Alternative titles; symbols
HGNC Approved Gene Symbol: ACE2
Cytogenetic location: Xp22.2 Genomic coordinates (GRCh38) : X:15,518,197-15,607,211 (from NCBI)
By EST database searching for sequences showing homology to the zinc metalloprotease angiotensin-I converting enzyme (ACE; 106180) and by screening a human lymphoma cDNA library, Tipnis et al. (2000) cloned a full-length ACE2 cDNA, which they called ACEH, encoding a deduced 805-amino acid protein that shares approximately 40% identity with the N- and C-terminal domains of ACE. ACE2 contains a potential 17-amino acid N-terminal signal peptide and a putative 22-amino acid C-terminal membrane anchor. It has a conserved zinc metalloprotease consensus sequence (HEXXH) and a conserved glutamine residue that is predicted to serve as a third zinc ligand. Northern blot analysis detected high expression of ACE2 in kidney, testis, and heart, and moderate expression in colon, small intestine, and ovary.
By quantitative RT-PCR, Harmer et al. (2002) found ACE2 expressed in all 72 human tissues and cells examined except red blood cells. Highest expression was detected in testis, renal and cardiovascular tissues, and in all portions of the gastrointestinal tract, particularly the ilium. Central nervous system and lymphoid tissues expressed relatively low ACE2 levels.
Itoyama et al. (2005) cloned full-length ACE2 cDNA from human lung and identified different splicing sites and an alternative 5-prime untranslated exon. RT-PCR detected expression of the alternative 5-prime exon in lung, testis, trachea, bronchial epithelial cells, small intestine, and various major organs.
Tipnis et al. (2000) determined that the ACE2 gene contains 18 exons, with some similarity in exon size and organization to those of ACE, and spans approximately 40 kb of genomic DNA. Itoyama et al. (2005) identified an alternative untranslated exon 5-prime to the original exon 1.
Tipnis et al. (2000) mapped the ACE2 gene by sequence similarity to a sequence in GenBank (AC003669) mapping to Xp22.
Tipnis et al. (2000) expressed a soluble, truncated form of ACE2 lacking transmembrane and cytosolic domains in CHO cells and found that it produced a glycosylated protein that was able to cleave angiotensin I and angiotensin II (see 106150), but not bradykinin. In the hydrolysis of the angiotensins, ACE2 functioned exclusively as a carboxypeptidase. Tipnis et al. (2000) showed that ACE2 was not inhibited by benzylsuccinate, a carboxypeptidase A inhibitor, or by other ACE inhibitors such as lisinopril.
Boehm and Nabel (2002) reviewed the work of Crackower et al. (2002) and others in characterizing ACE2, which has direct effects on cardiac function. ACE2 is expressed predominantly in vascular endothelial cells of the heart and kidney. Whereas ACE converts angiotensin I to angiotensin II, which has 8 amino acids, ACE2 converts angiotensin I to angiotensin 1-9, which has 9 amino acids. Whereas angiotensin II is a potent blood vessel constrictor, angiotensin 1-9 has no effect on blood vessels but can be converted by ACE to a shorter peptide, angiotensin 1-7, which is a blood vessel dilator.
Hashimoto et al. (2012) reported that deficiency in murine Ace2, which encodes a key regulatory enzyme of the renin-angiotensin system (RAS), results in highly increased susceptibility to intestinal inflammation induced by epithelial damage. The RAS is involved in acute lung failure, cardiovascular functions, and SARS infections. Mechanistically, ACE2 has a RAS-independent function, regulating intestinal amino acid homeostasis, expression of antimicrobial peptides, and the ecology of the gut microbiome. Transplantation of the altered microbiota from Ace2 mutant mice into germ-free wildtype hosts was able to transmit the increased propensity to develop severe colitis. ACE2-dependent changes in epithelial immunity and the gut microbiota can be directly regulated by the dietary amino acid tryptophan. Hashimoto et al. (2012) concluded that their results identified ACE2 as a key regulator of dietary amino acid homeostasis, innate immunity, gut microbial ecology, and transmissible susceptibility to colitis. They also concluded that their results provided a molecular explanation for how amino acid malnutrition can cause intestinal inflammation and diarrhea.
Role of ACE2 in Coronavirus Infection
Spike (S) proteins of coronaviruses, including the coronavirus that causes severe acute respiratory syndrome (SARS), associate with cellular receptors to mediate infection of their target cells. Li et al. (2003) found that ACE2, isolated from SARS coronavirus-permissive Vero E6 cells, efficiently bound the S1 domain of the SARS coronavirus S protein. Li et al. (2003) found that a soluble form of ACE2, but not of the related enzyme ACE1, blocked association of the S1 domain with Vero E6 cells. HE293T cells transfected with ACE2, but not those transfected with HIV-1 receptors, formed multinucleated syncytia with cells expressing S protein. Furthermore, SARS coronavirus replicated efficiently on ACE2-transfected but not mock-transfected HEK293T cells. Finally, anti-ACE2 but not anti-ACE1 antibody blocked viral replication on Vero E6 cells. Li et al. (2003) concluded that ACE2 is a functional receptor for SARS coronavirus.
Jeffers et al. (2004) demonstrated that another human cellular glycoprotein, namely CD209L (605872), can serve as an alternative receptor for the SARS coronavirus.
Using retroviral pseudotypes to analyze cell tropism and receptor engagement, Hofmann et al. (2005) found that the S protein of NL63, a novel group I human coronavirus isolated from infants and immunocompromised adults, engaged the SARS receptor ACE2 for cellular entry. They also showed that replication of NL63 depended on ACE2. NL63 did not use CD13 (ANPEP; 151530), the receptor for the closely related group I coronavirus 229E. Neutralization assays demonstrated that sera from adults and children, but not infants, inhibited replication of NL63. In contrast, only a minority of sera inhibited replication of 229E, suggesting that NL63 infection is more frequent and typically occurs during childhood.
Kuba et al. (2005) hypothesized that the SARS coronavirus S protein could adversely affect acute lung injury through modulation of ACE2. Pull-down and FACS analyses demonstrated that S protein bound to ACE2 and downregulated ACE2 surface expression. Treatment of wildtype mice with S protein or with its truncated ACE2-binding domain worsened lung function. Acid challenge of these mice further augmented pathology to lung parenchyma. The S protein localized to bronchial epithelial cells, inflammatory exudates, and alveolar pneumocytes. Furthermore, S protein downregulated Ace2 expression in acid-treated wildtype mice and increased lung levels of angiotensin II. Blockage of angiotensin II receptor-1 (AGTR1; 106165), which mediates angiotensin II-induced vascular permeability and severe acute lung injury, attenuated lung injury in S protein-treated mice. Kuba et al. (2005) concluded that SARS coronavirus S protein can exaggerate acute lung failure through deregulation of the renin-angiotensin system, and that lung failure can be rescued by inhibition of AGTR1.
Hoffmann et al. (2020) showed that, like the SARS virus CoV-1, the CoV-2 virus enters cells by attachment to ACE2 receptors. Further, the viral S protein is processed (or primed) by the cellular protease TMPRSS2 (602060). The authors also showed that inhibitors of TMPRSS2 could block viral entry in cell culture, as could serum from convalescent patients.
Using immunostaining and flow cytometric assays in transfected HEK293T cells, Wang et al. (2020) identified the S1 C-terminal domain (CTD) as the key region of SARS-CoV-2 involved in interaction with human ACE2.
Crystal Structure
Wang et al. (2020) determined the 2.5-angstrom crystal structure of SARS-CoV-2 CTD in complex with human ACE2 and found that the receptor-binding mode was similar to that of SARS-CoV-1, but that SARS-CoV-2 had slightly stronger affinity due to key substitutions in the binding interface. Antibodies against the SARS-CoV-1 receptor-binding domain did not interact with the SARS-CoV-2 S protein, confirming important structural differences between the 2 viruses.
Lan et al. (2020) determined the crystal structure of the RBD of the S protein of SARS-CoV-2 bound to ACE2 at 2.45-angstrom resolution. The structure revealed that the overall ACE2-binding mode of the SARS-CoV-2 RBD is nearly identical to that of SARS-CoV, which also uses ACE2 as its cell receptor. Structural analysis identified residues in the SARS-CoV-2 RBD essential for ACE2 binding, most of which either are highly conserved or share similar side-chain properties with those in the SARS-CoV RBD. The authors noted that such similarity in structure and sequence indicates convergent evolution between the SARS-CoV-2 and SARS-CoV RBDs for improved binding to ACE2, even though SARS-CoV-2 does not cluster within SARS and SARS-related coronaviruses.
Independently, Shang et al. (2020) determined the crystal structure of the RBD of the S protein of SARS-CoV-2 in complex with ACE2 at 2.68-angstrom resolution. Compared with the SARS-CoV RBD, the ACE2-binding ridge in the SARS-CoV-2 RBD has a more compact conformation. Moreover, several residue changes in the SARS-CoV-2 RBD stabilize 2 virus-binding hotspots at the RBD-ACE2 interface. These structural features of the SARS-CoV-2 RBD increase its ACE2-binding affinity. Additionally, Shang et al. (2020) showed that RaTG13, a bat coronavirus closely related to SARS-CoV-2, also uses human ACE2 as its receptor.
Yuan et al. (2020) analyzed 294 anti-SARS-CoV-2 antibodies and found that immunoglobulin G heavy-chain variable region 3-53 (IGHV3-53) is the most frequently used IGHV gene for targeting the receptor-binding domain of the spike protein. Cocrystal structures of 2 IGHV3-53-neutralizing antibodies with receptor-binding domain, with or without Fab CR3022, at 2.33- to 3.20-angstrom resolution revealed that the germline-encoded residues dominate recognition of the ACE2-binding site. This binding mode limits the IGHV3-53 antibodies to short complementarity-determining region H3 loops but accommodates light-chain diversity. These IGHV3-53 antibodies show minimal affinity maturation and high potency.
Cryoelectron Microscopy
ACE2 is the cellular receptor for SARS-CoV and SARS-CoV-2. Yan et al. (2020) presented cryoelectron microscopy structures of full-length human ACE2 in the presence of the neutral amino acid transporter B(0)AT1 (SLC6A19; 608893) with or without the receptor-binding domain of the surface spike glycoprotein of SARS-CoV-2, both at an overall resolution of 2.9 angstroms, with a local resolution of 3.5 angstroms at the ACE2-receptor-binding domain interface. The ACE2-B(0)AT1 complex is assembled as a dimer of heterodimers, with the collectrin-like domain of ACE2 mediating homodimerization. The receptor-binding domain is recognized by the extracellular peptidase domain of ACE2 mainly through polar residues.
Wrapp et al. (2020) determined a 3.5-angstrom-resolution cryoelectron microscopy structure of the novel coronavirus SARS-CoV-2 spike glycoprotein (2019-nCoV S) trimer in the prefusion conformation. The predominant state of the trimer has 1 of the 3 receptor-binding domains (RBDs) rotated up in a receptor-accessible conformation. Wrapp et al. (2020) also provided biophysical and structural evidence that the 2019-nCoV S protein binds ACE2 with higher affinity than does the SARS-CoV spike protein. Additionally, the authors tested several published SARS-CoV RBD-specific monoclonal antibodies and found that they do not have appreciable binding to 2019-nCoV S, suggesting that antibody crossreactivity may be limited between the 2 RBDs.
Itoyama et al. (2005) identified 19 SNPs in the ACE2 gene. A case-control study found no association between these SNPs and SARS in the Vietnamese population.
Crackower et al. (2002) demonstrated that Ace2 maps to a defined quantitative trait locus (QTL) on the X chromosome in 3 different rat models of hypertension. In all hypertensive rat strains, Ace2 mRNA and protein expression were markedly reduced, suggesting that Ace2 is a candidate gene for this QTL. Targeted disruption of Ace2 in mice resulted in a severe cardiac contractility defect, increased angiotensin II (see 106150) levels, and upregulation of hypoxia-induced genes in the heart. Genetic ablation of Ace on an Ace2 mutant background completely rescues the cardiac phenotype. Crackower et al. (2002) showed that disruption of Acer, a Drosophila Ace2 homolog, resulted in a severe defect of heart morphogenesis. Crackower et al. (2002) concluded that Ace2 is an essential regulator of heart function in vivo.
Imai et al. (2005) reported that ACE2 and the angiotensin II type 2 receptor (300034) protect mice from severe acute lung injury induced by acid aspiration or sepsis. However, other components of the renin-angiotensin system, including ACE (106180), angiotensin II, and the angiotensin II type 1a receptor (106165), promote disease pathogenesis, induce lung edemas, and impair lung function. Imai et al. (2005) showed that mice deficient for ACE show markedly improved disease, and also that recombinant ACE2 can protect mice from severe acute lung injury. Imai et al. (2005) concluded that their data identified a critical function for ACE2 in acute lung injury.
Gurley et al. (2006) generated Ace2-deficient mice and found that they were viable, fertile, and had normal cardiac dimensions and function. After acute angiotensin II (AT2) infusion, plasma concentrations of AT2 increased almost 3-fold higher in Ace2-deficient mice than in controls. In a model of AT2-dependent hypertension, blood pressures were substantially higher in the Ace2-deficient mice than in wildtype mice, and severe hypertension in Ace2-deficient mice was associated with exaggerated accumulation of AT2 in the kidney. Although absence of functional ACE2 caused enhanced susceptibility to AT2-induced hypertension, the authors found no evidence for a role of ACE2 in the regulation of cardiac structure or function. Gurley et al. (2006) suggested that ACE2 is a functional component of the renin-angiotensin system, metabolizing AT2 and thereby contributing to the regulation of blood pressure.
Boehm, M., Nabel, E. G. Angiotensin-converting enzyme 2--a new cardiac regulator. New Eng. J. Med. 347: 1795-1797, 2002. [PubMed: 12456857] [Full Text: https://doi.org/10.1056/NEJMcibr022472]
Crackower, M. A., Sarao, R., Oudit, G. Y., Yagil, C., Kozieradzki, I., Scanga, S. E., Oliveira-dos-Santos, A. J., da Costa, J., Zhang, L., Pei, Y., Scholey, J., Ferrario, C. M., Manoukian, A. S., Chappell, M. C., Backx, P. H., Yagil, Y., Penninger, J. M. Angiotensin-converting enzyme 2 is an essential regulator of heart function. Nature 417: 822-828, 2002. [PubMed: 12075344] [Full Text: https://doi.org/10.1038/nature00786]
Gurley, S. B., Allred, A., Le, T. H., Griffiths, R., Mao, L., Philip, N., Haystead, T. A., Donoghue, M., Breitbart, R. E., Acton, S. L., Rockman, H. A., Coffman, T. M. Altered blood pressure responses and normal cardiac phenotype in ACE2-null mice. J. Clin. Invest. 116: 2218-2225, 2006. [PubMed: 16878172] [Full Text: https://doi.org/10.1172/JCI16980]
Harmer, D., Gilbert, M., Borman, R., Clark, K. L. Quantitative mRNA expression profiling of ACE 2, a novel homologue of angiotensin converting enzyme. FEBS Lett. 532: 107-110, 2002. [PubMed: 12459472] [Full Text: https://doi.org/10.1016/s0014-5793(02)03640-2]
Hashimoto, T., Perlot, T., Rehman, A., Trichereau, J., Ishiguro, H., Paolino, M., Sigl, V., Hanada, T., Hanada, R., Lipinski, S., Wild, B., Camargo, S. M. R., and 9 others. ACE2 links amino acid malnutrition to microbial ecology and intestinal inflammation. Nature 487: 477-481, 2012. [PubMed: 22837003] [Full Text: https://doi.org/10.1038/nature11228]
Hoffmann, M., Kleine-Weber, H., Schoeder, S., Kruger, N., Herrier, T., Erichsen, S., Schiergens, T. S., Herrier, G., Wu, N.-H., Nitsche, A., Muller, M. A., Drosten, C., Pohlmann, S. SARS-CoV-2 cell entry depends on ACE2 and TMPRESS2 and is blocked by a clinically proven protease inhibitor. Cell 181: 271-280, 2020. [PubMed: 32142651] [Full Text: https://doi.org/10.1016/j.cell.2020.02.052]
Hofmann, H., Pyrc, K., van der Hoek, L., Geier, M., Berkhout, B., Pohlmann, S. Human coronavirus NL63 employs the severe acute respiratory syndrome coronavirus receptor for cellular entry. Proc. Nat. Acad. Sci. 102: 7988-7993, 2005. [PubMed: 15897467] [Full Text: https://doi.org/10.1073/pnas.0409465102]
Imai, Y., Kuba, K., Rao, S., Huan, Y., Guo, F., Guan, B., Yang, P., Sarao, R., Wada, T., Leong-Poi, H., Crackower, M. A., Fukamizu, A., Hui, C.-C., Hein, L., Uhlig, S., Slutsky, A. S., Jiang, C., Penninger, J. M. Angiotensin-converting enzyme 2 protects from severe acute lung failure. Nature 436: 112-116, 2005. [PubMed: 16001071] [Full Text: https://doi.org/10.1038/nature03712]
Itoyama, S., Keicho, N., Hijikata, M., Quy, T., Phi, N. C., Long, H. T., Ha, L. D., Ban, V. V., Matsushita, I., Yanai, H., Kirikae, F., Kirikae, T., Kuratsuji, T., Sasazuki, T. Identification of an alternative 5-prime-untranslated exon and new polymorphisms of angiotensin-converting enzyme 2 gene: lack of association with SARS in the Vietnamese population. Am. J. Med. Genet. 136A: 52-57, 2005. [PubMed: 15937940] [Full Text: https://doi.org/10.1002/ajmg.a.30779]
Jeffers, S. A., Tusell, S. M., Gillim-Ross, L., Hemmila, E. M., Achenbach, J. E., Babcock, G. J., Thomas, W. D., Jr., Thackray, L. B., Young, M. D., Mason, R. J., Ambrosino, D. M., Wentworth, D. E., DeMartini, J. C., Holmes, K. V. CD209L (L-SIGN) is a receptor for severe acute respiratory syndrome coronavirus. Proc. Nat. Acad. Sci. 101: 15748-15753, 2004. [PubMed: 15496474] [Full Text: https://doi.org/10.1073/pnas.0403812101]
Kuba, K., Imai, Y., Rao, S., Gao, H., Guo, F., Guan, B., Huan, Y., Yang, P., Zhang, Y., Deng, W., Bao, L., Zhang, B., and 12 others. A crucial role of angiotensin converting enzyme 2 (ACE2) in SARS coronavirus-induced lung injury. Nature Med. 11: 875-879, 2005. [PubMed: 16007097] [Full Text: https://doi.org/10.1038/nm1267]
Lan, J., Ge, J., Yu, J., Shan, S., Zhou, H., Fan, S., Zhang, Q., Shi, X., Wang, Q., Zhang, L., Wang, X. Structure of the SARS-CoV-2 spike receptor-binding domain bound to the ACE2 receptor. Nature 581: 215-220, 2020. [PubMed: 32225176] [Full Text: https://doi.org/10.1038/s41586-020-2180-5]
Li, W., Moore, M. J., Vasilieva, N., Sui, J., Wong, S. K., Berne, M. A., Somasundaran, M., Sullivan, J. L., Luzuriaga, K., Greenough, T. C., Choe, H., Farzan, M. Angiotensin-converting enzyme 2 is a functional receptor for the SARS coronavirus. Nature 426: 450-454, 2003. [PubMed: 14647384] [Full Text: https://doi.org/10.1038/nature02145]
Shang, J., Ye, G., Shi, K., Wan, Y., Luo, C., Aihara, H., Geng, Q., Auerbach, A., Li, F. Structural basis of receptor recognition by SARS-CoV-2. Nature 581: 221-224, 2020. [PubMed: 32225175] [Full Text: https://doi.org/10.1038/s41586-020-2179-y]
Tipnis, S. R., Hooper, N. M., Hyde, R., Karran, E., Christie, G., Turner, A. J. A human homolog of angiotensin-converting enzyme: cloning and functional expression as a captopril-insensitive carboxypeptidase. J. Biol. Chem. 275: 33238-33243, 2000. [PubMed: 10924499] [Full Text: https://doi.org/10.1074/jbc.M002615200]
Wang, Q., Zhang, Y., Wu, L., Niu, S., Song, C., Zhang, Z., Lu, G., Qiao, C., Hu, Y., Yuen, K.-Y., Wang, Q., Zhou, H., Yan, J., Qi, J. Structural and functional basis of SARS-CoV-2 entry by using human ACE2. Cell 181: 894-904, 2020. [PubMed: 32275855] [Full Text: https://doi.org/10.1016/j.cell.2020.03.045]
Wrapp, D., Wang, N., Corbett, K. S., Goldsmith, J. A., Hsieh, C.-L., Abiona, O., Graham, B. S., McLellan, J. S. Cryo-EM structure of the 2019-nCoV spike in the prefusion conformation. Science 367: 1260-1263, 2020. [PubMed: 32075877] [Full Text: https://doi.org/10.1126/science.abb2507]
Yan, R., Zhang, Y., Li, Y., Xia, L., Guo, Y., Zhou, Q. Structural basis for the recognition of SARS-CoV-2 by full-length human ACE2. Science 367: 1444-1448, 2020. [PubMed: 32132184] [Full Text: https://doi.org/10.1126/science.abb2762]
Yuan, M., Liu, H., Wu, N. C., Lee, C.-C. D., Zhu, X., Zhao, F., Huang, D., Yu, W., Hua, Y., Tien, H., Rogers, T. F., Landais, E., Sok, D., Jardine, J. G., Burton, D. R., Wilson, I. A. Structural basis of a shared antibody response to SARS-CoV-2. Science 369: 1119-1123, 2020. [PubMed: 32661058] [Full Text: https://doi.org/10.1126/science.abd2321]