The molecular mechanisms of nutrient- and stress-dependent mTORC1 regulation mediated by human Sestrin2.
The molecular mechanisms of nutrient- and stress-dependent mTORC1 regulation mediated by human Sestrin2.
批准号:
9214387
负责人:
Uhn-Soo Cho
金额:
$50.1万
依托单位国家:
美国
项目类别:
财政年份:
2016
资助国家:
美国
项目状态:
已结题
起止时间:
2016-09-19 至 2021-08-31
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
中文摘要
题目:营养和应激依赖的分子机制
英文摘要
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.
期刊论文(0)
专著(0)
科研奖励(0)
会议论文
Structural insights into the MLL core complexes
-
批准号:10246904
-
项目类别:
-
资助金额:$59.92万
-
财政年份:2020
-
负责人:Uhn-Soo Cho
-
依托单位:
Structural insights into the MLL core complexes
-
批准号:10414123
-
项目类别:
-
资助金额:$58.82万
-
财政年份:2020
-
负责人:Uhn-Soo Cho
-
依托单位:
Structural insights into the MLL core complexes
-
批准号:10632136
-
项目类别:
-
资助金额:$59.57万
-
财政年份:2020
-
负责人:Uhn-Soo Cho
-
依托单位:
Structure-based biochemical understanding of Sestrins in aging and metabolism
-
批准号:9134679
-
项目类别:
-
资助金额:$23.25万
-
财政年份:2015
-
负责人:Uhn-Soo Cho
-
依托单位:
Structure-based biochemical understanding of Sestrins in aging and metabolism
-
批准号:8953514
-
项目类别:
-
资助金额:$19.38万
-
财政年份:2015
-
负责人:Uhn-Soo Cho
-
依托单位:
海外基金