Evidence of DISC1 as an arsenic binding protein and implications regarding its role as a translational activator.
Evidence of DISC1 as an arsenic binding protein and implications regarding its role as a translational activator.
复制标题
DOI：
10.3389/fmolb.2023.1308693
复制
发表时间：
2023
影响因子：
5
通讯作者：
中科院分区：
文献类型：
--
作者：
DISC 1（Disrupted-in-schizophrenia-1）是一种支架蛋白，在协调参与神经发育、神经迁移和突触发生的信号通路中发挥关键作用。其中，最近有报道说，DISC 1在Akt/mTOR通路中的作用可以从一个整体的翻译抑制剂转变为一个翻译激活剂，以响应砷诱导的氧化应激。在这项研究中，我们提供的证据表明，DISC 1可以直接结合砷通过C-末端半胱氨酸基序（C-X-C-X-C）。一系列基于荧光的结合试验进行了一个截短的C-末端结构域构建的DISC 1和一系列的单，双，和三重半胱氨酸突变体。我们发现，亚砷酸，一种三价砷衍生物，特异性地结合到DISC 1的C-末端半胱氨酸基序，具有低微摩尔亲和力。基序的所有三个半胱氨酸都是高亲和力结合所必需的。电子显微镜实验结合计算机结构预测表明，DISC 1的C-末端形成一个细长的四聚体复合物。半胱氨酸基序被一致地预测为位于环内，完全暴露于溶剂，提供了一个简单的分子框架来解释DISC 1对亚砷酸的高亲和力。这项研究揭示了DISC 1作为砷结合蛋白的一个新的功能方面，并强调了其作为Akt/mTOR通路中的传感器和翻译调节剂的潜在作用。
Disrupted-in-schizophrenia-1 (DISC1) is a scaffolding protein that plays a pivotal role in orchestrating signaling pathways involved in neurodevelopment, neural migration, and synaptogenesis. Among those, it has recently been reported that the role of DISC1 in the Akt/mTOR pathway can shift from a global translational repressor to a translational activator in response to oxidative stress induced by arsenic. In this study we provide evidence that DISC1 can directly bind arsenic via a C-terminal cysteine motif (C-X-C-X-C). A series of fluorescence-based binding assays were conducted with a truncated C-terminal domain construct of DISC1 and a series of single, double, and triple cysteine mutants. We found that arsenous acid, a trivalent arsenic derivative, specifically binds to the C-terminal cysteine motif of DISC1 with low micromolar affinity. All three cysteines of the motif are required for high-affinity binding. Electron microscopy experiments combined with in silico structural predictions reveal that the C-terminal of DISC1 forms an elongated tetrameric complex. The cysteine motif is consistently predicted to be located within a loop, fully exposed to solvent, providing a simple molecular framework to explain the high-affinity of DISC1 toward arsenous acid. This study sheds light on a novel functional facet of DISC1 as an arsenic binding protein and highlights its potential role as both a sensor and translational modulator within Akt/mTOR pathway.
影响因子：
3.7
作者：
Tomppo L;Ekelund J;Lichtermann D;Veijola J;Järvelin MR;Hennah W
通讯作者：
Hennah W
影响因子：
--
作者：
Tomppo, Liisa;Hennah, William;Miettunen, Jouko;Jarvelin, Marjo-Riitta;Veijola, Juha;Ripatti, Samuli;Lahermo, Paivi;Lichtermann, Dirk;Peltonen, Leena;Ekelund, Jesper
通讯作者：
Ekelund, Jesper