The Role of the O-GlcNAc Modification in X-linked Intellectual Disability
O-GlcNAc 修饰在 X 连锁智力障碍中的作用
基本信息
- 批准号:10607367
- 负责人:
- 金额:$ 37.07万
- 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:2023-02-01 至 2028-01-31
- 项目状态:未结题
- 来源:
- 关键词:AffectAmino Acid SubstitutionAutomobile DrivingBindingBiochemicalBiologyCatalysisCatalytic DomainCellsCharacteristicsChromatinClinicalComplexDataDefectDisability phenotypeDiseaseEngineeringEnzymesEpigenetic ProcessEvolutionExhibitsGene DuplicationGene ExpressionGene Expression RegulationGenerationsGenesGenetic ScreeningHydrolaseIn VitroIntellectual functioning disabilityIsotopesKnockout MiceLeadLigationLinkMammalsMass Spectrum AnalysisMediatingMicroelectrodesMissense MutationModelingModificationMolecularMutationNuclearNutrientO-GlcNAc transferaseOutcomePathway interactionsPatientsPhenotypePhosphoric Monoester HydrolasesPhosphorylationPhosphotransferasesPlayPolysaccharidesPost-Translational Protein ProcessingProteinsPublishingRegulationResearchRoleSamplingScaffolding ProteinSiteStructureSubstrate SpecificitySynapsesSynaptosomesTestingTransferaseVariantWorkX-linked intellectual disabilitycausal variantclinical phenotypedisabilityembryonic stem cellexperimental studygenome wide screenglucose transporthuman embryonic stem cellmalemolecular modelingnerve stem cellneuralnoveloverexpressionprotein protein interactionsample collectionscreeningsensorstem cell differentiationstem cellssugar nucleotidesynaptic functionsynaptogenesistandem mass spectrometrytooltranscriptome
项目摘要
PROJECT SUMMARY
X-linked intellectual disability (XLID) affects approximately 1 in 500 males. Recently, we, and others, have
discovered multiple unique missense mutations in the X-linked gene encoding O-GlcNAc transferase (OGT) that
are causal for XLID. These mutations generate variants with amino acid substitutions in either the TPR domain
or catalytic domain of OGT. The modification of Ser/Thr residues of thousands of nuclear and cytosolic proteins
by the addition of a single glycan (O-linked N-acetylglucosamine, O-GlcNAc) by OGT can impact the stability,
localization, activity, and protein-protein interactions of the modified proteins. Similar to phosphorylation, the O-
GlcNAc modification is inducible and dynamic. However, unlike phosphorylation, which is mediated by hundreds
of kinases and a smaller set of phosphatases, O-GlcNAc modification results from the activity of a single
transferase (OGT) that can be removed by a single hydrolase (O-GlcNAc hydrolase, OGA). We have generated
considerable published and preliminary data including biochemical characterization of several OGT-TPR
variants, engineering of an isotope-based approach to quantitatively compare site-specific O-GlcNAc between
samples and establish turnover rates, generation of Cas9-engineered RUES-1 stem cells harboring the XLID
missense mutations, and defining the OGT TPR interactome including defining interactors, such as the
epigenetic regulator TET2 and the synapse scaffolding protein PCLO, that show reduced interactions with XLID
TPR variants. Based on our preliminary data, we will test the hypothesis that OGT-TPR variants have an altered
interactome and define the impact of loss of interaction (Aim 1A). In Aim 1B, we will characterize novel XLID
variants in the catalytic domain of OGT that, based on modeling and in cellulo expression studies, we
hypothesize will be Km variants for the sugar nucleotide donor and perform genome wide screens to identify
regulators of OGT expression that might be able to ameliorate the deficits of a catalytic variant. Finally, given the
nearly identical and overlapping patient phenotypes for both TPR and catalytic domain XLID OGT variants, we
will test the hypothesis that all variants share common downstream alterations, likely in gene regulation that may
be modulated by TET2 and associated proteins (Aim 2) and/or synaptic activity modulated by PCLO and
associated proteins (Aim 3) based on preliminary and published data. The successful completion of these aims,
geared towards elucidating a mechanistic understanding of the impact of XLID OGT variants, will advance both
the intellectual disability and O-GlcNAc fields.
项目摘要
X连锁智力残疾(XLID)影响大约1/500的男性。最近,我们和其他人,
在编码O-GlcNAc转移酶(OGT)的X连锁基因中发现了多个独特的错义突变,
与XLID有因果关系。这些突变产生在TPR结构域中具有氨基酸取代的变体,
或OGT的催化结构域。数千种核蛋白和胞浆蛋白的Ser/Thr残基的修饰
通过OGT添加单个聚糖(O-连接的N-乙酰葡糖胺,O-GlcNAc)可影响稳定性,
修饰蛋白的定位、活性和蛋白质-蛋白质相互作用。与磷酸化类似,O-
GlcNAc修饰是可诱导的和动态的。然而,与磷酸化不同的是,磷酸化是由数百个
激酶和磷酸酶的一个较小的集合,O-GlcNAc修饰的结果从一个单一的活性,
在一个实施方案中,所述酶是可通过单一水解酶(O-GlcNAc水解酶,OGA)去除的葡萄糖转移酶(OGT)。我们已经生成
相当多的已发表和初步数据,包括几种OGT-TPR的生化表征
变体,工程化基于同位素的方法以定量比较
样品并建立周转率,产生携带XLID的Cas9工程化的RUES-1干细胞
错义突变,以及定义OGT TPR相互作用物组,包括定义相互作用物,如
表观遗传调节因子TET 2和突触支架蛋白PCLO,显示与XLID的相互作用减少
TPR变体。基于我们的初步数据,我们将检验OGT-TPR变体改变了
相互作用组,并定义相互作用丧失的影响(目标1A)。在目标1B中,我们将表征新型XLID
OGT催化结构域中的变体,基于建模和细胞表达研究,我们
假设将是糖核苷酸供体的Km变体,并进行全基因组筛选以鉴定
OGT表达的调节剂,其可能能够改善催化变体的缺陷。最后,鉴于
TPR和催化结构域XLID OGT变体几乎相同和重叠的患者表型,我们
将测试所有变体共享共同下游改变的假设,可能在基因调控中,
由TET 2和相关蛋白(Aim 2)调节和/或由PCLO调节的突触活性,
相关蛋白(目标3)的基础上初步和公布的数据。这些目标的圆满实现,
旨在阐明XLID OGT变体影响的机械理解,将推进
智力残疾和O-GlcNAc领域。
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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Lance Wells其他文献
Lance Wells的其他文献
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{{ truncateString('Lance Wells', 18)}}的其他基金
O-GlcNAc dynamics and the OGT interactome in variants causal for X-linked intellectual disability
导致 X 连锁智力障碍的变异中的 O-GlcNAc 动力学和 OGT 相互作用组
- 批准号:
10011894 - 财政年份:2019
- 资助金额:
$ 37.07万 - 项目类别:
Structure and Function in alpha-Dystroglycan Glycosylation
α-肌营养不良聚糖糖基化的结构和功能
- 批准号:
10678139 - 财政年份:2014
- 资助金额:
$ 37.07万 - 项目类别:
SITE-SPECIFIC GLYCOSYLATION OF ALPHA-DYSTROGLYCAN FROM RAT BRAIN
大鼠脑中 α-抗肌聚糖的位点特异性糖基化
- 批准号:
8363022 - 财政年份:2011
- 资助金额:
$ 37.07万 - 项目类别:
O-MANNOSYLATION ON DROSOPHILA ALPHA-DYSTROGLYCAN
果蝇α-抗肌聚糖上的O-甘露糖基化
- 批准号:
8363045 - 财政年份:2011
- 资助金额:
$ 37.07万 - 项目类别:
VALIDATION OF IDAWG IN MESC AND HESC
IDAWG 在 MESC 和 HESC 中的验证
- 批准号:
8363032 - 财政年份:2011
- 资助金额:
$ 37.07万 - 项目类别:
QUANTIFICATION OF GLYCOSYLTRANSFERASE PROTEIN LEVELS IN HESC & DERIVED CELLS
HESC 中糖基转移酶蛋白水平的定量
- 批准号:
8363120 - 财政年份:2011
- 资助金额:
$ 37.07万 - 项目类别:
LAMININ-BINDING O-GLYCANS ON ALPHA-DYSTROGLYCAN
α-抗肌聚糖上的层粘连蛋白结合 O-聚糖
- 批准号:
8363043 - 财政年份:2011
- 资助金额:
$ 37.07万 - 项目类别:
MAPPING SITES OF N-LINKED GLYCOSYLATION ON PGIP
PGIP 上 N-连接糖基化位点的图谱
- 批准号:
8363046 - 财政年份:2011
- 资助金额:
$ 37.07万 - 项目类别:
O-MANNOSYLATION ON DROSOPHILA ALPHA-DYSTROGLYCAN
果蝇α-抗肌聚糖上的O-甘露糖基化
- 批准号:
8170808 - 财政年份:2010
- 资助金额:
$ 37.07万 - 项目类别:
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