Enhanced binding of SARS-CoV-2 Envelope protein to tight junction-associated PALS1 could play a key role in COVID-19 pathogenesis

Background: The Envelope (E) protein of SARS-CoV-2 is the most enigmatic protein among the four structural ones on the viral genome. Most of the current knowledge on the E protein is based on the direct comparison to the SARS E protein, initially mistakenly undervalued and subsequently proved to be a key factor in the ER-Golgi localization and in tight junction disruption. Methods: We compared the genomic sequences of E protein of SARS-CoV-2, SARS-CoV and the closely related genomes of bats and pangolins obtained from the GISAID and GenBank databases. Multiple sequence alignments were done with the Geneious software using the MAFFT algorithm. In silico modelling analyses of E proteins conformation and docking with PALS1 were performed with the Schrodinger Suite.Results: When compared to the known SARS E protein, we observed a different amino acidic sequence in the C-terminal of SARS-CoV-2 E protein which might have a key role in the current COVID-19 pathogenesis. In silico docking results provide evidence of a strengthened binding of SARS-CoV-2 E protein with the tight junction-associated PALS1 protein.Conclusions: We suggest that SARS-CoV-2 E protein may interfere with the tight junction stability and formation leading to an enhanced epithelial barrier disruption, amplifying the inflammatory processes, and promoting tissue remodelling. These findings raise a warning on the underestimated role of the E protein in the pathogenic mechanism and could open the route to detailed experimental investigations.