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The ebola virus interferon antagonist VP24 directly binds STAT1 and has a novel, pyramidal fold.

Zhang AP, Bornholdt ZA, Liu T, Abelson DM, Lee DE, Li S, Woods VL, Saphire EO - PLoS Pathog. (2012)

Bottom Line: One of the proteins likely responsible for this effect is VP24.A site on a particular face of the pyramid exhibits reduced solvent exchange when in complex with STAT1.This site is above two highly conserved pockets in VP24 that contain key residues previously implicated in virulence.

View Article: PubMed Central - PubMed

Affiliation: Department of Immunology and Microbial Science, The Scripps Research Institute, La Jolla, California, USA.

ABSTRACT
Ebolaviruses cause hemorrhagic fever with up to 90% lethality and in fatal cases, are characterized by early suppression of the host innate immune system. One of the proteins likely responsible for this effect is VP24. VP24 is known to antagonize interferon signaling by binding host karyopherin α proteins, thereby preventing them from transporting the tyrosine-phosphorylated transcription factor STAT1 to the nucleus. Here, we report that VP24 binds STAT1 directly, suggesting that VP24 can suppress at least two distinct branches of the interferon pathway. Here, we also report the first crystal structures of VP24, derived from different species of ebolavirus that are pathogenic (Sudan) and nonpathogenic to humans (Reston). These structures reveal that VP24 has a novel, pyramidal fold. A site on a particular face of the pyramid exhibits reduced solvent exchange when in complex with STAT1. This site is above two highly conserved pockets in VP24 that contain key residues previously implicated in virulence. These crystal structures and accompanying biochemical analysis map differences between pathogenic and nonpathogenic viruses, offer templates for drug design, and provide the three-dimensional framework necessary for biological dissection of the many functions of VP24 in the virus life cycle.

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Alternate views of VP24 secondary structure.The overall shape of VP24 resembles a three-sided pyramid with Faces 1 (a), 2 (b), and 3 (c) as illustrated. Only SUDV1–233 is shown for clarity. Arrows indicate conserved pockets on Faces 1 and 3.
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ppat-1002550-g002: Alternate views of VP24 secondary structure.The overall shape of VP24 resembles a three-sided pyramid with Faces 1 (a), 2 (b), and 3 (c) as illustrated. Only SUDV1–233 is shown for clarity. Arrows indicate conserved pockets on Faces 1 and 3.

Mentions: VP24 adopts a compact, single domain, α/β structure of novel fold (DaliLite v.3 [47]). The overall shape of VP24 resembles a triangular pyramid of dimensions 73 Å×30 Å×30 Å. The three faces of the pyramid are numbered 1, 2 and 3 (Figures 2 and S1b). A collection of α helices (α1 and α5-10) and a small, three-stranded, antiparallel β sheet (β1-3) form the top of the pyramid with the N-terminus at the apex. A five-stranded antiparallel β sheet (β4-8) forms the center, while a second collection of α helices (α2-4) forms the base. Portions of the C-terminal region resemble prior de novo predictions: as predicted, helices 5–8 are indeed observed, helix 8 is quite long, and a β sheet exists at the base of the structure. Differences between the prediction and the experimental structure are that a three-stranded sheet was predicted, but a five-stranded sheet is observed [48] and that an armadillo repeat-type domain structure was predicted, but no such domain is observed in VP24.


The ebola virus interferon antagonist VP24 directly binds STAT1 and has a novel, pyramidal fold.

Zhang AP, Bornholdt ZA, Liu T, Abelson DM, Lee DE, Li S, Woods VL, Saphire EO - PLoS Pathog. (2012)

Alternate views of VP24 secondary structure.The overall shape of VP24 resembles a three-sided pyramid with Faces 1 (a), 2 (b), and 3 (c) as illustrated. Only SUDV1–233 is shown for clarity. Arrows indicate conserved pockets on Faces 1 and 3.
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Related In: Results  -  Collection

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getmorefigures.php?uid=PMC3285596&req=5

ppat-1002550-g002: Alternate views of VP24 secondary structure.The overall shape of VP24 resembles a three-sided pyramid with Faces 1 (a), 2 (b), and 3 (c) as illustrated. Only SUDV1–233 is shown for clarity. Arrows indicate conserved pockets on Faces 1 and 3.
Mentions: VP24 adopts a compact, single domain, α/β structure of novel fold (DaliLite v.3 [47]). The overall shape of VP24 resembles a triangular pyramid of dimensions 73 Å×30 Å×30 Å. The three faces of the pyramid are numbered 1, 2 and 3 (Figures 2 and S1b). A collection of α helices (α1 and α5-10) and a small, three-stranded, antiparallel β sheet (β1-3) form the top of the pyramid with the N-terminus at the apex. A five-stranded antiparallel β sheet (β4-8) forms the center, while a second collection of α helices (α2-4) forms the base. Portions of the C-terminal region resemble prior de novo predictions: as predicted, helices 5–8 are indeed observed, helix 8 is quite long, and a β sheet exists at the base of the structure. Differences between the prediction and the experimental structure are that a three-stranded sheet was predicted, but a five-stranded sheet is observed [48] and that an armadillo repeat-type domain structure was predicted, but no such domain is observed in VP24.

Bottom Line: One of the proteins likely responsible for this effect is VP24.A site on a particular face of the pyramid exhibits reduced solvent exchange when in complex with STAT1.This site is above two highly conserved pockets in VP24 that contain key residues previously implicated in virulence.

View Article: PubMed Central - PubMed

Affiliation: Department of Immunology and Microbial Science, The Scripps Research Institute, La Jolla, California, USA.

ABSTRACT
Ebolaviruses cause hemorrhagic fever with up to 90% lethality and in fatal cases, are characterized by early suppression of the host innate immune system. One of the proteins likely responsible for this effect is VP24. VP24 is known to antagonize interferon signaling by binding host karyopherin α proteins, thereby preventing them from transporting the tyrosine-phosphorylated transcription factor STAT1 to the nucleus. Here, we report that VP24 binds STAT1 directly, suggesting that VP24 can suppress at least two distinct branches of the interferon pathway. Here, we also report the first crystal structures of VP24, derived from different species of ebolavirus that are pathogenic (Sudan) and nonpathogenic to humans (Reston). These structures reveal that VP24 has a novel, pyramidal fold. A site on a particular face of the pyramid exhibits reduced solvent exchange when in complex with STAT1. This site is above two highly conserved pockets in VP24 that contain key residues previously implicated in virulence. These crystal structures and accompanying biochemical analysis map differences between pathogenic and nonpathogenic viruses, offer templates for drug design, and provide the three-dimensional framework necessary for biological dissection of the many functions of VP24 in the virus life cycle.

Show MeSH
Related in: MedlinePlus