Envelope protein | |||||||||
---|---|---|---|---|---|---|---|---|---|
Identifiers | |||||||||
Symbol | CoV_E | ||||||||
Pfam | PF02723 | ||||||||
InterPro | IPR003873 | ||||||||
PROSITE | PS51926 | ||||||||
|
The envelope (E) protein is the smallest and least well-characterized of the four major structural proteins found in coronavirus virions. [2] [3] [4] It is an integral membrane protein less than 110 amino acid residues long; [2] in SARS-CoV-2, the causative agent of Covid-19, the E protein is 75 residues long. [5] Although it is not necessarily essential for viral replication, absence of the E protein may produce abnormally assembled viral capsids or reduced replication. [2] [3] E is a multifunctional protein [6] and, in addition to its role as a structural protein in the viral capsid, it is thought to be involved in viral assembly, likely functions as a viroporin, and is involved in viral pathogenesis. [2] [5]
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). [2] [5] This feature appears to be conserved only in the alpha and beta coronavirus groups, but not gamma. [2] 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. [2]
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. [5] Both viruses' E protein pentamers have been structurally characterized by nuclear magnetic resonance spectroscopy. [5] [7]
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. [3] The balance of evidence suggests the most common orientation has the C-terminus oriented toward the cytoplasm. [8] Studies of SARS-CoV-2 E protein are consistent with this orientation. [5] [9]
In some, but not all, coronaviruses, the E protein is post-translationally modified by palmitoylation on conserved cysteine residues. [2] [8] In the SARS-CoV E protein, one glycosylation 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]
NCBI genome ID | 86693 |
---|---|
Genome size | 29,903 bases |
Year of completion | 2020 |
Genome browser ( UCSC) |
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. [2] [4] 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. [2] [5]
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. [10] In others, including mouse coronavirus [11] and SARS-CoV, E is not essential, though its absence reduces viral 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 forms protein-protein interactions with the coronavirus membrane protein (M), the most abundant of the four structural proteins contained in the viral capsid. [2] [4] The interaction between E and M occurs through their respective C-termini on the cytoplasmic side of the membrane. [2] In most coronaviruses, E and M are sufficient to form virus-like particles, [2] [4] though SARS-CoV has been reported to depend on N as well. [14] There is good evidence that E is involved in inducing membrane curvature to create the typical spherical coronavirus virion. [2] [15] It is likely that E is involved in viral budding or scission, although its role in this process has not been well characterized. [2] [4] [15]
In its pentameric state, E forms cation-selective ion channels and likely functions as a viroporin. [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 ion homeostasis, alter membrane permeability, and modulate pH in the host cell, which may facilitate viral release. [2] [4]
The E protein's role as a viroporin appears to be involved in
pathogenesis and may be related to activation of the
inflammasome.
[3]
[18] In SARS-CoV, mutations that disrupt E's ion channel function result in attenuated pathogenesis in
animal models despite little effect on viral growth.
[10]
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. [2] The interaction with PALS1 may be related to pathogenesis via the resulting disruption in tight junctions. [3] [10] This interaction has also been identified in SARS-CoV-2. [19]
The sequence of the E protein is not well conserved across coronavirus genera, with sequence identities reaching under 30%. [12] 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. [20] The SARS-CoV-2 E protein is very similar to that of SARS-CoV, with three substitutions and one deletion. [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 for universal coronavirus vaccine development. [22] [23]
Envelope protein | |||||||||
---|---|---|---|---|---|---|---|---|---|
Identifiers | |||||||||
Symbol | CoV_E | ||||||||
Pfam | PF02723 | ||||||||
InterPro | IPR003873 | ||||||||
PROSITE | PS51926 | ||||||||
|
The envelope (E) protein is the smallest and least well-characterized of the four major structural proteins found in coronavirus virions. [2] [3] [4] It is an integral membrane protein less than 110 amino acid residues long; [2] in SARS-CoV-2, the causative agent of Covid-19, the E protein is 75 residues long. [5] Although it is not necessarily essential for viral replication, absence of the E protein may produce abnormally assembled viral capsids or reduced replication. [2] [3] E is a multifunctional protein [6] and, in addition to its role as a structural protein in the viral capsid, it is thought to be involved in viral assembly, likely functions as a viroporin, and is involved in viral pathogenesis. [2] [5]
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). [2] [5] This feature appears to be conserved only in the alpha and beta coronavirus groups, but not gamma. [2] 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. [2]
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. [5] Both viruses' E protein pentamers have been structurally characterized by nuclear magnetic resonance spectroscopy. [5] [7]
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. [3] The balance of evidence suggests the most common orientation has the C-terminus oriented toward the cytoplasm. [8] Studies of SARS-CoV-2 E protein are consistent with this orientation. [5] [9]
In some, but not all, coronaviruses, the E protein is post-translationally modified by palmitoylation on conserved cysteine residues. [2] [8] In the SARS-CoV E protein, one glycosylation 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]
NCBI genome ID | 86693 |
---|---|
Genome size | 29,903 bases |
Year of completion | 2020 |
Genome browser ( UCSC) |
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. [2] [4] 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. [2] [5]
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. [10] In others, including mouse coronavirus [11] and SARS-CoV, E is not essential, though its absence reduces viral 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 forms protein-protein interactions with the coronavirus membrane protein (M), the most abundant of the four structural proteins contained in the viral capsid. [2] [4] The interaction between E and M occurs through their respective C-termini on the cytoplasmic side of the membrane. [2] In most coronaviruses, E and M are sufficient to form virus-like particles, [2] [4] though SARS-CoV has been reported to depend on N as well. [14] There is good evidence that E is involved in inducing membrane curvature to create the typical spherical coronavirus virion. [2] [15] It is likely that E is involved in viral budding or scission, although its role in this process has not been well characterized. [2] [4] [15]
In its pentameric state, E forms cation-selective ion channels and likely functions as a viroporin. [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 ion homeostasis, alter membrane permeability, and modulate pH in the host cell, which may facilitate viral release. [2] [4]
The E protein's role as a viroporin appears to be involved in
pathogenesis and may be related to activation of the
inflammasome.
[3]
[18] In SARS-CoV, mutations that disrupt E's ion channel function result in attenuated pathogenesis in
animal models despite little effect on viral growth.
[10]
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. [2] The interaction with PALS1 may be related to pathogenesis via the resulting disruption in tight junctions. [3] [10] This interaction has also been identified in SARS-CoV-2. [19]
The sequence of the E protein is not well conserved across coronavirus genera, with sequence identities reaching under 30%. [12] 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. [20] The SARS-CoV-2 E protein is very similar to that of SARS-CoV, with three substitutions and one deletion. [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 for universal coronavirus vaccine development. [22] [23]