ACE2/structural biology project

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Angiotensin-converting enzyme 2 (ACE2) is a type I integral membrane protein. ACE2 is known to be localized in various organs such as lungs, stomach, small intestine, heart, testis and kidney [1]. It is also a component of the renin-angiotensin system (RAS), which plays mediating role in cardiovascular system [2]. The most recent studies shows, that the ACE2 has been identified as a functional receptor for the acute respiratory syndrome viruses [3][4].


FunctionFunction

ACE2 is a carboxypeptidase, which plays role in renin-angiotensin system (RAS)[5] as an antagonist of the ACE. Angiotensin II plays the central role in the RAS; and its production is catalized by ACE. ACE2 inactivates peptide angiotensine II (Ang II) by removing the C-terminal amino acid phenylalanine [6] Both ACE and ACE2 cleave Ang I, but instead of bechave as dipeptidase, The N-terminal domain of ACE2 cleaves Angiotensin I to produce Ang-(1-9), by removing the single C-terminal Leu residue [7].


Coexpression of ACE2 with B0AT1 plays role in amino acid transport. Specific interaction of both ACE2 and B0AT1 inrease expression of the B0AT1[8] Also ACE2 functions as a chaperone for the B0AT1[9].

Over- and/or underrepresented expression of the enzyme define a critical role in cardiovascular diseases [10].

ACE2 facilitates HCoV-NL63[11], SARS-CoV and SARS-CoV-2 entry, that is causing COVID-19 epidemic[12]. B0AT1 interacts with aminopeptidase N, another coronavirus receptor [13], but possibility of blocking of the ACE2 cleavage and suppressing of the SARS-CoV-2 infection will have been studying[14]


StructureStructure

The protein has considerable homology to human angeotensin converting enzyme (ACE); Single catalitic domain (amino acids 147-555) residues shared 41,8% identity with the human ACE. C-terminal end (amino acids 614-805) of the ACE2 protein shares 47,8% identity with its paralogue protein called collectrin [15].

Human ACE2 enzyme is composed of 805 amino acids. Extracelular region of the human ACE2 enzyme is composed of an N-terminal zinc metallopeptidase domain (PD) and a C-terminal collectrin-like domain (CLD) ends with a transmembrane helix and intracellular segment of 40 residues.

Subdomains I(N-terminus) and II(C-terminus) of the metallopeptidase domain of ACE2 form two sides of a cleft and connected at the floor of the active site of the cleft. Helix 17 (residues 511-531) connects to the subdomains and forms part of the floor.

The secondary structure of the metallopeptidase domain of the ACE2 is composed of 20 alpha-helical segments and 9 more helical segments. Only 6 short betta-structural segments are present[16]. Near the bottom and subdomain I sidethere is a location of the zinc-binding site. Zinc is coordinate by His374, His378, Glu402 and a water molecule [17].

A chloride ion is coordinated by Arg169, Trp477, and Lys481 in subdomain II.

Srtuctural information is limited to the PD domain because of transmembrane helix which makes the determination of the structure troubling.

ACE2-B0AT1 complexACE2-B0AT1 complex

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In the context of the complex, dimerisation of the ACE2 is mediated by neck domain. That complex has both open and closed conformations observed[18]. B0AT1 is coded by SLC6A19 gene. Mutations in that gene cause reduced activity of the B0AT1 protein, which leads to inability to absorb certain amino acids; and such condition is known as a Hurtnup disorder and may be inherited.


LocationLocation

ACE2 gene is located in Chromosome X on forward strand.

DeseaseDesease

Cardiovascular disease is associated with activation of the signaling pathways. ACE2 is localized in various tissues of the cardiovascular system [19]. Underexpression of the ACE2 results neutrophic inflamation in the infarct and pre-infarct regions[20].

Also ACE2 plays role in regulation of the blood pressure[21]. Highly expressed enzyme protects against hypertension.

ACE2 as a microbal entry receptorACE2 as a microbal entry receptor

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As a membrane protein, ACE2 serves as a functional receptor for coronaviruses, including SARS-CoV[22], SARS-CoV-2(causes COVID19)[23] and HCoV-NL63. S protein, also known as spike glycoprotein, mediates receptor recognition and fusion of the membrane[24]. During infection the cleavage of the S protein produces S1 and S2 subunits. S1 contains the receptor binding domain (RBD) and directly binds to the peptidase domain of ACE2 on the surface of cells. This spiking results in endocytosis and translocation of both virus and the enzyme, where S2 is responsible for the membrane fusion[25].

SARS-CoV RBD and SARS-CoV-2 RBD shares similarity[26]; but various conformational deviations are found. Substitution from SARS-CoV_RBD to SARS-CoV-2-RBD of Val404→Lys417, Tyr442→Leu455, Leu443→Phe456, Phe460→Tyr473, and Asn479→Gln493 may change affinity for ACE2.


ReferencesReferences

  1. ↑ Hamming I, Timens W, Bulthuis ML, Lely AT, Navis GJ, van Goor H. Tissue distribution of ACE2 protein, the functional receptor for SARS coronavirus. A first step in understanding SARS pathogenesis. J Pathol. 2004 Jun;203(2):631-7. PMID:15141377 doi:http://dx.doi.org/10.1002/path.1570
  2. ↑ Donoghue M, Hsieh F, Baronas E, Godbout K, Gosselin M, Stagliano N, Donovan M, Woolf B, Robison K, Jeyaseelan R, Breitbart RE, Acton S. A novel angiotensin-converting enzyme-related carboxypeptidase (ACE2) converts angiotensin I to angiotensin 1-9. Circ Res. 2000 Sep 1;87(5):E1-9. PMID:10969042
  3. ↑ Prabakaran P, Xiao X, Dimitrov DS. A model of the ACE2 structure and function as a SARS-CoV receptor. Biochem Biophys Res Commun. 2004 Jan 30;314(1):235-41. doi:, 10.1016/j.bbrc.2003.12.081. PMID:14715271 doi:http://dx.doi.org/10.1016/j.bbrc.2003.12.081
  4. ↑ Yan R, Zhang Y, Li Y, Xia L, Guo Y, Zhou Q. Structural basis for the recognition of the SARS-CoV-2 by full-length human ACE2. Science. 2020 Mar 4. pii: science.abb2762. doi: 10.1126/science.abb2762. PMID:32132184 doi:http://dx.doi.org/10.1126/science.abb2762
  5. ↑ Burrell LM, Johnston CI, Tikellis C, Cooper ME. ACE2, a new regulator of the renin-angiotensin system. Trends Endocrinol Metab. 2004 May-Jun;15(4):166-9. doi:, 10.1016/j.tem.2004.03.001. PMID:15109615 doi:http://dx.doi.org/10.1016/j.tem.2004.03.001
  6. ↑ Clayton D, Hanchapola I, Thomas WG, Widdop RE, Smith AI, Perlmutter P, Aguilar MI. Structural determinants for binding to angiotensin converting enzyme 2 (ACE2) and angiotensin receptors 1 and 2. Front Pharmacol. 2015 Jan 30;6:5. doi: 10.3389/fphar.2015.00005. eCollection, 2015. PMID:25688208 doi:http://dx.doi.org/10.3389/fphar.2015.00005
  7. ↑ Donoghue M, Hsieh F, Baronas E, Godbout K, Gosselin M, Stagliano N, Donovan M, Woolf B, Robison K, Jeyaseelan R, Breitbart RE, Acton S. A novel angiotensin-converting enzyme-related carboxypeptidase (ACE2) converts angiotensin I to angiotensin 1-9. Circ Res. 2000 Sep 1;87(5):E1-9. PMID:10969042
  8. ↑ Kowalczuk S, Broer A, Tietze N, Vanslambrouck JM, Rasko JE, Broer S. A protein complex in the brush-border membrane explains a Hartnup disorder allele. FASEB J. 2008 Aug;22(8):2880-7. doi: 10.1096/fj.08-107300. Epub 2008 Apr 18. PMID:18424768 doi:http://dx.doi.org/10.1096/fj.08-107300
  9. ↑ Gheblawi M, Wang K, Viveiros A, Nguyen Q, Zhong JC, Turner AJ, Raizada MK, Grant MB, Oudit GY. Angiotensin Converting Enzyme 2: SARS-CoV-2 Receptor and Regulator of the Renin-Angiotensin System. Circ Res. 2020 Apr 8. doi: 10.1161/CIRCRESAHA.120.317015. PMID:32264791 doi:http://dx.doi.org/10.1161/CIRCRESAHA.120.317015
  10. ↑ Patel VB, Zhong JC, Grant MB, Oudit GY. Role of the ACE2/Angiotensin 1-7 Axis of the Renin-Angiotensin System in Heart Failure. Circ Res. 2016 Apr 15;118(8):1313-26. doi: 10.1161/CIRCRESAHA.116.307708. PMID:27081112 doi:http://dx.doi.org/10.1161/CIRCRESAHA.116.307708
  11. ↑ 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 Natl Acad Sci U S A. 2005 May 31;102(22):7988-93. Epub 2005 May 16. PMID:15897467 doi:http://dx.doi.org/0409465102
  12. ↑ Yan R, Zhang Y, Li Y, Xia L, Guo Y, Zhou Q. Structural basis for the recognition of the SARS-CoV-2 by full-length human ACE2. Science. 2020 Mar 4. pii: science.abb2762. doi: 10.1126/science.abb2762. PMID:32132184 doi:http://dx.doi.org/10.1126/science.abb2762
  13. ↑ Jando J, Camargo SMR, Herzog B, Verrey F. Expression and regulation of the neutral amino acid transporter B0AT1 in rat small intestine. PLoS One. 2017 Sep 15;12(9):e0184845. doi: 10.1371/journal.pone.0184845., eCollection 2017. PMID:28915252 doi:http://dx.doi.org/10.1371/journal.pone.0184845
  14. ↑ Yan R, Zhang Y, Li Y, Xia L, Guo Y, Zhou Q. Structural basis for the recognition of the SARS-CoV-2 by full-length human ACE2. Science. 2020 Mar 4. pii: science.abb2762. doi: 10.1126/science.abb2762. PMID:32132184 doi:http://dx.doi.org/10.1126/science.abb2762
  15. ↑ Zhang Y, Wada J. Collectrin, a homologue of ACE2, its transcriptional control and functional perspectives. Biochem Biophys Res Commun. 2007 Nov 9;363(1):1-5. doi:, 10.1016/j.bbrc.2007.08.136. Epub 2007 Aug 31. PMID:17825789 doi:http://dx.doi.org/10.1016/j.bbrc.2007.08.136
  16. ↑ Towler P, Staker B, Prasad SG, Menon S, Tang J, Parsons T, Ryan D, Fisher M, Williams D, Dales NA, Patane MA, Pantoliano MW. ACE2 X-ray structures reveal a large hinge-bending motion important for inhibitor binding and catalysis. J Biol Chem. 2004 Apr 23;279(17):17996-8007. Epub 2004 Jan 30. PMID:14754895 doi:10.1074/jbc.M311191200
  17. ↑ Towler P, Staker B, Prasad SG, Menon S, Tang J, Parsons T, Ryan D, Fisher M, Williams D, Dales NA, Patane MA, Pantoliano MW. ACE2 X-ray structures reveal a large hinge-bending motion important for inhibitor binding and catalysis. J Biol Chem. 2004 Apr 23;279(17):17996-8007. Epub 2004 Jan 30. PMID:14754895 doi:10.1074/jbc.M311191200
  18. ↑ Towler P, Staker B, Prasad SG, Menon S, Tang J, Parsons T, Ryan D, Fisher M, Williams D, Dales NA, Patane MA, Pantoliano MW. ACE2 X-ray structures reveal a large hinge-bending motion important for inhibitor binding and catalysis. J Biol Chem. 2004 Apr 23;279(17):17996-8007. Epub 2004 Jan 30. PMID:14754895 doi:10.1074/jbc.M311191200
  19. ↑ Patel VB, Clarke N, Wang Z, Fan D, Parajuli N, Basu R, Putko B, Kassiri Z, Turner AJ, Oudit GY. Angiotensin II induced proteolytic cleavage of myocardial ACE2 is mediated by TACE/ADAM-17: a positive feedback mechanism in the RAS. J Mol Cell Cardiol. 2014 Jan;66:167-76. doi: 10.1016/j.yjmcc.2013.11.017. Epub, 2013 Dec 9. PMID:24332999 doi:http://dx.doi.org/10.1016/j.yjmcc.2013.11.017
  20. ↑ Kassiri Z, Zhong J, Guo D, Basu R, Wang X, Liu PP, Scholey JW, Penninger JM, Oudit GY. Loss of angiotensin-converting enzyme 2 accelerates maladaptive left ventricular remodeling in response to myocardial infarction. Circ Heart Fail. 2009 Sep;2(5):446-55. doi: 10.1161/CIRCHEARTFAILURE.108.840124. , Epub 2009 Jun 15. PMID:19808375 doi:http://dx.doi.org/10.1161/CIRCHEARTFAILURE.108.840124
  21. ↑ Diez-Freire C, Vazquez J, Correa de Adjounian MF, Ferrari MF, Yuan L, Silver X, Torres R, Raizada MK. ACE2 gene transfer attenuates hypertension-linked pathophysiological changes in the SHR. Physiol Genomics. 2006 Oct 3;27(1):12-9. doi: 10.1152/physiolgenomics.00312.2005., Epub 2006 Jun 20. PMID:16788004 doi:http://dx.doi.org/10.1152/physiolgenomics.00312.2005
  22. ↑ Fehr AR, Perlman S. Coronaviruses: an overview of their replication and pathogenesis. Methods Mol Biol. 2015;1282:1-23. doi: 10.1007/978-1-4939-2438-7_1. PMID:25720466 doi:http://dx.doi.org/10.1007/978-1-4939-2438-7_1
  23. ↑ Yan R, Zhang Y, Li Y, Xia L, Guo Y, Zhou Q. Structural basis for the recognition of the SARS-CoV-2 by full-length human ACE2. Science. 2020 Mar 4. pii: science.abb2762. doi: 10.1126/science.abb2762. PMID:32132184 doi:http://dx.doi.org/10.1126/science.abb2762
  24. ↑ Simmons G, Zmora P, Gierer S, Heurich A, Pohlmann S. Proteolytic activation of the SARS-coronavirus spike protein: cutting enzymes at the cutting edge of antiviral research. Antiviral Res. 2013 Dec;100(3):605-14. doi: 10.1016/j.antiviral.2013.09.028. Epub, 2013 Oct 8. PMID:24121034 doi:http://dx.doi.org/10.1016/j.antiviral.2013.09.028
  25. ↑ Wang H, Yang P, Liu K, Guo F, Zhang Y, Zhang G, Jiang C. SARS coronavirus entry into host cells through a novel clathrin- and caveolae-independent endocytic pathway. Cell Res. 2008 Feb;18(2):290-301. doi: 10.1038/cr.2008.15. PMID:18227861 doi:http://dx.doi.org/10.1038/cr.2008.15
  26. ↑ Yan R, Zhang Y, Li Y, Xia L, Guo Y, Zhou Q. Structural basis for the recognition of the SARS-CoV-2 by full-length human ACE2. Science. 2020 Mar 4. pii: science.abb2762. doi: 10.1126/science.abb2762. PMID:32132184 doi:http://dx.doi.org/10.1126/science.abb2762

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This page was developed for the course on Structural biology of the cell at Charles University.

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