Journal
NATURE STRUCTURAL & MOLECULAR BIOLOGY
Volume 12, Issue 1, Pages 10-16Publisher
NATURE PUBLISHING GROUP
DOI: 10.1038/nsmb881
Keywords
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Funding
- NATIONAL INSTITUTE OF DIABETES AND DIGESTIVE AND KIDNEY DISEASES [R37DK049835, R01DK049835] Funding Source: NIH RePORTER
- NATIONAL INSTITUTE OF GENERAL MEDICAL SCIENCES [T32GM007062] Funding Source: NIH RePORTER
- NIDDK NIH HHS [R37 DK049835, R01 DK049835, DK49835] Funding Source: Medline
- NIGMS NIH HHS [T32 GM007062, GM07062] Funding Source: Medline
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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.
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