Molecular characterization of the multi-modal regulation of inositol 1,4,5-trisphosphate receptors
肌醇1,4,5-三磷酸受体多模式调节的分子表征
基本信息
- 批准号:10371021
- 负责人:
- 金额:$ 40万
- 依托单位:
- 依托单位国家:美国
- 项目类别:
- 财政年份:2019
- 资助国家:美国
- 起止时间:2019-04-01 至 2024-01-31
- 项目状态:已结题
- 来源:
- 关键词:AddressApoptoticArchitectureBCL-2 ProteinBCL2 geneBCL2L1 geneBindingBinding ProteinsBinding SitesBiochemicalBiological AssayBiophysicsCationsCell DeathCell Differentiation processCell physiologyCellsComplexCoupledCryoelectron MicroscopyCytoplasmCytoplasmic TailCytosolDataDefectDiseaseElectrophysiology (science)Endoplasmic ReticulumEnsureEnzymesEquilibriumFamilyFertilizationGoalsGrowthHealthHeart DiseasesHomeostasisHumanITPR1 geneInositolIon ChannelIonsLengthLigand BindingLigandsLinkLipid BilayersLipidsLocationMCL1 geneMaintenanceMalignant NeoplasmsMeasuresMediatingMembrane ProteinsMigration AssayMitochondriaMolecularMolecular ConformationMutagenesisNeurobiologyPathologyPermeabilityPhysiologicalPhysiological ProcessesPhysiologyPlayProcessProtein FamilyProteinsRattusRecombinantsRegulationResearchResolutionRoleSecond Messenger SystemsSideSignal TransductionStimulusStructurebiophysical techniquesexperimental studyimprovedmembermultimodalitymutantnervous system disorderprogramsprotein functionprotein protein interactionreceptorsmall molecule
项目摘要
PROJECT SUMMARY
The objective of this project is to characterize the molecular mechanisms of the multi-modal ligand-
dependent gating of inositol 1,4,5-trisphosphate receptors (IP3Rs). IP3Rs are ubiquitously expressed
endoplasmic reticulum (ER) Ca2+ channels that play a key role in the maintenance of Ca2+ homeostasis by
conducting Ca2+ stored in the ER into the cytoplasm. In the cytosol, numerous Ca2+-regulated proteins sense
changes in local and global Ca2+ concentrations to regulate diverse cellular process including fertilization, cell
death and differentiation. Because of the diversity of processes regulated by cytoplasmic Ca2+, IP3R-mediated
Ca2+ conductance is precisely regulated by ions, small molecules and protein co-factors. The two primary
regulatory ligands of IP3Rs are inositol 1,4,5-trisphosphate (IP3) and cytoplasmic Ca2+, both of which bind the
channel to modulate the gating state of the pore. Whereas IP3 binding activates IP3Rs, cytoplasmic Ca2+ both
activates the channel at low concentrations and inhibits the channel at high concentrations. The biphasic
relationship between Ca2+ and IP3R activity ensures that cytoplasmic Ca2+ concentrations are properly
regulated. Besides IP3 and Ca2+, IP3R activity is further shaped in cell-specific manner by other small
molecules such as ATP, by enzymes that post-translationallly modify IP3Rs and by numerous protein co-
factors. How the effects of these various factors are synthesized to determine IP3R gating state and thus
regulate cellular Ca2+ signalling remain poorly understood at a molecular level. As dysregulation of IP3R activity
is linked to cardiac disease, cancer, neurological disorders and other pathologies, understanding the regulation
of IP3Rs will have broad relevance to human health and disease.
The proposal aims to employ structural, biochemical and biophysical approaches to develop a mechanistic
understanding of IP3R regulation, focusing on Ca2+, IP3 and three protein co-factors of the Bcl-2 family: Bcl-2,
Mcl-1 and Bcl-xL. With these approaches we aim to understand i) how IP3 and Ca2+ binding jointly stabilize
IP3Rs in an active conformation, ii) how excess Ca2+ inhibits ion conduction and iii) how the protein co-factors
Bcl-2, Mcl-1 and Bcl-xL modulate channel activity in the presence of IP3 and Ca2+. The proposed studies will
reveal principles of how multiple stimuli are integrated to regulate ion channel function. Due to the broad
physiological role of IP3Rs, the finding derived from these studies will be relevant to a number of fields
including ion channels, Ca2+ signaling, cell death and neurobiology.
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项目总结
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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Richard Kevin Hite其他文献
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{{ truncateString('Richard Kevin Hite', 18)}}的其他基金
Mechanisms of lysosomal ion transport proteins involved in pH homeostasis
溶酶体离子转运蛋白参与 pH 稳态的机制
- 批准号:
10365563 - 财政年份:2021
- 资助金额:
$ 40万 - 项目类别:
Mechanisms of lysosomal ion transport proteins involved in pH homeostasis
溶酶体离子转运蛋白参与 pH 稳态的机制
- 批准号:
10532170 - 财政年份:2021
- 资助金额:
$ 40万 - 项目类别:
Molecular characterization of the multi-modal regulation of inositol 1,4,5-trisphosphate receptors
肌醇1,4,5-三磷酸受体多模式调节的分子表征
- 批准号:
9899264 - 财政年份:2019
- 资助金额:
$ 40万 - 项目类别:
Molecular characterization of the multi-modal regulation of inositol 1,4,5-trisphosphate receptors
肌醇1,4,5-三磷酸受体多模式调节的分子表征
- 批准号:
10557801 - 财政年份:2019
- 资助金额:
$ 40万 - 项目类别:
Molecular characterization of the multi-modal regulation of inositol 1,4,5-trisphosphate receptors
肌醇1,4,5-三磷酸受体多模式调节的分子表征
- 批准号:
10089457 - 财政年份:2019
- 资助金额:
$ 40万 - 项目类别:
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