Ca2+-dependent lipid scrambling and ion transport by TMEM16 proteins
Ca2+-dependent lipid scrambling and ion transport by TMEM16 proteins
批准号:
10798983
负责人:
Alessio Accardi
金额:
$10.77万
依托单位国家:
美国
项目类别:
财政年份:
2014
资助国家:
美国
项目状态:
已结题
起止时间:
2014-06-04 至 2024-05-31
关键词:
AddressAffectApoptoticBindingBinding SitesBiological AssayBlood CellsBlood coagulationCell membraneCellsCellular MembraneCellular StructuresCeramidesCharacteristicsChargeComplexCouplingCryoelectron MicroscopyDataElementsEndothelial CellsEnvironmentFaceFamilyGenetic DiseasesGoalsGrantHumanImpairmentIn VitroIntegral Membrane ProteinInterventionIon TransportIonsLigand BindingLigandsLipid BilayersLipidsMediatingMembraneMembrane FusionMembrane ProteinsModelingMolecularMolecular ConformationMovementPathway interactionsPhosphatidylserinesPhospholipid InteractionPhospholipidsPhysiologicalPhysiologyProcessPropertyProteinsProtocols documentationRegulationResolutionRoleSignal TransductionSignal Transduction PathwaySiteStrokeStructureTestingThinnessVisualizationdesignexperimental studyextracellularin vitro activityin vivoinsightlipid transportmechanical propertiesmembermolecular dynamicsmutantnanodisknovelnovel strategiesnovel therapeuticsparticlepharmacologicphospholipid scramblasereconstitutionrepairedresponsevesicular release
中文摘要
摘要
英文摘要
ABSTRACT
Members of the TMEM16 family of integral membrane proteins are Ca2+-dependent phospholipid scramblases.
Because mechanisms of lipid scrambling by the TMEM16s remain poorly understood, the ability to interpret their
function in human physiology and to design targeted pharmacological interventions that would selectively
manipulate the activity of these proteins, is limited. Our goal is to overcome these limitations by determining how
the TMEM16 scramblases are activated in response to Ca2+ binding, how and for what purpose they remodel
cellular membranes, and how they are affected by specific components of these membranes. We address this
mechanistic goal with an integrated strategy combining experimentation with structural, functional, and
computational approaches. To understand how these proteins are modulated in vivo we will focus on ceramides
as the first class of molecules found to inhibit the function of TMEM16 scramblases and to be associated in vivo
with excessive exposure of PS in endothelial cells. Our 1st aim is to determine the Ca2+-dependent gating
mechanism of the TMEM16 scramblases using a combination of cryo-electron microscopy (cryoEM), molecular
dynamics (MD) simulations and functional assays. These experiments will reveal the allosteric coupling
mechanism between the Ca2+ binding site and the structural elements gating the lipid pathway. Our 2nd aim is
to determine how the TMEM16 scramblases interact with, and alter the structure of, their surrounding membrane
environment in support of their function. Using structure determination with cryoEM we will visualize afTMEM16
complexes with membranes with a variety of physicochemical properties and compositions, in different functional
states. In combination with MD simulations and functional assays we will identify the energetic and molecular
determinants for membrane-protein interactions and membrane remodeling, and their role in scrambling. Our
3rd aim is to determine the mechanism and in vivo role of ceramide regulation of TMEM16 scramblases using
functional assays to identify the molecular determinants of ceramide inhibition, and structural and computational
experiments to determine their mechanism of action, and the role of specific ceramides in the in vivo regulation
of TMEM16F.
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DOI:
10.1016/j.plipres.2016.08.003
发表时间:
2016-10
期刊:
PROGRESS IN LIPID RESEARCH
影响因子:
13.6
作者:
[Pomorski, Thomas Guenther, Menon, Anant K.]
通讯作者:
Menon, Anant K.
DOI:
10.1109/tcbb.2019.2945291
发表时间:
2021-07
期刊:
IEEE/ACM transactions on computational biology and bioinformatics
影响因子:
--
作者:
[]
通讯作者:
DOI:
10.1016/j.bbalip.2016.02.025
发表时间:
2016-08
期刊:
Biochimica et biophysica acta
影响因子:
--
作者:
[Chauhan N, Farine L, Pandey K, Menon AK, Bütikofer P]
通讯作者:
Bütikofer P
The permeation of potassium ions through the lipid scrambling path of the membrane protein nhTMEM16.
DOI:
10.3389/fmolb.2022.903972
发表时间:
2022
期刊:
Frontiers in molecular biosciences
影响因子:
5
作者:
[]
通讯作者:
DOI:
10.1039/c5pp00195a
发表时间:
2015-11
期刊:
Photochemical & photobiological sciences : Official journal of the European Photochemistry Association and the European Society for Photobiology
影响因子:
--
作者:
[Ernst OP, Menon AK]
通讯作者:
Menon AK
共 7 条
2020 Ligand Recognition & Molecular Gating GRC/GRS
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财政年份:2019
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依托单位:
Atomic basis for chloride channel and transporter gating and selectivity
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Atomic basis for chloride channel and transporter gating and selectivity
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Ca2+-dependent lipid scrambling and ion transport by TMEM16 proteins
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资助金额:$51.4万
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Ca2+-dependent lipid scrambling and ion transport by TMEM16 proteins
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资助金额:$41.53万
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Ca2+-dependent lipid scrambling and ion transport by TMEM16 proteins
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资助金额:$41.53万
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Ca2+-dependent lipid scrambling and ion transport by TMEM16 proteins
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资助金额:$51.4万
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Ca2+-dependent lipid scrambling and ion transport by TMEM16 proteins
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批准号:10406928
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资助金额:$41.53万
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Ca2+-dependent lipid scrambling and ion transport by TMEM16 proteins
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资助金额:$57.42万
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依托单位:
Structure and function of chloride channels and transporters
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批准号:7802969
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项目类别:
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资助金额:$34.29万
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财政年份:2009
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依托单位:
Structure and function of chloride channels and transporters
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批准号:8243567
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项目类别:
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资助金额:$33.9万
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财政年份:2009
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负责人:Alessio Accardi
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依托单位:
Structure and function of chloride channels and transporters
-
批准号:8450114
-
项目类别:
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资助金额:$32.69万
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财政年份:2009
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负责人:Alessio Accardi
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依托单位:
Structure and function of chloride channels and transporters
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批准号:8101423
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项目类别:
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资助金额:$15.24万
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财政年份:2009
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负责人:Alessio Accardi
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依托单位:
Structure and function of chloride channels and transporters
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批准号:8141955
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项目类别:
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资助金额:$33.93万
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财政年份:2009
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负责人:Alessio Accardi
-
依托单位:
海外基金