Slc26a Is Inhibited by the R-region of the Cystic Fibrosis Transmembrane Conductance Regulator via the STAS Domain
Slc26a Is Inhibited by the R-region of the Cystic Fibrosis Transmembrane Conductance Regulator via the STAS Domain
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DOI：
10.1074/jbc.m109.001669
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发表时间：
2009-10-09
影响因子：
4.8
通讯作者：
Romero, Michael F.
中科院分区：
文献类型：
--
作者：
Chang, Min-Hwang;Plata, Consuelo;Romero, Michael F.
SLC 26蛋白作为阴离子交换剂、通道和传感器发挥功能。先前的细胞研究已经表明，Slc 26 a3和Slc 26 a6通过Slc 26-STAS（硫酸盐转运蛋白抗σ）结构域与囊性纤维化跨膜传导调节因子（CFTR）（R）CFTR的R区相互作用，导致相互转运激活。我们最近发现Slc 26 a9具有nCl（-）-HCO_3-交换器和Cl-通道功能。在本研究中，我们显示Slc 26 a9的纯化的STAS结构域（a9 STAS）结合纯化的（R）CFTR。当Slc 26 a9和（R）CFTR片段在爪蟾卵母细胞中共表达时，Slc 26 a9介导的nCl（-）-HCO 3-交换和Cl-电流几乎完全被抑制。Slc 26 a9 STAS结构域的缺失（a9-Δ STAS）实际上消除了Cl-电流，对nCl（-）-HCO 3-交换活性仅有适度影响。α 9-δ STAS和（R）CFTR片段的共表达不改变残留的α 9-δ STAS功能。用Slc 26 a6 STAS结构域（a6-a9-a6）替换Slc 26 a9 STAS结构域不改变Slc 26 a9功能并且不再被（R）CFTR抑制。这些数据表明，Slc 26 a9-STAS结构域与其他Slc 26-STAS结构域一样，结合R区中的CFTR。然而，与先前报道的数据不同，这种结合相互作用抑制Slc 26 a9离子转运活性。这些结果意味着Slc 26-STAS结构域可能都与（R）CFTR相互作用，但生理结果对不同的Slc 26蛋白是特异性的，从而允许对各种上皮细胞的离子转运进行动态和急性微调。
SLC26 proteins function as anion exchangers, channels, and sensors. Previous cellular studies have shown that Slc26a3 and Slc26a6 interact with the R-region of the cystic fibrosis transmembrane conductance regulator (CFTR), (R)CFTR, via the Slc26-STAS (sulfate transporter anti-sigma) domain, resulting in mutual transport activation. We recently showed that Slc26a9 has both nCl(-)-HCO3- exchanger and Cl- channel function. In this study, we show that the purified STAS domain of Slc26a9 (a9STAS) binds purified (R)CFTR. When Slc26a9 and (R)CFTR fragments are co-expressed in Xenopus oocytes, both Slc26a9-mediated nCl(-)-HCO3- exchange and Cl- currents are almost fully inhibited. Deletion of the Slc26a9 STAS domain (a9-Delta STAS) virtually eliminated the Cl- currents with only a modest affect on nCl(-)-HCO3- exchange activity. Co-expression of a9-Delta STAS and the (R)CFTR fragment did not alter the residual a9-Delta STAS function. Replacing the Slc26a9 STAS domain with the Slc26a6 STAS domain (a6-a9-a6) does not change Slc26a9 function and is no longer inhibited by (R)CFTR. These data indicate that the Slc26a9-STAS domain, like other Slc26-STAS domains, binds CFTR in the R-region. However, unlike previously reported data, this binding interaction inhibits Slc26a9 ion transport activity. These results imply that Slc26-STAS domains may all interact with (R)CFTR but that the physiological outcome is specific to differing Slc26 proteins, allowing for dynamic and acute fine tuning of ion transport for various epithelia.