The Nedd4-like protein KIAA0439 is a potential regulator of the epithelial sodium channel
The Nedd4-like protein KIAA0439 is a potential regulator of the epithelial sodium channel
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DOI：
10.1074/jbc.c000906200
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发表时间：
2001-03-16
影响因子：
4.8
通讯作者：
Kumar, S
中科院分区：
文献类型：
--
作者：
Harvey, KF;Dinudom, A;Kumar, S
阿米洛利敏感上皮钠通道（ENaC）在体液和电解质稳态中起关键作用，由α、β和γ亚基组成。每个博命的羧基末端单元包含一个PPxY,图案也被认为是重要的交互的WW域ubiquitin-protein连接酶,Nedd4,中断的互动,就像Liddle综合症,在突变删除或改变PPxYβ和γ亚基的主题,提出了导致钠活动增加,我们目前的证据表明KIAA0439蛋白质,Nedd4的近亲,也是一个潜在的钠调节器,我们证明KTAA0439 WW结构域结合了所有三个ENaC亚基。在全细胞膜片钳实验中，我们发现重组KIAA0439 WW结构域蛋白作为显性负突变体，可以干扰Na+依赖的ENaC反馈抑制。我们认为KIAA0439和Nedd4蛋白要么在ENaC调控中发挥冗余作用，要么以组织和/或信号特异性的方式下调ENaC。
The amiloride-sensitive epithelial sodium channel (ENaC) plays a critical role in fluid and electrolyte homeostasis and consists of alpha, beta, and gamma subunits. The carboxyl terminus of each ENaC subunit contains a PPxY, motif which is believed to be important for interaction with the WW domains of the ubiquitin-protein ligase, Nedd4, Disruption of this interaction, as in Liddle's syndrome, where mutations delete or alter the PPxY motif of either the beta or gamma subunits, has been proposed to result in increased ENaC activity, Here we present evidence that KIAA0439 protein, a close relative of Nedd4, is also a potential regulator of ENaC, We demonstrate that KTAA0439 WW domains bind all three ENaC subunits. We show that a recombinant KIAA0439 WW domain protein acts as a dominant negative mutant that can interfere with the Na+-dependent feedback inhibition of ENaC in whole-cell patch clamp experiments. We propose that KIAA0439 and Nedd4 proteins either play a redundant role in ENaC regulation or function in a tissue- and/or signal-specific manner to down-regulate ENaC.