ACE2 fragment as a decoy for novel SARS-Cov-2 virus

Fabiana Renzi; Dario Ghersi

The entry of the novel SARS-Cov-2 into the host cell is mediated by the interaction between the viral transmembrane spike (S) glycoprotein and the cellular membrane receptor angiotensin-converting enzyme 2 (ACE2) (1) . The S glycoprotein is synthesized as a precursor of about 1,300 amino acids that is then cleaved into an amino N-terminal S1 subunit of about 700 amino acids and a carboxyl C-terminal S2 subunit of about 600 amino acids. Three S1-S2 heterodimers assemble to form a trimer protruding from the viral surface. The S1 subunit contains a receptor-binding domain (RBD), while the S2 subunit contains a hydrophobic fusion peptide. Upon receptor binding, the S1 subunit is cleaved, and the fusion S2 subunit undergoes a conformational rearrangement to form a six-helix bundle that mediates viral and cellular membrane fusion (2) . The angiotensin-converting enzyme (ACE)-related carboxypeptidase, ACE2, is a type I integral membrane protein of about 805 amino acids that contains one HEXXH + E zinc-binding consensus sequence. ACE2 is a close homolog of the somatic angiotensin-converting enzyme (ACE; EC 3.4.15.1), a peptidyl dipeptidase that plays an important role in the renin-angiotensin system. ACE2 sequence includes an N-terminal signal sequence (amino acids 1 to 18), a potential transmembrane domain (amino acids 740 to 763), and a potential metalloprotease zinc-binding site (amino acids 374 to 378, HEMGH). The internal cavity hosts the angiotensinI substrate (consisting of aminoacids 1 to 10 of the angiotensinogen precursor) that ACE2 converts into angiotensinII (amino acids 1 to 8) (3, 4) . ACE2 is expressed mainly in heart, kidney, testis, smooth muscle, and in coronary vessels and it seems to increase in lately differentiated epithelial tissues (5) . The expression of ACE2 seems inversely regulated by the expression levels of ACE, a key regulator of blood pressure and the target of the pharmacological ACE inhibitors that control blood pressure (6). X-ray and cryo-EM structures of complexes between the viral S protein from different Coronaviruses both alone and in complex with ACE2 have been solved (7) (8) (9) (10) (11) . Here we analyzed the crystallographic and cryo-Electron Microscopy (cryo-EM) structures of the S-proteins from SARS-Cov and SARS-Cov-2, human ACE2, and their complexes. We studied the structural features of the binding of ACE2 to S-protein, and performed molecular docking experiments in order to determine the interaction energy between the S protein and ACE2 residues.