Coronaviruses have four main structural proteins, nucleocapsid protein (N), spike protein (S), membrane protein (M), and envelope protein (E). The E-protein is the smallest of all the structural proteins and is involved in a wide spectrum of functional collection. It comprises of three domains, short hydrophilic N-terminus domain, hydrophobic transmembrane domain, and long hydrophilic C terminal region. The hydrophobic transmembrane domain oligomerizes to form pentameric ion channels having low or no ion selectivity, and thus might act as a viroporin.Oligomerization is the production of an oligomer from monomers bonding together.
Pentameric protein is a quaternary protein structure that consists of five protein subunits.
Viroporins are small and usually hydrophobic multifunctional viral proteins that modify cellular membranes, thereby facilitating virus release from infected cells.
Viroporins are small membrane-embedded proteins present in different pathogenic viruses including SARS-CoV having ion-conducting properties. They localize on host membrane and help in the viral production and maturation processes along with its release, which is synergistically regulated by alteration of ion homeostasis of cellular organelles and are ideal therapeutic targets. Elimination of E-protein from mouse hepatitis virus (MHV) and SARS-CoV-1 did not affect viral production significantly, but led to a significant reduction in the maturation and release of viral titers. Additionally, deletion of E-protein in transmissible gastroenteritis coronavirus (TGEV) and MERS-CoV led to a replication-competent phenotype which was deficient in propagation. In SARS-CoV-1, E-protein deletion resulted in increased stress and expression of apoptotic markers in the cells infected compared to wild type, pointing towards reduced infectivity of the virus. NF-κB signaling pathway was implicated in the decreased inflammation in E-protein deleted SARS-CoV-1.NF-κB or nuclear factor kappa-light-chain-enhancer of activated B cells is a protein complex that controls transcription of DNA, cytokine production and cell survival.
All these deletions led to viral attenuation in three animal models, and conferred protection in immunized hamsters and young or old mice, when infected with the wild type SARS-CoV-1. This points to E-protein as a promising vaccine target against this pathogen. The possibility of E-protein being a vaccine candidate has already been explored with the SARS-CoV. An E-protein deletion in a SARS-CoV causing lethal respiratory diseases like SARS or MERS was explored as an attenuated and effective vaccine, but it underwent a reversion and became virulent in cell cultures or in vivo. Deletion mutants in the C-terminal regions of the E-protein without disturbing the PDZ binding motif led to an attenuated and stable vaccine in mice.PDZ stands for postsynaptic density protein 95 (PSD95)/drosophila disc large tumor suppressor (Dlg1)/zonula occludens-1 protein (zo-1).
Keywords: COVID-19, spike protein, e-protein, COVID-19 vaccine, vaccine target
Sarkar M, Saha S (2020) Structural insight into the role of novel SARS-CoV-2 E protein: A potential target for vaccine development and other therapeutic strategies. PLoS ONE 15(8): e0237300. https://doi.org/10.1371/journal.pone.0237300
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