How does a SARS-CoV-2 Virion Bind to ACE2?

By Benedette Cuffari, M.Sc.Reviewed by Sophia Coveney

Studies on the novel severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) have shown that these virus particles can bind to the alveolar pneumocytes of humans through their interaction with the angiotensin I converting enzyme 2 (ACE2) surface receptor.

Image Credit: Kateryna Kon/Shutterstock.com

What is the ACE2 receptor?

ACE2 is a peptidase that is active and expressed in most tissues; however, the kidney, endothelium, lungs, and heart have the highest expression of ACE2 throughout the body.

The main role of ACE2 is the degradation of angiotensin II within the renin-angiotensin system (RAS). The RAS, which regulates blood flow, blood pressure, natriuresis, and blood volume control, is comprised of several different components that allow for the body to have a coordinated response to different triggers.

For example, angiotensin I is metabolized by ACE to form angiotensin II, which is then subsequently metabolized by ACE2.

ACE2 and the lungs

Within the lungs, ACE2 has a crucial responsibility in regulating the production of circulating angiotensin II, as well as several other types of angiotensin molecules. When a patient is hypoxic, angiotensin II can promote pulmonary vasoconstriction, which can contribute to shunting in patients with pneumonia or lung injury.

Comparatively, pulmonary edema can be further exasperated by increased angiotensin II production, as this peptide hormone can increase vascular permeability, thereby allowing even more fluid to build up within the lungs.

By breaking down abnormally high levels of angiotensin II levels within the lungs, ACE2 can mitigate these types of extreme responses to prevent permanent lung damage from occurring.

SARS-CoV and ACE2

The entry of SARS-CoV-2 into host cells is largely dependent upon the spike (S) glycoprotein present on the surface of this virus particle, as it binds to host cell receptors to allow for the fusion between the viral membrane and the host cell membrane to occur.

When studying the SARS-CoV that quickly spread around the world in 2002, researchers found that the S protein of this virus associates with ACE2.

However, it has since been determined to be an insufficient entry mechanism for host cell infection, as the S protein needs to be further processed and cleaved at specific sites by the proteases of the host cell to allow for total viral membrane fusion.

More specifically, the entry of SARS-CoV through endocytosis is more dependent upon the action of cysteine protease cathepsin that is present within lysosomes.

Although ACE2 has not been shown to have a direct effect on the entry of SARS-CoV into host cells, different studies have suggested that the binding of the S protein of this virus to ACE2 might provoke a change in the three-dimensional structure of this viral glycoprotein. This structural change can expose a cleavage site that increases the susceptibility of the virus to cleavage by cathepsin L, thereby enhancing viral fusion within host cells.

SARS-CoV-2 and ACE2

The S protein of both SARS-CoV and SARS-CoV-2 is comprised of two functional regions known as S1 and S2. Whereas the different subunits of the S1 domain are responsible for receptor association and stabilization, the S2 domain promotes structural rearrangements that are necessary for the fusion of the viral and host cell membranes.

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.

As compared to SARS-CoV, SARS-CoV-2 appears to have a functional advantage regarding the ectodomain of the S protein and its affinity to ACE2 receptors on host cells. It is estimated that SARS-CoV-2 has an ACE2 binding affinity of approximately 15 nano Molar (nM), which is up to 20-fold higher than that of SARS-CoV.

Lots of research has pointed towards the PRRAR sequence furin-like cleavage site in the SARS-CoV-2 spike protein being responsible for the high transmissibility and infectivity of the virus. This site is not present in other lineage B beta coronaviruses, including SARS-CoV, and likely makes interaction with ACE2 more efficient.

Increased susceptibility to COVID-19

In addition to people over the age of 60, those with comorbid conditions such as hypertension, diabetes and cardiovascular disease (CVD) have been shown to suffer from a more severe clinical course as compared to infected patients with no comorbidities.

Since the RAS is immediately affected by health conditions affecting both the cardiovascular system and kidneys, it appears that the system acts as a double-edged sword in SARS-CoV-2 patients.

To this end, although these patients might benefit from the fact that their health conditions result in an upregulation in ACE2, which could protect against lung damage by SARS-CoV-2, this upregulation also increases the susceptibility that these individuals will be infected and ultimately suffer from more severe effects following exposure to this virus.

Similarly, patients with chronic respiratory conditions that result in the downregulation of ACE2 might be at a reduced risk for contracting the virus, whereas those with other respiratory conditions that cause ACE2 levels to be at higher levels may also be at a higher risk.

References

• Devaux, C. A., Rolain, J., & Raoult, D. (2020). ACE2 receptor polymorphism: Susceptibility to SARS-CoV-2 hypertension, multi-organ failure, and COVID-19 disease outcome. Journal of Microbiology, Immunology and Infection 53(3); 425-435. doi:10.1016/j.jmii.2020.04.015.
• Giron, C. C., Laaksonen, A., & Barroso da Silva, F. L. (2020). On the interactions of the receptor-binding domain of SARS-CoV-1 and SARS-CoV-2 spike proteins with monoclonal antibodies and the receptor ACE2. Virus Research 285. doi:10.1016/j.virusres.2020.198021.Perotta, F., Matera, M. G., Cazzola, M., & Bianco, A. (2020). Severe respiratory SARS-CoV2 infection: Does ACE2 receptor matter? Respiratory Medicine 168. doi:10.1016/j.rmed.2020.105996.
• Mahmoud, I. S., Jarrar, Y. B., Alshaer, W., & Ismail, S. (2020). SARS-CoV-2 entry in host cells – multiple targets for treatment and prevention. BIochimie 175; 93-98. doi:10.1016/j.biochi.2020.05.012.
• Tikellis, C., & Thomas, M. C. (2012). Angiotensin-Converting Enzyme 2 (ACE2) Is a Key Modulator of the Renin-Angiotensin System in Health and Disease. International Journal of Peptides. doi:10.1155/2012/256294.
• Xia, S., Lan, Q., Su, S. et al. (2020). The role of furin cleavage site in SARS-CoV-2 spike protein-mediated membrane fusion in the presence or absence of trypsin. Sig Transduct Target Ther 5, 92. doi:10.1038/s41392-020-0184-0

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Further Reading

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• Unlocking our clinical understanding of SARS-CoV-2 infection, Post-Acute COVID Syndrome (PACS), and systemic recovery