Proteopedia - User contributions [en]

ACE2/structural biology project

2020-04-17T05:49:49Z

Aleksandra Shumilova:

<Structure load='1r42' size='350' frame='true' align='right' caption='Insert caption here' scene='Insert optional scene name here' />

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 <ref>PMID:15141377</ref>. It is also a component of the renin-angiotensin system (RAS), which plays mediating role in cardiovascular system <ref>PMID:10969042</ref>. The most recent studies shows, that the ACE2 has been identified as a functional receptor for the acute respiratory syndrome viruses <ref>PMID:14715271</ref><ref>DOI:10.1126/science.abb2762</ref>.

== Function ==
ACE2 is a carboxypeptidase, which plays role in renin-angiotensin system (RAS)<ref>PMID:15109615</ref> 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 <ref>PMID:25688208</ref> 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 <ref>PMID:10969042</ref>.

Coexpression of ACE2 with B0AT1 plays role in amino acid transport. Specific interaction of both ACE2 and B0AT1 inrease expression of the B0AT1<ref>PMID:18424768</ref> Also ACE2 functions as a chaperone for the B0AT1<ref>PMID:32264791</ref>.

Over- and/or underrepresented expression of the enzyme define a critical role in cardiovascular diseases <ref>PMID:27081112</ref>.

ACE2 facilitates HCoV-NL63<ref>PMID: 15897467</ref>, SARS-CoV and SARS-CoV-2 entry, that is causing COVID-19 epidemic<ref>DOI: 10.1126/science.abb2762</ref>. B0AT1 interacts with aminopeptidase N, another coronavirus receptor <ref>PMID:28915252</ref>, but possibility of blocking of the ACE2 cleavage and suppressing of the SARS-CoV-2 infection will have been studying<ref>DOI: 10.1126/science.abb2762</ref>

== Structure==

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 <ref>PMID:17825789</ref>.

[[Image:1-s2.0-S0006291X07018402-gr2.jpg]]

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<ref>PMID: 14754895</ref>.
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 <ref>PMID: 14754895</ref>.

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 complex ==
<Structure load='6M18' size='350' frame='true' align='right' caption='Insert caption here' scene='Insert optional scene name here' />

In the context of the complex, dimerisation of the ACE2 is mediated by neck domain. That complex has both open and closed conformations observed<ref>PMID: 14754895</ref>. 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.

== Location ==

ACE2 gene is located in Chromosome X on forward strand.

== Desease ==

Cardiovascular disease is associated with activation of the signaling pathways. ACE2 is localized in various tissues of the cardiovascular system <ref>PMID: 24332999 </ref>. Underexpression of the ACE2 results neutrophic inflamation in the infarct and pre-infarct regions<ref>PMID: 19808375 </ref>.

Also ACE2 plays role in regulation of the blood pressure<ref>PMID: 16788004</ref>. Highly expressed enzyme protects against hypertension.

== ACE2 as a microbal entry receptor ==

<Structure load='2AJF' size='350' frame='true' align='right' caption='Insert caption here' scene='Insert optional scene name here' />
As a membrane protein, ACE2 serves as a functional receptor for coronaviruses, including SARS-CoV<ref>PMID:25720466</ref>, SARS-CoV-2(causes COVID19)<ref>DOI: 10.1126/science.abb2762</ref> and HCoV-NL63. S protein, also known as spike glycoprotein, mediates receptor recognition and fusion of the membrane<ref>PMID:24121034</ref>. 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<ref>PMID:18227861</ref>.

SARS-CoV RBD and SARS-CoV-2 RBD shares similarity<ref>DOI: 10.1126/science.abb2762</ref>; 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.

== References ==
<references/>

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

ACE2/structural biology project

2020-04-17T05:40:21Z

Aleksandra Shumilova:

ACE2/structural biology project

2020-04-17T05:36:13Z

Aleksandra Shumilova:

<Structure load='1r42' size='350' frame='true' align='right' caption='Insert caption here' scene='Insert optional scene name here' />

Angiotensin-converting enzyme 2 (ACE2) is a type I integral membrane protain.
ACE2 is known to be localized in various organs such as lungs, stomach, small intestine, heart, testis and kidney <ref>PMID:15141377</ref>. It is also a component of the renin-angiotensin system (RAS), which plays mediating role in cardiovascular system <ref>PMID:10969042</ref>. The most recent studies shows, that the ACE2 has been identified as a functional receptor for the acute respiratory syndrome viruses <ref>PMID:14715271</ref><ref>DOI:10.1126/science.abb2762</ref>.

== Function ==
ACE2 is a carboxypeptidase, which plays role in renin-angiotensin system (RAS)<ref>PMID:15109615</ref> 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 <ref>PMID:25688208</ref> 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 <ref>PMID:10969042</ref>.

Coexpression of ACE2 with B0AT1 plays role in amino acid transport. Specific interaction of both ACE2 and B0AT1 inrease expression of the B0AT1<ref>PMID:18424768</ref> Also ACE2 functions as a chaperone for the B0AT1<ref>PMID:32264791</ref>.

Over- and/or underrepresented expression of the enzyme define a critical role in cardiovascular diseases <ref>PMID:27081112</ref>.

ACE2 facilitates HCoV-NL63<ref>PMID: 15897467</ref>, SARS-CoV and SARS-CoV-2 entry, that is causing COVID-19 epidemic<ref>DOI: 10.1126/science.abb2762</ref>. B0AT1 interacts with aminopeptidase N, another coronavirus receptor <ref>PMID:28915252</ref>, but possibility of blocking of the ACE2 cleavage and suppressing of the SARS-CoV-2 infection will have been studying<ref>DOI: 10.1126/science.abb2762</ref>

== Structure==

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 <ref>PMID:17825789</ref>.

[[Image:1-s2.0-S0006291X07018402-gr2.jpg]]

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<ref>PMID: 14754895</ref>.
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 <ref>PMID: 14754895</ref>.

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 complex ==
<Structure load='6M18' size='350' frame='true' align='right' caption='Insert caption here' scene='Insert optional scene name here' />

In the context of the complex, dimerisation of the ACE2 is mediated by neck domain. That complex has both open and closed conformations observed<ref>PMID: 14754895</ref>. 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.

== Location ==

ACE2 gene is located in Chromosome X on forward strand.

== Desease ==

Cardiovascular disease is associated with activation of the signaling pathways. ACE2 is localized in various tissues of the cardiovascular system <ref>PMID: 24332999 </ref>. Underexpression of the ACE2 results neutrophic inflamation in the infarct and pre-infarct regions<ref>PMID: 19808375 </ref>.

Also ACE2 plays role in regulation of the blood pressure<ref>PMID: 16788004</ref>. Highly expressed enzyme protects against hypertension.

== ACE2 as a microbal entry receptor ==

<Structure load='2AJF' size='350' frame='true' align='right' caption='Insert caption here' scene='Insert optional scene name here' />
As a membrane protein, ACE2 serves as a functional receptor for coronaviruses, including SARS-CoV<ref>PMID:25720466</ref>, SARS-CoV-2(causes COVID19)<ref>DOI: 10.1126/science.abb2762</ref> and HCoV-NL63. S protein, also known as spike glycoprotein, mediates receptor recognition and fusion of the membrane<ref>PMID:24121034</ref>. 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<ref>PMID:18227861</ref>.

SARS-CoV RBD and SARS-CoV-2 RBD shares similarity<ref>DOI: 10.1126/science.abb2762</ref>; 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.

== References ==
<references/>

ACE2/structural biology project

2020-04-17T05:34:50Z

Aleksandra Shumilova:

<Structure load='1r42' size='350' frame='true' align='right' caption='Insert caption here' scene='Insert optional scene name here' />

Angiotensin-converting enzyme 2 (ACE2) is a type I integral membrane protain.
ACE2 is known to be localized in various organs such as lungs, stomach, small intestine, heart, testis and kidney <ref>PMID:15141377</ref>. It is also a component of the renin-angiotensin system (RAS), which plays mediating role in cardiovascular system <ref>PMID:10969042</ref>. The most recent studies shows, that the ACE2 has been identified as a functional receptor for the acute respiratory syndrome viruses <ref>PMID:14715271</ref><ref>DOI:10.1126/science.abb2762</ref>.

== Function ==
ACE2 is a carboxypeptidase, which plays role in renin-angiotensin system (RAS)<ref>PMID:15109615</ref> 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 <ref>PMID:25688208</ref> 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 <ref>PMID:10969042</ref>.

Coexpression of ACE2 with B0AT1 plays role in amino acid transport. Specific interaction of both ACE2 and B0AT1 inrease expression of the B0AT1<ref>PMID:18424768</ref> Also ACE2 functions as a chaperone for the B0AT1<ref>PMID:32264791</ref>.

Over- and/or underrepresented expression of the enzyme define a critical role in cardiovascular diseases <ref>PMID:27081112</ref>.

ACE2 facilitates HCoV-NL63<ref>PMID: 15897467</ref>, SARS-CoV and SARS-CoV-2 entry, that is causing COVID-19 epidemic<ref>DOI: 10.1126/science.abb2762</ref>. B0AT1 interacts with aminopeptidase N, another coronavirus receptor <ref>PMID:28915252</ref>, but possibility of blocking of the ACE2 cleavage and suppressing of the SARS-CoV-2 infection will have been studying<ref>DOI: 10.1126/science.abb2762</ref>

== Structure==

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 <ref>PMID:17825789</ref>.

[[Image:1-s2.0-S0006291X07018402-gr2.jpg]]

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<ref>PMID: 14754895</ref>.
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 <ref>PMID: 14754895</ref>.

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 complex ==
<Structure load='6M18' size='350' frame='true' align='right' caption='Insert caption here' scene='Insert optional scene name here' />

In the context of the complex, dimerisation of the ACE2 is mediated by neck domain. That complex has both open and closed conformations observed<ref>PMID: 14754895</ref>. 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.

== Location ==

ACE2 gene is located in Chromosome X on forward strand.

== Desease ==

Cardiovascular disease is associated with activation of the signaling pathways. ACE2 is localized in various tissues of the cardiovascular system <ref>PMID: 24332999 </ref>. Underexpression of the ACE2 results neutrophic inflamation in the infarct and pre-infarct regions<ref>PMID: 19808375 </ref>.

Also ACE2 plays role in regulation of the blood pressure<ref>PMID: 16788004</ref>. Highly expressed enzyme protects against hypertension.

== ACE2 as a microbal entry receptor ==
As a membrane protein, ACE2 serves as a functional receptor for coronaviruses, including SARS-CoV<ref>PMID:25720466</ref>, SARS-CoV-2(causes COVID19)<ref>DOI: 10.1126/science.abb2762</ref> and HCoV-NL63. S protein, also known as spike glycoprotein, mediates receptor recognition and fusion of the membrane<ref>PMID:24121034</ref>. 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<ref>PMID:18227861</ref>.

SARS-CoV RBD and SARS-CoV-2 RBD shares similarity<ref>DOI: 10.1126/science.abb2762</ref>; 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.

<Structure load='2AJF' size='350' frame='true' align='right' caption='Insert caption here' scene='SARS-CoV-RBD' />

== References ==
<references/>

ACE2/structural biology project

2020-04-17T00:46:41Z

Aleksandra Shumilova:

ACE2/structural biology project

2020-04-16T23:45:12Z

Aleksandra Shumilova: New page: <Structure load='1r42' size='350' frame='true' align='right' caption='Insert caption here' scene='Insert optional scene name here' /> Angiotensin-converting enzyme 2 (ACE2) is a type I in...

File:1-s2.0-S0006291X07018402-gr2.jpg

2020-04-16T18:52:33Z

Aleksandra Shumilova: