WNK3 and WNK4 amino-terminal domain defines their effect on the renal Na+-Cl- cotransporter.
WNK3 and WNK4 amino-terminal domain defines their effect on the renal Na+-Cl- cotransporter.
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WNK3 和 WNK4 氨基末端结构域定义了它们对肾脏 Na-Cl- 协同转运蛋白的作用。
DOI：
10.1152/ajprenal.90396.2008
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发表时间：
2008
期刊：
影响因子：
--
通讯作者：
Gamba,Gerardo
中科院分区：
文献类型：
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作者：
San-Cristobal,Pedro;Ponce-Coria,Jose;Vazquez,Norma;Bobadilla,NormaA;Gamba,Gerardo
突变型 WNK1 或 WNK4 对肾噻嗪敏感的 Na+-Cl−协同转运蛋白 (NCC) 的生理调节丧失，导致 II 型假性醛固酮增多症 (PHAII)，其特征是动脉高血压和高钾血症。 WNK4 通常抑制 NCC，但通过消除 WNK4 催化活性或通过 PHAII 型突变，这种效果会消失。相比之下，WNK 家族的另一个成员 WNK3 则激活 NCC。 WNK3对NCC的积极作用还需要其催化活性。由于在同一表达系统中观察到 WNK3 和 WNK4 对 NCC 的相反作用，因此 WNK 内的序列应赋予这些激酶激活或抑制特性。为了深入了解 WNK 和 NCC 之间的结构功能关系，我们使用 WNK3 和 WNK4 之间的嵌合方法来阐明 WNK 负责影响 NCC 的结构域。通过在 WNK3 和 WNK4 之间交换位于中央激酶结构域两侧的氨基或羧基末端结构域来构建嵌合体。我们的结果表明，嵌合体对 NCC 的影响遵循氨基末端结构域。因此，WNK 的氨基末端包含其激活或抑制 NCC 特性所需的序列。
Loss of physiological regulation of the renal thiazide-sensitive Na+-Cl−cotransporter (NCC) by mutant WNK1 or WNK4 results in pseudohypoaldosteronism type II (PHAII) characterized by arterial hypertension and hyperkalemia. WNK4 normally inhibits NCC, but this effect is lost by eliminating WNK4 catalytic activity or through PHAII-type mutations. In contrast, another member of the WNK family, WNK3, activates NCC. The positive effect of WNK3 on NCC also requires its catalytic activity. Because the opposite effects of WNK3 and WNK4 on NCC were observed in the same expression system, sequences within the WNKs should endow these kinases with their activating or inhibiting properties. To gain insight into the structure-function relationships between the WNKs and NCC, we used a chimera approach between WNK3 and WNK4 to elucidate the domain of the WNKs responsible for the effects on NCC. Chimeras were constructed by swapping the amino or carboxyl terminus domains, which flank the central kinase domain, between WNK3 and WNK4. Our results show that the effect of chimeras toward NCC follows the amino-terminal domain. Thus the amino terminus of the WNKs contains the sequences that are required for their activating or inhibiting properties on NCC.