title: Crystal Structure of Marburg Virus VP40 Reveals a Broad, Basic Patch for Matrix Assembly and a Requirement of the N-Terminal Domain for Immunosuppression.
abstract: Marburg virus (MARV), a member of the filovirus family, causes severe hemorrhagic fever with up to 90% lethality. MARV matrix protein VP40 is essential for assembly and release of newly copied viruses and also suppresses immune signaling in the infected cell. Here we report the crystal structure of MARV VP40. We found that MARV VP40 forms a dimer in solution, mediated by N-terminal domains, and that formation of this dimer is essential for budding of virus-like particles. We also found the N-terminal domain to be necessary and sufficient for immune antagonism. The C-terminal domains of MARV VP40 are dispensable for immunosuppression but are required for virus assembly. The C-terminal domains are only 16% identical to those of Ebola virus, differ in structure from those of Ebola virus, and form a distinct broad and flat cationic surface that likely interacts with the cell membrane during virus assembly.
  
  
  OBJECTIVE
  Marburg virus, a cousin of Ebola virus, causes severe hemorrhagic fever, with up to 90% lethality seen in recent outbreaks. Molecular structures and visual images of the proteins of Marburg virus are essential for the development of antiviral drugs. One key protein in the Marburg virus life cycle is VP40, which both assembles the virus and suppresses the immune system. Here we provide the molecular structure of Marburg virus VP40, illustrate differences from VP40 of Ebola virus, and reveal surfaces by which Marburg VP40 assembles progeny and suppresses immune function.
authors.affiliation: Department of Immunology and Microbial Science, The Scripps Research Institute, La Jolla, California, USA.
authors.forename: Shun-Ichiro
authors.initials: S
authors.lastname: Oda
authors.affiliation: International Research Center for Infectious Diseases, Institute of Medical Science, The University of Tokyo, Tokyo, Japan.
authors.forename: Takeshi
authors.initials: T
authors.lastname: Noda
authors.affiliation: Department of Chemistry and Biochemistry, the Eck Institute for Global Health, and the Boler-Parsegh Center for Rare and Neglected Diseases, University of Notre Dame, Notre Dame, Indiana, USA.
authors.forename: Kaveesha J
authors.initials: KJ
authors.lastname: Wijesinghe
authors.affiliation: Department of Pathobiological Sciences, School of Veterinary Medicine, University of Wisconsin-Madison, Madison, Wisconsin, USA.
authors.forename: Peter
authors.initials: P
authors.lastname: Halfmann
authors.affiliation: Department of Immunology and Microbial Science, The Scripps Research Institute, La Jolla, California, USA.
authors.forename: Zachary A
authors.initials: ZA
authors.lastname: Bornholdt
authors.affiliation: Department of Immunology and Microbial Science, The Scripps Research Institute, La Jolla, California, USA.
authors.forename: Dafna M
authors.initials: DM
authors.lastname: Abelson
authors.affiliation: Department of Pathobiological Sciences, School of Veterinary Medicine, University of Wisconsin-Madison, Madison, Wisconsin, USA.
authors.forename: Tammy
authors.initials: T
authors.lastname: Armbrust
authors.affiliation: Department of Chemistry and Biochemistry, the Eck Institute for Global Health, and the Boler-Parsegh Center for Rare and Neglected Diseases, University of Notre Dame, Notre Dame, Indiana, USA Department of Biochemistry & Molecular Biology, Indiana University School of Medicine-South Bend, South Bend, Indiana, USA.
authors.forename: Robert V
authors.initials: RV
authors.lastname: Stahelin
authors.affiliation: International Research Center for Infectious Diseases, Institute of Medical Science, The University of Tokyo, Tokyo, Japan Department of Pathobiological Sciences, School of Veterinary Medicine, University of Wisconsin-Madison, Madison, Wisconsin, USA Division of Virology, Department of Microbiology and Immunology, Institute of Medical Science, The University of Tokyo, Tokyo, Japan.
authors.forename: Yoshihiro
authors.initials: Y
authors.lastname: Kawaoka
authors.affiliation: Department of Immunology and Microbial Science, The Scripps Research Institute, La Jolla, California, USA Skaggs Institute for Chemical Biology, The Scripps Research Institute, La Jolla, California, USA erica@scripps.edu.
authors.forename: Erica Ollmann
authors.initials: EO
authors.lastname: Saphire
mesh_terms: D000595:Amino Acid Sequence; D018360:Crystallography, X-Ray; D007108:Immune Tolerance; D029024:Marburgvirus / Q000737:chemistry* / Q000502:physiology*; D008958:Models, Molecular; D008969:Molecular Sequence Data; D011487:Protein Conformation; D055503:Protein Multimerization; D016415:Sequence Alignment; D015678:Viral Structural Proteins / Q000737:chemistry* / Q000378:metabolism*; D019065:Virus Assembly; D057074:Virus Release
chemical_list: D015678:Viral Structural Proteins