User:Letícia Oliveira Rojas Cruz/Sandbox 1

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Besides its general aspects, the ACE2 protein can be divided into 4 portions: Peptidase Domain (Residues 19–615), Collectrin-like Domain (Residues 616–740), Transmembrane Domain (Residues 741–761) and Intracellular C-terminal Tail (Residues 762–805).
Besides its general aspects, the ACE2 protein can be divided into 4 portions: Peptidase Domain (Residues 19–615), Collectrin-like Domain (Residues 616–740), Transmembrane Domain (Residues 741–761) and Intracellular C-terminal Tail (Residues 762–805).
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The '''<scene name='10/1083732/Peptidase_domain/2'>Peptidase Domain</scene>''' is responsible for the enzymatic activity of ACE2. This domain can be divided in two subdomains: <scene name='10/1083732/Subdominio_1_nterm/2'>Subdomain I</scene> (residues 19–400) and <scene name='10/1083732/Subdominio_2_cterm/2'>Subdomain II</scene> (residues 401–615). Together, they form a substrate-binding cleft, where is located the '''<scene name='10/1083732/Sitio_zinco_com_residuos/1'>catalytic site</scene>''', denominated '''HEXXH+E zinc-binding motif'''. Within this site, a '''{{Font color|lime|zinc-ion}}''' is associated with the residues '''His374''', '''His378''', and '''Glu402''', which are going to perform a nucleophilic attack on the peptide bond of the substrate, leading to its cleavage. '''<scene name='10/1083732/Peptidase_domain_hydrofobic/2'>Hydrophobic portions</scene>''' within each subdomain, composed mainly of nonpolar residues provide tertiary structural stability, maintaining the correct spatial arrangement of catalytic residues. In the animation, we can observe a concentration of the '''{{Font color|gray|hydrophobic residues}}''' towards the center of the molecule, while the '''{{Font color|orchid|polar}}''' ones are towards the outside part of the molecule.
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The '''<scene name='10/1083732/Peptidase_domain/2'>Peptidase Domain</scene>''' is responsible for the enzymatic activity of ACE2. This domain can be divided in two subdomains: <scene name='10/1083732/Subdominio_1_nterm/2'>Subdomain I</scene> (residues 19–400) and <scene name='10/1083732/Subdominio_2_cterm/2'>Subdomain II</scene> (residues 401–615). Together, they form a substrate-binding cleft, where is located the '''<scene name='10/1083732/Sitio_zinco_com_residuos/1'>catalytic site</scene>''', denominated '''HEXXH+E zinc-binding motif'''. Within this site, a '''{{Font color|lime|zinc-ion}}''' is associated with the residues '''His374''', '''His378''', and '''Glu402''', which are going to perform a nucleophilic attack on the peptide bond of the substrate, leading to its cleavage. '''<scene name='10/1083732/Peptidase_domain_hydrofobic/2'>Hydrophobic portions</scene>''' within each subdomain, composed mainly of nonpolar residues provide tertiary structural stability, maintaining the correct spatial arrangement of catalytic residues. In the animation, we can observe a concentration of the '''{{Font color|gray|hydrophobic residues}}''' towards the center of the molecule, while the '''{{Font color|orchid|polar}}''' ones are towards the outside part of the molecule.
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An important structure within the Subdomain II is the '''Ferredoxin-like fold''', also known as the neck domain, formed by residues approximately between 616 and 726.
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This region connects the Peptidase Domain to the Transmembrane Domain and is structurally characterized by four alpha helices and four beta sheets arranged in a compact and stable configuration, with a central beta-sheet flanked by alpha helices, contributing to the overall tertiary structure of ACE2.
The following domain is the '''<scene name='10/1083732/Collectrin-like_domain/3'>Collectrin-like Domain</scene>''' (CLD), formed by '''{{Font color|gold|4 beta sheets}}''' and '''{{Font color|deeppink|3 alpha-helices}}''' that make a hydrophobic core, structure that is important for stabilizing ACE2 dimers, which will be represented later on this page.
The following domain is the '''<scene name='10/1083732/Collectrin-like_domain/3'>Collectrin-like Domain</scene>''' (CLD), formed by '''{{Font color|gold|4 beta sheets}}''' and '''{{Font color|deeppink|3 alpha-helices}}''' that make a hydrophobic core, structure that is important for stabilizing ACE2 dimers, which will be represented later on this page.
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=== Structure highlights ===
=== Structure highlights ===
==== ACE2-B0AT1 Complex ====
==== ACE2-B0AT1 Complex ====
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===== Association with B0AT1 =====
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'''''Association with B0AT1'''''
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The ACE2 protein can associate with the neutral amino acid transporter B0AT1, also known as SLC6A19. In this context, ACE2 first forms a homodimer, where two ACE2 molecules interact side by side. Each ACE2 monomer then binds to one B0AT1 molecule. This results in a complex composed of two ACE2 and two B0AT1 molecules, which is commonly described as a dimer of heterodimers. This association is essential for the transport of neutral amino acids in intestinal cells and the anchoring of ACE2 in the cell membrane, keeping the catalytic site facing the extracellular environment. Although ACE2 dimerization occurs independently of B0AT1, the transporter plays a stabilizing role by interacting with the Collectrin-like Domain
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The ACE2 protein can associate with the neutral amino acid transporter B0AT1, also known as SLC6A19. In this context, ACE2 first forms a homodimer, where two ACE2 molecules interact side by side. Each ACE2 monomer then binds to one B0AT1 molecule. This results in a complex composed of two ACE2 and two B0AT1 molecules, which is commonly described as a dimer of heterodimers. This association is essential for the transport of neutral amino acids in intestinal cells and the anchoring of ACE2 in the cell membrane, keeping the catalytic site facing the extracellular environment. Although ACE2 dimerization occurs independently of B0AT1, the transporter plays a stabilizing role by interacting with the Collectrin-like Domain.
This ACE2-B0AT1 complex is anchored to the cell plasma membrane, keeping the ACE2 protein in an extracellular environment. The intermembrane region has apolar characteristics, since it must interact with the hydrophobic tails of the phospholipids. Analyzing the polarity of the complex, an apolar (in gray) region is observed in the B0AT1 region, showing that it is in this region where the complex is in contact with the plasma membrane. The polar regions (CLD and PD domains of ACE2) are located in the external region, without contact with the apolar region of the phospholipids.
This ACE2-B0AT1 complex is anchored to the cell plasma membrane, keeping the ACE2 protein in an extracellular environment. The intermembrane region has apolar characteristics, since it must interact with the hydrophobic tails of the phospholipids. Analyzing the polarity of the complex, an apolar (in gray) region is observed in the B0AT1 region, showing that it is in this region where the complex is in contact with the plasma membrane. The polar regions (CLD and PD domains of ACE2) are located in the external region, without contact with the apolar region of the phospholipids.
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ACE2 protein dimerization occurs independently of B0AT1 and presents interaction of the CLD domain, with contribution from the PD domain.
ACE2 protein dimerization occurs independently of B0AT1 and presents interaction of the CLD domain, with contribution from the PD domain.
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''''' CLD Domain Interaction'''''
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'''''CLD Domain Interaction'''''
In this region, there is an extensive network of polar interactions that stabilizes the ACE2 dimer. The most actively involved amino acid residues are between 636 and 658 and between 708 and 717, corresponding to the second and fourth helices of the CLD domain, respectively.
In this region, there is an extensive network of polar interactions that stabilizes the ACE2 dimer. The most actively involved amino acid residues are between 636 and 658 and between 708 and 717, corresponding to the second and fourth helices of the CLD domain, respectively.

Revision as of 19:22, 22 June 2025

Introduction

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References

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Letícia Oliveira Rojas Cruz

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