Angiotensin-converting enzyme 2 (ACE2): SARS-CoV-2 receptor and RAS modulator

Abstract

The coronavirus disease 2019 (COVID-19) outbreak is caused by severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2). Angiotensin-converting enzyme 2 (ACE2) was rapidly identified as the critical functional receptor for SARS-CoV-2. ACE2 is well-known as a counter-regulator of the renin-angiotensin system (RAS) and plays a key role in the cardiovascular system. Given that ACE2 functions as both a SARS-CoV-2 receptor and a RAS modulator, the treatment for COVID-19 presents a dilemma of how to limit virus entry but protect ACE2 physiological functions. Thus, an in-depth summary of the recent progress of ACE2 research and its relationship to the virus is urgently needed to provide possible solution to the dilemma. Here, we summarize the complexity and interplay between the coronavirus, ACE2 and RAS (including anti-RAS drugs). We propose five novel working modes for functional receptor for SARS-CoV-2 infection and the routes of ACE2-mediated virus entering host cells, as well as its regulatory mechanism. For the controversy of anti-RAS drugs application, we also give theoretical analysis and discussed for drug application. These will contribute to a deeper understanding of the complex mechanisms of underlying the relationship between the virus and ACE2, and provide guidance for virus intervention strategies.

Keywords: Angiotensin-converting enzyme 2; Anti-RAS drug; COVID-19; Drug target; Modulator; Receptor; Renin-angiotensin system; SARS-CoV-2.

Graphical abstract

Figure 1

The potential working modes of functional receptors. Five major working modes of functional receptors. (A) SARS-CoV-2 directly binds to ACE2 monomer. (B) SARS-CoV-2 binds to ACE2 homodimer. (C) SARS-CoV-2 infects cells by binding to alternative receptors. (D) SARS-CoV-2 infects cells by co-receptors, and (E) SARS-CoV-2 is presented by dendritic cells to host cells by transmissive receptor (DC-SIGN). ACE2, angiotensin-converting enzyme 2; B⁰AT1, a neutral amino acid transporter; CD209L (also called L-SIGN), liver/lymph node-specific intercellular adhesion molecule-3-grabbing integrin; DC-SIGN, dendritic cell-specific intercellular adhesion molecule-3-grabbing integrin; SARS-CoV-2, severe acute respiratory syndrome coronavirus 2; S-protein, Spike protein.

Figure 2

Domain structure and function of angiotensin-converting enzyme 2 (ACE2). ACE2 consists of 805 amino acids (805 aa) with an extracellular N-terminal domain and an intracellular C-terminal tail. The transmembrane domain is shown in black. The zinc-binding motif (HEMGH), depicted in yellow, is located within the carboxypeptidase domain (blue). The carboxypeptidase domain functions as an enzyme for formation of Ang (1–7). In addition, SARS-CoV-2 S-protein binds to this domain. Collectrin domain denoted in green is crucial for interacting with neutral amino acid transporters. ① and ② represent two sites of ACE2 shedding with ADAM17 and TMPPSS2, respectively. ACE2, angiotensin-converting enzyme 2; ADAM17, a disintegrin and metallopeptidase domain 17; Ang (1–7), angiotensin (1–7); TM, transmembrane; TMPPSS2, type II transmembrane serine proteases.

Figure 3

The comparative map of ACE2 expression and vulnerability to SARS-CoV-2 in different organs. ACE2 distribution in major organs is shown in the left panel. The vulnerability to SARS-CoV-2 in different organs is shown in the right panel. Different levels of ACE2 expression (left) or vulnerability to SARS-CoV-2 (right) is shown by color scale. ACE2, angiotensin-converting enzyme 2.

Figure 4

The routes of ACE2-mediated virus entering host cells. There are two routes of ACE2-mediated virus entering host cells. (A) The first route is dependent on the ACE2-mediated virus endocytosis. There are two potential endocytic routes. One is the clathrin-dependent pathway. Another is the lipid raft-dependent pathway. Caveolae-dependent pathway does not involve ACE2-mediated endocytosis after SARS-CoV-2 binding. (B) The second route is dependent on the TMPRSS2-mediated membrane fusion. After binding with ACE2, S-protein is cleaved and activated by TMPRSS2 to promote membrane fusion. ACE2, angiotensin-converting enzyme 2; EEA1, Early endosomal autoantigen 1; S-protein, Spike protein; TMPPSS2, type II transmembrane serine proteases.

Figure 5

The modes for ACE2 shedding. SARS-CoV S-protein binding initiates ACE2 shedding and further induces viral entry into cell. There are two major modes of ACE2 shedding: ADAM17-dependent and TMPRSS2-dependent. The arginine and lysine residues within ACE2 amino acids 652 to 659 are essential for ACE2 cleavage by ADAM17. Different from ADAM17, the arginine and lysine residues within ACE2 amino acids 697 to 716 are essential for cleavage by TMPRSS2. However, the neutral amino acid transporter B⁰AT1 might inhibit TMPRSS2-dependent ACE2 shedding. ACE2, angiotensin-converting enzyme 2; ADAM17, a disintegrin and metallopeptidase domain 17; S-protein, Spike protein; TMPPSS2, type II transmembrane serine proteases.

Figure 6

Schematic diagram of ACE2 in the renin-angiotensin system. ACE2 functions as a major enzyme to metabolize Ang II into Ang (1–7). Ang (1–7) binds the Mas receptor to form the ACE2-Ang (1–7)-Mas receptor axis, which opposes the effect of ACE–Ang II–AT1R axis. The ACE–Ang II–AT1R axis is well-established to mediate vasoconstriction and increases blood pressure. ACEI and ARB are highly effective drugs for the treatment of hypertension. ACE, angiotensin-converting enzyme; ACE2, angiotensin-converting enzyme 2; ACEI, ACE inhibitor; Ang, angiotensin; ARB, angiotensin receptor blocker; AT1R, angiotensin II type 1 receptor; AT2R, angiotensin II type 2 receptor; MasR, Mas receptor.

Figure 7

Potential targets for anti-coronaviral drugs. Five major steps are key targets against virus infection, including the binding between coronavirus and ACE2 (①), virus entry mediated by ACE2, including ACE2-mediated virus endocytosis (②a) and TMPRSS2-mediated membrane fusion (②b), virus replication (③), virus assembly (④), and virus exit (⑤). ACE2, angiotensin-converting enzyme 2; TMPRSS2, type II transmembrane serine proteases.