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Title: Structural basis for dsRNA recognition and interferon antagonism by Ebola VP35

Abstract

Ebola viral protein 35 (VP35), encoded by the highly pathogenic Ebola virus, facilitates host immune evasion by antagonizing antiviral signaling pathways, including those initiated by RIG-I-like receptors. Here we report the crystal structure of the Ebola VP35 interferon inhibitory domain (IID) bound to short double-stranded RNA (dsRNA), which together with in vivo results reveals how VP35-dsRNA interactions contribute to immune evasion. Conserved basic residues in VP35 IID recognize the dsRNA backbone, whereas the dsRNA blunt ends are 'end-capped' by a pocket of hydrophobic residues that mimic RIG-I-like receptor recognition of blunt-end dsRNA. Residues critical for RNA binding are also important for interferon inhibition in vivo but not for viral polymerase cofactor function of VP35. These results suggest that simultaneous recognition of dsRNA backbone and blunt ends provides a mechanism by which Ebola VP35 antagonizes host dsRNA sensors and immune responses.

Authors:
; ; ; ; ; ; ; ; ; ; ;  [1]
  1. Sinai
Publication Date:
Research Org.:
Argonne National Lab. (ANL), Argonne, IL (United States). Advanced Photon Source (APS)
Sponsoring Org.:
USDOE
OSTI Identifier:
1002274
Resource Type:
Journal Article
Journal Name:
Nat. Struct. Mol. Biol.
Additional Journal Information:
Journal Volume: 17; Journal Issue: (2) ; 02, 2010; Journal ID: ISSN 1545-9993
Country of Publication:
United States
Language:
ENGLISH
Subject:
36 MATERIALS SCIENCE; CRYSTAL STRUCTURE; IN VIVO; INTERFERON; POLYMERASES; PROTEINS; RESIDUES; RNA

Citation Formats

Leung, Daisy W, Prins, Kathleen C, Borek, Dominika M, Farahbakhsh, Mina, Tufariello, JoAnn M, Ramanan, Parameshwaran, Nix, Jay C, Helgeson, Luke A, Otwinowski, Zbyszek, Honzatko, Richard B, Basler, Christopher F, Amarasinghe, Gaya K, Iowa State), LBNL), and UTSMC). Structural basis for dsRNA recognition and interferon antagonism by Ebola VP35. United States: N. p., 2010. Web. doi:10.1038/nsmb.1765.
Leung, Daisy W, Prins, Kathleen C, Borek, Dominika M, Farahbakhsh, Mina, Tufariello, JoAnn M, Ramanan, Parameshwaran, Nix, Jay C, Helgeson, Luke A, Otwinowski, Zbyszek, Honzatko, Richard B, Basler, Christopher F, Amarasinghe, Gaya K, Iowa State), LBNL), & UTSMC). Structural basis for dsRNA recognition and interferon antagonism by Ebola VP35. United States. doi:10.1038/nsmb.1765.
Leung, Daisy W, Prins, Kathleen C, Borek, Dominika M, Farahbakhsh, Mina, Tufariello, JoAnn M, Ramanan, Parameshwaran, Nix, Jay C, Helgeson, Luke A, Otwinowski, Zbyszek, Honzatko, Richard B, Basler, Christopher F, Amarasinghe, Gaya K, Iowa State), LBNL), and UTSMC). Fri . "Structural basis for dsRNA recognition and interferon antagonism by Ebola VP35". United States. doi:10.1038/nsmb.1765.
@article{osti_1002274,
title = {Structural basis for dsRNA recognition and interferon antagonism by Ebola VP35},
author = {Leung, Daisy W and Prins, Kathleen C and Borek, Dominika M and Farahbakhsh, Mina and Tufariello, JoAnn M and Ramanan, Parameshwaran and Nix, Jay C and Helgeson, Luke A and Otwinowski, Zbyszek and Honzatko, Richard B and Basler, Christopher F and Amarasinghe, Gaya K and Iowa State) and LBNL) and UTSMC)},
abstractNote = {Ebola viral protein 35 (VP35), encoded by the highly pathogenic Ebola virus, facilitates host immune evasion by antagonizing antiviral signaling pathways, including those initiated by RIG-I-like receptors. Here we report the crystal structure of the Ebola VP35 interferon inhibitory domain (IID) bound to short double-stranded RNA (dsRNA), which together with in vivo results reveals how VP35-dsRNA interactions contribute to immune evasion. Conserved basic residues in VP35 IID recognize the dsRNA backbone, whereas the dsRNA blunt ends are 'end-capped' by a pocket of hydrophobic residues that mimic RIG-I-like receptor recognition of blunt-end dsRNA. Residues critical for RNA binding are also important for interferon inhibition in vivo but not for viral polymerase cofactor function of VP35. These results suggest that simultaneous recognition of dsRNA backbone and blunt ends provides a mechanism by which Ebola VP35 antagonizes host dsRNA sensors and immune responses.},
doi = {10.1038/nsmb.1765},
journal = {Nat. Struct. Mol. Biol.},
issn = {1545-9993},
number = (2) ; 02, 2010,
volume = 17,
place = {United States},
year = {2010},
month = {3}
}