Elevated transmission in open spike conformations of SARS-CoV-2 variants

The first strain of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) was found in Wuhan, China. Due to the high transmission rates, the virus quickly spread around the world. Over 4.87 million people have died so far, and many countries have plunged into economic crises due to the tight restrictions required to prevent the disease from spreading further. This included social distancing measures, face masks and, in many countries, full bans.

Study: SARS-CoV-2 variants show, as an evolutionary strategy, an increased kinetic stability of open spike conformations. Image source: Adao / Shutterstock

Mass vaccination programs are gradually making it possible to lift some of these restrictions, but concerns remain about dangerous variants of concern (VOCs), which are becoming increasingly common. One of the most worrying strains is the Delta variant – currently the most common cause of new infections worldwide. The Delta variant and other strains carrying the D614G mutation are known to elude both vaccine-induced and natural immunity. Researchers from Yale University and the University of Texas worked together to study mutations in some VOCs.

A preprint version of the study is available on the bioRxiv * server while the article is being peer-reviewed.

background

Among other mutations, the D614G changes the conformation of the highly glycosylated spike protein. The spike protein is the key to the pathogenicity of SARS-CoV-2. The S1 subunit’s receptor binding domain (RBD) can bind to angiotensin converting enzyme 1 (ACE1) and neuropilin 1 to allow entry into viral cells, and the N-terminal domain is essential for membrane fusion.

Because of this, most vaccines target a specific area of ​​the spike protein, and many studies examining the seroprevalence of the anti-SARS-CoV-2 immune response use assays that look for antibodies that target the spike protein aim. E484K is another well-known mutation that can help bypass the immune response, and several other mutations such as L452R, N501Y, and P681R are known to play similar roles.

The study

The spike protein has four different possible conformations based on the orientation of the individual protomer – these are “one RBD-up”, “two-RBD-up”, “all-RBD-up” and “all-RBD-down” . “Using single-molecule Forster Resonance Energy Transfer (smFRET), the researchers examined the virus’ ability to move between these states in real time and the conformations that exist when transitioning between the various states. These changes were observed over milliseconds to They imaged lentivirus particles that carry only a single SARS-CoV-2 spike protomer labeled with FRET-paired dyes under unlabeled wild-type spike proteins on a prism-based TIRF microscope.

Protein tags were inserted at specific positions before and after the receptor binding motif of spike variants in order to introduce dyes. Their analysis showed that D614G mutations would shift the conformation from the “all-RBD-down” conformation, which is inaccessible to ACE2, to other conformations that would allow binding. This is supported by several studies which show an increased transmission of D614G-carrying variants compared to the wild type. An examination of the changes that E484K and N501Y can cause found that spike proteins in variants that carry these mutations are more likely to change conformation and more likely to move towards an “all-RBD-up” conformation than any other .

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The authors emphasize the importance of their study in understanding how these mutations affect the behavior and functionality of the spike protein, especially since many of the worrying variants now share some of the more dangerous mutations that may increase transmissibility or aid immune evasion.

As expected, they found that the D614G mutation showed signs of increased infectivity compared to the wild-type strain. It helped figure out how the mutation affected the changing conformations of the spike protein trimer.

They also helped uncover which mutations changed the conformation from the mostly “everything-RBD-down” – a closed conformation that prevents the host’s immune system from attacking the virus – to an open conformation that is better for rapid growth infection and increased transmission is appropriate.

In addition, the researchers showed that the E484K mutations increase the binding affinity of the spike protein by helping to change the conformation to a more open state, as well as helping immune evasion by creating an electrostatic charge that neutralizes antibodies makes it less likely to bind to the RBD.

The researchers argue that SARS-CoV-2 is now showing an altered survival strategy, selected from mass vaccination programs, in which strains with immune evasion and rapid transmission have an evolutionary advantage.

*Important NOTE

bioRxiv publishes preliminary scientific reports that are not peer-reviewed and therefore should not be considered conclusive, that guide clinical practice / health-related behavior or are treated as established information

Journal reference:

Yang, Z. et al. (2021) “As an evolutionary strategy, SARS-CoV-2 variants have increased kinetic stability of open spike conformations”. bioRxiv. doi: 10.1101 / 2021.10.11.463956.

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