title: Residues in a highly conserved claudin-1 motif are required for hepatitis C virus entry and mediate the formation of cell-cell contacts.
abstract: Claudin-1, a component of tight junctions between liver hepatocytes, is a hepatitis C virus (HCV) late-stage entry cofactor. To investigate the structural and functional roles of various claudin-1 domains in HCV entry, we applied a mutagenesis strategy. Putative functional intracellular claudin-1 domains were not important. However, we identified seven novel residues in the first extracellular loop that are critical for entry of HCV isolates drawn from six different subtypes. Most of the critical residues belong to the highly conserved claudin motif W(30)-GLW(51)-C(54)-C(64). Alanine substitutions of these residues did not impair claudin-1 cell surface expression or lateral protein interactions within the plasma membrane, including claudin-1-claudin-1 and claudin-1-CD81 interactions. However, these mutants no longer localized to cell-cell contacts. Based on our observations, we propose that cell-cell contacts formed by claudin-1 may generate specialized membrane domains that are amenable to HCV entry.
authors.affiliation: Department of Microbiology and Immunology, Albert Einstein College of Medicine, Bronx, NY 10461, USA.
authors.forename: Lisa
authors.initials: L
authors.lastname: Cukierman
authors.forename: Laurent
authors.initials: L
authors.lastname: Meertens
authors.forename: Claire
authors.initials: C
authors.lastname: Bertaux
authors.forename: Francis
authors.initials: F
authors.lastname: Kajumo
authors.forename: Tatjana
authors.initials: T
authors.lastname: Dragic
mesh_terms: D020816:Amino Acid Motifs; D002450:Cell Communication; D002460:Cell Line; D002462:Cell Membrane / Q000378:metabolism; D062445:Claudin-1; D005110:Extracellular Space / Q000378:metabolism; D016174:Hepacivirus / Q000502:physiology*; D006801:Humans; D008565:Membrane Proteins / Q000737:chemistry / Q000235:genetics / Q000378:metabolism*; D008969:Molecular Sequence Data; D009154:Mutation / Q000235:genetics; D053586:Virus Internalization
chemical_list: C568108:CLDN1 protein, human; D062445:Claudin-1; D008565:Membrane Proteins