Engagement and Communication Between Proteasonal Subcomplexes
蛋白酶子复合物之间的参与和交流
基本信息
- 批准号:9892109
- 负责人:
- 金额:$ 9.38万
- 依托单位:
- 依托单位国家:美国
- 项目类别:
- 财政年份:2017
- 资助国家:美国
- 起止时间:2017-04-01 至 2022-02-28
- 项目状态:已结题
- 来源:
- 关键词:ATP HydrolysisATP phosphohydrolaseActive SitesAffectAlzheimer&aposs DiseaseAntineoplastic AgentsArchitectureAreaBindingBiochemical GeneticsBiogenesisBiological AssayBiologyBortezomibCatalysisCell CycleCellsCellular biologyChemicalsCleaved cellClinicCommunicationComplexCoupledCouplingDNA RepairDeubiquitinating EnzymeDiabetes MellitusDiseaseDrug resistanceElementsEventGarbageGoalsHeartHumanIn VitroIndividualInflammatoryLinkMacromolecular ComplexesMalignant NeoplasmsMediatingMolecularMolecular BiologyMolecular ConformationMovementMutationNeurodegenerative DisordersNon-Insulin-Dependent Diabetes MellitusNucleosome Core ParticleNucleotidesPatientsPeptidesProcessProteasome InhibitionProteasome InhibitorProteinsProteolysisRecombinantsReporterResearchRoleRouteSignal TransductionStructureTestingVelcadeWorkadaptive immunitybasecombinatorialdrug developmentgenetic approachhigh throughput screeninghuman diseasein vivoinsightmulticatalytic endopeptidase complexnovelnovel therapeuticsprotein degradationprotein misfoldingsmall moleculesmall molecule inhibitortool
项目摘要
Project Summary/Abstract
The proteasome is a multisubunit macromolecular machine that mediates most regulatory protein
degradation and removes toxic proteins from cells. It is essential for activities as diverse as the cell cycle,
adaptive immunity, and DNA repair. Alterations to proteasome activity impact numerous human diseases,
including cancer, neurodegenerative disorders, and diabetes. The proteasome consists of three functional
subcomplexes: the lid, the base, and the core particle. Each subcomplex performs distinct functions during
substrate degradation. The lid removes the proteasomal targeting signal, the base uses energy from ATP
hydrolysis to unfold the substrate, and the core particle then cleaves it into short peptides. These activities—as
well as the subcomplexes that harbor them—are intimately linked by static and dynamic inter-subcomplex
interactions. Recent structural studies have unexpectedly revealed that the proteasome exists in at least two
well-defined conformational states—an apo state, in which the substrate passageways and the enzymatic active
sites within these subcomplexes are blocked, and an engaged state, in which these passageways and active
sites are opened and aligned, ready to accept and process substrates. Thus, these states reflect “off” and “on”
conformations for the proteasome, respectively.
Proteolytic inhibitors of the proteasome such as Velcade (bortezomib) are proven anticancer drugs, but
resistance to these agents is already emerging. This necessitates alternative approaches to control proteasome
function. Manipulation of the conformational state of the proteasome could allow for their selective activation or
inactivation at will. This strategy could permit treatment of proteasome-addicted cancers via proteasome
inactivation, as well as treatment of proteinopathies such as Alzheimer’s and type II diabetes, via enhancement
of proteolysis to clear toxic inclusions. The long-term goal of this project is to understand the molecular
mechanisms regulating engagement and communication between proteasomal subcomplexes, and how
they relate to the proteasome’s conformational state. We seek to determine how individual conformation-
specific contacts between lid and base subunits control proteasome structure and function (Aim1), dissect the
critical role of nucleotide binding in reorganization of the lid-base interface to promote the engaged state (Aim
2), and to develop small molecules that disrupt lid-base coordination to be used as tools for studying proteasome
function in human cells or in vitro (Aim 3). We anticipate our studies will yield insights into allosteric
communication, energy use, and substrate processing by the proteasome, as well as yielding new information
on proteasome biogenesis and structure. Further, the functional elements of the proteasome are found in many
other multiprotein machines, so our studies could reveal general principles governing the function of diverse
macromolecular complexes, and thus will impact numerous areas of cell and molecular biology.
项目总结/文摘
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(2)
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ROBERT JOSEPH TOMKO其他文献
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Engagement and Communication Between Proteasomal Subcomplexes
蛋白酶体亚复合物之间的参与和通讯
- 批准号:
10659372 - 财政年份:2017
- 资助金额:
$ 9.38万 - 项目类别:














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