title: An Intrinsically Disordered Peptide from Ebola Virus VP35 Controls Viral RNA Synthesis by Modulating Nucleoprotein-RNA Interactions.
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.
authors: Department of Pathology and Immunology, Washington University School of Medicine, St Louis, MO 63110, USA.
authors: Daisy W
authors: DW
authors: Leung
authors: 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.
authors: Dominika
authors: D
authors: Borek
authors: Department of Microbiology, Icahn School of Medicine at Mount Sinai, New York, NY 10029, USA.
authors: Priya
authors: P
authors: Luthra
authors: Department of Pathology and Immunology, Washington University School of Medicine, St Louis, MO 63110, USA.
authors: Jennifer M
authors: JM
authors: Binning
authors: Department of Virology and Immunology, Texas Biomedical Research Institute, San Antonio, TX 78227, USA.
authors: Manu
authors: M
authors: Anantpadma
authors: Department of Pathology and Immunology, Washington University School of Medicine, St Louis, MO 63110, USA.
authors: Gai
authors: G
authors: Liu
authors: Department of Pathology and Immunology, Washington University School of Medicine, St Louis, MO 63110, USA.
authors: Ian B
authors: IB
authors: Harvey
authors: National Center for Macromolecular Imaging, Verna and Marrs McLean Department of Biochemistry and Molecular Biology, Baylor College of Medicine, Houston, TX 77030, USA.
authors: Zhaoming
authors: Z
authors: Su
authors: Department of Microbiology, Icahn School of Medicine at Mount Sinai, New York, NY 10029, USA.
authors: Ariel
authors: A
authors: Endlich-Frazier
authors: Department of Pathology and Immunology, Washington University School of Medicine, St Louis, MO 63110, USA.
authors: Juanli
authors: J
authors: Pan
authors: Department of Microbiology, Icahn School of Medicine at Mount Sinai, New York, NY 10029, USA.
authors: Reed S
authors: RS
authors: Shabman
authors: National Center for Macromolecular Imaging, Verna and Marrs McLean Department of Biochemistry and Molecular Biology, Baylor College of Medicine, Houston, TX 77030, USA.
authors: Wah
authors: W
authors: Chiu
authors: Department of Virology and Immunology, Texas Biomedical Research Institute, San Antonio, TX 78227, USA.
authors: Robert A
authors: RA
authors: Davey
authors: 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.
authors: Zbyszek
authors: Z
authors: Otwinowski
authors: Department of Microbiology, Icahn School of Medicine at Mount Sinai, New York, NY 10029, USA.
authors: Christopher F
authors: CF
authors: Basler
authors: Department of Pathology and Immunology, Washington University School of Medicine, St Louis, MO 63110, USA. Electronic address: gamarasinghe@path.wustl.edu.
authors: Gaya K
authors: GK
authors: Amarasinghe
mesh_terms: D002151:Calorimetry; D020285:Cryoelectron Microscopy; D018360:Crystallography, X-Ray; D029043:Ebolavirus / Q000502:physiology*; D006367:HeLa Cells; D019142:Hemorrhagic Fever, Ebola / Q000378:metabolism; D006801:Humans; D019590:Nucleocapsid Proteins; D009698:Nucleoproteins / Q000378:metabolism*; D020836:Protein Structure, Quaternary; D012367:RNA, Viral / Q000378:metabolism*; D014758:Viral Core Proteins / Q000378:metabolism*; D014779:Virus Replication
chemical_list: D019590:Nucleocapsid Proteins; D009698:Nucleoproteins; D012367:RNA, Viral; D014758:Viral Core Proteins; C084818:nucleoprotein VP35, Ebola virus