KCNE3 truncation mutants reveal a bipartite modulation of KCNQ1 K+ channels.
KCNE3 truncation mutants reveal a bipartite modulation of KCNQ1 K+ channels.
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DOI：
10.1085/jgp.200409114
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发表时间：
2004-12
期刊：
影响因子：
--
通讯作者：
Kobertz WR
中科院分区：
文献类型：
--
作者：
Gage SD;Kobertz WR
这五个KCNE基因编码一个I型跨膜肽家族，该家族与KCNQ 1和其他电压门控K+通道组装，产生具有不同通道门控特性的钾传导复合物。最近已经提出，KCNE 1和KCNE 3的跨膜结构域内的氨基酸三联体赋予肽调节特异性，因为这三个残基的交换基本上将受体KCNE转化为供体（Melman，Y.F.，A. Domenech，S. de la Luna和T.V. McDonald。2001. J.Biol.Chem.276：6439-6444）。然而，这些结果与早期的KCNE 1缺失研究形成鲜明对比，早期的KCNE 1缺失研究表明，KCNE 1和KCNE 3之间高度保守的COOH末端区域负责KCNE 1对KCNQ 1的调节（Tapper，A.R.，和A.L.乔治。116：379-389）。为了确定KCNE 3肽的行为是否与KCNE 1相似，我们检查了一组NH 2-和COOH-末端KCNE 3截短突变体，以直接确定组装和调节KCNQ 1通道所需的区域。截断缺乏大部分的NH 2末端，COOH末端，或突变体窝藏两个截断引起KCNQ 1通道复合物与基础激活，KCNE 3调制的标志。这些结果表明，KCNE 3跨膜结构域是足够的组装和调制的KCNQ 1通道，并提出了一个二分模型KCNE 1和KCNE 3亚基KCNQ 1调制。在该模型中，KCNE 3跨膜结构域在调节中是主动的，并且覆盖COOH末端的贡献，而KCNE 1跨膜结构域是被动的，并且揭示了KCNQ 1通道的COOH末端调节。我们还测试了该模型的有效性，通过使用活性KCNE 3跨膜结构域的功能拯救一个不导电的，但组装和运输能力，长QT突变位于保守的COOH-末端区域的KCNE 1。
The five KCNE genes encode a family of type I transmembrane peptides that assemble with KCNQ1 and other voltage-gated K+ channels, resulting in potassium conducting complexes with varied channel-gating properties. It has been recently proposed that a triplet of amino acids within the transmembrane domain of KCNE1 and KCNE3 confers modulation specificity to the peptide, since swapping of these three residues essentially converts the recipient KCNE into the donor (Melman, Y.F., A. Domenech, S. de la Luna, and T.V. McDonald. 2001. J. Biol. Chem. 276:6439–6444). However, these results are in stark contrast with earlier KCNE1 deletion studies, which demonstrated that a COOH-terminal region, highly conserved between KCNE1 and KCNE3, was responsible for KCNE1 modulation of KCNQ1 (Tapper, A.R., and A.L. George. 2000 J. Gen. Physiol. 116:379–389.). To ascertain whether KCNE3 peptides behave similarly to KCNE1, we examined a panel of NH2- and COOH-terminal KCNE3 truncation mutants to directly determine the regions required for assembly with and modulation of KCNQ1 channels. Truncations lacking the majority of their NH2 terminus, COOH terminus, or mutants harboring both truncations gave rise to KCNQ1 channel complexes with basal activation, a hallmark of KCNE3 modulation. These results demonstrate that the KCNE3 transmembrane domain is sufficient for assembly with and modulation of KCNQ1 channels and suggests a bipartite model for KCNQ1 modulation by KCNE1 and KCNE3 subunits. In this model, the KCNE3 transmembrane domain is active in modulation and overrides the COOH terminus' contribution, whereas the KCNE1 transmembrane domain is passive and reveals COOH-terminal modulation of KCNQ1 channels. We furthermore test the validity of this model by using the active KCNE3 transmembrane domain to functionally rescue a nonconducting, yet assembly and trafficking competent, long QT mutation located in the conserved COOH-terminal region of KCNE1.
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