Ebola viral protein 24
eVP24 | |||||||||
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Identifiers | |||||||||
Symbol | eVP24 | ||||||||
Pfam | PF06389 | ||||||||
InterPro | IPR009433 | ||||||||
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Ebola viral protein 24 (eVP24) is considered a multifunctional secondary
History
Research
The first recorded human outbreak of
Characterization
eVP24 was initially described as a matrix protein that had similar properties and functions of eVP40. eVP24 was found to have characteristics of typical viral matrix proteins, such as a strong association with lipid bilayers and the ability to oligomerize to form tetramers. Like eVP40, eVP24 was found to be essential in virion assembly and budding. Later research indicated that the expression of eVP24 was required to switch from viral transcription and replication to virion assembly.[1] A new role for eVP24 was found when its expression was monitored in rodent species where changes in eVP24 seemed to be responsible for enhancing virulence, indicating that adaption of Ebola in animal models occurs through mutations in eVP24.[1] Additionally, eVP24 inhibits interferon signaling by competitively binding to karyopherins which blocks phosphorylated STAT1 nuclear import. In 2014, it was found that this mechanism interferes with the cells response to viral infection, which suppressed the innate immune response, allowing the virus to proliferate in the body.[6]
Function
eVP24 disrupts the signaling pathway of STAT1. The STAT1 protein is phosphorylated by interferons in response to viral infection causing it to express a
Mechanism
eVP24 prevents the function of KPNA by binding in a region which overlaps with the binding region of STAT1. This is accomplished by the high binding affinity between KNPA and eVP24.[3] These proteins have very high complementarity in the binding interface, similar to the complementarity shown between antibodies and antigens. In addition, the binding interface is large; over 2000 angstroms squared of solvent accessible surface is buried by the binding. Overall binding takes place with very little conformational change in either protein.[3] There are three clusters of residues on eVP24 which form contacts to KPNA. These are located at residue positions 115 to 140, 184 to 186, and 201 to 207. Mutation of any single residue does not significantly reduce the binding of eVP24 to KPNA which demonstrates the robust mechanism of the viral protein.[3] KPNA proteins have 10 armadillo repeats each consisting of three alpha helices which determine their binding specificity, the second helix from ARM 9 and 10 form a hydrophobic core with helix 6 of eVP24 adding to the stability of the complex.[3] The binding sites for eVP24 and STAT1 have been shown to overlap. Mutation in any one of four residues in KPNA at positions 434, 474, 477 or 484 prevent binding to STAT1. Similarly, the mutations in residues 474, 477 or 484 of KPNA reduce the binding of eVP24. Additionally and critically, the binding of eVP24 does not prevent the binding of cargo proteins with classical nuclear localization signals as, like STAT1, eVP24 causes very little conformational changes in KPNA.[3]
Effects on symptom progression
eVP24 acts as an antagonist to PY-STAT1 on KPNA. With eVP24 being transported to the nucleus instead of STAT1, the interferon-stimulated genes IFN-α/IFN-β and IFN-γ are disrupted and the cell does not enter an antiviral state.[6] STAT1 has been shown to regulate the expression of certain
Current and future research
The evasion of the host cell immune system is key in to the rapid replication and dispersion through the body by the Ebola virus. Current research is exploring how eVP24 enables this phenomenon to occur. The discovery of STAT1 nuclear import disruption by eVP24 binding to KPNA has already provided scientists with one mechanism for the inhibition of the immune response in the cell. Other current Ebola research is focused on developing treatments or vaccines against the virus. Early investigations into potential vaccines showed that in mice models, the highest levels of protection occurred after vaccination with viral-like particles expressing eVP24.