The F508 cystic fibrosis mutation impairs domain-domain interactions and arrests post-translational folding of CFTR
The F508 cystic fibrosis mutation impairs domain-domain interactions and arrests post-translational folding of CFTR
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DOI：
10.1038/nsmb882
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发表时间：
2005-01-01
影响因子：
16.8
通讯作者：
Lukacs, GL
中科院分区：
文献类型：
--
作者：
Du, K;Sharma, M;Lukacs, GL
错误折叠是突变的囊性纤维化跨膜传导调节因子(CFTRs)内质网相关降解的原因，包括核苷酸结合结构域1(NBD1)中Phe508(DeltaF508)的缺失。为了研究Phe508的作用，结合对Phe508的诱变，比较了Nbd1、Nbd2和CFtr的从头折叠和稳定性。DeltaF508和阻止CFTR折叠的氨基酸替换破坏了Nbd2折叠及其与NBD1的天然相互作用。DeltaF508使NBD1的构象发生了有限的变化。非极性残基和部分脂肪族残基是允许的，带电残基和甘氨酸影响了Nbd2和CFTR的翻译后折叠和稳定性。结果表明，Nbd2的载体折叠和CFTR的结构域组装需要Phe508疏水的侧链相互作用，这代表了一种可用于其他多结构域膜蛋白的联合共翻译和翻译后折叠机制。
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.