title: Structural basis for host membrane remodeling induced by protein 2B of hepatitis A virus.
abstract: The complexity of viral RNA synthesis and the numerous participating factors require a mechanism to topologically coordinate and concentrate these multiple viral and cellular components, ensuring a concerted function. Similarly to all other positive-strand RNA viruses, picornaviruses induce rearrangements of host intracellular membranes to create structures that act as functional scaffolds for genome replication. The membrane-targeting proteins 2B and 2C, their precursor 2BC, and protein 3A appear to be primarily involved in membrane remodeling. Little is known about the structure of these proteins and the mechanisms by which they induce massive membrane remodeling. Here we report the crystal structure of the soluble region of hepatitis A virus (HAV) protein 2B, consisting of two domains: a C-terminal helical bundle preceded by an N-terminally curved five-stranded antiparallel β-sheet that displays striking structural similarity to the β-barrel domain of enteroviral 2A proteins. Moreover, the helicoidal arrangement of the protein molecules in the crystal provides a model for 2B-induced host membrane remodeling during HAV infection.
  
  
  OBJECTIVE
  No structural information is currently available for the 2B protein of any picornavirus despite it being involved in a critical process in viral factory formation: the rearrangement of host intracellular membranes. Here we present the structure of the soluble domain of the 2B protein of hepatitis A virus (HAV). Its arrangement, both in crystals and in solution under physiological conditions, can help to understand its function and sheds some light on the membrane rearrangement process, a putative target of future antiviral drugs. Moreover, this first structure of a picornaviral 2B protein also unveils a closer evolutionary relationship between the hepatovirus and enterovirus genera within the Picornaviridae family.
authors.affiliation: Institut de Biologia Molecular de Barcelona, CSIC, Parc Científic de Barcelona, Barcelona, Spain Enteric Virus Laboratory, Department of Microbiology, University of Barcelona, Barcelona, Spain.
authors.forename: Laia
authors.initials: L
authors.lastname: Vives-Adrián
authors.affiliation: Institut de Biologia Molecular de Barcelona, CSIC, Parc Científic de Barcelona, Barcelona, Spain Centro Nacional de Biotecnología, CSIC, Madrid, Spain.
authors.forename: Damià
authors.initials: D
authors.lastname: Garriga
authors.affiliation: Institut de Biologia Molecular de Barcelona, CSIC, Parc Científic de Barcelona, Barcelona, Spain.
authors.forename: Mònica
authors.initials: M
authors.lastname: Buxaderas
authors.affiliation: IBMC-Instituto de Biologia Molecular e Celular, Universidade do Porto, Porto, Portugal.
authors.forename: Joana
authors.initials: J
authors.lastname: Fraga
authors.affiliation: IBMC-Instituto de Biologia Molecular e Celular, Universidade do Porto, Porto, Portugal.
authors.forename: Pedro José Barbosa
authors.initials: PJ
authors.lastname: Pereira
authors.affiliation: IBMC-Instituto de Biologia Molecular e Celular, Universidade do Porto, Porto, Portugal sribeiro@ibmc.up.pt nvmcri@ibmb.csic.es.
authors.forename: Sandra
authors.initials: S
authors.lastname: Macedo-Ribeiro
authors.affiliation: Institut de Biologia Molecular de Barcelona, CSIC, Parc Científic de Barcelona, Barcelona, Spain sribeiro@ibmc.up.pt nvmcri@ibmb.csic.es.
authors.forename: Núria
authors.initials: N
authors.lastname: Verdaguer
mesh_terms: D018360:Crystallography, X-Ray; D030041:Hepatitis A virus / Q000737:chemistry* / Q000502:physiology; D054884:Host-Pathogen Interactions; D006801:Humans; D007425:Intracellular Membranes / Q000378:metabolism / Q000821:virology; D046911:Macromolecular Substances / Q000648:ultrastructure; D046529:Microscopy, Electron, Transmission; D008954:Models, Biological; D008958:Models, Molecular; D011487:Protein Conformation; D017361:Viral Nonstructural Proteins / Q000737:chemistry* / Q000378:metabolism; D014779:Virus Replication
chemical_list: C116507:2B protein, hepatitis A virus; D046911:Macromolecular Substances; D017361:Viral Nonstructural Proteins