| Envelope protein | |||||||||
|---|---|---|---|---|---|---|---|---|---|
 Model of the external structure of the SARS-CoV-2virion[1] ● Blue:envelope ● Turquoise:spike glycoprotein (S) ● Bright Pink:envelope proteins (E) ● Green:membrane proteins (M) ● Orange:glycans | |||||||||
| Identifiers | |||||||||
| Symbol | CoV_E | ||||||||
| Pfam | PF02723 | ||||||||
| InterPro | IPR003873 | ||||||||
| PROSITE | PS51926 | ||||||||
| |||||||||
Theenvelope (E) protein is the smallest and least well-characterized of the four majorstructural proteins found incoronavirusvirions.[2][3][4] It is anintegral membrane protein less than 110amino acid residues long;[2] inSARS-CoV-2, the causative agent ofCOVID-19, the E protein is 75 residues long.[5] Although it is not necessarilyessential forviral replication, absence of the E protein may produce abnormally assembledviral capsids or reduced replication.[2][3] E is a multifunctional protein[6] and, in addition to its role as a structural protein in theviral capsid, it is thought to be involved in viral assembly, likely functions as aviroporin, and is involved in viralpathogenesis.[2][5]
The E protein consists of a shorthydrophilicN-terminal region, ahydrophobichelicaltransmembrane domain, and a somewhat hydrophilicC-terminal region. InSARS-CoV andSARS-CoV-2, the C-terminal region contains aPDZ-binding motif (PBM).[2][5] This feature appears to beconserved only in thealpha andbeta coronavirus groups, but notgamma.[2] In the beta and gamma groups, a conservedproline residue is found in the C-terminal region likely involved in targeting the protein to theGolgi.[2]
The transmembrane helices of the E proteins of SARS-CoV and SARS-CoV-2 canoligomerize and have been shownin vitro to form pentameric structures with central pores that serve ascation-selectiveion channels.[5] Both viruses' E proteinpentamers have been structurally characterized bynuclear magnetic resonance spectroscopy.[5][7]
Themembrane 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.[3] The balance of evidence suggests the most common orientation has the C-terminus oriented toward thecytoplasm.[8] Studies of SARS-CoV-2 E protein are consistent with this orientation.[5][9]
In some, but not all, coronaviruses, the E protein ispost-translationally modified bypalmitoylation on conservedcysteine residues.[2][8] In the SARS-CoV E protein, oneglycosylation site has been observed, which may influence membrane topology;[8] however, the functional significance of E glycosylation is unclear.[2]Ubiquitination of SARS-CoV E has also been described, though its functional significance is also not known.[2]
 Genomic organisation of isolate Wuhan-Hu-1, the earliest sequenced sample of SARS-CoV-2, indicating the location of the E gene | |
| NCBI ID | MN908947 |
|---|---|
| Genome size | 29,903 bases |
| Year of completion | 2020 |
| UCSC Genome Browser assembly ID | wuhCor1 |
The E protein isexpressed at high abundance in infected cells. However, only a small amount of the total E protein produced is found in assembledvirions.[2][4] E protein islocalized to theendoplasmic reticulum,Golgi apparatus, andendoplasmic-reticulum–Golgi intermediate compartment (ERGIC), the intracellular compartment that gives rise to the coronavirusviral envelope.[2][5]
Studies in different coronaviruses have reached different conclusions about whether E isessential to viral replication. In some coronaviruses, includingMERS-CoV, E has been reported to be essential.[10] In others, includingmouse coronavirus[11] and SARS-CoV, E is not essential, though its absence reducesviral titer,[12] in some cases by introducing propagation defects or causing abnormal capsid morphology.[2]
The E protein is found in assembled virions where it formsprotein-protein interactions with thecoronavirus membrane protein (M), the most abundant of the fourstructural proteins contained in theviral capsid.[2][4] The interaction between E and M occurs through their respective C-termini on thecytoplasmic side of the membrane.[2] In most coronaviruses, E and M are sufficient to formvirus-like particles,[2][4] though SARS-CoV has been reported to depend onN as well.[14] There is good evidence that E is involved in inducingmembrane curvature to create the typical spherical coronavirus virion.[2][15] It is likely that E is involved inviral budding or scission, although its role in this process has not been well characterized.[2][4][15]
In itspentameric state, E formscation-selectiveion channels and likely functions as aviroporin.[5] 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.[16] 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.[17]
The cation leakage may disrupt ionhomeostasis, altermembrane permeability, and modulatepH in the host cell, which may facilitate viral release.[2][4]
The E protein's role as a viroporin appears to be involved inpathogenesis and may be related to activation of theinflammasome.[3][18] In SARS-CoV, mutations that disrupt E's ion channel function result in attenuated pathogenesis inanimal models despite little effect on viral growth.[10]
Protein-protein interactions between E and proteins in the host cell are best described inSARS-CoV and occur via the C-terminalPDZ 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, andstomatin.[2] The interaction with PALS1 may be related to pathogenesis via the resulting disruption intight junctions.[3][10] This interaction has also been identified inSARS-CoV-2.[19]
The sequence of the E protein is not wellconserved across coronavirus genera, withsequence identities reaching under 30%.[12] In laboratory experiments onmouse 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.[20] The SARS-CoV-2 E protein is very similar to that of SARS-CoV, with threesubstitutions and onedeletion.[4] A study of SARS-CoV-2 sequences suggests that the E protein is evolving relatively slowly compared to other structural proteins.[21] 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 foruniversal coronavirus vaccine development.[22][23]
