The prickly proteins protruding from its shell are the “trademark” of the Sars-CoV-2 coronavirus – and their binding site for infestation of our cells. Now a study reveals that these so-called spike proteins are much more mobile than previously thought. Their stems have three joint-like hinges that give the protein head great freedom of movement – this could help the virus to attach itself to our cell surfaces. The new recordings also show that the Sars-CoV-2 spike protein has more sugar deposits than expected. That could be important for vaccine development.
The coronaviruses have their most prominent feature in their name: The name Corona – crown – goes back to the proteins protruding from their surface. These spike proteins play a critical role in Sars-CoV-2 replication and its ability to infect a host. On the one hand, the structure of the spike protein enables this pathogen to infect humans. Only when a certain subunit had changed in such a way that it fitted and docked onto the ACE2 receptor of human cells did the virus acquire the ability to penetrate our cells. This binding point of the spike protein is also the starting point of our immune defense: the immune system recognizes the pathogen and produces antibodies that bind precisely to this point and thus block their function. The vaccines currently being developed also use the structure of the spike protein to trigger a protective immune response.
Three joints on the protein stalk
Knowing the exact structure of this Sars-CoV-2 protein is therefore particularly important. In fact, there are structural models of the isolated protein that are almost accurate to the atom. However, it was less clear how the spike protein is configured when it sits on the surface of the virus that is still intact. That is why researchers led by Beata Turonova from the European Molecular Biology Laboratory (EMBL) in Heidelberg have carried out the most precise mapping of the spike protein to date in situ – i.e. on the virus. To do this, they used cryo-electron microscopy to create high-resolution snapshots of 1,000 freeze-dried viruses including their proteins. These cryotomograms already showed individual protein subunits of the around 40 spike proteins per virus. Computer-aided processing of the tomograms then made it possible to map the head and stem of the spike proteins with almost atomic accuracy.
As the models and pictures revealed, the stems of the viral spike protein are much more agile than previously thought. “It was expected that the handle would be pretty rigid,” says co-author Gerhard Hummer from the Max Planck Institute for Biophysics in Frankfurt am Main. “But in our models and pictures we discovered that the stems are extremely flexible.” This allows the protein head with the binding site to tilt almost at a right angle. “The stems seem to move on the surface of the virus like a balloon on a string and can search for the receptor for docking with the target cell,” explains co-author Jacomine Krijnse Locker from the Paul Ehrlich Institute. The researchers discovered that this mobility is caused by three joints on the stem of the spike protein. These hinges – hips, knees and ankles – can be tilted between 18 and 28 degrees, giving the head great freedom of movement.
Protective sugar deposits
As the researchers found, the Sars-CoV-2 spike protein is also covered by many sugar-like deposits. These so-called glycans hide parts of the recognizable protein structures and make it difficult for the immune system to recognize the virus. At the same time, they hinder antibodies and immune cells from docking at crucial points on the surface protein. Knowing where the glycans are and how numerous they are is therefore important to be able to gauge the effectiveness of antibody therapies or vaccines. The good news, however, is that the binding site of the spike protein looks pretty much exactly the same in situ as known from previous studies on isolated proteins.
“The top spherical part of the spike protein has a structure that is well reproduced by recombinant proteins used in vaccine development,” explains co-author Martin Beck of EMBL. This means that the vaccine candidates at least do not run into void, but present the right structures to the immune system.
Source: Beata Turonova (European Molecular Biology Laboratory (EMBL), Heidelberg) et al., Science, doi: 10.1126 / science.abd5223