Molecular Mechanisms Of V-ATPases: Assembly,Biogenesis, Regulation, And Function
V-ATP 酶的分子机制:组装、生物发生、调节和功能
基本信息
- 批准号:10798892
- 负责人:
- 金额:$ 8.61万
- 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:2022-08-01 至 2027-06-30
- 项目状态:未结题
- 来源:
- 关键词:ATP phosphohydrolaseAcquired Immunodeficiency SyndromeAddressAdenosineAffectAntibody FormationBacteriaBacterial ProteinsBindingBiochemicalBiogenesisBiological AssayBiophysicsCellsComplementComplexCruciform DNACryoelectron MicroscopyDNADNA RepairDiabetes MellitusDiseaseEmbryoEndosomesEukaryotic CellExcisionGlycolipidsGolgi ApparatusHumanInfectionLinkLipidsLiposomesLysosomesMalignant NeoplasmsMammalsMeasuresMediatingMeiosisMembraneMethodsModelingModificationMolecularMolecular ConformationNeurodegenerative DisordersOrganellesOrganismOsteoporosisPathway interactionsPhysiological ProcessesPlayPolysaccharidesProcessProteinsProton PumpProtonsRegulationRenal tubular acidosisResolutionRoleSensorineural Hearing LossSignal TransductionStructureSurfaceTestingVesicleWorkYeastsdimerds-DNAexperimental studyextracellularfascinategenetic analysisglycosylationhomologous recombinationhuman diseaseinnovationinsightmicrobialmigrationmutantnovelnovel therapeutic interventionpH Homeostasisreconstitutionrecruitsuccessvacuolar H+-ATPaseyeast genetics
项目摘要
SUMMARY
Vesicular- or vacuolar-type adenosine triphosphatases (V-ATPases) are multi-component, ATP-driven proton
pumps consisting of a V1 complex that possesses ATPase activity and a Vo complex for proton transfer across
the membrane. V-ATPases play important roles in the acidification of intracellular vesicles, organelles, and the
extracellular milieu, and are essential for maintaining the pH homeostasis of endosomes, lysosomes, and the
Golgi apparatus in all eukaryotic cells. V-ATPase deficiency in mammals is embryonic lethal, and malfunction of
V-ATPases is associated with numerous diseases, including microbial infection, renal tubular acidosis,
osteoporosis, sensorineural deafness, neurodegenerative diseases, and cancer. Despite the critical functions of
V-ATPases, we have limited understanding on the biogenesis, assembly, regulation, and signaling of mammalian
V-ATPases. A major challenge in studying mammalian V-ATPases is that the pure complexes are difficult to
obtain for biochemical and biophysical experiments. We developed an innovative method to purify large amounts
of human V-ATPase to homogeneity directly from cells. Our preliminary cryo-electron microscopy (cryo-EM)
structures of human V-ATPases show three functional states at up to 3.1 Å resolution and with all known subunits,
which together represent the most complete mechanistic model of V-ATPase to date. Our study revealed that
mammalian V-ATPases are composed of proteins, glycans, glycolipids, and lipids. Therefore, we defined the V-
ATPase as a glycoproteolipid complex. Our study opens the field for thoroughly understanding the biogenesis,
assembly, regulation, and signaling of V-ATPases. Based on our prior work, we will complement structure
determination with biochemical and functional assays and yeast genetics to address fundamental questions in
the field, including the roles of glycolipids in the V-ATPase assembly and function, the regulation of V-ATPases
by reversible assembly, the detailed mechanism of proton transfer, and the mechanisms of V-ATPase mediated
cell signaling. The completion of this project will not only provide conceptual innovations regarding the V-
ATPases assembly, regulation, and signaling, but also inspire new therapeutic strategies for treating V-ATPase-
related diseases.
总结
项目成果
期刊论文数量(0)
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Tianmin Fu其他文献
Tianmin Fu的其他文献
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{{ truncateString('Tianmin Fu', 18)}}的其他基金
MOLECULAR MECHANISMS OF V-ATPASES: ASSEMBLY, BIOGENESIS, REGULATION, AND FUNCTION
V-ATP酶的分子机制:组装、生物发生、调节和功能
- 批准号:
10501202 - 财政年份:2022
- 资助金额:
$ 8.61万 - 项目类别:
MOLECULAR MECHANISMS OF V-ATPASES: ASSEMBLY, BIOGENESIS, REGULATION, AND FUNCTION
V-ATP酶的分子机制:组装、生物发生、调节和功能
- 批准号:
10664015 - 财政年份:2022
- 资助金额:
$ 8.61万 - 项目类别:
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