SARS-CoV-2 Binds to ACE2: What are ACE2 Receptors?
SARS-CoV-2 binds to ACE2 receptors on our cells but what are ACE2 receptors and what do they do?
We’ve known for some months now that the novel coronavirus — SARS-CoV-2 — binds to ACE2 receptors on the surface of some of our cells. In fact, the first SARS-CoV, which caused an epidemic in 2002–3, was also found to bind to these same ACE2 receptors. But what does this actually mean? And what are these ACE2 receptors and what do they even do?
SARS-CoV-2 Binding
You may be familiar with the typical representation we see in the media of a generic virus (like the one above) and this is actually quite accurate to the way coronaviruses look.
The term “coronavirus” is actually an umbrella term for a large subfamily of viruses called Coronavirinae. All coronaviruses contain RNA (genetic material) within a spherical-like capsid which is covered in spike-like protrusions often referred to as spike proteins (sometimes scientists make it easy). These spike proteins are what facilitate these kind of viruses to bind to our cells and infect them (Fig.1).
The virus’ spike proteins are very specifically shaped and therefore need a very specific protein to bind with before they can infect a cell. They can’t just bind with anything. The most common analogy used for this is a lock and its key. In this analogy, these spike proteins are the key. But what about the lock?
Continuing with the analogy, the ACE2 receptors on some of our cells are the lock. The SARS-CoV-2 spike proteins have the ability to bind to ACE2 receptors on the surface of our cells and thus ‘unlock’ the ability to fuse with our cells. Once bound, the virus capsid — its membrane — fuses to our cell’s membrane, which allows it to release its viral RNA into our cell, infecting it and essentially using it as a virus factory. You can imagine this as kind of like when a smaller bubble fuses with, and becomes part of, a larger bubble on your bathwater.
ACE2 receptors aren’t found on all of our cells but they are abundant. They are mostly found on lung, kidney, and other capillary-rich organs. They are also found on cells in the small intestine, testes, and brain.
What Are ACE2 Receptors?
Angiotensin converting enzyme-2 — usually simplified to ACE2 because most scientists aren’t masochists — is a type I membrane-bound glycoprotein, which is a fancy way of saying ACE2 is basically a protein which is situated inside the cell membrane.
Many, many proteins lie in and on our cells’ membranes and they all serve an intended purpose. ACE2 is, as its name suggests, an enzyme which converts angiotensin I into angiotensin 1–9, and angiotensin II into angiotensin 1–7 (Fig. 2). Now that may sound very mundane but it’s actually a very important regulatory system.
Angiotensin (Ang) I and Ang II are protein hormones which are part of a regulatory system which helps to control things such water retention and blood pressure. So, what is the role of ACE2 in this regulatory system?
What Is The Role of ACE2?
So, we now know what ACE2 is and what ACE2 does, but what is the purpose of converting these protein hormones? To answer this we need to understand the regulatory system that ACE2 is a part of, beginning with the renin-angiotensin system (RAS). Stick with me here.
Renin, an enzyme secreted by the kidneys into the blood, converts angiotensinogen into Ang I. ACE (a related enzyme to ACE2) converts Ang I into Ang II. This is necessary as Ang II is a hormone that binds to (angiotensin II type 1) AT1 and (angiotensin II type 2) AT2 receptors in the cell membrane. This can result in the retention of sodium and water, vasoconstriction (narrowing of blood vessels therefore raising blood pressure), cell proliferation, and cell death. This is known as the ACE/RAS pathway (Fig. 3).
Of course, we don’t want to retain sodium and water, and have high blood pressure forever, nor do we want all of these cells to either continuously proliferate or die. This is where the ACE2/Mas pathway regulates the ACE/RAS pathway just described. Don’t worry, we’re almost there.
As previously stated, ACE2 converts Ang I into Ang 1–9, and Ang II into Ang 1–7. This effectively prohibits the results of the ACE/RAS pathway by preventing Ang II from binding with AT1 and AT2. Ang 1–9 and Ang 1–7 can then bind (separately) with Mas protein receptors also in the cell membrane. The downstream processes of this Ang 1–9/Mas and Ang 1–7/Mas binding result in preventing cell death, vasodilation (widening of blood vessels and therefore lowering blood pressure), and inhibiting cell proliferation (Fig. 4).
Putting aside all the abbreviations we scientists love, what we have now is a more complete picture of a regulatory pathway for blood vessel constriction/dilation, water retention, cell proliferation, and cell death.
As the adage goes, too much of anything is a bad thing. Here, our ACE2 receptors are counterbalancing the deleterious effects of continued ACE/RAS activity: high blood pressure, excessive water retention, continuous cell division, and cell death (Fig. 5). Our ACE2 receptors moderate this process, preventing it from running out of control. This is actually a very common way our cells regulate many processes, by introducing an inhibiting factor and essentially restraining a process.
So, what happens when we introduce a virus which binds to ACE2 and prevents it from performing its intended role as a counterbalance to this ACE/RAS pathway?
Disruption of the ACE2/Mas Pathway
By binding with our ACE2 receptors, SARS-CoV-2 is effectively acting as an inhibitor for the ACE2/Mas pathway. To predict what could occur in this event, we can look to research into the inhibition of ACE2 or production of dysfunctional ACE2, as these should produce comparable results.
Previous research has linked dysfunctional ACE2 receptors, meaning they can’t perform their function properly, to conditions such as hypertension, cardiovascular disease, strokes, and diabetes. And these make sense when we consider that ACE2 is the inhibitor of the ACE/RAS pathway, a pathway that results in constricting our blood vessels and causing high blood pressure (hypertension).
We do have medication that can fulfil the intended function of ACE2, known as angiotensin receptor blockers (ARBs). ARBs act as inhibitors for those AT1 receptors with which Ang II bind with. Research has shown that the use of ARBs can also result in the upregulation of ACE2. This would normally be considered a good thing in cases of hypertension, as the body is beginning to regulate itself again. However, in the case of SARS-CoV-2 this is a double-edged sword, as the more ACE2 that is produced by our cells the more binding sites the SARS-CoV-2 virus has to infect our cells. This has the potential to lead to much higher viral loads which was linked to poorer prognoses in the 2002–3 SARS-CoV epidemic.
ACE2 doesn’t just regulate our blood pressure, though. It is well established as a factor in preventing lung damage such as cell death (apoptosis) and the formation of scar tissue (fibrosis). This is particularly true for the alveolar epithelial cells within our lungs. These alveolar epithelial cells are where our blood exchanges gases with the air we breathe in and out. With diminished ACE2 activity due to SARS-CoV-2 binding, these cells could begin to die more often, potentially leading to diminished gas exchange capability and contributing towards pneumonia (as I discussed further here).
We have discussed that by inhibiting the ACE/RAS pathway, ACE2 inhibits cell proliferation. Any protein in the body that restrains or inhibits cell proliferation (cell division) is often found to be what is called a tumour suppressor. Tumours are the result of uncontrolled cell division. Therefore ACE2 can be regarded as a tumour suppressor. It is therefore reasonable to assume that where we have the inhibition, dysfunction, or downregulation of ACE2 we may also see tumours (including cancers). And this is exactly what research has suggested in some lung and breast cancers, with ACE2 being shown to restrain non-small cell lung cancer and inhibit breast cancel cell migration.
For more on how SARS-CoV-2 works and how it affects us more broadly, including our own immune response to it, you can check my previous article: But What Actually is Coronavirus?
Further Reading
Bhf.org.uk (2020). Angiotensin receptor blockers (ARBs). Available at: https://www.bhf.org.uk/informationsupport/heart-matters-magazine/medical/drug-cabinet/arbs
Jia, H., Look, D., Shi, L., Hickey, M., Pewe, L., Netland, J., Farzan, M., Wohlford-Lenane, C., Perlman, S. and McCray, P. (2005). ACE2 Receptor Expression and Severe Acute Respiratory Syndrome Coronavirus Infection Depend on Differentiation of Human Airway Epithelia. Journal of Virology, 79(23), 14614–14621.
Samavati, L. and Uhal, B. (2020). ACE2, Much More Than Just a Receptor for SARS-COV-2. Frontiers in Cellular and Infection Microbiology, 10.
Walls, A., Park, Y., Tortorici, M., Wall, A., McGuire, A. and Veesler, D. (2020). Structure, Function, and Antigenicity of the SARS-CoV-2 Spike Glycoprotein. Cell, 181(2), 281–292.e6.
Zhang, Q., Lu, S., Li, T., Yu, L., Zhang, Y., Zeng, H., Qian, X., Bi, J. and Lin, Y. (2019). ACE2 inhibits breast cancer angiogenesis via suppressing the VEGFa/VEGFR2/ERK pathway. Journal of Experimental & Clinical Cancer Research, 38(1).
