Investigation of the proteasome assembly landscape
蛋白酶体组装景观的研究
基本信息
- 批准号:10344955
- 负责人:
- 金额:$ 43.02万
- 依托单位:
- 依托单位国家:美国
- 项目类别:
- 财政年份:2022
- 资助国家:美国
- 起止时间:2022-09-01 至 2026-08-31
- 项目状态:未结题
- 来源:
- 关键词:26S proteasomeATP phosphohydrolaseATP-Dependent ProteasesAffinityBindingBiogenesisBiological AssayBiological ProcessBiologyBiophysicsCellsChemicalsCollectionComplexDevelopmentDimensionsDiseaseDissociationDockingEnsureEnvironmentEnzyme KineticsExogenous FactorsFluorescenceGeneticGoalsHumanImpairmentIn VitroIndividualInvestigationKineticsKnowledgeLigandsLiteratureMalignant NeoplasmsMeasurementMeasuresModelingMolecularMolecular ChaperonesMolecular ConformationMonitorMutationNatureNerve DegenerationNeurodegenerative DisordersNucleosome Core ParticleOutcome StudyPathologicPathway interactionsPhysiologicalProteinsRecyclingRouteSiteSpectrum AnalysisSpeedStimulusStressTestingThinkingTimeWorkYeastsbasechemical geneticsdesignexperimental studyflexibilitygenetic approachhuman diseasein vivointerestkinetic modelmacromolecular assemblymulticatalytic endopeptidase complexmutantnovel therapeutic interventionnovel therapeuticsparticlepolypeptideprotein degradationresponsesingle moleculestoichiometrytargeted treatmenttool
项目摘要
Project Summary Abstract
The 26S proteasome conducts most regulated protein degradation and eliminates toxic proteins in vivo. The
proteasome is an unusually large and complex ATP-dependent protease comprising nearly 70 individual
polypeptide subunits. Although the conventional thinking has been that the proteasome is assembled from these
subunits in a single, rigid stepwise sequence, recent evidence from our group and others unexpectedly suggests
a broader “landscape” of assembly routes may exist in vivo. Although this possibility has not yet been tested,
such an assembly landscape would ensure that this essential biological process can continue effectively in the
face of assembly roadblocks, and would provide a powerful means to adjust the speed or volume of proteasome
biogenesis in response to the cellular environment. There is an increasing interest in harnessing proteasome
biogenesis to help treat conditions as diverse as cancer and neurodegenerative disorders. Understanding
whether such an assembly landscape exists, and if so, how it is harnessed to ensure rapid and faithful
proteasome biogenesis, will be critical to guide development of such assembly-targeted therapies.
The goal of this multi-PI application is to test the hypothesis that a proteasome assembly landscape exists in
vivo, and that the relative flux through possible routes within this landscape is governed largely by kinetic factors
that change in response to the intracellular environment. By combining the PIs’ respective expertise in
proteasome biology and in enzyme kinetics and single molecular biophysics, we hope to validate this new
paradigm for proteasome biogenesis. The proposed studies, described below, will add a critical new dimension—
time—to our understanding of proteasome assembly in vivo.
Our experimental approach contains two complementary but independent Aims. In Aim 1, we will utilize a newly
established collection of cutting-edge single-molecule and ensemble fluorescence assays to characterize the
kinetics of specific proteasome assembly steps. Experiments under this aim are designed to test the hypothesis
that the relative flux through two possible assembly routes is primarily under kinetic control, but can be tuned by
exogenous factors such as ligands or proteasome-interacting accessory proteins. Aim 2 will employ a suite of
newly developed chemical-genetic approaches to assess the relative flux through two possible assembly routes
in vivo, and to understand how the flux changes in response to environmental stimuli. Experiments under this
Aim will also test in living cells the predictions derived from our in vitro kinetic model of assembly established in
Aim 1. The outcomes of these studies will lead to a deeper understanding of proteasome biology and of
macromolecular assembly in general, and also promise to illuminate new therapeutic avenues for cancer,
neurodegeneration, and other diseases.
项目摘要
项目成果
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{{ truncateString('Zucai Suo', 18)}}的其他基金
Investigation of the proteasome assembly landscape
蛋白酶体组装景观的研究
- 批准号:
10685939 - 财政年份:2022
- 资助金额:
$ 43.02万 - 项目类别:
Mechanistic and Structure-Function Studies of Human DNA Polymerase Lambda
人类 DNA 聚合酶 Lambda 的机理和结构功能研究
- 批准号:
7898989 - 财政年份:2009
- 资助金额:
$ 43.02万 - 项目类别:
Mechanistic and Structure-Function Studies of Human DNA Polymerase Lambda
人类 DNA 聚合酶 Lambda 的机理和结构功能研究
- 批准号:
7672475 - 财政年份:2007
- 资助金额:
$ 43.02万 - 项目类别:
Mechanistic and Structure-Function Studies of Human DNA Polymerase Lambda
人类 DNA 聚合酶 Lambda 的机理和结构功能研究
- 批准号:
7496471 - 财政年份:2007
- 资助金额:
$ 43.02万 - 项目类别:
Mechanistic and Structure-Function Studies of Human DNA Polymerase Lambda
人类 DNA 聚合酶 Lambda 的机理和结构功能研究
- 批准号:
8134223 - 财政年份:2007
- 资助金额:
$ 43.02万 - 项目类别:
Mechanistic and Structure-Function Studies of Human DNA Polymerase Lambda
人类 DNA 聚合酶 Lambda 的机理和结构功能研究
- 批准号:
7372560 - 财政年份:2007
- 资助金额:
$ 43.02万 - 项目类别:














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