initial mechanistic description of the pre-to-post rearrangement, an all-atom model with simplified energetics was used to perform thousands of simulations in which the protein transitions between the prefusion and postfusion conformations. These simulations indicate that the steric composition of the glycans can induce a pause during the Spike protein conformational change. We additionally show that this glycan-induced delay provides a critical opportunity for the fusion peptides to capture the host cell. In contrast, in the absence of glycans, the viral particle would likely fail to enter the host. This analysis reveals how the glycosylation state can regulate infectivity, while providing a much-needed structural framework for studying the dynamics of this pervasive pathogen.
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spelling pubmed-84566232021-09-23 Sterically confined rearrangements of SARS-CoV-2 Spike protein control cell invasion Dodero-Rojas, Esteban Onuchic, Jose N Whitford, Paul Charles eLife Structural Biology and Molecular Biophysics Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) is highly contagious, and transmission involves a series of processes that may be targeted by vaccines and therapeutics. During transmission, host cell invasion is controlled by a large-scale (200–300 Å) conformational change of the Spike protein. This conformational rearrangement leads to membrane fusion, which creates transmembrane pores through which the viral genome is passed to the host. During Spike-protein-mediated fusion, the fusion peptides must be released from the core of the protein and associate with the host membrane. While infection relies on this transition between the prefusion and postfusion conformations, there has yet to be a biophysical characterization reported for this rearrangement. That is, structures are available for the endpoints, though the intermediate conformational processes have not been described. Interestingly, the Spike protein possesses many post-translational modifications, in the form of branched glycans that flank the surface of the assembly. With the current lack of data on the pre-to-post transition, the precise role of glycans during cell invasion has also remained unclear. To provide an initial mechanistic description of the pre-to-post rearrangement, an all-atom model with simplified energetics was used to perform thousands of simulations in which the protein transitions between the prefusion and postfusion conformations. These simulations indicate that the steric composition of the glycans can induce a pause during the Spike protein conformational change. We additionally show that this glycan-induced delay provides a critical opportunity for the fusion peptides to capture the host cell. In contrast, in the absence of glycans, the viral particle would likely fail to enter the host. This analysis reveals how the glycosylation state can regulate infectivity, while providing a much-needed structural framework for studying the dynamics of this pervasive pathogen. eLife Sciences Publications, Ltd 2021-08-31 /pmc/articles/PMC8456623/ /pubmed/34463614 http://dx.doi.org/10.7554/eLife.70362 Text en © 2021, Dodero-Rojas et al https://creativecommons.org/licenses/by/4.0/This article is distributed under the terms of the Creative Commons Attribution License (https://creativecommons.org/licenses/by/4.0/) , which permits unrestricted use and redistribution provided that the original author and source are credited.
spellingShingle Structural Biology and Molecular Biophysics
Dodero-Rojas, Esteban
Onuchic, Jose N
Whitford, Paul Charles
Sterically confined rearrangements of SARS-CoV-2 Spike protein control cell invasion
title Sterically confined rearrangements of SARS-CoV-2 Spike protein control cell invasion
title_full Sterically confined rearrangements of SARS-CoV-2 Spike protein control cell invasion
title_fullStr Sterically confined rearrangements of SARS-CoV-2 Spike protein control cell invasion
title_full_unstemmed Sterically confined rearrangements of SARS-CoV-2 Spike protein control cell invasion
title_short Sterically confined rearrangements of SARS-CoV-2 Spike protein control cell invasion
title_sort sterically confined rearrangements of sars-cov-2 spike protein control cell invasion
topic Structural Biology and Molecular Biophysics
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC8456623/
https://www.ncbi.nlm.nih.gov/pubmed/34463614
http://dx.doi.org/10.7554/eLife.70362
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