title: Functional rescue of DeltaF508-CFTR by peptides designed to mimic sorting motifs.
abstract: The cystic fibrosis (CF)-causing mutant, deltaF508-CFTR, is misfolded and fails to traffic out of the endoplasmic reticulum (ER) to the cell surface. Introduction of second site mutations that disrupt a diarginine (RXR)-based ER retention motif in the first nucleotide binding domain rescues the trafficking defect of deltaF508-CFTR, supporting a role for these motifs in mediating ER retention of the major mutant. To determine if these RXR motifs mediate retention of the native deltaF508-CFTR protein in situ, we generated peptides that mimic these motifs and should antagonize mistrafficking mediated via their aberrant exposure. Here we show robust rescue of deltaF508-CFTR in cell lines and in respiratory epithelial tissues by transduction of RXR motif-mimetics, showing that abnormal accessibility of this motif is a key determinant of mistrafficking of the major CF-causing mutant.
authors.affiliation: Research Institute, Hospital for Sick Children, University of Toronto, ON, Canada.
authors.forename: Patrick
authors.initials: P
authors.lastname: Kim Chiaw
authors.forename: Ling-Jun
authors.initials: LJ
authors.lastname: Huan
authors.forename: Stephane
authors.initials: S
authors.lastname: Gagnon
authors.forename: Diane
authors.initials: D
authors.lastname: Ly
authors.forename: Neil
authors.initials: N
authors.lastname: Sweezey
authors.forename: Daniela
authors.initials: D
authors.lastname: Rotin
authors.forename: Charles M
authors.initials: CM
authors.lastname: Deber
authors.forename: Christine E
authors.initials: CE
authors.lastname: Bear
mesh_terms: D020816:Amino Acid Motifs; D000595:Amino Acid Sequence; D002460:Cell Line; D019005:Cystic Fibrosis Transmembrane Conductance Regulator / Q000235:genetics* / Q000378:metabolism; D006801:Humans; D050505:Mutant Proteins / Q000378:metabolism; D010455:Peptides / Q000138:chemical synthesis / Q000378:metabolism / Q000494:pharmacology*; D020545:Respiratory Mucosa / Q000378:metabolism
chemical_list: D050505:Mutant Proteins; D010455:Peptides; D019005:Cystic Fibrosis Transmembrane Conductance Regulator