The molecular mechanisms of nutrient- and stress-dependent mTORC1 regulation mediated by human Sestrin2.
由人 Sestrin2 介导的营养和应激依赖性 mTORC1 调节的分子机制。
基本信息
- 批准号:9214387
- 负责人:
- 金额:$ 50.1万
- 依托单位:
- 依托单位国家:美国
- 项目类别:
- 财政年份:2016
- 资助国家:美国
- 起止时间:2016-09-19 至 2021-08-31
- 项目状态:已结题
- 来源:
- 关键词:Amino AcidsArchitectureAttenuatedBindingBiochemicalBiologicalCellsCellular biologyChemicalsChronicComplexCryoelectron MicroscopyCrystallographyDevelopmentDiabetes MellitusDietDrosophila genusDrug TargetingElectron MicroscopyExposure toFRAP1 geneFutureGTPase-Activating ProteinsGeneticGenetic EpistasisGoalsGuanosine Triphosphate PhosphohydrolasesHumanHuman ActivitiesInsulinInsulin ResistanceKnock-inLeucineLiverLiver diseasesMammalian CellMediatingMedicineMetabolicModificationMolecularMolecular TargetMusMutationNegative StainingNon-Insulin-Dependent Diabetes MellitusNutrientObesityObesity associated diseaseOvernutritionPaperPathologyPathway interactionsPharmacologic SubstancePhysiologicalPlayPost-Translational Protein ProcessingPropertyProtein FamilyProteinsPublicationsRegulationResearchRoleShapesSignal PathwaySignal TransductionSignal Transduction PathwayStressStructural ModelsStructureTechniquesTestingTherapeuticTransgenic OrganismsX-Ray Crystallographybasebiological systemsclinically significantdesigndiabeticinsulin signalingknowledge basemTOR Inhibitornew therapeutic targetnon-alcoholic fatty liveroverexpressionparticleprotein functionresearch studysensor
项目摘要
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.
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。
项目成果
期刊论文数量(0)
专著数量(0)
科研奖励数量(0)
会议论文数量(0)
专利数量(0)
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Uhn-Soo Cho其他文献
Uhn-Soo Cho的其他文献
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{{ truncateString('Uhn-Soo Cho', 18)}}的其他基金
Structural insights into the MLL core complexes
MLL 核心复合体的结构见解
- 批准号:
10246904 - 财政年份:2020
- 资助金额:
$ 50.1万 - 项目类别:
Structural insights into the MLL core complexes
MLL 核心复合体的结构见解
- 批准号:
10414123 - 财政年份:2020
- 资助金额:
$ 50.1万 - 项目类别:
Structural insights into the MLL core complexes
MLL 核心复合体的结构见解
- 批准号:
10632136 - 财政年份:2020
- 资助金额:
$ 50.1万 - 项目类别:
Structure-based biochemical understanding of Sestrins in aging and metabolism
基于结构的生化理解 Sestrins 在衰老和代谢中的作用
- 批准号:
9134679 - 财政年份:2015
- 资助金额:
$ 50.1万 - 项目类别:
Structure-based biochemical understanding of Sestrins in aging and metabolism
基于结构的生化理解 Sestrins 在衰老和代谢中的作用
- 批准号:
8953514 - 财政年份:2015
- 资助金额:
$ 50.1万 - 项目类别:
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