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: Patrick Kim Chiaw, Ling-Jun Huan, Stephane Gagnon, Diane Ly, Neil Sweezey, Daniela Rotin, Charles M Deber, Christine E Bear
• Journal: Chemistry & biology (Chem Biol) Vol. 16 Issue 5 Pg. 520-30 (May 29 2009) ISSN: 1879-1301 [Electronic] United States
• PMID: 19477416 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)

Chemical References

• Mutant Proteins
• Peptides
• Cystic Fibrosis Transmembrane Conductance Regulator

Topics

• Amino Acid Motifs
• Amino Acid Sequence
• Cell Line
• Cystic Fibrosis Transmembrane Conductance Regulator (genetics, metabolism)
• Humans
• Mutant Proteins (metabolism)
• Peptides (chemical synthesis, metabolism, pharmacology)
• Respiratory Mucosa (metabolism)