Determining the role of retromer and P4-ATPase interactions in cellular functions
确定逆转录酶和 P4-ATP 酶相互作用在细胞功能中的作用
基本信息
- 批准号:10677963
- 负责人:
- 金额:$ 3.3万
- 依托单位:
- 依托单位国家:美国
- 项目类别:
- 财政年份:2023
- 资助国家:美国
- 起止时间:2023-05-01 至 2025-04-30
- 项目状态:未结题
- 来源:
- 关键词:ATP HydrolysisATP phosphohydrolaseAllelesAlzheimer&aposs DiseaseAmino Acid MotifsApoptosisBackBinding SitesBiologicalC-terminalCapsid ProteinsCarrier ProteinsCell membraneCell physiologyCellsChargeChimeric ProteinsClathrinClathrin-Coated VesiclesCoat Protein Complex ICollectionComplexCytoplasmCytoplasmic TailDataDiseaseEndosomesExcisionFamilyFunctional disorderGlucosylceramidesGoalsGolgi ApparatusHealthHumanKnock-outLecithinLengthLifeLinkLipidsLysosomesMediatingMembraneMetabolicMinorModelingMonitorMorphologyMultivesicular BodyMutationN-terminalNeurologicOrganellesOrthologous GeneParkinson DiseasePathway interactionsPatternPhosphatidylethanolaminePhosphatidylserinesPhospholipidsPlayPoint MutationProcessPropertyProteinsRecyclingRegulationRoleRouteSaccharomyces cerevisiaeSignal TransductionSortingSphingolipidsStructureSystemTailTemperatureTestingTranscription Factor AP-1TravelVacuoleVesicleYeastsendosome membraneextracellularlate endosomelipid transportnervous system disordernovelprotein transportsorting nexinstraffickingtrans-Golgi Networkvesicle transport
项目摘要
PROJECT SUMMARY/ABSTRACT
The transport of proteins and lipids throughout the cell is crucial for cellular function and organelles, including
those of the endolysosomal system, require the correct lipid and protein composition to complete their roles. One
important aspect of vesicular trafficking is the asymmetric organization of lipid species across the exofacial and
cytofacial leaflets of the membrane. This membrane asymmetry has been shown to be critical for protein
trafficking, signal transduction and apoptosis. Membrane asymmetry is established by type-IV P-type ATPases
(P4-ATPase), which utilize ATP hydrolysis to transport lipid substrates from the luminal or extracellular leaflet to
the cytofacial leaflet of membranes. P4-ATPase deficiency disrupts vesicle-mediated protein transport from Golgi
and endosomal membranes and causes hyperacidification of endosomes and lysosomes. Our goal is to
understand the role of P4-ATPases in vesicle-mediated protein transport. For proper P4-ATPase function,
correct localization to appropriate membranes is essential. Of the five P4-ATPases in Saccharomyces
cerevisiae, Dnf1, Dnf2, Neo1 and Drs2 are known to localize to the plasma membrane (PM) and/or Golgi and
travel through the endocytic pathway as part of their trafficking itineraries. In this study, I seek to determine the
recycling and retrograde trafficking pathways traveled by P4-ATPases, and how these flippases interact with
components of those pathways. Key components of four major trafficking pathways between endosomes and
the Golgi including Drs2/Rcy1/COPI, Snx4, retromer and AP-1/Clathrin, were deleted to determine the routes
required for Dnf1/Dnf2 PM localization and Neo1/Drs2 Golgi localization. Deletion of retromer components
including Vps35, Vps5, Vps17, and Snx3 led to mislocalization of Dnf1, Dnf2, Neo1 and Drs2 to the vacuole.
These data suggest a primary role for retromer in proper localization of P4-ATPases although a minor role for
Rcy1 and Snx4 was detected. In addition, preliminary data suggest that there is a novel retromer recognition
motif within the C-terminal tail of Dnf1 and Dnf2. These results indicate that loss of retromer leads to a substantial
loss of P4-ATPases to the vacuole and should therefore cause major changes in membrane organization.
Deficiencies in the human orthologs of Dnf1/Dnf2 and retromer have been linked to endosomal dysfunction
leading to Parkinson's Disease. This study could help elucidate why mutations in these proteins cause the
disease.
项目总结/文摘
项目成果
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Mariana De Jesus Jimenez其他文献
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