The molecular mechanisms of nutrient- and stress-dependent mTORC1 regulation mediated by human Sestrin2.

标题：营养和压力依赖的分子机制 由人Sestrin 2介导的mTORC 1调节。 项目摘要 mTOR复合物1（mTORC 1）是一种重要的营养传感器，其慢性 由营养过剩引起的激活可引起多种代谢病理学， 抵抗和II型糖尿病。然而，大多数mTORC 1的药理学抑制剂， 非特异性抑制mTORC 2-另一种mTOR复合物， 介导胰岛素信号转导，因此不适合糖尿病治疗。 Sestrins（Sesns）是最近鉴定的mTORC 1抑制因子。mTORC 1抑制 Sesns的功能减弱了大多数营养过剩和肥胖的发展， 相关的代谢病理学。重要的是，Sesns不抑制mTORC 2， 而是通过抑制mTORC 1来上调其活性。相应地，转基因 Sesn过表达在保护肝脏免受慢性mTORC 1 激活、胰岛素抵抗的发展和糖尿病病理学的进展。 这些结果表明，Sesns及其下游信号通路可能具有一定的生物学活性。 作为肥胖相关疾病的药物靶点的治疗潜力。 最近，我们的实验室和其他人的一些研究已经澄清了分子 Sesns的靶点，从而更清楚地了解Sesns如何抑制mTORC 1。作为 这是广泛的遗传学和细胞生物学研究的结果， GATOR 2、GATOR 1、Rag GTP酶和mTORC 1之间的关系。 此外，最近的几篇论文也表明，氨基酸亮氨酸可以 与Sesns结合并调节它们的活动。 尽管它具有生理意义，但其生物化学和分子基础 这些蛋白质之间的相互作用和信号传递仍然完全未知。没有 如果不了解分子水平的机制，几乎不可能理性地 设计化学探针来调节这个信号级联。作为这项工作的一部分，我们 最近确定了人Sestrin 2（hSesn 2）的第一个晶体结构， 目前正计划将其作为理解依赖于Sesn的 信号转导途径我们的长期目标是确定生物化学和 Sesn依赖性信号传导中每个信号传导组分的结构特性 级联，并揭示可药用的结构基序，这是至关重要的功能， 信号通路结合X射线晶体学分子电子 显微镜（EM），细胞生物学和果蝇/小鼠遗传学实验，我们将 阐明hSesn 2的结构、生物化学和细胞生物学作用及其信号传导 中间体GATOR 1和GATOR 2在mTORC 1抑制中的作用。分子 从这些研究中确定的机制和结构基序有望揭示 许多新的药物靶点，用于未来开发mTORC 1调节药物 药物，这将是临床上显着的，以减少不同的进展， 由营养过剩和肥胖症引起的代谢疾病。

Title: The molecular mechanisms of nutrient- and stress-dependent mTORC1 regulation mediated by human Sestrin2. Project Summary The mTOR complex 1 (mTORC1) is an important nutrient sensor whose chronic activation by overnutrition can provoke diverse metabolic pathologies such as insulin resistance and type II diabetes. Most pharmacological inhibitors of mTORC1, however, non-specifically suppress mTORC2—another mTOR complex that is critical for mediating insulin signal transduction—and thus inappropriate for diabetes treatment. Sestrins (Sesns) are recently identified mTORC1 suppressors. mTORC1-inhibitory function of Sesns attenuates development of most hypernutrition- and obesity- associated metabolic pathologies. Importantly, Sesns does not inhibit mTORC2 and rather upregulates its activity by suppressing mTORC1. Correspondingly, transgenic Sesn overexpression was highly effective in protecting liver from chronic mTORC1 activation, development of insulin resistance and progression of diabetic pathologies. These results suggest that Sesns and their downstream signaling pathway may have a therapeutic potential as a drug target toward the obesity-associated diseases. Recently, a number of studies by our labs and others have clarified the molecular targets of Sesns, which led to a clearer understanding of how Sesns inhibit mTORC1. As a result of extensive genetics and cell biology studies, a clear epistatic relationship between GATOR2, GATOR1, Rag GTPases and mTORC1 was established. Furthermore, a couple of recent papers also suggested that an amino acid leucine can bind to Sesns and modulates their activities. Despite its physiological significance, the biochemical and molecular basis by which these proteins interact with and signal to each other is still completely unknown. Without an understanding of the molecular level mechanism, it is nearly impossible to rationally design chemical probes to modulate this signaling cascade. As a part of this effort, we have recently determined the first crystal structure of human Sestrin2 (hSesn2), and are currently planning to use it as a starting platform for understanding the Sesn-dependent signal transduction pathway. Our long-term goal is to define the biochemical and structural properties of each signaling component within the Sesn-dependent signaling cascade and to reveal druggable structural motifs that are critical for functionality of this signaling pathway. Using a combination of X-ray crystallography, molecular electron microscopy (EM), cell biology and Drosophila/mouse genetics experiments, we will elucidate the structural, biochemical and cell-biological role of hSesn2 and its signaling intermediates—GATOR1 and GATOR2—in mTORC1 suppression. The molecular mechanisms and structural motifs identified from these studies are expected to reveal many new drug targets for future development of mTORC1-modulating pharmaceutical agents, which will be clinically significant for reducing the progression of diverse metabolic pathologies caused by hypernutrition and obesity.