Abstract
BackgroundEbolaviruses have been known to cause deadly disease in humans for 40 years and have recently been demonstrated in West Africa to be able to cause large outbreaks. Four Ebolavirus species cause severe disease associated with high mortality in humans. Reston viruses are the only Ebolaviruses that do not cause disease in humans. Conserved amino acid changes in the Reston virus protein VP24 compared to VP24 of other Ebolaviruses have been suggested to alter VP24 binding to host cell karyopherins resulting in impaired inhibition of interferon signalling, which may explain the difference in human pathogenicity. Here we used protein structural analysis and molecular dynamics to further elucidate the interaction between VP24 and KPNA5.ResultsAs a control experiment, we compared the interaction of wild-type and R137A-mutant (known to affect KPNA5 binding) Ebola virus VP24 with KPNA5. Results confirmed that the R137A mutation weakens direct VP24-KPNA5 binding and enables water molecules to penetrate at the interface. Similarly, Reston virus VP24 displayed a weaker interaction with KPNA5 than Ebola virus VP24, which is likely to reduce the ability of Reston virus VP24 to prevent host cell interferon signalling.ConclusionOur results provide novel molecular detail on the interaction of Reston virus VP24 and Ebola virus VP24 with human KPNA5. The results indicate a weaker interaction of Reston virus VP24 with KPNA5 than Ebola virus VP24, which is probably associated with a decreased ability to interfere with the host cell interferon response. Hence, our study provides further evidence that VP24 is a key player in determining Ebolavirus pathogenicity.
Highlights
Ebolaviruses have been known to cause deadly disease in humans for 40 years and have recently been demonstrated in West Africa to be able to cause large outbreaks
We used mCSM [9] and FoldX [10] to predict the effect of the investigated mutations on the stability of the Ebola virus VP24-KPNA5 complex and the affinity of the proteins. mCSM predicted that both point mutations, R137A and Q139A, reduce the binding affinity and the stability of the complex, with the R137A mutation, having a greater effect (predicted (ΔΔG −1.07 kcal/mol change in complex affinity) than Q139A (Table 1)
Correlation of the conformational changes analysis supported this with the Ebola virus VP24-KPNA5 complex having a denser network of inter-subunit correlations than did the Reston virus VP24KPNA5 complex, which reflects the results obtained for the R137A mutant Ebola virus VP24-KPNA5 complex (Fig. 4). These findings suggest that Reston virus VP24 forms a less stable complex with KPNA5 than Ebola virus VP24, in particular due to the similarity of the results obtained for Reston virus VP24 and R137Amutated Ebola virus VP24, which is known not to bind human KPNA5 [3]
Summary
Ebolaviruses have been known to cause deadly disease in humans for 40 years and have recently been demonstrated in West Africa to be able to cause large outbreaks. Reston viruses are the only Ebolaviruses that do not cause disease in humans. Conserved amino acid changes in the Reston virus protein VP24 compared to VP24 of other Ebolaviruses have been suggested to alter VP24 binding to host cell karyopherins resulting in impaired inhibition of interferon signalling, which may explain the difference in human pathogenicity. The potential of Ebolaviruses to cause large outbreaks has been highlighted by the recent Ebola virus outbreak in West Africa [1] resulting in 28,657 confirmed cases and 11,325 deaths as of 8th May 2016 (http:// www.who.int/csr/disease/ebola/en/). Karyopherins would normally bind STAT1 and transport it to the nucleus, a key step during interferon signalling. VP24 prevents this transport and the subsequent accumulation of STAT1 in the nucleus [2,3,4,5,6]
Sign-in/Register to view highlights & summary Talk to us
Join us for a 30 min session where you can share your feedback and ask us any queries you have
Schedule a callDisclaimer: All third-party content on this website/platform is and will remain the property of their respective owners and is provided on "as is" basis without any warranties, express or implied. Use of third-party content does not indicate any affiliation, sponsorship with or endorsement by them. Any references to third-party content is to identify the corresponding services and shall be considered fair use under The CopyrightLaw.
