Crimean-Congo hemorrhagic fever virus nucleoprotein reveals endonuclease activity in bunyaviruses

Proc Natl Acad Sci U S A. 2012 Mar 27;109(13):5046-51. doi: 10.1073/pnas.1200808109. Epub 2012 Mar 14.

Abstract

Crimean-Congo hemorrhagic fever virus (CCHFV), a virus with high mortality in humans, is a member of the genus Nairovirus in the family Bunyaviridae, and is a causative agent of severe hemorrhagic fever (HF). It is classified as a biosafety level 4 pathogen and a potential bioterrorism agent due to its aerosol infectivity and its ability to cause HF outbreaks with high case fatality (∼30%). However, little is known about the structural features and function of nucleoproteins (NPs) in the Bunyaviridae, especially in CCHFV. Here we report a 2.3-Å resolution crystal structure of the CCHFV nucleoprotein. The protein has a racket-shaped overall structure with distinct "head" and "stalk" domains and differs significantly with NPs reported so far from other negative-sense single-stranded RNA viruses. Furthermore, CCHFV NP shows a distinct metal-dependent DNA-specific endonuclease activity. Single residue mutations in the predicted active site resulted in a significant reduction in the observed endonuclease activity. Our results present a new folding mechanism and function for a negative-strand RNA virus nucleoprotein, extend our structural insight into bunyavirus NPs, and provide a potential target for antiviral drug development to treat CCHFV infection.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Chromatography, Gel
  • Crystallography, X-Ray
  • DNA, Viral / metabolism
  • Endonucleases / chemistry
  • Endonucleases / metabolism*
  • Hemorrhagic Fever Virus, Crimean-Congo / enzymology*
  • Host-Pathogen Interactions / immunology
  • Models, Molecular
  • Nucleoproteins / chemistry
  • Nucleoproteins / metabolism*
  • Orthobunyavirus / enzymology*
  • Protein Structure, Secondary
  • Protein Structure, Tertiary
  • RNA Caps / metabolism
  • RNA-Binding Proteins / metabolism
  • Viral Proteins / chemistry
  • Viral Proteins / metabolism*

Substances

  • DNA, Viral
  • Nucleoproteins
  • RNA Caps
  • RNA-Binding Proteins
  • Viral Proteins
  • Endonucleases

Associated data

  • PDB/3U3I