September 28, 2022

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CryoET analyzes the whole process of new coronavirus entering cells

CryoET analyzes the whole process of new coronavirus entering cells



 

CryoET analyzes the whole process of new coronavirus entering cells.

Many studies have clarified the structure of the new coronavirus spike protein before and after fusion, but the specific process of the spike protein-mediated membrane fusion has not been studied in detail.

A new study , “Intermediates in SARS-CoV-2 spike-mediated cell entry,” published in Science Advances, provides refined structural biology information for understanding the intermediate states of spike protein fusions.

 

When SARS-CoV-2 infects cells, first S1 binds to the host cell membrane ACE2 and then undergoes secondary protease cleavage at S2′, and S2 undergoes a distinct structural transition from a prefusion conformation to a transiently extended intermediate inserted into the target host membrane.

The extended S2 intermediate is refolded through a “zipper” from the C-terminal heptapeptide repeat region (HRC/HR2) to the N-terminal heptapeptide repeat region (HRN/HR1), pulling the virus and host membranes together to initiate the activation of the viral cell membrane. Fusion and entry.

The final folded S2′ is a stable six-helix bundle, and the antiviral fusion inhibitory peptide can act on the HRC domain to interfere with the structural transition and inhibit fusion.

 

To capture the transient state of the structural transition, the researchers utilized a fusion inhibitory peptide [SARS HRC -PEG 4 ] 2 -chol .

The researchers used virus-like particles and targeted outer membrane vesicles to simulate the fusion of viruses and cells.

Under trypsin treatment, the two fused to produce fluorescence, which was blocked by the addition of peptide inhibitors.

This membrane fusion process is affected by temperature, and at 4°C the spike protein binds to the receptor without undergoing a conformational transition.

 

CryoET analyzes the whole process of new coronavirus entering cells

 

Using cryo-electron tomography, the researchers analyzed the conformation of the S2 extended intermediate and found that this region still retains considerable flexibility.

Fusion peptide inhibitors block viral entry mainly by locking S2 in a partially folded conformation.

 

CryoET analyzes the whole process of new coronavirus entering cells

 

Finally, based on the CryoET data, the researchers reconstructed the dynamic process of spike protein fusion.

First, the spike protein binds to the receptor, S2 activates elongation, S1 is released, and S2 refolds to form a partially folded intermediate state, and finally changes to post-membrane fusion.

 

CryoET analyzes the whole process of new coronavirus entering cells

 

Reference:

doi/10.1126/sciadv.abo3153

CryoET analyzes the whole process of new coronavirus entering cells

(source:internet, reference only)


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