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

Abstract

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.

Is There a Link Between the Pathogenic Human Coronavirus Envelope Protein and Immunopathology? A Review of the Literature

“…A more recent in silico study used molecular docking to show that the deletion of glutamic acid 69 (E69) and glycine 70 (G70) residues from SARS-CoV E and the substitution thereof with arginine 69 (R69) in SARS-CoV-2 E enhances binding between SARS-CoV-2 E and PALS1 ( De Maio et al, 2020 ). Acquisition of R69 produced a salt bridge and several hydrogen bonds between E and the PALS1 binding pocket, strengthening the interaction between E and PALS1.…”

Computational Immune Proteomics Approach to Target COVID-19

“… 70 The envelope protein (E) is mainly involved in viral assembly and budding, besides taking part in the pathogenic processes. 71 The membrane protein (M) is the major constituent of the viral membrane; it is constituted of three transmembrane domains responsible for the viral shape and the binding with the nucleocapsid (NC) protein. 72 NC is the fourth structural protein at the interface between the outer surface and the inner viral particle.…”

“…The spike (S) protein is a homotrimeric molecule that constitutes the spikes on the viral surface for the recognition and attachment of the viral particle to the host cell . The envelope protein (E) is mainly involved in viral assembly and budding, besides taking part in the pathogenic processes . The membrane protein (M) is the major constituent of the viral membrane; it is constituted of three transmembrane domains responsible for the viral shape and the binding with the nucleocapsid (NC) protein .…”

“…Immunoinformatics-based study of the SARS-CoV-2 spans from complementing the genomics-based studies to providing guidance for the development of effective diagnostics and prophylactic oriented studies . By following the One-Health approach, our research group employed immunoinformatics, as a means of computational immune proteomics, and investigated three major structural proteins of the SARS-CoV-2 (i.e., Spike, S; Membrane, M; Envelope, E) and compared them with the protein sequences of other coronaviruses with tropism for other synanthropic and domestic animals such as dog, bovine, camel, and dromedary. ,,, All studies reported a high level of similarity between the structural protein of SARS-CoV-2 and the counterparts of the bat and pangolin coronaviruses, confirming the results of molecular studies aimed at tracking the origin of the novel pathogen. ,, …”

The Novel Insight of SARS-CoV-2 Molecular Biology and Pathogenesis and Therapeutic Options

“…Post-translational changes with critical roles, including glycosylation, palmitoylation, myristoylation, and ubiquitination, occur in proteins (Schoeman and Fielding, 2019). Several studies show that E protein has a role in pathway signaling, for example, one study of E protein showed that the E protein in SARS-CoV-2 in the CT region had changed in several amino acids, which could affect the PALS1, which plays a key role in tight junction, causing the virus to become more pathogenic than other coronaviruses (De Maio et al, 2020).…”