The Kir channel immunoglobulin domain is essential for Kir1.1 (ROMK) thermodynamic stability, trafficking and gating.
The Kir channel immunoglobulin domain is essential for Kir1.1 (ROMK) thermodynamic stability, trafficking and gating.
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DOI：
10.4161/chan.3.1.7817
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发表时间：
2009-01
期刊：
影响因子：
--
通讯作者：
Denton JS
中科院分区：
文献类型：
--
作者：
Fallen K;Banerjee S;Sheehan J;Addison D;Lewis LM;Meiler J;Denton JS
肾脏内向整流钾通道Kir1.1在调节电解质稳态和血压方面起着关键作用。该通道的功能丧失突变会导致婴儿出现危及生命的盐和水平衡紊乱，称为产前巴特综合征（ABS）。在鉴定的30多个ABS突变中，大约一半位于通道的细胞内结构域中。大多数这些突变的通道功能障碍的机制是未知的。通过将细胞内突变映射到Kir1.1的原子模型上，我们发现其中几个定位于先前未被表征的遗传学上古老的免疫球蛋白（IG）样结构域（IgLD），促使我们详细研究这种结构。IgLD由两个面对面包装的β折叠片组装而成，产生β折叠界面或核心，由高度保守的侧链填充。计算突变通道的热力学计算表明，IgLD核心残基是决定胞质结构域稳定性的最重要的残基之一。与这一概念相一致，我们表明，两个ABS突变（A198T和Y314C）位于IgLD核心损害通道的生物合成和运输在哺乳动物细胞。一小部分核心突变通道到达细胞表面，但由于螺旋束门的关闭而电沉默。补偿性突变诱导的通道功能的拯救揭示了IgLD核心突变体未能纠正。我们的研究为ABS的发病机制提供了新的线索，并将IgLD确立为Kir通道家族中的重要结构。
The renal inward rectifying potassium channel Kir1.1 plays key roles in regulating electrolyte homeostasis and blood pressure. Loss-of-function mutations in the channel cause a life-threatening salt and water balance disorder in infants called antenatal Bartter syndrome (ABS). Of more than 30 ABS mutations identified, approximately half are located in the intracellular domain of the channel. The mechanisms underlying channel dysfunction for most of these mutations are unknown. By mapping intracellular mutations onto an atomic model of Kir1.1, we found that several of these are localized to a phylogenetically ancient immunoglobulin (Ig)-like domain (IgLD) that has not been characterized previously, prompting us to examine this structure in detail. The IgLD is assembled from two β-pleated sheets packed face-to-face, creating a β-sheet interface or core, populated by highly conserved side chains. Thermodynamic calculations on computationally mutated chan-nels suggest that IgLD core residues are among the most important residues for determining cytoplasmic domain stability. Consistent with this notion, we show that two ABS mutations (A198T and Y314C) located within the IgLD core impair channel biosynthesis and trafficking in mammalian cells. A fraction of core mutant channels reach the cell surface, but are electrically silent due to closure of the helix-bundle gate. Compensatory mutation-induced rescue of channel function revealed that IgLD core mutants fail to rectify. Our study sheds new light on the pathogenesis of ABS and establishes the IgLD as an essential structure within the Kir channel family.
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DOI：
10.1085/jgp.117.5.395
发表时间：
2001-05
期刊：
The Journal of general physiology
影响因子：
--
作者：
Guo D;Lu Z
通讯作者：
Lu Z
影响因子：
5.6
作者：
Chothia, C;Gelfand, I;Kister, A
通讯作者：
Kister, A
DOI：
10.1152/ajprenal.1997.273.4.f516
发表时间：
1997-10-01
影响因子：
4.2
作者：
Choe, H;Zhou, H;Sackin, H
通讯作者：
Sackin, H
影响因子：
3.5
作者：
Dong, Elizabeth;Smith, Jarrod;Meiler, Jens
通讯作者：
Meiler, Jens
影响因子：
2.9
作者：
Jin, WL;Lu, Z
通讯作者：
Lu, Z