Trilogy of ACE2: a peptidase in the renin-angiotensin system, a SARS receptor, and a partner for amino acid transporters

Abstract

Angiotensin-converting enzyme (ACE) 2 is a homolog to the carboxypeptidase ACE, which generates angiotensin II, the main active peptide of renin-angiotensin system (RAS). After the cloning of ACE2 in 2000, three major ACE2 functions have been described so far. First ACE2 has emerged as a potent negative regulator of the RAS counterbalancing the multiple functions of ACE. By targeting angiotensin II ACE2 exhibits a protective role in the cardiovascular system and many other organs. Second ACE2 was identified as an essential receptor for the SARS coronavirus that causes severe acute lung failure. Downregulation of ACE2 strongly contributes to the pathogenesis of severe lung failure. Third, both ACE2 and its homologue Collectrin can associate with amino acid transporters and play essential role in the absorption of amino acids in the kidney and gut. In this review, we will discuss the multiple biological functions of ACE2.

Fig. 1

Domain structures of ACE, ACE2 and Collectrin. Each protein is a type I integral protein with a signal peptide, depicted in gray, and a transmembrane domain shown in black. The zinc-binding motif (HEMGH) repeats two times in ACE and once in ACE2, and is located within the homology region denoted by the yellow box. Regions of homology between ACE2 and Collectrin are denoted in green. The numbers refer to the amino acids in each human protein.

Fig. 2

Schematic diagram of the role of ACE2 in the renin–angiotensin system. Angiotensin I (Ang I; DRVYIHPFHL) serves as a substrate for ACE, a dipeptidyl carboxypeptidase, and is converted to Angiotensin II (Ang II; DRVYIHPF), the main active peptide of the classical RAS. ACE2 catalyzes and inactivates Angiotensin II and produces the vasodilator peptide Angiotensin 1–7 (Ang 1–7; DRVYIHPF), which binds the Mas receptor and/or is degraded to inactive peptides. Red arrowheads indicate the ACE cleavage site; blue arrowheads show the ACE2 cleavage sites. It should be noted that ACE2 is an unspecific protease and can cleave multiple additional substrates such as Apelin.

Fig. 3

Post-translational modifications of ACE2; internalization and shedding. SARS coronavirus (SARS-CoV) binds to and internalizes with ACE2 for its cellular entry in a Clathrin-dependent manner. Membrane fusion is mediated via activation of Spike by proteases, such as trypsin or furin, and viral RNAs are released into cytoplasm, establishing SARS infection. The transmembrane proteinase (ADAM17) cleaves the extracellular juxtamembrane region of ACE2, releasing the catalytically active ectodomain into the extracellular milieu. Whether such ACE2 cleavage contributes to SARS pathogenesis is not known yet.

Fig. 4

Interaction of ACE2 with the B⁰AT1 amino acid transporter. ACE2 interacts with the B⁰AT1 amino acid transporter (SLC6A19) which is required for polarized surface expression of the transporter in gut epithelial cells. Whether ACE2 cleavage contributes to supplying neutral amino acids for the B⁰AT1 is not known yet.