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首页> 外文期刊>Proceedings of the National Academy of Sciences of the United States of America >Regulation of cystic fibrosis transmembrane conductance regulator single-channel gating by bivalent PDZ-domain-mediated interaction
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Regulation of cystic fibrosis transmembrane conductance regulator single-channel gating by bivalent PDZ-domain-mediated interaction

机译：二价PDZ-结构域介导的相互作用对囊性纤维化跨膜电导调节剂单通道门控的调节

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摘要

The cystic fibrosis transmembrane conductance regulator (CFTR) is a cAMP-dependent protein kinase- and ATP-regulated chloride channel, the activity of which determines the rate of electrolyte and fluid transport in a variety of epithelial tissues. Here we describe a mechanism that regulates CFTR channel activity, which is mediated by PDZ domains. a family of conserved protein- interaction modules. The Na~+/H~+ exchanger regulatory factor (NHERF) binds to the cytoplasmic tail of CFTR through either of its two PDZ (PDZ1 and PDZ2) domains. A recombinant fragment of NHERF (PDZ1--2) containing the two PDZ domains increases the open probability (P_o) of single CFTR channels in excised membrane patches from a lung submucosal gland cell line. Both PDZ domains are required for this functional effect, because peptides containing mutations in either domain are unable to increase channel Po. The concentration dependence of the regulation by the bivalent PDZ1--2 domain is biphasic, i.e., activating at lower concentrations and inhibiting at higher concentrations. Furthermore, either PDZ domain alone or together is without effect on P_o, but either domain can competitively inhibit the PDZ1--2-mediated stimulation of CFTR. Our results support a molecular model in which bivalent NHERF PDZ domains regulate channel gating by crosslinking the C-terminal tails in a single dimeric CFTR channel, and the magnitude of this regulation is coupled to the stoichiometry of these interactions.
机译：囊性纤维化跨膜电导调节剂（CFTR）是cAMP依赖性蛋白激酶和ATP调节的氯离子通道，其活性决定了各种上皮组织中电解质和液体运输的速率。在这里，我们描述了一种调节CFTR通道活性的机制，该通道由PDZ域介导。保守的蛋白质相互作用模块家族。 Na〜+ / H〜+交换子调节因子（NHERF）通过其两个PDZ（PDZ1和PDZ2）结构域之一与CFTR的胞质尾结合。包含两个PDZ域的NHERF重组片段（PDZ1--2）增加了从肺粘膜下腺细胞系切除的膜片中单个CFTR通道的开放概率（P_o）。这两个功能域都需要两个PDZ域，因为任一域中都包含突变的肽无法增加通道Po。由二价PDZ1--2结构域调节的浓度依赖性是双相的，即在较低浓度下活化而在较高浓度下抑制。此外，单独的PDZ结构域或一起对PD0没有影响，但是任何一个结构域都可以竞争性地抑制PDZ1--2-介导的CFTR刺激。我们的结果支持了一个分子模型，其中二价NHERF PDZ域通过在单个二聚CFTR通道中交联C末端尾部来调节通道门控，并且这种调节的强度与这些相互作用的化学计量有关。

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