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Ttm50 facilitates calpain activation by anchoring it to calcium stores and increasing its sensitivity to calcium.
Cell Research ( IF 44.1 ) Pub Date : 2020-08-26 , DOI: 10.1038/s41422-020-0388-4
Elsayed Metwally 1, 2, 3 , Guoli Zhao 1, 4, 5 , Qifu Wang 1 , Yong Q Zhang 1, 2
Affiliation  

Calcium-dependent proteolytic calpains are implicated in a variety of physiological processes, as well as pathologies associated with calcium overload. However, the mechanism by which calpain is activated remains elusive since intracellular calcium levels under physiological conditions do not reach the high concentration range required to trigger calpain activation. From a candidate screening using the abundance of the calpain target glutamate receptor GluRIIA at the Drosophila neuromuscular junction as a readout, we uncovered that calpain activity was inhibited upon knockdown of Ttm50, a subunit of the Tim23 complex known to be involved in the import of proteins across the mitochondrial inner membrane. Unexpectedly, Ttm50 and calpain are co-localized at calcium stores Golgi and endoplasmic reticulum (ER), and Ttm50 interacts with calpain via its C-terminal domain. This interaction is required for calpain localization at Golgi/ER, and increases calcium sensitivity of calpain by roughly an order of magnitude. Our findings reveal the regulation of calpain activation by Ttm50, and shed new light on calpain-associated pathologies.



中文翻译:

Ttm50 通过将其锚定到钙储存并增加其对钙的敏感性来促进钙蛋白酶的激活。

钙依赖性蛋白水解钙蛋白酶与多种生理过程以及与钙超载相关的病理有关。然而,激活钙蛋白酶的机制仍然难以捉摸,因为生理条件下的细胞内钙水平没有达到触发钙蛋白酶激活所需的高浓度范围。使用果蝇中丰富的钙蛋白酶靶谷氨酸受体 GluRIIA 进行候选筛选神经肌肉接头作为读数,我们发现钙蛋白酶活性在敲除 Ttm50 时受到抑制,Ttm50 是 Tim23 复合物的一个亚基,已知参与线粒体内膜的蛋白质输入。出乎意料的是,Ttm50 和钙蛋白酶共同定位于钙储存高尔基体和内质网 (ER),并且 Ttm50 通过其 C 末端结构域与钙蛋白酶相互作用。这种相互作用是钙蛋白酶在高尔基体/ER 定位所必需的,并且将钙蛋白酶的钙敏感性提高了大约一个数量级。我们的研究结果揭示了 Ttm50 对钙蛋白酶激活的调节,并为钙蛋白酶相关的病理提供了新的启示。

更新日期:2020-08-26
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