Sterically confined rearrangements of SARS-CoV-2 Spike protein control cell invasion
| Autor: | Esteban Dodero-Rojas, Jose N Onuchic, Paul Charles Whitford |
|---|---|
| Rok vydání: | 2021 |
| Předmět: |
Conformational change
Glycosylation Protein Conformation QH301-705.5 Structural Biology and Molecular Biophysics Science membrane fusion Plasma protein binding Molecular Dynamics Simulation General Biochemistry Genetics and Molecular Biology chemistry.chemical_compound Protein structure Humans Biology (General) Binding site Binding Sites General Immunology and Microbiology SARS-CoV-2 Chemistry General Neuroscience COVID-19 Lipid bilayer fusion General Medicine Virus Internalization Transmembrane protein Virus Structural biology energy landscapes Spike Glycoprotein Coronavirus Biophysics Receptors Virus Medicine Protein Processing Post-Translational Protein Binding Research Article |
| Zdroj: | eLife, Vol 10 (2021) eLife |
| ISSN: | 2050-084X |
| Popis: | 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. |
| Databáze: | OpenAIRE |
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