SARS-CoV-2 mutations strengthen RBD-ACE2 binding, making the virus more infectious (2024)

SARS-CoV-2 mutations strengthen RBD-ACE2 binding, making the virus more infectious (1)By Susha Cheriyedath, M.Sc.May 22 2021

In January 2020, the first complete severe acute respiratory syndrome coronavirus-2 (SARS-CoV-2) genome sequence was deposited to GenBank. Since then, the amount of new genome sequences has increased rapidly at GenBank and GISAID. This has laid the foundations for analyzing the virulence, antigenicity, pathogenicity, and transmissibility of SARS-CoV-2 mutations.

Structural and non-structural proteins of SARS-CoV-2

SARS-CoV-2 is a positive-sense single-stranded RNA virus that encodes 29 structural and non-structural proteins (NSPs) using 29,903 nucleotides. The structural proteins help with the formation of the viral particle, while the NSPs play a significant role in replicating viral RNA. SARS-CoV-2 has 4 structural proteins, namely, spike (S), membrane (M), envelope (E), and nucleocapsid (N) proteins.

Of these, the spike (S) protein has 1,273 residues of SARS-CoV-2 and has a critical role in viral infection. It is essential for interaction with host cell receptors and the fusion of the viral envelope with the host cell membrane to allow entry of the virus. It is also the site of most SARS-CoV-2 mutations. Hence scientists have been focusing their attention on the Spike protein to develop antibody-based drugs and vaccines.

Identifying other fast-growing mutations on the SARS-CoV-2 spike (S) protein

The new variants of SARS-CoV-2 from the UK, Brazil, and South Africa have garnered a lot of attention recently for their increased infectivity, possibly high pathogenicity, and potential threats to currently available vaccines and antibody-based therapies. However, it is not clear if there are more variants with higher infectivity that are being transmitted across the world.

“N501Y involved in the United Kingdom (UK), South Africa, and Brazil variants may moderately weaken the binding between the RBD and many known antibodies.”

Researchers from Michigan State University recently carried out a large-scale study with 506,768 SARS-CoV-2 genome isolates gathered from COVID-19 patients. Their objective was to identify other rapidly growing mutations on the SARS-CoV-2 spike (S) protein receptor-binding domain (RBD). The research is published in the journal Genomics.

Commonly observed mutations strengthen the binding between RBD and host ACE2 receptor

The findings reveal that all 100 of the most observed mutations strengthen the binding between the RBD and the angiotensin-converting enzyme 2 (ACE2) of the host, which indicates that SARS-CoV-2 evolves into more infectious variants. In particular, this enhancement of the binding between RBD and ACE2 is observed in fast-growing RBD mutations such as N439K, S477N, S477R, and N501T.

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The researchers further found that the N501Y mutation found in the UK, Brazil, and South Africa variants may modestly weaken the binding between many known antibodies and the RBD. The E484K and K417N mutations found in the Brazilian and South African variants and the L452R and E484Q mutations found in the Indian variants of SARS-CoV-2 can disrupt the binding between the RBD and many antibodies. The L452R RBD mutation is also known to be a part of the California variant named B.1.427.

T478K mutation makes the Mexico strain the most infectious SARS-CoV-2 variant

The mutations most likely to have vaccine-escape capabilities include S494P, K417N, Q493L, F490S, R403K, F486L, L452R, E484K, K417T, E484Q, F490L, and A475S. Also, the T478K mutation seems to make the B.1.1.222 variant found in Mexico the most infectious variant. According to the authors, the RBD mutations that can simultaneously disrupt the existing antibodies (vaccine escape mutations) and make SARS-CoV-2 more infectious may pose a looming threat to the current set of approved vaccines.

The comprehensive genetic analysis and protein-protein binding study by the authors show that the SARS-CoV-2 genetic evolution on the RBD may be regulated by viral proofreading, host gene editing, natural selection, and random genetic drift. This gives rise to more infectious SARS-CoV-2 variants that may compromise existing antibody-based COVID-19 treatment strategies and vaccines.

“Finally, we hypothesize that RBD mutations that can simultaneously make SARS-CoV-2 more infectious and disrupt the existing antibodies, called vaccine escape mutations, will pose an imminent threat to the current crop of vaccines.”

Journal reference:

SARS-CoV-2 mutations strengthen RBD-ACE2 binding, making the virus more infectious (2024)

FAQs

How does SARS-CoV-2 bind to ACE2? ›

SARS-CoV-2 and ACE2

For both SARS-CoV and SARS-CoV-2, the receptor-binding domain (RBD) of the S1 region is necessary for the binding of these virions to ACE2, thereby contributing to the ability of these particles to cause host cell infection.

What does SARS-CoV-2 mutation do? ›

Although most mutations in the severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) genome are expected to be either deleterious and swiftly purged or relatively neutral, a small proportion will affect functional properties and may alter infectivity, disease severity or interactions with host immunity.

Does SARS-CoV-2 bind to human ACE2 more strongly than does SARS-CoV? ›

Wrapp et al. (Science2020, 367, 1260–1263) showed that the spike protein of SARS-CoV-2 binds to the ACE2 peptidase domain (ACE2-PD) more strongly than does SARS-CoV, and this fact may be associated with a greater severity of the new virus.

Why do viruses like SARS-CoV-2 mutate? ›

As a virus replicates, its genes undergo random “copying errors” (i.e. genetic mutations). Over time, these genetic copying errors can, among other changes to the virus, lead to alterations in the virus' surface proteins or antigens. Our immune system uses these antigens to recognize and fight the virus.

How does SARS-CoV-2 infect cells? ›

SARS-CoV-2 infects cells by attaching its spike proteins to ACE2 proteins that lie on the surface of the cells. Researchers are developing a “decoy” ACE2 to prevent SARS-CoV-2 from attaching to cells. SARS-CoV-2 infects cells by attaching its spike proteins to ACE2 proteins that lie on the surface of the cells.

What is the role of ACE2? ›

ACE cleaves vasodilator angiotensin I into angiotensin II. ACE2 is also responsible for cleaving several peptide hormones. The most important being the removal of carboxyl-terminal amino acid phenylalanine from vasoconstricting angiotensin II and hydrolyses it back into angiotensin.

How fast does SARS-CoV-2 mutate? ›

Virus mutation happens quickly over weeks to months due to the high number of viruses and infected people. Since it was first discovered, SARS-CoV2 has been acquiring two mutations in its genome (complete set of DNA) every two weeks.

What does SARS-CoV-2 E gene do? ›

SARS-CoV-2 Envelope (E) Protein Binds and Activates TLR2 Pathway: A Novel Molecular Target for COVID-19 Interventions. Structure and dynamics of the SARS-CoV-2 envelope protein monomer. Surface Proteins of SARS-CoV-2 Drive Airway Epithelial Cells to Induce IFN-Dependent Inflammation.

What is the genetic material of SARS-CoV-2? ›

Like other coronaviruses, the genome of SARS-CoV-2 is composed of a single strand of RNA with a positive strand (ready for translation and consequent synthesis of its proteins).

How does SARS-CoV-2 invade the immune system? ›

SARS-CoV-2 enters into a host cell by binding angiotensin-converting enzyme 2 (ACE2) on the cell surface, a process that can be facilitated by transmembrane protease serine 2 (TMPRSS2), which provides proteolytic cleavage of the viral spike (S) protein to promote virus–host fusion.

What virus does SARS-CoV-2 share the most genomic similarities? ›

In summary, SARS-CoV-2 shares a high degree of genomic similarity between other beta coronaviruses, including human SARS-CoV and bat SARS-like-CoVs/RaTG13.

What are SARS-CoV-2 virulence factors? ›

SARS-CoV-2 is thought to have virulence factors directed against host immune responses. Current data suggests that the SARS-CoV-2 tricks the host into a delayed hyperactive innate immune response, leading to the cytokine storm commonly seen in severe COVID-19 cases.

What are the mutations in SARS-CoV-2 proteins? ›

The mutations that include deletion mutants were associated with 1252 of the 1273 residue positions and correspond to 6129 different mutation types. Besides, there were sequences also comprising insertion mutations. A single SARS-CoV-2 spike protein comprised anywhere between 1 and 55 mutations.

What is SARS-CoV-2 the virus that causes COVID-19? ›

The virus that causes a respiratory disease called coronavirus disease 19 (COVID-19). SARS-CoV-2 is a member of a large family of viruses called coronaviruses. These viruses can infect people and some animals. SARS-CoV-2 was first known to infect people in 2019.

Which of these receptors does SARS-CoV-2 bind to? ›

Two new receptors that specifically bind S protein of SARS-CoV-2 have recently been identified [73]. These proteins are ASGR1 (asialoglycoprotein receptor-1) and KREMEN1 (Kringle Containing Transmembrane Protein 1).

What is the mechanism of action of SARS-CoV-2? ›

Binding of SARS-CoV-2 to the host cell receptor. SARS-CoV-2 S protein binds to the ACE2 receptor at the surface of host cells, initially through the S1 RBD. S1 is then shed from the viral surface, allowing S2 to fuse to the host cell membrane.

What is the role of ACE2 shedding in COVID-19? ›

Previous studies have pointed out that sACE2 plays a role in the pathology of the disease, but the underlying mechanism is not yet clear. Recent studies have confirmed that sACE2 can also act as the receptor of SARS-COV-2, mediating viral entry into the cell and then spreading to the infective area.

Do ACE inhibitors protect you from coronavirus? ›

Inhibiting ACE-2 glycosylation has shown to significantly reduce the infection of host cells by SARS-CoV-2 in a laboratory. This is the process by which chloroquine, hydroxychloroquine, and serine protease inhibitors are thought to work.

References

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