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According to a study published today in eLife.
Research shows that a structure activated by sugar molecules on the spike protein could be essential for entry into cells and that disrupting this structure could be a strategy to stop transmission of the virus.
An essential aspect of the SARS-CoV-2 life cycle is its ability to attach to host cells and transfer its genetic material. It does this through its spike protein, which is made up of three distinct components – a transmembrane bundle that anchors the spike to the virus and two S subunits (S1 and S2) outside the virus.
To infect a human cell, the S1 subunit binds to a molecule on the surface of human cells called ACE2, and the S2 subunit detaches and fuses viral and human cell membranes. Although this process is known, the exact order in which it occurs has not yet been discovered. Yet understanding the microsecond-scale and atomic-level movements of these protein structures could reveal potential targets for COVID-19 treatment.
“Most of the current SARS-CoV-2 treatments and vaccines have focused on the ACE2 recognition step of the viral invasion, but an alternative strategy is to target the structural change that allows the virus to fuse with the cell. human host, “says study co-author José N. Onuchic, Harry C & Olga K Wiess professor of physics at Rice University, Houston, United States, and co-director of the Center for Theoretical Biological Physics. “But experimentally probing these intermediate transient structures is extremely difficult, so we used a computer simulation that was simplified enough to study this large system but which retains enough physical detail to capture the dynamics of the S2 subunit as it transitions between the pre-fusion and post-fusion. -forms of fusion. “
The team was particularly interested in the role of sugar molecules on the spike protein called glycans. To see if the number, type and position of glycans play a role in the membrane fusion step of viral cell entry by mediating these intermediate spike formations, they performed thousands of simulations using ‘a model based on the structure of all atoms.
Such models allow you to predict the trajectory of atoms over time taking into account steric forces – that is, how neighboring atoms affect the movement of others.
The simulations revealed that the glycans form a “cage” which traps the “head” of the S2 subunit, causing it to stop in a form intermediate between the time it detaches from the S1 subunit and the time it is released. where the viral and cell membranes are fused. When the glycans were not there, the S2 subunit spent much less time in this conformation.
The simulations also suggest that keeping the S2 head in a particular position helps the S2 subunit recruit human host cells and fuse with their membranes, allowing the extension of short proteins called virus fusion peptides.
Indeed, glycosylation of S2 significantly increased the likelihood of a fusion peptide spreading to the host cell membrane, whereas when glycans were absent there was only a marginal possibility that it happens.
Our simulations indicate that glycans can induce a pause during the peak protein transition. This offers a crucial opportunity for the fusion peptides to capture the host cell. In the absence of glycans, the virus particle would probably fail to penetrate the host. Our study reveals how sugars can control infectivity, and it provides a basis for experimentally studying the factors that influence the dynamics of this ubiquitous and deadly pathogen. “
Paul C. Whitford, study co-author and associate professor, Center for Theoretical Biological Physics and Department of Physics, Northeastern University
Source:
Journal reference:
Dodero-Rojas, E., et al. (2021) Sterically confined rearrangements of the controlling cell invasion of the SARS-CoV-2 Spike protein. eLife. doi.org/10.7554/eLife.70362.
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