Human–mouse cystic fibrosis transmembrane conductance regulator (CFTR) chimeras identify regions that partially rescue CFTR-ΔF508 processing and alter its gating defect

Qian Dong; Lynda S Ostedgaard; Christopher Rogers; Daniel W Vermeer; Yuping Zhang; Michael J Welsh

doi:10.1073/pnas.1120065109

Back

Human–mouse cystic fibrosis transmembrane conductance regulator (CFTR) chimeras identify regions that partially rescue CFTR-ΔF508 processing and alter its gating defect

Journal article

Open access

Peer reviewed

Human–mouse cystic fibrosis transmembrane conductance regulator (CFTR) chimeras identify regions that partially rescue CFTR-ΔF508 processing and alter its gating defect

Qian Dong, Lynda S Ostedgaard, Christopher Rogers, Daniel W Vermeer, Yuping Zhang and Michael J Welsh

Proceedings of the National Academy of Sciences - PNAS, Vol.109(3), pp.917-922

01/17/2012

DOI: 10.1073/pnas.1120065109

PMCID: PMC3271874

PMID: 22210114

Files and links (1)

url

https://doi.org/10.1073/pnas.1120065109View

Published (Version of record) Open Access

Abstract

The Î” F508 mutation in the cystic fibrosis transmembrane conductance regulator ( CFTR ) gene is the most common cause of cystic fibrosis. The mutation disrupts biosynthetic processing, reduces channel opening rate, and decreases protein lifetime. In contrast to human CFTR (hCFTR)-Î”F508, mouse CFTR-Î”F508 is partially processed to the cell surface, although it exhibits a functional defect similar to hCFTR-Î”F508. To explore Î” F508 abnormalities, we generated humanâ€“mouse chimeric channels. Substituting mouse nucleotide-binding domain-1 (mNBD1) into hCFTR partially rescued the Î”F508-induced maturation defect, and substituting mouse membrane-spanning domain-2 or its intracellular loops (ICLs) into hCFTR prevented further Î” F508 -induced gating defects. The protective effect of the mouse ICLs was reverted by inserting mouse NBDs. Our results indicate that the Î” F508 mutation affects maturation and gating via distinct regions of the protein; maturation of CFTR-Î”F508 depends on NBD1, and the Î” F508 -induced gating defect depends on the interaction between the membrane-spanning domain-2 ICLs and the NBDs. These appear to be distinct processes, because none of the chimeras repaired both defects. This distinction was exemplified by the I539T mutation, which improved CFTR-Î”F508 processing but worsened the gating defect. Our results, together with previous studies, suggest that many different NBD1 modifications improve CFTR-Î”F508 maturation and that the effect of modifications can be additive. Thus, it might be possible to enhance processing by targeting several different regions of the domain or by targeting a network of CFTR-associated proteins. Because no one modification corrected both maturation and gating, perhaps more than a single agent will be required to correct all CFTR-Î”F508 defects.

Biological Sciences

protein biosynthesis

anion channel

Details

Title: Subtitle: Human–mouse cystic fibrosis transmembrane conductance regulator (CFTR) chimeras identify regions that partially rescue CFTR-ΔF508 processing and alter its gating defect
Creators: Qian Dong - Departments of
Lynda S Ostedgaard - Departments of
Christopher Rogers - Departments of
Daniel W Vermeer - Departments of
Yuping Zhang - Departments of
Michael J Welsh - Departments of
Resource Type: Journal article
Publication Details: Proceedings of the National Academy of Sciences - PNAS, Vol.109(3), pp.917-922
DOI: 10.1073/pnas.1120065109
PMID: 22210114
PMCID: PMC3271874
NLM abbreviation: Proc Natl Acad Sci U S A
ISSN: 0027-8424
eISSN: 1091-6490
Publisher: National Academy of Sciences
Language: English
Date published: 01/17/2012
Academic Unit: Neurology; Molecular Physiology and Biophysics; Pulmonary, Critical Care, and Occupational Medicine; Stead Family Department of Pediatrics; Obstetrics and Gynecology; Neurosurgery; Internal Medicine
Record Identifier: 9984020759402771

Metrics

18 Record Views

21 Times Cited - Web of Science