The F508 cystic fibrosis mutation impairs domain-domain interactions and arrests post-translational folding of CFTR

被引:291
作者
Du, K
Sharma, M
Lukacs, GL [1 ]
机构
[1] Univ Toronto, Hosp Sick Children, Res Inst, Program Cell & Lung Biol, Toronto, ON M5G 1X8, Canada
[2] Univ Toronto, Dept Lab Med & Pathobiol, Toronto, ON M5G 1X8, Canada
关键词
D O I
10.1038/nsmb882
中图分类号
Q5 [生物化学]; Q7 [分子生物学];
学科分类号
071010 ; 081704 ;
摘要
Misfolding accounts for the endoplasmic reticulum-associated degradation of mutant cystic fibrosis transmembrane conductance regulators (CFTRs), including deletion of Phe508 (DeltaF508) in the nucleotide-binding domain 1 (NBD1). To study the role of Phe508, the de novo folding and stability of NBD1, NBD2 and CFTR were compared in conjunction with mutagenesis of Phe508. DeltaF508 and amino acid replacements that prevented CFTR folding disrupted the NBD2 fold and its native interaction with NBD1. DeltaF508 caused limited alteration in NBD1 conformation. Whereas nonpolar and some aliphatic residues were permissive, charged residues and glycine compromised the post-translational folding and stability of NBD2 and CFTR. The results suggest that hydrophobic side chain interactions of Phe508 are required for vectorial folding of NBD2 and the domain-domain assembly of CFTR, representing a combined co- and post-translational folding mechanism that may be used by other multidomain membrane proteins.
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页码:17 / 25
页数:9
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