A study by researchers at Yale School of Medicine (YSM), Northeastern University, and Rice University in Science (not open access) in August 2024 presents new views of an “intricate molecular dance” between human cells and SARS-CoV-2. Their findings could allow more effective vaccine development as variants emerge. The authors used cry-electron tomography to capture intermediates of the S2 domain “refolding” and to understand inhibition by antibodies to the S2 stem-helix. They hope that their research provides insights into the process of SARS-CoV-2 entry and reveals how pan-betacoronavirus S2-targeting antibodies neutralise infectivity by “arresting prehairpin intermediates”.
Spike protein
YSM states that the viral spike protein comprises two parts: one binds the human protein ACE2, on the surface of many cells, and the other adapts its shape to bring the virus closer to the cell after it is attached. This proximity enables the membranes of the virus and cell to fuse, allowing the virus to enter the cell. Current COVID-19 vaccines were designed to include the ACE2-binding element of the spike protein; this is “prone to pick up mutations as the virus evolves”. Keeping up with these mutations, even with annual updates”, would be impossible.
“A different potential target of opportunity – the shape-changing part of the protein – is very unlikely to mutate, because its structure is so critical for narrowing the gap between virus and cell.”
Vaccines that target this “stable structure” could be “universally effective” against more dangerous variants, and even other coronaviruses.
Cutting-edge technology
The scientists used virus-like particles coated with either the spike protein or ACE2 to simulate binding. With a microscopy technique, cryogenic electron tomography (cryo-ET), they imaged this interaction to capture “detailed 3D structures”. Next, the teams at Northeastern and Rice used this data to develop computational simulations of the process. This research allowed the teams to view the spike-ACE2 interaction and subsequent fusion intermediates that had previously not been seen to such a high level of detail.
A key revelation was in the details of the spike protein’s “dramatic shape change”, which PhD researcher and first author Michael Grunst likens to a “jackknife folding shut”. Dr Wenwei Li, associate research scientist, was excited to see the structure of the “intermediate stages”.
“We found that this region is even more dynamic than what we thought before.”
The researchers also captured images of the two proteins together, with antibodies that bind to the “shape-changing region”. Their simulations revealed that the antibody blocks the spike protein from “folding in on itself”, thus preventing it from bringing the virus and cell membranes together for fusion. Grunst highlights the implications of this for vaccine development as the virus mutates rapidly.
“Understanding how these antibodies work to block the fusion machine can help understand how to better design immunogens.”
They also showed that antibodies bind to a “transient folded form” of the spike protein, which could explain why these antibodies are quite rare; the immune system is only exposed to the specific shape for a “short window of time”. Dr Walter Mothes, Paul B. Beeson Professor of Medicine at YSM, states that these details could help vaccine developers select the right part of the virus to simulate the production of more antibodies.
“COVID variants can escape our immune systems and vaccines by mutating, but these fusion machines have only one pattern of how to do their job. It’s a hardwired, conserved machine; you can’t change them. So this is why understanding more about how that mechanism works means we can learn more about their vulnerability.”
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