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Title: Side chain and backbone contributions of Phe508 to CFTR folding

Abstract

Mutations in the cystic fibrosis transmembrane conductance regulator (CFTR), an integral membrane protein, cause cystic fibrosis (CF). The most common CF-causing mutant, deletion of Phe508, fails to properly fold. To elucidate the role Phe508 plays in the folding of CFTR, missense mutations at this position were generated. Only one missense mutation had a pronounced effect on the stability and folding of the isolated domain in vitro. In contrast, many substitutions, including those of charged and bulky residues, disrupted folding of full-length CFTR in cells. Structures of two mutant nucleotide-binding domains (NBDs) reveal only local alterations of the surface near position 508. These results suggest that the peptide backbone plays a role in the proper folding of the domain, whereas the side chain plays a role in defining a surface of NBD1 that potentially interacts with other domains during the maturation of intact CFTR.

Authors:
; ; ;  [1]
  1. U. of Texas-SMED
Publication Date:
Research Org.:
Argonne National Lab. (ANL), Argonne, IL (United States). Advanced Photon Source (APS)
Sponsoring Org.:
USDOE
OSTI Identifier:
1008495
Resource Type:
Journal Article
Journal Name:
Nat. Struct. Mol. Biol.
Additional Journal Information:
Journal Volume: 12; Journal Issue: 12, 2005; Journal ID: ISSN 1545-9993
Country of Publication:
United States
Language:
ENGLISH
Subject:
59 BASIC BIOLOGICAL SCIENCES; 60 APPLIED LIFE SCIENCES; CHAINS; FIBROSIS; IN VITRO; MEMBRANE PROTEINS; MUTANTS; MUTATIONS; PEPTIDES; RESIDUES; STABILITY

Citation Formats

Thibodeau, Patrick H, Brautigam, Chad A, Machius, Mischa, and Thomas, Philip J. Side chain and backbone contributions of Phe508 to CFTR folding. United States: N. p., 2010. Web.
Thibodeau, Patrick H, Brautigam, Chad A, Machius, Mischa, & Thomas, Philip J. Side chain and backbone contributions of Phe508 to CFTR folding. United States.
Thibodeau, Patrick H, Brautigam, Chad A, Machius, Mischa, and Thomas, Philip J. Tue . "Side chain and backbone contributions of Phe508 to CFTR folding". United States.
@article{osti_1008495,
title = {Side chain and backbone contributions of Phe508 to CFTR folding},
author = {Thibodeau, Patrick H and Brautigam, Chad A and Machius, Mischa and Thomas, Philip J},
abstractNote = {Mutations in the cystic fibrosis transmembrane conductance regulator (CFTR), an integral membrane protein, cause cystic fibrosis (CF). The most common CF-causing mutant, deletion of Phe508, fails to properly fold. To elucidate the role Phe508 plays in the folding of CFTR, missense mutations at this position were generated. Only one missense mutation had a pronounced effect on the stability and folding of the isolated domain in vitro. In contrast, many substitutions, including those of charged and bulky residues, disrupted folding of full-length CFTR in cells. Structures of two mutant nucleotide-binding domains (NBDs) reveal only local alterations of the surface near position 508. These results suggest that the peptide backbone plays a role in the proper folding of the domain, whereas the side chain plays a role in defining a surface of NBD1 that potentially interacts with other domains during the maturation of intact CFTR.},
doi = {},
journal = {Nat. Struct. Mol. Biol.},
issn = {1545-9993},
number = 12, 2005,
volume = 12,
place = {United States},
year = {2010},
month = {12}
}