VP24

VP24VP24

Introduction VP24 is a protein present in the Ebola and Marburg viruses, both of which are members of Filoviridae family. Presently there are five strains of Ebola: Sudan, Reston, Zaire, Bundibugyo, and Taï Forest, each with minor differences in VP24 sequences(1). Function Ebola In a normal immune response interferons (IFN) are produced to alert surrounding cells to the presence of a pathogen, which activates STAT1 by phosphorylation(2). STAT1 is a transcription factor that increases production of immune fighting genes in cells, STAT1 is brought to the nucleus by karyopherin α proteins(2). Ebola protein VP24 α1, α5, and α6, which normally bring the P-STAT1 to the nucleus(3). With the karyopherin proteins bound, P-STAT1 does not make it to the nucleus which greatly weakens the immune response in cells (3). Marburg Keap1 is a protein that degrades the transcription factor Nrf2(4). VP24 in the Marburg virus targets and binds the Keap1 protein, and as a result leaves Nrf2 unaltered(4). High levels of Nrf2 triggers antioxidant response elements(ARE)(4). This causes cells to become defensive, which protects the Marburg virus inside the cell(4). Structural Characteristics The Ebola and Marburg VP24 proteins are 30% identical(1). They share a similar pyramidal shaped domain, as well as a few structures. Both viruses have two highly conserved pockets underneath the "pyramid's" base (1). Additionally, the N termini of Ebola (Zaire) and the Marburg virus are very similar in function. They are both used for oligomer and nucleocapsid formation(1,5). (Reston) There are a few structural characteristics only found in the Ebola viruses. At the top of the pyramidal domain, there are α helices present which are thought to interact with the α karyopherin(1). An α helix formed by the N-terminus runs from the top of the "pyramid" to another nearby VP24, where it binds to one of the pockets located underneath the "pyramid"(1). The Marburg domain has a beta shelf present that sticks out from the structure(1). The Marburg VP24 doesn't use an alpha helix to bind to another VP24 like the Ebola VP24(1). Instead, it uses a flexible strand that binds to a groove of a close-by VP24(1).

spinqualitylabelsall models VP24 from the Reston Ebola Virus Show:Asymmetric Unit Biological Assembly Drag the structure with the mouse to rotate   Export Animated Image

ReferencesReferences

1. Zhang, A.P.P., Bornholdt, Z.A., Abelson, D.M., Saphire, E.O. Crystal Structure of Marburg Virus VP24. J. Virol.2014, Feb 26;88(10):5859

2. Zhang, P.P., Abelson, D.M., Bornholdt, Z.A., Liu, T., Woods, V.L. Jr., Saphire, E. O. The ebolavirus VP24 interferon antagonist: Know your enemy. Virulence. 2012, Aug 15;3(5)440-445

3. Xu, W., Edwards, M.R., Borek, D.M., Feagins, A.R., Mittal, A., Alinger, J.B., Berry, K.N., Yen, B., Hamilton, J., Brett, T.J., Pappu, R.V., Leung, D.W., Basler, C.F., Amarasinghe, G.K. Ebola Virus VP24 Targets a Unique NLS Binding Site on Karyopherin Alpha 5 to Selectively Compete with Nuclear Import of Phosphorylated STAT1. Cell Host & Microbe. 2014, Aug 13;16 187-200

4. Edwards, R. M., Johnson, B., Mire, C.E., Xu, W., Shabman, R.S., Speller, L.N., Leung, D.W., Geisbert, T.W., Amarasinghe, G.K., Basler, C.F. The Marburg Virus VP24 Protein Interacts with Keap1 to Activate the Cytoprotective Antioxidant Response Pathway. Cell. 2014, Mar 27. 6 1017-1025

5. Bharat, T.A.M., Noda, T., Riches, J.D., Kraehling, V., Kolesnikova, L., Becker, S., Kawaoka, Y., Briggs, J.A.G. Structural dissection of Ebola virus and its assembly determinants using cryo-electron tomography. PNAS. 2012, Feb 6 109(11) 4275-4280.