The Caenorhabditis elegans iodotyrosine deiodinase ortholog SUP-18 functions through a conserved channel SC-box to regulate the muscle two-pore domain potassium channel SUP-9.
The Caenorhabditis elegans iodotyrosine deiodinase ortholog SUP-18 functions through a conserved channel SC-box to regulate the muscle two-pore domain potassium channel SUP-9.
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秀丽隐杆线虫碘酪氨酸脱碘酶直系同源物 SUP-18 通过保守通道 SC-box 发挥作用，调节肌肉双孔结构域钾通道 SUP-9
DOI：
10.1371/journal.pgen.1004175
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发表时间：
2014-02
期刊：
影响因子：
4.5
通讯作者：
Horvitz HR
中科院分区：
文献类型：
--
作者：
de la Cruz IP;Ma L;Horvitz HR
秀丽隐杆线虫基因sup-18中的功能丧失突变抑制了肌肉收缩中的缺陷，该缺陷由与肌肉膜相关的<$9双孔结构域K+通道的假定调节亚基<$10中的功能获得突变所赋予。我们克隆了sup-18，发现它编码C。哺乳动物碘酪氨酸脱碘酶（IYD）的直向同源物，IYD是一种NADH氧化酶/黄素还原酶，其在碘再循环中起作用并且对于调节代谢的甲状腺激素的生物合成是重要的。哺乳动物IYD的FMN-结合位点是保守的，其似乎需要催化活性才能发挥作用。遗传分析表明，α-10可以与α-18一起发挥作用，通过一种独立于假定的α-9调节亚基α-93的途径激活α-9。我们发现了一个新的进化保守的丝氨酸-半胱氨酸丰富的区域中的C-末端胞质结构域的α-9所需的特异性激活的α-10和α-18，但不是由α-93。由于双孔结构域K+通道调节许多细胞类型的静息膜电位，因此我们认为，IYD使用NADH作为辅酶调节IYD-9通道的活性，从而将肌细胞的代谢状态与肌膜兴奋性偶联。碘酪氨酸脱碘酶（IYD）控制甲状腺激素生物合成中碘的再循环，调节代谢。IYD缺陷导致先天性甲状腺功能减退症，这是一种多系统疾病，可导致生长障碍和严重的智力迟钝。我们鉴定了线虫线虫的基因sup-18作为<$-9/<$-93/<$-10双孔结构域钾通道复合物的调节剂，并表明<$-18是IYD的直系同源物，IYD是NADH氧化酶/黄素还原酶家族的成员。通道复合物的激活需要通过β-10蛋白的功能获得性突变来实现，β-18 IYD是必需的。通过ERK-18激活ERK-9通道需要在ERK-9的C-末端中的保守的富含丝氨酸-半胱氨酸的区域，并且独立于保守的多跨膜蛋白ERK-93的功能。我们认为，肌钙蛋白-18利用NADH作为辅酶激活肌钙蛋白-9通道，以响应肌钙蛋白-10的活性和肌细胞的代谢状态。
Loss-of-function mutations in the Caenorhabditis elegans gene sup-18 suppress the defects in muscle contraction conferred by a gain-of-function mutation in SUP-10, a presumptive regulatory subunit of the SUP-9 two-pore domain K+ channel associated with muscle membranes. We cloned sup-18 and found that it encodes the C. elegans ortholog of mammalian iodotyrosine deiodinase (IYD), an NADH oxidase/flavin reductase that functions in iodine recycling and is important for the biosynthesis of thyroid hormones that regulate metabolism. The FMN-binding site of mammalian IYD is conserved in SUP-18, which appears to require catalytic activity to function. Genetic analyses suggest that SUP-10 can function with SUP-18 to activate SUP-9 through a pathway that is independent of the presumptive SUP-9 regulatory subunit UNC-93. We identified a novel evolutionarily conserved serine-cysteine-rich region in the C-terminal cytoplasmic domain of SUP-9 required for its specific activation by SUP-10 and SUP-18 but not by UNC-93. Since two-pore domain K+ channels regulate the resting membrane potentials of numerous cell types, we suggest that the SUP-18 IYD regulates the activity of the SUP-9 channel using NADH as a coenzyme and thus couples the metabolic state of muscle cells to muscle membrane excitability. Iodotyrosine deiodinase (IYD) controls the recycling of iodide in the biogenesis of thyroid hormones that regulate metabolism. Defects in IYD result in congenital hypothyroidism, a multisystem disorder that can lead to growth failure and severe mental retardation. We identified the gene sup-18 of the nematode Caenorhabditis elegans as a regulator of the SUP-9/UNC-93/SUP-10 two-pore domain potassium channel complex and showed that SUP-18 is an ortholog of IYD, a member of the NADH oxidase/flavin reductase family. SUP-18 IYD is required for the activation of the channel complex by a gain-of-function mutation of the SUP-10 protein. SUP-9 channel activation by SUP-18 requires a conserved serine-cysteine-rich region in the C-terminus of SUP-9 and is independent of the function of the conserved multi-transmembrane protein UNC-93. We propose that SUP-18 uses NADH as a coenzyme to activate the SUP-9 channel in response to the activity of SUP-10 and the metabolic state of muscle cells.
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影响因子：
5.8
作者：
CHOUFOER, JC;KASSENAAR, AAH;QUERIDO, A
通讯作者：
QUERIDO, A
影响因子：
4.8
作者：
Czirják, G;Enyedi, P
通讯作者：
Enyedi, P
影响因子：
4.8
作者：
Gnidehou, S;Caillou, B;Dupuy, C
通讯作者：
Dupuy, C
影响因子：
5.6
作者：
FROSHAUER, S;GREEN, GN;BECKWITH, J
通讯作者：
BECKWITH, J
影响因子：
11.4
作者：
Duprat, F;Lesage, F;Lazdunski, M
通讯作者：
Lazdunski, M