Understanding Spatial Interactions Between STIM and Orai
了解 STIM 和 Orai 之间的空间相互作用
基本信息
- 批准号:9401912
- 负责人:
- 金额:$ 3.05万
- 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:2017-08-01 至 2019-07-31
- 项目状态:已结题
- 来源:
- 关键词:A kinase anchoring proteinAddressAdenylate CyclaseAffectAmino AcidsBindingBinding ProteinsBiological AssayC-terminalCREB1 geneCalciumCell Differentiation processCell membraneCell physiologyCellsCharacteristicsComplexCouplingCyclic AMPCyclic AMP-Dependent Protein KinasesDiffusionDimerizationEndoplasmic ReticulumEukaryotic CellEventFOS geneFluorescence Recovery After PhotobleachingFluorescence Resonance Energy TransferGene ExpressionGenesGenetic TranscriptionGoalsImmuneImmunoprecipitationIon ChannelLabelLigandsLinkMammalsMeasuresMediatingMembraneMembrane LipidsMetabolismMicroscopyModelingMolecular ConformationMutationNatureNeuronsPancreasPathway interactionsPositioning AttributeProtein IsoformsProteinsRNA SplicingRegulationReporterReportingResearchResolutionRestRoleSTIM1 geneSarcoplasmic ReticulumSerineSignal PathwaySignal TransductionSignaling ProteinStructural ModelsTestingThree-Dimensional ImageTranscriptVariantbasecell typecrosslinkdimerfunctional mimicsimage reconstructionnovelpreventpublic health relevancescaffoldsensor
项目摘要
Project Summary/Abstract:
DESCRIPTION: Store-operated calcium entry (SOCE) is a ubiquitous signaling mechanism in eukaryotic cells
crucial for mediating longer–term Ca2+ signals and restoring endoplasmic/sarcoplasmic reticulum Ca2+ after
ligand induced depletion. The key operators in SOCE are the Ca2+ selective PM hexameric Orai channels
(predominantly Orai1) and the ER/SR resident, dimeric transmembrane calcium sensor proteins, STIM1 and
STIM2. STIM1 is activated when ER/SR luminal Ca2+ is depleted, inducing it to unfold and bind to Orai1
channels in the PM. Active Orai1 channels create discrete microdomains of high Ca2+ within ER-PM junctions
that contain roughly 100-fold greater Ca2+ concentrations than resting cytoplasmic levels. New EM studies
reveal Orai1 channels within ER-PM junctions are closely spaced (9-13 nm), roughly the distance spanned by
the STIM-Orai Activating Regions (SOAR) of dimeric STIM1. Although clustering of Orai channels is critical for
generating such Ca2+-saturated microdomains, the actual mechanism by which clustering occurs is not
understood. My studies address how clustering of Orai1 channels locally controls SOCE-mediated Ca2+
signals in junctions by “concentrating” or spatially confining Ca2+ entry through cross-linking Orai1 channels
mediated by the dimeric SOAR domains in STIM1. The studies use soluble SOAR-dimers containing the
critical F394H mutation that prevents SOAR binding to the Orai1 channels. I will investigate how a newly
discovered and widely expressed splice variant of the STIM2 isoform (STIM2.1), containing an 8 amino acid
insert adjacent to the critical F394 STIM-Orai1 binding domain in SOAR, functionally mimics the
SOAR1(F394H) mutation. My aims address a critical gap in our understanding of how clustering of Orai1
spatially controls Ca2+ signals and their downstream effectors. My overall hypothesis is that STIM2.1 functions
as an important negative regulator of STIM1 that prevents clustering of Orai1 channels, and controls the spatial
characteristics of Ca2+ entry signals. Using new SOAR2.1 concatemeric dimers as probes, my aims are: (1) to
use super-resolution microscopy to create 3D-image reconstructions of YFP-SOAR2.1 concatemer interactions
with Orai1-CFP, and fluorescence recovery after photobleaching (FRAP) to assess membrane diffusion rates
and size of YFP-OAR2.1 concatemers bound to Orai1; (2) to use genetically encoded Ca2+ indicators to
measure localized Ca2+ signals in clusters, and a FRET-based cyclic AMP sensor, Epac2, to functionally report
downstream Ca2+-dependent adenylyl cyclase (AC8) closely associated with Orai1 channels. Overall, these
studies will determine how SOAR2.1 may mediate important control Orai1 channel clustering by preventing
Orai1 cross-linking, and will assess how STIM2.1 may regulate Orai1 spacing and local Ca2+ microdomains
mediated through downstream AC8 activity. Such studies bring together new understanding of the
interdependence of local Ca2+ and cyclic AMP signals of major importance in pancreatic, neuronal, and
immune cell function.
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)
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Robert M Nwokonko其他文献
Robert M Nwokonko的其他文献
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{{ truncateString('Robert M Nwokonko', 18)}}的其他基金
Understanding Spatial Interactions Between STIM and Orai
了解 STIM 和 Orai 之间的空间相互作用
- 批准号:
9538071 - 财政年份:2017
- 资助金额:
$ 3.05万 - 项目类别:
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