Coronavirus Latest: Study Shows Spike Protein On The Surface Of SARS-CoV-2 Can Adopt At Least Ten Distinct Structural States When In Contact With ACE2
: Researchers from the Crick's Structural Biology of Disease Processes Laboratory at the Francis Crick Institute-London have found that the spike protein on the surface of the SARS-CoV-2 coronavirus can adopt at least ten distinct structural states, when in contact with the human virus receptor ACE2.
The structural states of the SARS-CoV-2 spike protein, binding to the human cell
receptor ACE2. Credit: The Francis Crick Institute
SARS-CoV-2 infection is initiated by virus binding to ACE2 cell surface receptor, followed by fusion of virus and cell membranes to release the virus genome into the cell. Both receptor binding and membrane fusion activities are mediated by the virus Spike glycoprotein, S. As with other class I membrane fusion proteins, S is post-translationally cleaved, in this case by furin, into S1 and S2 components that remain associated following cleavage. Fusion activation following receptor binding is proposed to involve the exposure of a second proteolytic site (S2’), cleavage of which is required for the fusion peptide release.
The study team investigated the binding of ACE2 to the furin-cleaved form of SARS-CoV-2 S by cryoEM. They managed to classify ten different molecular species including the unbound, closed spike trimer, the fully open ACE2-bound trimer, and dissociated monomeric S1 bound to ACE2.
The ten structures describe ACE2 binding events which destabilize the spike trimer, progressively opening up, and out, the individual S1 components. The opening process reduces S1 contacts and un-shields the trimeric S2 core, priming fusion activation and dissociation of ACE2-bound S1 monomers. The structures also reveal refolding of an S1 subdomain following ACE2 binding, that disrupts interactions with S2, notably involving Asp614, leading to destabilization of the structure of S2 proximal to the secondary (S2’) cleavage site.
The research findings were published in the journal: Nature https://www.nature.com/articles/s41586-020-2772-0
The discovery and insight into the mechanism of infection will equip research groups with the understanding needed to inform studies into vaccines and treatments.
Studies have shown that the surface of SARS-CoV-2, the virus that causes COVID-19, is covered in proteins called spikes, which enable the virus to infect human cells. The infection begins when a spike protein binds with ACE2 cell surface receptors and, at later stages, catalyzes the release of the virus genome into the cell.
Till now the exact nature of the ACE2 binding to the SARS-CoV-2 spike was not known in detail especially from a molecular perspective.
For the first part of study to examine the binding mechanism between ACE2 and the spike protein in its entirety, study team from the Crick's Structural Biology of Disease Processes Laboratory; have characterized ten distinct structures that are associated with different stages of receptor binding and infection.
The study team incubated a mixture of spike protein and ACE2 before trapping di
fferent forms of the protein by rapid freezing in liquid ethane.
The team then examined these samples using cryo-electron microscopy, obtaining tens of thousands of high-resolution images of the different binding stages.
The study team observed that the spike protein exists as a mixture of closed and open structures.
It was found that following ACE2 binding at a single open site, the spike protein becomes more open, leading to a series of favorable conformational changes, priming it for additional binding. Once the spike is bound to ACE2 at all three of its binding sites, its central core becomes exposed, which may help the virus to fuse to the cell membrane, permitting infection.
Dr Donald Benton, co-lead author and postdoctoral training fellow in the Structural Biology of Disease Processes Laboratory at the Crick told Thailand Medical News, "By examining the binding event in its entirety, we've been able to characterize spike structures that are unique to SARS-CoV-2. We can see that as the spike becomes more open, the stability of the protein will reduce, which may increase the ability of the protein to carry out membrane fusion, allowing infection."
The study team hope that the more they can uncover about how SARS-CoV-2 differs from other coronaviruses, the more targeted they can be with the development of new treatments and vaccines.
Co-lead author and postdoctoral training fellow in the Structural Biology of Disease Processes Laboratory at the Crick, Dr Antoni Wrobel said, "As we unravel the mechanism of the earliest stages of infection, we could expose new targets for treatments or understand which currently available anti-viral treatments are more likely to work."
Dr Steve Gamblin, group leader of the Structural Biology of Disease Processes Laboratory at the Crick said, "There is so much we still do not know about SARS-CoV-2, but its basic biology contains the clues to managing this pandemic. By understanding what makes these virus distinctive, researchers could expose weaknesses to exploit."
The study team is continuing to examine the structures of spikes of SARS-CoV-2 and related coronaviruses in other species to better understand the mechanisms of viral infection and evolution.
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