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Cell Rep. 2015 Apr 21;11(3):376-89. doi: 10.1016/j.celrep.2015.03.034. Epub 2015 Apr 9.

An Intrinsically Disordered Peptide from Ebola Virus VP35 Controls Viral RNA Synthesis by Modulating Nucleoprotein-RNA Interactions.

Author information

1
Department of Pathology and Immunology, Washington University School of Medicine, St Louis, MO 63110, USA.
2
Departments of Biophysics and Biochemistry and Center for Structural Genomics of Infectious Diseases, University of Texas Southwestern Medical Center at Dallas, Dallas, TX 75390, USA.
3
Department of Microbiology, Icahn School of Medicine at Mount Sinai, New York, NY 10029, USA.
4
Department of Virology and Immunology, Texas Biomedical Research Institute, San Antonio, TX 78227, USA.
5
National Center for Macromolecular Imaging, Verna and Marrs McLean Department of Biochemistry and Molecular Biology, Baylor College of Medicine, Houston, TX 77030, USA.
6
Department of Pathology and Immunology, Washington University School of Medicine, St Louis, MO 63110, USA. Electronic address: gamarasinghe@path.wustl.edu.

Abstract

During viral RNA synthesis, Ebola virus (EBOV) nucleoprotein (NP) alternates between an RNA-template-bound form and a template-free form to provide the viral polymerase access to the RNA template. In addition, newly synthesized NP must be prevented from indiscriminately binding to noncognate RNAs. Here, we investigate the molecular bases for these critical processes. We identify an intrinsically disordered peptide derived from EBOV VP35 (NPBP, residues 20-48) that binds NP with high affinity and specificity, inhibits NP oligomerization, and releases RNA from NP-RNA complexes in vitro. The structure of the NPBP/ΔNPNTD complex, solved to 3.7 Å resolution, reveals how NPBP peptide occludes a large surface area that is important for NP-NP and NP-RNA interactions and for viral RNA synthesis. Together, our results identify a highly conserved viral interface that is important for EBOV replication and can be targeted for therapeutic development.

PMID:
25865894
PMCID:
PMC4599368
DOI:
10.1016/j.celrep.2015.03.034
[Indexed for MEDLINE]
Free PMC Article

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