PtdIns 4-Kinase Regulation of Protein Sorting in the Golgi Apparatus
高尔基体中蛋白质分选的 PtdIns 4 激酶调节
基本信息
- 批准号:8544482
- 负责人:
- 金额:$ 27.89万
- 依托单位:
- 依托单位国家:美国
- 项目类别:
- 财政年份:2011
- 资助国家:美国
- 起止时间:2011-09-30 至 2015-08-31
- 项目状态:已结题
- 来源:
- 关键词:1-Phosphatidylinositol 4-KinaseArchitectureBindingBinding SitesBiochemicalBiological AssayCancer EtiologyCarbohydratesCatalytic DomainCell membraneCellsCoat Protein Complex ICollaborationsComplexConflict (Psychology)DataDefectDegenerative DisorderDestinationsDiseaseEnzymesEquilibriumEukaryotic CellGlycolipidsGolgi ApparatusHomeostasisHormonesHumanIonsKnowledgeLightLipid BindingLipidsLiteratureLocationLysosomal Storage DiseasesMalignant NeoplasmsMannosyltransferasesMedialMedial GolgiMembraneMembrane ProteinsMetabolismModificationMuscleNutrientOncogenesOrganellesOrthologous GenePathway interactionsPeripheralPhosphatidylinositolsPhosphoric Monoester HydrolasesPositioning AttributeProcessProductionProtein FamilyProteinsProteomicsRNA InterferenceReactionReceptor SignalingRegulationReportingResearch Project GrantsResolutionRoleSaccharomyces cerevisiaeSaccharomycetalesSignal TransductionSorting - Cell MovementStructureSystemTestingTimeVesicleX-Ray CrystallographyYeastsbaseenzyme substrategenetic analysisglycoprotein biosynthesisglycosylationglycosyltransferasehuman diseasein vivomutantoverexpressionprotein functionresearch studyretrograde transportsugartooltrafficking
项目摘要
DESCRIPTION (provided by applicant): The Golgi apparatus has two primary functions: biosynthesis of glycoproteins and glycolipids, and sorting. These functions underlie the elemental architecture of eukaryotic cells, so understanding how the Golgi functions is of fundamentally important. In addition, many human diseases (muscular deficiencies, lysosomal storage diseases, degenerative disease, etc) result from deficiencies of Golgi function. The ordered addition of carbohydrate moieties to biosynthetic cargo in the Golgi is carried out by glycosyltransferases that function sequentially, such that the products of early acting enzymes are substrates for later-acting enzymes. The location of enzymes in the Golgi stack parallels the glycosylation reactions; early- acting glycosyltransferases are enriched in cis/medial Golgi compartments while later-acting enzymes are enriched in medial/trans compartments. How is secretory cargo distinguished from Golgi residents so that cargo moves anterograde through the Golgi while Golgi residents are retained? Using budding yeast (Saccharomyces cerevisiae) to investigate sorting reactions in the Golgi, we discovered that a cytosolic protein, Vps74, directly recognizes the cytosolic portions of a subset of Golgi mannosyltransferases and is required to retain them in the Golgi. We hypothesize that Vps74 sorts Golgi residents into the retrograde pathway, however, the human ortholog of Vps74, GOLPH3, is reported in the literature to promote anterograde secretory transport from the Golgi. Preliminary data show that recruitment of GOLPH3 and Vps74 to the cytosolic leaflets of Golgi membranes requires ongoing synthesis of PtdIns4P, a phosphoinositide that is enriched in Golgi membranes and is required for both anterograde and retrograde Golgi trafficking. Using X-ray crystallography and lipid binding assays, we have identified a candidate PtdIns4P binding site on GOLPH3 and Vps74 and will elucidate a structure of GOLPH3/Vps74 in complex with PtdIns4P. Preliminary data also show that in a yeast vps74 mutant, PtdIns4P metabolism is altered, leading us to hypothesize that Vps74 and GOLPH3 regulate the production and/or turnover of 4-phosphorylated phosphoinositides. Altered phosphoinositide signaling at the Golgi is postulated to underlie the sorting defects that result from a loss of Vps74 and GOLPH3 function. GOLPH3 has recently been identified as a candidate oncogene that results in transformation when overexpressed. By combining functional studies in yeast and cultured human cells with biochemical, biophysical, and structural analyses of Vps74 and GOLPH3, these studies will resolve fundamental roles of PtdIns4P regulation in the Golgi, and elucidate the function of GOLPH3, which will shed light on its role in both normal and disease states.
描述(由申请人提供):高尔基体具有两个主要功能:糖蛋白和糖脂的生物合成以及排序。这些功能是真核细胞的元素结构的基础,因此了解高尔基的功能在根本上至关重要。此外,许多人类疾病(肌肉缺乏症,溶酶体储存疾病,退行性疾病等)是由于高尔基功能的缺陷而引起的。 在高尔基体中为生物合成货物中有序添加碳水化合物部分是由依次发挥作用的糖基转移酶进行的,因此早期作用酶的产物是后期作用酶的底物。酶在高尔基体堆栈中的位置与糖基化反应相似。早期作用的糖基转移酶富含顺式/内侧高尔基体,而后来的作用酶则富含内侧/跨室室。分泌货物如何与高尔基居民区分开,以便在保留高尔基亚居民的同时,货物通过高尔基体移动?使用发芽的酵母(酿酒酵母)来研究高尔基体中的分类反应,我们发现胞质蛋白VPS74直接识别高尔基Mannosylansylansylansylansferase的胞质部分,并且需要将其保留在Golgi中。我们假设VPS74将高尔基人居民分类为逆行途径,但是,文献中报道了VPS74的人类直系同源物,以促进高尔基体促进顺序分泌运输。初步数据表明,Golph3和VPS74募集到高尔基膜的胞质小叶中,需要持续合成PTDINS4P,PTDINS4P是一种在高尔基膜中富集的磷酸肌醇,并且在地前和逆然戈尔吉氏菌中都需要。使用X射线晶体学和脂质结合测定,我们已经确定了Golph3和VPS74上的候选PTDINS4P结合位点,并将阐明与PTDINS4P复合物中Golph3/VPS74的结构。初步数据还表明,在酵母VPS74突变体中,PTDINS4P代谢发生了变化,这使我们假设VPS74和Golph3调节了4-磷酸化的磷酸化磷酸化素固醇的产生和/或周转。假定高尔基体处的磷酸肌醇信号传导是由VPS74和Golph3功能损失导致的分类缺陷的基础。 Golph3最近被确定为候选癌基因,在过表达时会导致转化。通过将酵母和培养的人类细胞中的功能研究与VPS74和Golph3的生化,生物物理和结构分析相结合,这些研究将解决PTDINS4P调节在高尔基体中的基本作用,并阐明Golph3的功能,从而使其在正常和疾病状态中的作用阐明。
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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Christopher G Burd其他文献
Christopher G Burd的其他文献
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{{ truncateString('Christopher G Burd', 18)}}的其他基金
2022 Lysosomes & Endocytosis Gordon Research Conference and Gordon Research Seminar
2022 溶酶体
- 批准号:
10461542 - 财政年份:2022
- 资助金额:
$ 27.89万 - 项目类别:
PtdIns 4-Kinase Regulation of Protein Sorting in the Golgi Apparatus
高尔基体中蛋白质分选的 PtdIns 4 激酶调节
- 批准号:
8338792 - 财政年份:2011
- 资助金额:
$ 27.89万 - 项目类别:
PtdIns 4-Kinase Regulation of Protein Sorting in the Golgi Apparatus
高尔基体中蛋白质分选的 PtdIns 4 激酶调节
- 批准号:
8022078 - 财政年份:2011
- 资助金额:
$ 27.89万 - 项目类别:
PtdIns 4-Kinase Regulation of Protein Sorting in the Golgi Apparatus
高尔基体中蛋白质分选的 PtdIns 4 激酶调节
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8721434 - 财政年份:2011
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6658929 - 财政年份:2000
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PtdIns 4-Kinase Regulation of Protein Sorting in the Golgi Apparatus
高尔基体中蛋白质分选的 PtdIns 4 激酶调节
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8338792 - 财政年份:2011
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