Functional Pangenome Analysis Shows Key Features of E Protein Are Preserved in SARS and SARS-CoV-2

Abstract

The spread of the novel coronavirus (SARS-CoV-2) has triggered a global emergency, that demands urgent solutions for detection and therapy to prevent escalating health, social, and economic impacts. The spike protein (S) of this virus enables binding to the human receptor ACE2, and hence presents a prime target for vaccines preventing viral entry into host cells. The S proteins from SARS and SARS-CoV-2 are similar, but structural differences in the receptor binding domain (RBD) preclude the use of SARS-specific neutralizing antibodies to inhibit SARS-CoV-2. Here we used comparative pangenomic analysis of all sequenced reference Betacoronaviruses, complemented with functional and structural analyses. This analysis reveals that, among all core gene clusters present in these viruses, the envelope protein E shows a variant cluster shared by SARS and SARS-CoV-2 with two completely-conserved key functional features, namely an ion-channel, and a PDZ-binding motif (PBM). These features play a key role in the activation of the inflammasome causing the acute respiratory distress syndrome, the leading cause of death in SARS and SARS-CoV-2 infections. Together with functional pangenomic analysis, mutation tracking, and previous evidence, on E protein as a determinant of pathogenicity in SARS, we suggest E protein as an alternative therapeutic target to be considered for further studies to reduce complications of SARS-CoV-2 infections in COVID-19.

Delivery of recombinant SARS-CoV-2 envelope protein into human cells

“…Within CoVs, there are four critically conserved structural proteins (6,7), each of which is of possible therapeutic importance due to their essential functions (8), Among these is the SARS-CoV-2 envelope (E) protein. The E protein is a single-pass transmembrane protein whose roles in pathogenesis are incompletely understood (9).…”

The SARS-CoV-2 envelope (E) protein has evolved towards membrane topology robustness

“…In addition to this structural role the E protein oligomerizes to form pentameric ion channels similar to viroporins [ [3] , [4] , [5] ] and possesses a C-terminal PDZ-binding motif that induce immunopathology by overexpression of inflammatory cytokines [ 6 ]. These features of E protein play a major role in the exacerbated immune response causing the acute respiratory syndrome, the leading cause of death in SARS-CoV and SARS-CoV-2 [ 7 ], and have been shown to be critical for propagation of other human coronaviruses. The assembly of E protein into the ER membrane in the correct orientation (topology) is critical for its functions.…”

SARS-CoV-2 Envelope (E) Protein Interacts with PDZ-Domain-2 of Host Tight Junction Protein ZO1

“…Modeling of the SARS-CoV-2 E protein suggests that E can form a broadly cation selective ion channel with dynamic open and closed states, and therefore may act as a viroporin similar to the SARS-CoV-1 E protein [21, 28]. Although the genome of SARS-CoV-2 only shares about 80% identity with that of SARS-CoV-1, the ECT of the SARS-CoV-2 E protein, including the DLLV core motif and adjacent amino acids, are highly conserved with those of SARS-CoV-1 E protein [21–23, 25, 27] (Fig. 1).…”