is an important protein expressed in several human tissues, such as the heart and kidneys. It plays a key role in the Renin-Angiotensin System - "RAS" - by catalyzing the conversion of angiotensin II (Ang II), promoting blood pressure regulation.
Another function of ACE2 is related to SARS-CoV-2 infection, the virus responsible for the COVID-19 pandemic. In this context, ACE2 serves as the entry receptor for the virus.
General structure information
The ACE2 protein gene has 40 kb and 18 exons. Its protein has 805 amino acids with a molecular weight of approximately 120 kDa. Here, we have a view of the , going from the N-terminal to C-terminal region. Some other ways to represent the ACE2 protein include showing its , such as alpha helices and beta sheets, and mapping the polarity of its residues, differentiating and areas across its surface.
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).
The is responsible for the enzymatic activity of ACE2. This domain can be divided in two subdomains: (residues 19–400) and (residues 401–615). Together, they form a substrate-binding cleft, where is located the , denominated HEXXH+E zinc-binding motif. Within this site, a 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. 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 hydrophobic residues towards the center of the molecule, while the polar ones are towards the outside part of the molecule.
The following domain is the , formed by 4 beta sheets and 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 is composed of a single alpha helix, made of a majority of (in gray). This characteristic allows ACE2 to be anchored in the plasma membrane, due to its hydrophobic nature.
The final domain is the Intracellular C-terminal Tail but its function remains uncertain.
Physiological Function
ACE2 is a transmembrane glycoprotein that has an extracellular catalytic domain. It is classified as a hydrolase, more specifically a carboxypeptidase-type peptidase, responsible for the cleavage of peptide bonds at the C-terminal site.
The ACE2 acts to cleave a single C-terminal residue of some substrates. One of those substrates is Angiotensin II (Ang II), which is degrated into Angiotensin-(1-7); to a lesser extent, Angiotensin I (Ang I) is also a substrate, turning in into Angiotensin-(1-9).
The Renin-Angiotensin System - "RAS" -, in which ACE2 acts, is an important signaling pathway responsible for vascular homeostasis.
In general, Ang II, generated by the action of ACE on Ang I, and this one by the action of Renin on Angiotensinogen, acts on AT1 and AT2 receptors. Its main action is vasoconstriction (by AT1 receptor), increasing blood pressure. On the other hand, Angiotensin (1-7), generated from Ang II by ACE2, has the opposite function, leading to a decline in blood pressure through vasodilation and release of Nitric Oxide (NO) through its action on the MAS oncogene receptor, antagonizing the actions of Ang II.
Pathological Relevance
The ACE2 protein became better known and widely publicized in 2020 due to its role in the infection by SARS-CoV-2, the virus responsible for the Covid-19 pandemic.
In this disease, ACE2 acts as a viral receptor, to which the Spike (S) viral protein binds, promoting the entry of the virus into the host cell. The specific region of the S protein responsible for binding to the ACE2 receptor is called receptor-binding domain (RBD), and is located in the S1 subunit of the Spike protein.
Disease
Relevance
Structural highlights
