A Bioinformatics-Based Study of
Angiotensin I Converting Enzyme 2 (ACE2) in Homo sapiens
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Jeffrey Joseph and James Martinez
Published: December 17, 2020
PROTEIN STRUCTURE
Figure 1: 3D Structure of ACE2
Background:
Currently, the structure of the Angiotensin I Converting Enzyme II (ACE2), specifically the structure of isoform 1 of ACE2, is still under study. Databases such as NCBI or PDB mainly show different isoforms of ACE2 bound to other specific proteins such as the spike glycoprotein of the SARS-CoV-2 virus (19). However, the Uniprot database has developed a single structure of ACE2 that contains a sequence of the same number of amino acids present in isoform 1 of the protein.
The ACE2 receptor protein (Isoform 1) is composed of 805 amino acids and approximately weighs 92,463 Da (14) (20). It contains a 17–amino acid N-terminal signal peptide and is inferred to have a 22-amino acid C-terminal membrane anchor (21) (22).
Active Site:
Figure 2: Close Up View of ACE2’s Primary Active Site
The primary active site of ACE2 is established by a conserved zinc-binding motif consensus sequence (HEXXH) + E, which allows ACE2 to serve as a zinc dependent metalloprotease (22) (23).
This zinc-binding motif consists of two histidines (His374 and His378 ), glutamate (Glu402), and an additional glutamate (Glu375) residue that altogether serve as zinc ligands. The superscripts indicate the amino acid residue locations. Glu375 specifically is conserved and plays an important interactive role during the cleaving of a substrate’s peptide bond during hydrolysis (23).
A close up view of the active site of ACE2, taken from Uniprot, can be viewed in Figure 2 (14). This figure shows zinc (purple sphere) binded to His374 , His378, and Glu402 with Glu375 (shown in red).
Secondary Structures:
Figure 3: ACE2’s Secondary Structures
As indicated by Figure 3, ACE2 is made up of 32 helices, 19 beta sheets, and 14 turn secondary structures (14). A majority of the secondary structures that make up ACE2 are helix structures, while only a few are turns. ACE2 itself does not have a quaternary structure since it is made up of one polypeptide chain. However, ACE2 has the capability of conducting homodimerization with the B0AT1 protein, thus forming a quaternary structure (24).
Functional Domain:
ACE2 contains one functional domain as part of its structure. The zinc metallopeptidase domain serves as ACE2’s functional domain, which is composed of 593 amino acid residues and is located within 19 to 611 of the total amino acid residues (14). The secondary structures that make up this domain are alpha helices, 310-helices, and a few beta sheets. Moreover, a majority of this domain is made up of alpha and 310-helices (23). Since ACE2 is a transmembrane protein, this explains why ACE2 is composed of several alpha helices. In addition, this domain is composed of disulfide bonds between amino acid residues 133-141, 344-361, and 530-542 (14). The structure of the zinc metallopeptidase domain, taken from the Conserved Domains Database (CDD), can be viewed below in Figure 4.
Figure 4: Zinc Metallopeptidase Domain of ACE2
The zinc metallopeptidase domain’s main function is to cleave peptide bonds using a metal ion such as zinc to activate a water molecule which will then conduct a hydrolysis reaction on the particular substrate (25). This specific catalytic domain of ACE2 has a 42% similarity to that of the angiotensin I converting enzyme (ACE), which is known for converting the hormone angiotensin I into angiotensin II in the Renin-Angiotensin-Aldosterone System (23). The zinc metallopeptidase domain allows ACE2 to act as a carboxypeptidase, thus removing an amino acid at the C-terminal end. Moreover, this aids ACE2’s ability to convert angiotensin I into angiotensin 1-9 and angiotensin II into angiotensin 1-7, both playing a role in prevention of cardiac remodeling and vasoconstriction (14) .
Topological Domain:
ACE2 is also composed of another domain that is related to the Collectrin protein. According to Uniprot, collection is classified as a topological domain (26). Although it does not have a catalytic function such as carboxypeptidase activity, the collectrin domain helps to stabilize ACE2 within the transmembrane of a cell. In addition, the collectrin domain helps to regulate other interacting proteins with ACE2, and aids in neutral amino acid transport (27). The Collectrin domain is located in the C-terminal region of ACE2 and contains 128 amino acids, located within amino acid residues 612 to 740. (14)