Coronavirus envelope protein

File:7k3g.png structure of the pentameric pore formed by the transmembrane helices of the SARS-CoV-2 E protein, which forms a viroporin permeable to cations. Rendered from {{PDB|7K3G}}.]]

The E protein consists of a short hydrophilic N-terminal region, a hydrophobic helical transmembrane domain, and a somewhat hydrophilic C-terminal region. In SARS-CoV and SARS-CoV-2, the C-terminal region contains a PDZ-binding motif (PBM). This feature appears to be conserved only in the alpha and beta coronavirus groups, but not gamma. In the beta and gamma groups, a conserved proline residue is found in the C-terminal region likely involved in targeting the protein to the Golgi.

The transmembrane helices of the E proteins of SARS-CoV and SARS-CoV-2 can oligomerize and have been shown in vitro to form pentameric structures with central pores that serve as cation-selective ion channels. Both viruses' E protein pentamers have been structurally characterized by nuclear magnetic resonance spectroscopy.{{cite journal | vauthors = Surya W, Li Y, Torres J | title = Structural model of the SARS coronavirus E channel in LMPG micelles | journal = Biochimica et Biophysica Acta (BBA) - Biomembranes | volume = 1860 | issue = 6 | pages = 1309–1317 | date = June 2018 | pmid = 29474890 | pmc = 7094280 | doi = 10.1016/j.bbamem.2018.02.017 }}

The membrane topology of the E protein has been studied in a number of coronaviruses with inconsistent results; the protein's orientation in the membrane may be variable. The balance of evidence suggests the most common orientation has the C-terminus oriented toward the cytoplasm.{{cite journal | vauthors = Fung TS, Liu DX | title = Post-translational modifications of coronavirus proteins: roles and function | journal = Future Virology | volume = 13 | issue = 6 | pages = 405–430 | date = June 2018 | pmid = 32201497 | pmc = 7080180 | doi = 10.2217/fvl-2018-0008 }} Studies of SARS-CoV-2 E protein are consistent with this orientation.{{cite journal | vauthors = Duart G, García-Murria MJ, Grau B, Acosta-Cáceres JM, Martínez-Gil L, Mingarro I | title = SARS-CoV-2 envelope protein topology in eukaryotic membranes | journal = Open Biology | volume = 10 | issue = 9 | pages = 200209 | date = September 2020 | pmid = 32898469 | pmc = 7536074 | doi = 10.1098/rsob.200209 }}

In some, but not all, coronaviruses, the E protein is post-translationally modified by palmitoylation on conserved cysteine residues. In the SARS-CoV E protein, one glycosylation site has been observed, which may influence membrane topology; however, the functional significance of E glycosylation is unclear. Ubiquitination of SARS-CoV E has also been described, though its functional significance is also not known.

{{Infobox genome

| image = File:SARS-CoV-2 genome.svg

| caption = Genomic organisation of isolate Wuhan-Hu-1, the earliest sequenced sample of SARS-CoV-2, indicating the location of the E gene

| taxId = 86693

| size = 29,903 bases

| year = 2020

| ucsc_assembly = wuhCor1

}}

The E protein is expressed at high abundance in infected cells. However, only a small amount of the total E protein produced is found in assembled virions. E protein is localized to the endoplasmic reticulum, Golgi apparatus, and endoplasmic-reticulum–Golgi intermediate compartment (ERGIC), the intracellular compartment that gives rise to the coronavirus viral envelope.

Studies in different coronaviruses have reached different conclusions about whether E is essential to viral replication. In some coronaviruses, including MERS-CoV, E has been reported to be essential.{{cite journal | vauthors = DeDiego ML, Nieto-Torres JL, Jimenez-Guardeño JM, Regla-Nava JA, Castaño-Rodriguez C, Fernandez-Delgado R, Usera F, Enjuanes L | display-authors = 6 | title = Coronavirus virulence genes with main focus on SARS-CoV envelope gene | journal = Virus Research | volume = 194 | pages = 124–137 | date = December 2014 | pmid = 25093995 | pmc = 4261026 | doi = 10.1016/j.virusres.2014.07.024 }} In others, including mouse coronavirus{{cite journal | vauthors = Kuo L, Masters PS | title = The small envelope protein E is not essential for murine coronavirus replication | journal = Journal of Virology | volume = 77 | issue = 8 | pages = 4597–4608 | date = April 2003 | pmid = 12663766 | pmc = 152126 | doi = 10.1128/JVI.77.8.4597-4608.2003 }} and SARS-CoV, E is not essential, though its absence reduces viral titer,{{cite journal | vauthors = Ruch TR, Machamer CE | title = The coronavirus E protein: assembly and beyond | journal = Viruses | volume = 4 | issue = 3 | pages = 363–382 | date = March 2012 | pmid = 22590676 | pmc = 3347032 | doi = 10.3390/v4030363 | doi-access = free }} in some cases by introducing propagation defects or causing abnormal capsid morphology.

File:Pbio.3000815.g001.PNG L.png, showing the positions of the four structural proteins and components of the extracellular environment{{cite journal | vauthors = Goodsell DS, Voigt M, Zardecki C, Burley SK | title = Integrative illustration for coronavirus outreach | journal = PLOS Biology | volume = 18 | issue = 8 | pages = e3000815 | date = August 2020 | pmid = 32760062 | pmc = 7433897 | doi = 10.1371/journal.pbio.3000815 | doi-access = free }}]]

The E protein is found in assembled virions where it forms protein-protein interactions with the coronavirus membrane protein (M), the most abundant of the four structural proteins contained in the viral capsid. The interaction between E and M occurs through their respective C-termini on the cytoplasmic side of the membrane. In most coronaviruses, E and M are sufficient to form virus-like particles, though SARS-CoV has been reported to depend on N as well.{{cite journal | vauthors = Siu YL, Teoh KT, Lo J, Chan CM, Kien F, Escriou N, Tsao SW, Nicholls JM, Altmeyer R, Peiris JS, Bruzzone R, Nal B | display-authors = 6 | title = The M, E, and N structural proteins of the severe acute respiratory syndrome coronavirus are required for efficient assembly, trafficking, and release of virus-like particles | journal = Journal of Virology | volume = 82 | issue = 22 | pages = 11318–11330 | date = November 2008 | pmid = 18753196 | pmc = 2573274 | doi = 10.1128/JVI.01052-08 }} There is good evidence that E is involved in inducing membrane curvature to create the typical spherical coronavirus virion.{{cite journal | vauthors = J Alsaadi EA, Jones IM | title = Membrane binding proteins of coronaviruses | journal = Future Virology | volume = 14 | issue = 4 | pages = 275–286 | date = April 2019 | pmid = 32201500 | pmc = 7079996 | doi = 10.2217/fvl-2018-0144 }} It is likely that E is involved in viral budding or scission, although its role in this process has not been well characterized.

File:Viroporin E.png

In its pentameric state, E forms cation-selective ion channels and likely functions as a viroporin. NMR studies show that viroporin presents an open conformation at low pH or in the presence of calcium ions, while the closed conformation is favored at basic pH.{{cite journal | vauthors = Medeiros-Silva J, Somberg NH, Wang HK, McKay MJ, Mandala VS, Dregni AJ, Hong M | title = pH- and Calcium-Dependent Aromatic Network in the SARS-CoV-2 Envelope Protein | journal = Journal of the American Chemical Society | volume = 144 | issue = 15 | pages = 6839–6850 | date = April 2022 | pmid = 35380805 | pmc = 9188436 | doi = 10.1021/jacs.2c00973 }} The NMR structure shows a hydrophobic gate at leucine 28 in the middle of the pore. The passage of ions through the gate is thought to be facilitated by the polar residues at the C-terminus.{{cite journal | vauthors = Medeiros-Silva J, Dregni AJ, Somberg NH, Duan P, Hong M | title = Atomic structure of the open SARS-CoV-2 E viroporin | journal = Science Advances | volume = 9 | issue = 41 | pages = eadi9007 | date = October 2023 | pmid = 37831764 | pmc = 10575589 | doi = 10.1126/sciadv.adi9007 }}

The cation leakage may disrupt ion homeostasis, alter membrane permeability, and modulate pH in the host cell, which may facilitate viral release.

The E protein's role as a viroporin appears to be involved in pathogenesis and may be related to activation of the inflammasome.{{cite journal | vauthors = Nieto-Torres JL, DeDiego ML, Verdiá-Báguena C, Jimenez-Guardeño JM, Regla-Nava JA, Fernandez-Delgado R, Castaño-Rodriguez C, Alcaraz A, Torres J, Aguilella VM, Enjuanes L | display-authors = 6 | title = Severe acute respiratory syndrome coronavirus envelope protein ion channel activity promotes virus fitness and pathogenesis | journal = PLOS Pathogens | volume = 10 | issue = 5 | pages = e1004077 | date = May 2014 | pmid = 24788150 | pmc = 4006877 | doi = 10.1371/journal.ppat.1004077 | doi-access = free }} In SARS-CoV, mutations that disrupt E's ion channel function result in attenuated pathogenesis in animal models despite little effect on viral growth.

File:7m4r chainsAC.png structure of the interaction between the SARS-CoV-2 E protein PDZ-binding motif (magenta) and a construct containing the PDZ (blue), SH3 (yellow), and guanylate kinase-like (GK, green) domains from a host cell protein, human PALS1]]

Protein-protein interactions between E and proteins in the host cell are best described in SARS-CoV and occur via the C-terminal PDZ domain binding motif. The SARS-CoV E protein has been reported to interact with five host cell proteins: Bcl-xL, PALS1, syntenin, sodium/potassium (Na+/K+) ATPase α-1 subunit, and stomatin. The interaction with PALS1 may be related to pathogenesis via the resulting disruption in tight junctions. This interaction has also been identified in SARS-CoV-2.{{cite journal | vauthors = Chai J, Cai Y, Pang C, Wang L, McSweeney S, Shanklin J, Liu Q | title = Structural basis for SARS-CoV-2 envelope protein recognition of human cell junction protein PALS1 | journal = Nature Communications | volume = 12 | issue = 1 | pages = 3433 | date = June 2021 | pmid = 34103506 | pmc = 8187709 | doi = 10.1038/s41467-021-23533-x | bibcode = 2021NatCo..12.3433C }}

The sequence of the E protein is not well conserved across coronavirus genera, with sequence identities reaching under 30%. In laboratory experiments on mouse hepatitis virus, substitution of E proteins from different coronaviruses, even from different groups, could produce viable viruses, suggesting that significant sequence diversity can be tolerated in functional E proteins.{{cite journal | vauthors = Kuo L, Hurst KR, Masters PS | title = Exceptional flexibility in the sequence requirements for coronavirus small envelope protein function | journal = Journal of Virology | volume = 81 | issue = 5 | pages = 2249–2262 | date = March 2007 | pmid = 17182690 | pmc = 1865940 | doi = 10.1128/JVI.01577-06 }} The SARS-CoV-2 E protein is very similar to that of SARS-CoV, with three substitutions and one deletion. A study of SARS-CoV-2 sequences suggests that the E protein is evolving relatively slowly compared to other structural proteins.{{cite journal | vauthors = Rahman MS, Hoque MN, Islam MR, Islam I, Mishu ID, Rahaman MM, Sultana M, Hossain MA | display-authors = 6 | title = Mutational insights into the envelope protein of SARS-CoV-2 | journal = Gene Reports | volume = 22 | pages = 100997 | date = March 2021 | pmid = 33319124 | pmc = 7723457 | doi = 10.1016/j.genrep.2020.100997 }} The conserved nature of the envelope protein among SARS-CoV and SARS-CoV-2 variants has led it to be researched as a potential target for universal coronavirus vaccine development.{{cite journal | vauthors = Bhattacharya S, Banerjee A, Ray S | title = Development of new vaccine target against SARS-CoV2 using envelope (E) protein: An evolutionary, molecular modeling and docking based study | journal = International Journal of Biological Macromolecules | volume = 172 | pages = 74–81 | date = March 2021 | pmid = 33385461 | pmc = 7833863 | doi = 10.1016/j.ijbiomac.2020.12.192 }}{{cite journal | vauthors = Chen J, Deng Y, Huang B, Han D, Wang W, Huang M, Zhai C, Zhao Z, Yang R, Zhao Y, Wang W, Zhai D, Tan W | display-authors = 6 | title = DNA Vaccines Expressing the Envelope and Membrane Proteins Provide Partial Protection Against SARS-CoV-2 in Mice | journal = Frontiers in Immunology | volume = 13 | pages = 827605 | date = 2022-02-24 | pmid = 35281016 | pmc = 8907653 | doi = 10.3389/fimmu.2022.827605 | doi-access = free }}

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{{Coronavirus genomes}}

{{Viral proteins}}

Category:Coronavirus proteins

Category:Viral protein class

Category:Viral structural proteins