title: The pH Stability of Foot-and-Mouth Disease Virus Particles Is Modulated by Residues Located at the Pentameric Interface and in the N Terminus of VP1.
abstract: The picornavirus foot-and-mouth disease virus (FMDV) is the etiological agent of a highly contagious disease that affects important livestock species. The FMDV capsid is highly acid labile, and viral particles lose infectivity due to their disassembly at pH values slightly below neutrality. This acid sensitivity is related to the mechanism of viral uncoating and genome penetration from endosomes. In this study, we have analyzed the molecular basis of FMDV acid-induced disassembly by isolating and characterizing a panel of novel FMDV mutants differing in acid sensitivity. Amino acid replacements altering virion stability were preferentially distributed in two different regions of the capsid: the N terminus of VP1 and the pentameric interface. Even more, the acid labile phenotype induced by a mutation located at the pentameric interface in VP3 could be compensated by introduction of an amino acid substitution in the N terminus of VP1. These results indicate that the acid sensitivity of FMDV can be considered a multifactorial trait and that virion stability is the fine-tuned product of the interaction between residues from different capsid proteins, in particular those located within the N terminus of VP1 or close to the pentameric interface.
  
  
  OBJECTIVE
  The viral capsid protects the viral genome from environmental factors and contributes to virus dissemination and infection. Thus, understanding of the molecular mechanisms that modulate capsid stability is of interest for the basic knowledge of the biology of viruses and as a tool to improve the stability of conventional vaccines based on inactivated virions or empty capsids. Using foot-and-mouth disease virus (FMDV), which displays a capsid with extreme acid sensitivity, we have performed a genetic study to identify the molecular determinants involved in capsid stability. A panel of FMDV mutants with differential sensitivity to acidic pH was generated and characterized, and the results showed that two different regions of FMDV capsid contribute to modulating viral particle stability. These results provide new insights into the molecular mechanisms of acid-mediated FMDV uncoating.
authors.affiliation: Centro de Biología Molecular Severo Ochoa (CSIC-UAM), Cantoblanco, Madrid, Spain.
authors.forename: Flavia
authors.initials: F
authors.lastname: Caridi
authors.affiliation: Centro de Biología Molecular Severo Ochoa (CSIC-UAM), Cantoblanco, Madrid, Spain.
authors.forename: Angela
authors.initials: A
authors.lastname: Vázquez-Calvo
authors.affiliation: Centro de Biología Molecular Severo Ochoa (CSIC-UAM), Cantoblanco, Madrid, Spain fsobrino@cbm.csic.es.
authors.forename: Francisco
authors.initials: F
authors.lastname: Sobrino
authors.affiliation: Centro de Biología Molecular Severo Ochoa (CSIC-UAM), Cantoblanco, Madrid, Spain.
authors.forename: Miguel A
authors.initials: MA
authors.lastname: Martín-Acebes
mesh_terms: D019943:Amino Acid Substitution; D000818:Animals; D036022:Capsid Proteins / Q000737:chemistry / Q000235:genetics* / Q000502:physiology*; D002460:Cell Line; D029544:Foot-and-Mouth Disease Virus / Q000235:genetics* / Q000472:pathogenicity / Q000502:physiology*; D016679:Genome, Viral; D006863:Hydrogen-Ion Concentration; D008958:Models, Molecular; D016297:Mutagenesis, Site-Directed; D054730:Protein Interaction Domains and Motifs; D055550:Protein Stability; D020836:Protein Structure, Quaternary; D014771:Virion / Q000235:genetics / Q000502:physiology; D057646:Virus Uncoating
chemical_list: D036022:Capsid Proteins; C442501:VP1 protein, Foot-and-mouth disease virus; C442460:VP3 protein, Foot-and-mouth disease virus