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首页> 外文期刊>Cellular Physiology and Biochemistry >The H-loop in the Second Nucleotide-binding Domain of the Cystic Fibrosis Transmembrane Conductance Regulator is Required for Efficient Chloride Channel Closing
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The H-loop in the Second Nucleotide-binding Domain of the Cystic Fibrosis Transmembrane Conductance Regulator is Required for Efficient Chloride Channel Closing

机译：高效的氯离子通道关闭需要囊性纤维化跨膜电导调节剂的第二个核苷酸结合域中的H环。

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摘要

The cystic fibrosis transmembrane conductance regulator (CFTR) is an ATP-binding cassette (ABC) transporter that functions as a cAMP-activated chloride channel. The recent model of CFTR gating predicts that the ATP binding to both nucleotide-binding domains (NBD1 and NBD2) of CFTR is required for the opening of the channel, while the ATP hydrolysis at NBD2 induces subsequent channel closing. In most ABC proteins, efficient hydrolysis of ATP requires the presence of the invariant histidine residue within the H-loop located in the C-terminal part of the NBD. However, the contribution of the corresponding region (H-loop) of NBD2 to the CFTR channel gating has not been examined so far. Here we report that the alanine substitution of the conserved dipeptide HR motif (HR -> AA) in the H-loop of NBD2 leads to prolonged open states of CFTR channel, indicating that the H-loop is required for efficient channel closing. On the other hand, the HR -> AA substitution lead to the substantial decrease of CFTR-mediated current density (pA/pF) in transfected HEK 293 cells, as recorded in the whole-cell patch-clamp analysis. These results suggest that the H-loop of NBD2, apart from being required for CFTR channel closing, may be involved in regulating CFTR trafficking to the cell surface.
机译：囊性纤维化跨膜电导调节剂（CFTR）是ATP结合盒（ABC）转运蛋白，其功能是cAMP激活的氯离子通道。 CFTR门控的最新模型预测，打开通道需要与CFTR的两个核苷酸结合域（NBD1和NBD2）结合的ATP，而在NBD2处的ATP水解诱导随后的通道关闭。在大多数ABC蛋白中，ATP的有效水解需要在NBD C端部分的H环内存在不变的组氨酸残基。但是，到目前为止，尚未检查NBD2的相应区域（H环）对CFTR通道门控的贡献。在这里，我们报道保守的二肽HR基序（HR-> AA）在NBD2的H环中被丙氨酸取代导致CFTR通道的开放状态延长，这表明H环是有效关闭通道所必需的。另一方面，如全细胞膜片钳分析所记录，HR→AA置换导致转染的HEK 293细胞中CFTR介导的电流密度（pA / pF）大大降低。这些结果表明，除了CFTR通道关闭所需要的以外，NBD2的H环可能参与调节CFTR向细胞表面的运输。

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