2020-10-18| COVID-19In-DepthR&D

Structural Study of SARS-CoV-2 Spike Protein Aids in Better Understanding of COVID-19 Infection

by Sahana Shankar
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By Sahana Shankar, Ph.D. Candidate

It is now common knowledge that the Spike protein (S) on the surface of SARS-CoV-2 is responsible for host entry, a step that the virus achieves by binding to the ACE2 receptor. The extensively studied trimeric protein consists of an ectodomain head harboring receptor binding domains (RBDs) in either closed or open conformations. In the closed conformation, the N-terminus shields the RBD, and in the open conformation, the RBD can bind to ACE2. However, the stalk which connects to the viral membrane is not well understood.


New Findings

In a recent study, published in Science on 09 October 2020, a team of investigators from EMBL combined Cryogenic-electron tomography and molecular dynamics simulations to characterize the viral S protein and the stalk domain of S. They found that, unlike recombinant S, native viral S protein is heavily glycosylated (addition of sugar side chains), which may improve its binding to the host. The stalk contains 3 hinges that provide S protein the freedom to move around.

Using VeroE6 mammalian cells to maintain the SARS-CoV-2 virus and extracting the viral particles by centrifugation, the authors analyzed more than 1000 viruses in Cryo-EM to obtain a high-quality dataset. The reconstructions showed that each virus has ~40 copies of S randomly distributed on the surface. The native S protein was found mostly in the prefusion conformation. At high resolution, the authors could discern individual glycosylation sites and secondary structure elements of the head. While the head was either in a closed or open conformation, the stalk region was more dynamic.


Three Flexible Hinges

Analysis of over 3000 tomographic slices showed that the S stalk comprises 3 flexible hinges, dividing it into upper and lower legs. Molecular Dynamics (MD) simulations further divided the hinges into ‘hip’ (between S head and upper leg of the stalk), ‘knee’ (connecting the upper and lower legs), and ‘ankle’ (between the lower leg and the transmembrane domain). The ‘knee’ was the most flexible hinge, followed by ‘ankle’ and ‘hip’. There was good agreement between the MD simulations and the tomographic density of S.

The EM maps also revealed extensive N-glycosylation on the S surface, which may protect the S from antibody-binding and maintain the hinges’ flexibility. The MD trajectories could also account for glycosylation, all along with the S protein, especially at the hinges.

The new observations in this study were made possible due to the high-resolution structural model and confirmation with the MD analysis, rendering the two techniques highly complementary to each other. This enhances our understanding of SARS-CoV-2 infection. The authors indicate that the flexibility of the S on the viral surface may contribute to viral movement and robustness of infection since previous results of the post-fusion S protein shows that it is inflexible.

This in situ study revealed (a) the abundance of closed and prefusion S proteins on the viral surface, which could be a good candidate for vaccine development, (b) functionally-important domains of S- hinges of the stalk and glycosylation coat, made possible by analyzing intact viruses and (c) high-resolution structural information of the native SARS-CoV-2 virus, complete with nucleocapsid, M protein on the membrane.

Editor: Rajaneesh K. Gopinath, Ph.D.

Related Article: Mutations Observed in Coronavirus “Spike” Caution




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