A TRANSMEMBRANE DOMAIN OF THE PUTATIVE CHANNEL SUBUNIT MEC-4 INFLUENCES MECHANOTRANSDUCTION AND NEURODEGENERATION IN C-ELEGANS
A TRANSMEMBRANE DOMAIN OF THE PUTATIVE CHANNEL SUBUNIT MEC-4 INFLUENCES MECHANOTRANSDUCTION AND NEURODEGENERATION IN C-ELEGANS
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DOI：
10.1038/367470a0
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发表时间：
1994-02-03
期刊：
影响因子：
64.8
通讯作者：
DRISCOLL, M
中科院分区：
文献类型：
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作者：
HONG, KS;DRISCOLL, M
ABERRANT离子通道活性在几种人类疾病中起着致病作用1 -3。不适当调节的通道活性似乎也是由秀丽隐杆线虫mec-4（mec-4（d））显性突变诱导的神经变性的基础，所述mec-4（d）是假定编码机械感觉通道4的亚基的退化蛋白基因家族的成员。简并蛋白基因家族由两个C. elegans基因，mec-4和deg-1（参考文献5），其可以突变为诱导特定神经元组变性的功能获得等位基因。一个相关的哺乳动物基因，大鼠α-rENaC，诱导阿米洛利敏感的Na+电流时，引入非洲爪蟾卵母细胞6，强烈表明，退化基因编码离子通道蛋白。推导的氨基酸序列的退化包括两个预测的跨膜结构域6，7。在这里，我们表明，第二跨膜结构域（MSDII）内的保守氨基酸对MEC-4活性至关重要，MSDII内的特定取代，无论是顺式或反式编码的mec-4（d）突变，阻止或延迟变性的发生。值得注意的是，来自另外两个家庭成员C. elegans deg-1（参考文献5）和大鼠α-rENaC（参考文献6），可以在功能上替代嵌合蛋白中的MEC-4 MSDII。我们的研究结果支持一个mechanosensory通道的结构模型，其中多个MEC-4亚基的取向，使MSDII线的通道孔，和神经退行性疾病模型，其中异常离子流通过这个通道是一个关键事件。
ABERRANT ion channel activity plays a causative role in several human disorders1-3. Inappropriately regulated channel activity also appears to be the basis for neurodegeneration induced by dominant mutations of Caenorhabditis elegans mec-4 (mec-4(d)), a member of the degenerin gene family postulated to encode a subunit of a mechanosensory channel4. The degenerin gene family has been defined by two C. elegans genes, mec-4 and deg-1 (ref. 5), which can mutate to gain-of-function alleles that induce degeneration of specific groups of neurons. A related mammalian gene, rat alpha-rENaC, induces an amiloride-sensitive Na+ current when introduced to Xenopus oocytes6, strongly suggesting that degenerin genes encode ion channel proteins. Deduced amino-acid sequences of the degenerins include two predicted membrane-spanning domains6,7. Here we show that conserved amino acids within the second membrane-spanning domain (MSDII) are critical for MEC-4 activity and that specific substitutions within MSDII, whether encoded in cis or in trans to a mec-4(d) mutation, block or delay the onset of degeneration. Remarkably, MSDII from two other family members, C. elegans deg-1 (ref. 5) and rat alpha-rENaC (ref. 6), can functionally substitute for MEC-4 MSDII in chimaeric proteins. Our results support a structural model for a mechanosensory channel in which multiple MEC-4 subunits are oriented such that MSDII lines the channel pore, and a neurodegeneration model in which aberrant ion flow through this channel is a key event.