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首页> 外文期刊>Nature >CFTR channel opening by ATP-driven tight dimerization of its nucleotide-binding domains
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CFTR channel opening by ATP-driven tight dimerization of its nucleotide-binding domains

机译：CFTR通道通过其核苷酸结合域的ATP驱动的紧密二聚作用而打开

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摘要

ABC (ATP-binding cassette) proteins constitute a large family of membrane proteins that actively transport a broad range of substrates. Cystic fibrosis transmembrane conductance regulator ( CFTR), the protein dysfunctional in cystic fibrosis, is unique among ABC proteins in that its transmembrane domains comprise an ion channel. Opening and closing of the pore have been linked to ATP binding and hydrolysis at CFTR's two nucleotide-binding domains, NBD1 and NBD2 (see, for example, refs 1, 2). Isolated NBDs of prokaryotic ABC proteins dimerize upon binding ATP, and hydrolysis of the ATP causes dimer dissociation(3-5). Here, using single-channel recording methods on intact CFTR molecules, we directly follow opening and closing of the channel gates, and relate these occurrences to ATP-mediated events in the NBDs. We find that energetic coupling(6) between two CFTR residues, expected to lie on opposite sides of its predicted NBD1-NBD2 dimer interface, changes in concert with channel gating status. The two monitored side chains are independent of each other in closed channels but become coupled as the channels open. The results directly link ATP-driven tight dimerization of CFTR's cytoplasmic nucleotide-binding domains to opening of the ion channel in the transmembrane domains. This establishes a molecular mechanism, involving dynamic restructuring of the NBD dimer interface, that is probably common to all members of the ABC protein superfamily.
机译：ABC（ATP结合盒）蛋白构成膜蛋白家族，可主动转运各种底物。囊性纤维化跨膜电导调节剂（CFTR）是在囊性纤维化中功能异常的蛋白质，在ABC蛋白中是独特的，因为其跨膜结构域包含离子通道。孔的打开和关闭与CFTR的两个核苷酸结合域NBD1和NBD2上的ATP结合和水解有关（例如，参见参考文献1、2）。分离的原核ABC蛋白的NBD在结合ATP后会二聚，而ATP的水解会导致二聚体解离（3-5）。在这里，使用完整CFTR分子上的单通道记录方法，我们直接跟踪通道门的打开和关闭，并将这些事件与NBD中ATP介导的事件联系起来。我们发现，预期位于其预测的NBD1-NBD2二聚体界面相对侧的两个CFTR残基之间的能量耦合（6）与通道门控状态一致。两条受监视的侧链在封闭通道中彼此独立，但随着通道打开而耦合。结果直接将ATP驱动的CFTR细胞质核苷酸结合域的紧密二聚化与跨膜域中离子通道的开放联系起来。这建立了涉及NBD二聚体界面动态重组的分子机制，这可能是ABC蛋白超家族的所有成员所共有的。

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