Document Detail


The primary folding defect and rescue of ΔF508 CFTR emerge during translation of the mutant domain.
MedLine Citation:
PMID:  21152102     Owner:  NLM     Status:  MEDLINE    
Abstract/OtherAbstract:
In the vast majority of cystic fibrosis (CF) patients, deletion of residue F508 from CFTR is the cause of disease. F508 resides in the first nucleotide binding domain (NBD1) and its absence leads to CFTR misfolding and degradation. We show here that the primary folding defect arises during synthesis, as soon as NBD1 is translated. Introduction of either the I539T or G550E suppressor mutation in NBD1 partially rescues ΔF508 CFTR to the cell surface, but only I539T repaired ΔF508 NBD1. We demonstrated rescue of folding and stability of NBD1 from full-length ΔF508 CFTR expressed in cells to isolated purified domain. The co-translational rescue of ΔF508 NBD1 misfolding in CFTR by I539T advocates this domain as the most important drug target for cystic fibrosis.
Authors:
Hanneke Hoelen; Bertrand Kleizen; Andre Schmidt; John Richardson; Paraskevi Charitou; Philip J Thomas; Ineke Braakman
Publication Detail:
Type:  Journal Article; Research Support, N.I.H., Extramural; Research Support, Non-U.S. Gov't     Date:  2010-11-30
Journal Detail:
Title:  PloS one     Volume:  5     ISSN:  1932-6203     ISO Abbreviation:  PLoS ONE     Publication Date:  2010  
Date Detail:
Created Date:  2010-12-14     Completed Date:  2011-04-27     Revised Date:  2014-09-22    
Medline Journal Info:
Nlm Unique ID:  101285081     Medline TA:  PLoS One     Country:  United States    
Other Details:
Languages:  eng     Pagination:  e15458     Citation Subset:  IM    
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MeSH Terms
Descriptor/Qualifier:
Amino Acid Sequence
Animals
Binding Sites / genetics
CHO Cells
Cell Line, Tumor
Cricetinae
Cricetulus
Cystic Fibrosis / genetics,  therapy
Cystic Fibrosis Transmembrane Conductance Regulator / chemistry*,  genetics*
Genetic Complementation Test
Genetic Therapy
HeLa Cells
Humans
Molecular Sequence Data
Mutation*
Protein Biosynthesis
Protein Folding*
Sequence Homology, Amino Acid
Grant Support
ID/Acronym/Agency:
DE12309/DE/NIDCR NIH HHS; DK49835/DK/NIDDK NIH HHS; R37 DK049835/DK/NIDDK NIH HHS
Chemical
Reg. No./Substance:
0/cystic fibrosis transmembrane conductance regulator delta F508; 126880-72-6/Cystic Fibrosis Transmembrane Conductance Regulator
Comments/Corrections

From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine


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