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UniProt functional annotation for Q9BYF1 | ||
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| UniProt code: Q9BYF1. |
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| Organism: | |
Homo sapiens (Human). |
| Taxonomy: | |
Eukaryota; Metazoa; Chordata; Craniata; Vertebrata; Euteleostomi; Mammalia; Eutheria; Euarchontoglires; Primates; Haplorrhini; Catarrhini; Hominidae; Homo. |
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| Function: | |
Essential counter-regulatory carboxypeptidase of the renin- angiotensin hormone system that is a critical regulator of blood volume, systemic vascular resistance, and thus cardiovascular homeostasis (PubMed:27217402). Converts angiotensin I to angiotensin 1- 9, a nine-amino acid peptide with anti-hypertrophic effects in cardiomyocytes, and angiotensin II to angiotensin 1-7, which then acts as a beneficial vasodilator and anti-proliferation agent, counterbalancing the actions of the vasoconstrictor angiotensin II (PubMed:10969042, PubMed:10924499, PubMed:11815627, PubMed:19021774, PubMed:14504186). Also removes the C-terminal residue from three other vasoactive peptides, neurotensin, kinetensin, and des-Arg bradykinin, but is not active on bradykinin (PubMed:10969042, PubMed:11815627). Also cleaves other biological peptides, such as apelins (apelin-13, [Pyr1]apelin-13, apelin-17, apelin-36), casomorphins (beta-casomorphin- 7, neocasomorphin) and dynorphin A with high efficiency (PubMed:11815627, PubMed:27217402, PubMed:28293165). In addition, ACE2 C-terminus is homologous to collectrin and is responsible for the trafficking of the neutral amino acid transporter SL6A19 to the plasma membrane of gut epithelial cells via direct interaction, regulating its expression on the cell surface and its catalytic activity (PubMed:18424768, PubMed:19185582). {ECO:0000269|PubMed:10924499, ECO:0000269|PubMed:10969042, ECO:0000269|PubMed:11815627, ECO:0000269|PubMed:14504186, ECO:0000269|PubMed:18424768, ECO:0000269|PubMed:19021774, ECO:0000269|PubMed:19185582, ECO:0000269|PubMed:27217402}. |
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| Function: | |
[Isoform 2]: Non-functional as a carboxypeptidase. {ECO:0000269|PubMed:33077916}. |
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| Function: | |
(Microbial infection) Acts as a receptor for human coronaviruses SARS-CoV and SARS-CoV-2, as well as human coronavirus NL63/HCoV-NL63. {ECO:0000269|PubMed:14647384, ECO:0000269|PubMed:15452268, ECO:0000269|PubMed:15791205, ECO:0000269|PubMed:15897467, ECO:0000269|PubMed:19901337, ECO:0000269|PubMed:24227843, ECO:0000269|PubMed:32142651, ECO:0000269|PubMed:32155444, ECO:0000269|PubMed:32221306, ECO:0000269|PubMed:32225175, ECO:0000269|PubMed:33000221, ECO:0000269|PubMed:33082294, ECO:0000269|PubMed:33432067}. |
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| Function: | |
[Isoform 2]: (Microbial infection) Non-functional as a receptor for human coronavirus SARS-CoV-2. {ECO:0000269|PubMed:33077916, ECO:0000269|PubMed:33432184}. |
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| Catalytic activity: | |
Reaction=angiotensin II + H2O = angiotensin-(1-7) + L-phenylalanine; Xref=Rhea:RHEA:26554, ChEBI:CHEBI:15377, ChEBI:CHEBI:58095, ChEBI:CHEBI:58506, ChEBI:CHEBI:58922; EC=3.4.17.23; Evidence={ECO:0000269|PubMed:10924499, ECO:0000269|PubMed:11815627, ECO:0000269|PubMed:19021774, ECO:0000305|PubMed:14504186}; PhysiologicalDirection=left-to-right; Xref=Rhea:RHEA:26555; Evidence={ECO:0000269|PubMed:14504186}; |
| Catalytic activity: | |
Reaction=angiotensin I + H2O = angiotensin-(1-9) + L-leucine; Xref=Rhea:RHEA:63532, ChEBI:CHEBI:15377, ChEBI:CHEBI:57427, ChEBI:CHEBI:147350, ChEBI:CHEBI:147351; Evidence={ECO:0000269|PubMed:10924499, ECO:0000269|PubMed:10969042, ECO:0000269|PubMed:11815627, ECO:0000269|PubMed:19021774}; PhysiologicalDirection=left-to-right; Xref=Rhea:RHEA:63533; Evidence={ECO:0000305|PubMed:10924499, ECO:0000305|PubMed:10969042, ECO:0000305|PubMed:11815627, ECO:0000305|PubMed:19021774}; |
| Catalytic activity: | |
Reaction=[des-Arg(9)]-bradykinin + H2O = [des-Phe(8), des-Arg(9)]- bradykinin + L-phenylalanine; Xref=Rhea:RHEA:63536, ChEBI:CHEBI:15377, ChEBI:CHEBI:58095, ChEBI:CHEBI:133069, ChEBI:CHEBI:147352; Evidence={ECO:0000269|PubMed:10969042, ECO:0000269|PubMed:11815627}; PhysiologicalDirection=left-to-right; Xref=Rhea:RHEA:63537; Evidence={ECO:0000305|PubMed:10969042, ECO:0000305|PubMed:11815627}; |
| Catalytic activity: | |
Reaction=H2O + neurotensin = L-leucine + neurotensin-(1-12); Xref=Rhea:RHEA:63540, ChEBI:CHEBI:15377, ChEBI:CHEBI:57427, ChEBI:CHEBI:147362, ChEBI:CHEBI:147363; Evidence={ECO:0000269|PubMed:10969042}; PhysiologicalDirection=left-to-right; Xref=Rhea:RHEA:63541; Evidence={ECO:0000305|PubMed:10969042}; |
| Catalytic activity: | |
Reaction=H2O + neurotensin-(1-8) = L-arginine + neurotensin-(1-7); Xref=Rhea:RHEA:63572, ChEBI:CHEBI:15377, ChEBI:CHEBI:32682, ChEBI:CHEBI:147393, ChEBI:CHEBI:147394; Evidence={ECO:0000269|PubMed:11815627}; PhysiologicalDirection=left-to-right; Xref=Rhea:RHEA:63573; Evidence={ECO:0000305|PubMed:11815627}; |
| Catalytic activity: | |
Reaction=H2O + kinetensin = kinetensin-(1-8) + L-leucine; Xref=Rhea:RHEA:63544, ChEBI:CHEBI:15377, ChEBI:CHEBI:57427, ChEBI:CHEBI:147364, ChEBI:CHEBI:147365; Evidence={ECO:0000269|PubMed:10969042}; PhysiologicalDirection=left-to-right; Xref=Rhea:RHEA:63545; Evidence={ECO:0000305|PubMed:10969042}; |
| Catalytic activity: | |
Reaction=dynorphin A-(1-13) + H2O = dynorphin A-(1-12) + L-lysine; Xref=Rhea:RHEA:63556, ChEBI:CHEBI:15377, ChEBI:CHEBI:32551, ChEBI:CHEBI:147381, ChEBI:CHEBI:147383; Evidence={ECO:0000269|PubMed:11815627}; PhysiologicalDirection=left-to-right; Xref=Rhea:RHEA:63557; Evidence={ECO:0000305|PubMed:11815627}; |
| Catalytic activity: | |
Reaction=apelin-13 + H2O = apelin-12 + L-phenylalanine; Xref=Rhea:RHEA:63564, ChEBI:CHEBI:15377, ChEBI:CHEBI:58095, ChEBI:CHEBI:147395, ChEBI:CHEBI:147396; Evidence={ECO:0000269|PubMed:11815627}; PhysiologicalDirection=left-to-right; Xref=Rhea:RHEA:63565; Evidence={ECO:0000305|PubMed:11815627}; |
| Catalytic activity: | |
Reaction=[Pyr1]apelin-13 + H2O = [Pyr1]apelin-12 + L-phenylalanine; Xref=Rhea:RHEA:63604, ChEBI:CHEBI:15377, ChEBI:CHEBI:58095, ChEBI:CHEBI:147415, ChEBI:CHEBI:147416; Evidence={ECO:0000269|PubMed:27217402, ECO:0000269|PubMed:28293165}; PhysiologicalDirection=left-to-right; Xref=Rhea:RHEA:63605; Evidence={ECO:0000269|PubMed:27217402}; |
| Catalytic activity: | |
Reaction=apelin-17 + H2O = apelin-16 + L-phenylalanine; Xref=Rhea:RHEA:63608, ChEBI:CHEBI:15377, ChEBI:CHEBI:58095, ChEBI:CHEBI:147421, ChEBI:CHEBI:147422; Evidence={ECO:0000269|PubMed:27217402}; PhysiologicalDirection=left-to-right; Xref=Rhea:RHEA:63609; Evidence={ECO:0000269|PubMed:27217402}; |
| Catalytic activity: | |
Reaction=beta-casomorphin-7 + H2O = beta-casomorphin-6 + L-isoleucine; Xref=Rhea:RHEA:63568, ChEBI:CHEBI:15377, ChEBI:CHEBI:58045, ChEBI:CHEBI:147390, ChEBI:CHEBI:147391; Evidence={ECO:0000269|PubMed:11815627}; PhysiologicalDirection=left-to-right; Xref=Rhea:RHEA:63569; Evidence={ECO:0000305|PubMed:11815627}; |
| Catalytic activity: | |
Reaction=H2O + neocasomorphin = L-isoleucine + neocasomorphin-(1-5); Xref=Rhea:RHEA:63600, ChEBI:CHEBI:15377, ChEBI:CHEBI:58045, ChEBI:CHEBI:147417, ChEBI:CHEBI:147418; Evidence={ECO:0000269|PubMed:11815627}; PhysiologicalDirection=left-to-right; Xref=Rhea:RHEA:63601; Evidence={ECO:0000305|PubMed:11815627}; |
| Cofactor: | |
Name=Zn(2+); Xref=ChEBI:CHEBI:29105; Evidence={ECO:0000269|PubMed:11815627}; Note=Binds 1 zinc ion per subunit. {ECO:0000269|PubMed:11815627}; |
| Cofactor: | |
Name=chloride; Xref=ChEBI:CHEBI:17996; Evidence={ECO:0000269|PubMed:11815627}; Note=Binds 1 Cl(-) ion per subunit. {ECO:0000269|PubMed:11815627}; |
| Activity regulation: | |
Regulated by chloride and fluoride, but not bromide (PubMed:11815627). Chloride increases angiotensin I and decreases angiotensin II cleavage (PubMed:19021774). Inhibited by MLN- 4760, cFP_Leu, and EDTA (PubMed:15231706, PubMed:10924499), but not by the ACE inhibitors lisinopril, captopril and enalaprilat (PubMed:10969042, PubMed:10924499). Highly potent and selective in vitro ACE2 inhibitors were identified (PubMed:12358520). {ECO:0000269|PubMed:10924499, ECO:0000269|PubMed:10969042, ECO:0000269|PubMed:11815627, ECO:0000269|PubMed:12358520, ECO:0000269|PubMed:15231706, ECO:0000269|PubMed:19021774}. |
| Biophysicochemical properties: | |
Kinetic parameters: KM=6.9 uM for angiotensin I {ECO:0000269|PubMed:11815627}; KM=2.0 uM for angiotensin II {ECO:0000269|PubMed:11815627}; KM=6.8 uM for apelin-13 {ECO:0000269|PubMed:11815627}; KM=290 uM for [des-Arg(9)]-bradykinin {ECO:0000269|PubMed:11815627}; KM=130 uM for Lys-[des-Arg(9)]-bradykinin {ECO:0000269|PubMed:11815627}; KM=31 uM for beta-casomorphin {ECO:0000269|PubMed:11815627}; KM=5.5 uM for dynorphin A-(1-13) {ECO:0000269|PubMed:11815627}; KM=300 uM for neurotensin-(1-8) {ECO:0000269|PubMed:11815627}; KM=58.6 uM for angiotensin II {ECO:0000269|PubMed:19021774}; KM=12 uM for [Pyr1]apelin-13 {ECO:0000269|PubMed:27217402}; KM=19 uM for apelin-17 {ECO:0000269|PubMed:27217402}; Vmax=28.7 nmol/min/mg enzyme with angiotensin II as substrate {ECO:0000269|PubMed:19021774}; Note=kcat is 0.034 sec(-1) with angiotensin I as substrate. kcat is 3.5 sec(-1) with angiotensin II as substrate. kcat is 13 sec(-1) with apelin-13 as substrate. kcat is 62 sec(-1) with [des-Arg(9)]- bradykinin as substrate. kcat is 26 sec(-1) with Lys-[des-Arg(9)]- bradykinin as substrate. kcat is 6.8 sec(-1) with beta-casomorphin as substrate. kcat is 16 sec(-1) with dynorphin A-(1-13) as substrate. kcat is 57 sec(-1) with neurotensin-(1-8) as substrate (PubMed:11815627). kcat is 19.1 sec(-1) with [Pyr1]apelin-13 as substrate. kcat is 7.7 sec(-1) with apelin-17 as substrate (PubMed:27217402). {ECO:0000269|PubMed:11815627, ECO:0000269|PubMed:27217402}; pH dependence: Optimum pH is 6.5 in the presence of 1 M NaCl. Active from pH 6 to 9. {ECO:0000269|PubMed:11815627}; |
| Subunit: | |
Homodimer (PubMed:32132184). Interacts with the catalytically active form of TMPRSS2 (PubMed:21068237). Interacts with SLC6A19; this interaction is essential for expression and function of SLC6A19 in intestine (By similarity). Interacts with ITGA5:ITGB1 (PubMed:15276642, PubMed:33102950). Probably interacts (via endocytic sorting signal motif) with AP2M1; the interaction is inhibited by phosphorylation of Tyr-781 (PubMed:33436498). {ECO:0000250|UniProtKB:Q8R0I0, ECO:0000269|PubMed:15276642, ECO:0000269|PubMed:21068237, ECO:0000269|PubMed:32132184, ECO:0000269|PubMed:33102950, ECO:0000269|PubMed:33436498}. |
| Subunit: | |
(Microbial infection) Interacts with SARS coronavirus/SARS-CoV spike protein. {ECO:0000269|PubMed:14647384, ECO:0000269|PubMed:15452268, ECO:0000269|PubMed:15791205, ECO:0000269|PubMed:32225175}. |
| Subunit: | |
(Microbial infection) Interacts with SARS coronavirus-2/SARS- CoV-2 spike protein. {ECO:0000269|PubMed:32075877, ECO:0000269|PubMed:32132184, ECO:0000269|PubMed:32155444, ECO:0000269|PubMed:32225175, ECO:0000269|PubMed:32753553, ECO:0000269|PubMed:33102950, ECO:0000269|PubMed:33432067}. |
| Subunit: | |
(Microbial infection) Interacts with human coronavirus NL63 spike protein. {ECO:0000269|PubMed:19901337}. |
| Subunit: | |
(Microbial infection) Interacts with human coronavirus NL63/HCoV-NL63 spike glycoprotein. {ECO:0000269|PubMed:15897467}. |
| Subunit: | |
[Processed angiotensin-converting enzyme 2]: (Microbial infection) Interacts with SARS coronavirus-2/SARS-CoV-2 spike protein; the interaction is increased by AVP/Arg-vasopressin whith which they may form a complex. {ECO:0000269|PubMed:33713620}. |
| Subcellular location: | |
[Processed angiotensin-converting enzyme 2]: Secreted {ECO:0000269|PubMed:15983030, ECO:0000269|PubMed:33713620}. |
| Subcellular location: | |
Cell membrane {ECO:0000269|PubMed:18424768}; Single-pass type I membrane protein {ECO:0000255}. Cytoplasm {ECO:0000250|UniProtKB:Q8R0I0}. Cell projection, cilium {ECO:0000269|PubMed:33432184}. Apical cell membrane {ECO:0000269|PubMed:33432184}. Note=Detected in both cell membrane and cytoplasm in neurons. {ECO:0000250|UniProtKB:Q8R0I0}. |
| Subcellular location: | |
[Isoform 2]: Apical cell membrane {ECO:0000269|PubMed:33432184}. |
| Tissue specificity: | |
Expressed in endothelial cells from small and large arteries, and in arterial smooth muscle cells (at protein level) (PubMed:15141377). Expressed in enterocytes of the small intestine, Leydig cells and Sertoli cells (at protein level) (PubMed:15141377). Expressed in the renal proximal tubule and the small intestine (at protein level) (PubMed:18424768). Expressed in heart, kidney, testis, and gastrointestinal system (at protein level) (PubMed:10969042, PubMed:10924499, PubMed:15231706, PubMed:12459472, PubMed:15671045, PubMed:32715618, PubMed:32170560). In lung, expressed at low levels in some alveolar type 2 cells, the expression seems to be individual- specific (at protein level) (PubMed:32425701, PubMed:15141377, PubMed:32715618, PubMed:32170560, PubMed:33432184). Expressed in nasal epithelial cells (at protein level) (PubMed:33432184, PubMed:32333915). Coexpressed with TMPRSS2 within some lung alveolar type 2 cells, ileal absorptive enterocytes, intestinal epithelial cells, cornea, gallbladder and nasal goblet secretory cells (PubMed:32413319, PubMed:32327758, PubMed:32358202). Coexpressed with TMPRSS4 within mature enterocytes (PubMed:32404436). {ECO:0000269|PubMed:10924499, ECO:0000269|PubMed:10969042, ECO:0000269|PubMed:12459472, ECO:0000269|PubMed:15141377, ECO:0000269|PubMed:15231706, ECO:0000269|PubMed:15671045, ECO:0000269|PubMed:18424768, ECO:0000269|PubMed:32170560, ECO:0000269|PubMed:32327758, ECO:0000269|PubMed:32333915, ECO:0000269|PubMed:32358202, ECO:0000269|PubMed:32404436, ECO:0000269|PubMed:32413319, ECO:0000269|PubMed:32425701, ECO:0000269|PubMed:32715618, ECO:0000269|PubMed:33432184}. |
| Tissue specificity: | |
[Isoform 2]: Expressed in nasal and bronchial epithelial cells (at protein level). {ECO:0000269|PubMed:33432184}. |
| Induction: | |
Up-regulated in failing heart (PubMed:14504186, PubMed:15151696, PubMed:15671045). Expression is induced by IFNA and IFNG (PubMed:32413319, PubMed:32425701). Exposure to cigarette smoke increases expression in lungs (PubMed:32425701). Expression is decreased in nasal and bronchial epithelium of individuals with allergy after allergen challenge (PubMed:32333915). IL13 stimulation decreases expression in nasal and bronchial epithelium (PubMed:32333915). {ECO:0000269|PubMed:14504186, ECO:0000269|PubMed:15151696, ECO:0000269|PubMed:15671045, ECO:0000269|PubMed:32333915, ECO:0000269|PubMed:32413319, ECO:0000269|PubMed:32425701}. |
| Induction: | |
[Isoform 1]: Not induced by interferons such as IFNA, IFNB and IFNG. {ECO:0000269|PubMed:33077916}. |
| Induction: | |
[Isoform 2]: Expression is induced by interferons such as IFNA, IFNB and IFNG. It seems that isoform 2 is an interferon- stimulated gene (ISG) but not isoform 1. {ECO:0000269|PubMed:33077916}. |
| Induction: | |
(Microbial infection) In airway epithelial cells, expression is increased upon influenza A virus infection (PubMed:32413319). {ECO:0000269|PubMed:32413319}. |
| Induction: | |
[Isoform 2]: (Microbial infection) In airway epithelial cells, expression is induced by viruses such rhinoviruses and influenza virus. {ECO:0000269|PubMed:33077916, ECO:0000269|PubMed:33432184}. |
| Induction: | |
[Isoform 2]: (Microbial infection) Induced by human coronavirus SARS-CoV-2. {ECO:0000269|PubMed:33077916}. |
| Domain: | |
The extracellular region of the ACE2 enzyme is composed of two domains. The first is a zinc metallopeptidase domain (residues 19-611). The second domain is located at the C-terminus (residues 612-740) and is 48% identical to human collectrin. {ECO:0000269|PubMed:14754895}. |
| Domain: | |
The cytoplasmic tail contains several linear motifs such as LIR, PDZ-binding, PTB and endocytic sorting signal motifs that would allow interation with proteins that mediate endocytic trafficking and autophagy. {ECO:0000305|PubMed:33436497, ECO:0000305|PubMed:33436498}. |
| Ptm: | |
N-glycosylation on Asn-90 may limit SARS infectivity. {ECO:0000269|PubMed:10924499, ECO:0000269|PubMed:14647384, ECO:0000269|PubMed:14754895, ECO:0000269|PubMed:15084671, ECO:0000269|PubMed:19159218}. |
| Ptm: | |
Proteolytic cleavage by ADAM17 generates a secreted form (PubMed:15983030, PubMed:33713620). Also cleaved by serine proteases: TMPRSS2, TMPRSS11D and HPN/TMPRSS1. {ECO:0000269|PubMed:15983030, ECO:0000269|PubMed:21068237, ECO:0000269|PubMed:21563828, ECO:0000269|PubMed:24227843, ECO:0000269|PubMed:32132184, ECO:0000269|PubMed:33713620}. |
| Ptm: | |
Phosphorylated. Phosphorylation at Tyr-781 probably inhibits interaction with AP2M1 and enables interactions with proteins containing SH2 domains. {ECO:0000305|PubMed:33436497, ECO:0000305|PubMed:33436498}. |
| Biotechnology: | |
An engeneered stable, dimeric and secreted receptor with combined mutations that increase the affinity for human coronavirus SARS-CoV-2 spike protein shows potent SARS-CoV and SARS-CoV-2 neutralization in vitro. {ECO:0000269|PubMed:32753553}. |
| Similarity: | |
Belongs to the peptidase M2 family. {ECO:0000305}. |
| Sequence caution: | |
Sequence=AAQ89076.1; Type=Miscellaneous discrepancy; Evidence={ECO:0000305}; |
Annotations taken from UniProtKB at the EBI.