Tetrameric Assembly of K+ Channels Requires ER-Located Chaperone Proteins
Tetrameric Assembly of K+ Channels Requires ER-Located Chaperone Proteins
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K 通道四聚体组装需要位于内质网的伴侣蛋白。
DOI：
10.1016/j.molcel.2016.10.027
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发表时间：
2017-01-05
期刊：
影响因子：
16
通讯作者：
Cai, Shi-Qing
中科院分区：
文献类型：
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作者：
Li, Kai;Jiang, Qiang;Cai, Shi-Qing
通道亚基在内质网（ER）中的四聚体组装对于K+通道的表面表达和功能至关重要，但这一过程的分子机制尚不清楚。在这项研究中，我们通过遗传筛选发现，ER定位的J-结构域的伴侣蛋白（J-蛋白）是至关重要的醚-ago-go相关基因（ERG）的K+通道的生物发生和生理功能在秀丽隐杆线虫和人类细胞。人J蛋白DNAJB 12和DNAJB 14通过热休克蛋白（HSP）70非依赖性机制促进ERG（和Kv4.2）K+通道亚基的四聚体组装，而自身不经历寡聚化的突变DNAJB 12在体外和在C.优美的过表达DNAJB 14通过稳定突变的蛋白质，显著挽救了与长QT综合征（LQTS）相关的人类ether-ago-go相关基因（hERG）突变通道的功能缺陷，这种情况易导致危及生命的心律失常。因此，伴侣蛋白是亚基稳定性和K+通道组装所必需的。
Tetrameric assembly of channel subunits in the endoplasmic reticulum (ER) is essential for surface expression and function of K+ channels, but the molecular mechanism underlying this process remains unclear. In this study, we found through genetic screening that ER-located J-domain-containing chaperone proteins (J-proteins) are critical for the biogenesis and physiological function of ether-ago-go-related gene (ERG) K+ channels in both Caenorhabditis elegans and human cells. Human J-proteins DNAJB12 and DNAJB14 promoted tetrameric assembly of ERG (and Kv4.2) K+ channel subunits through a heat shock protein (HSP) 70-independent mechanism, whereas a mutated DNAJB12 that did not undergo oligomerization itself failed to assemble ERG channel subunits into tetramers in vitro and in C. elegans. Overexpressing DNAJB14 significantly rescued the defective function of human ether-ago- go-related gene (hERG) mutant channels associated with long QT syndrome (LQTS), a condition that predisposes to life-threatening arrhythmia, by stabilizing the mutated proteins. Thus, chaperone proteins are required for subunit stability and assembly of K+ channels.