Post-translocational protein folding in Gram-positive bacteria
革兰氏阳性菌中的易位后蛋白质折叠
基本信息
- 批准号:9773401
- 负责人:
- 金额:$ 27.79万
- 依托单位:
- 依托单位国家:美国
- 项目类别:
- 财政年份:2018
- 资助国家:美国
- 起止时间:2018-09-01 至 2020-02-29
- 项目状态:已结题
- 来源:
- 关键词:Actinobacteria classActinomycesAffectAlanineAnabolismAnti-Infective AgentsBacterial InfectionsBiochemistryBiological AssayBiophysicsC-terminalCell membraneCell physiologyCellsCorynebacterium diphtheriaeCoupledCouplingCrystallographyCysteineDefectDentalDental ModelsDental PlaqueDental cariesDevelopmentDiseaseDisulfidesEctopic ExpressionElectron TransportEnzymesEscherichia coliEukaryotaExperimental ModelsGenesGeneticGenomeGram-Negative BacteriaGram-Positive BacteriaHomologous GeneIn VitroKnowledgeLaboratoriesLibrariesMapsMass Spectrum AnalysisMediatingMembraneMicrobial BiofilmsModalityMutationMycobacterium tuberculosisNADH dehydrogenase (ubiquinone)OrganismOxidation-ReductionOxidesOxidoreductasePathogenesisPathway interactionsPlayPreventionPrevention strategyProcessProtein PrecursorsProteinsRoleSpectrum AnalysisStreptococcus oralisStructureSystemThiol Disulfide OxidoreductaseVirulenceVirulence FactorsVitamin K 2bacterial fitnessbasedesigndisulfide bondinhibitor/antagonistinterdisciplinary approachmutantoral biofilmpathogenperiplasmpreventprotein foldingpublic health relevancereconstitutionsingle moleculevitamin K epoxide reductase
项目摘要
DESCRIPTION (provided by applicant): Proper protein folding is critical to cellular function. Disulfide bond-forming machines that facilitate proper protein folding are well recognized in eukaryotes and Gram-negative bacteria. Disulfide bond formation contributes to the overall protein folding process, stabilizing structures and protecting against degradation. In Gram-negative bacteria, this process occurs in the oxidizing periplasmic space and is required a pair of oxidoreductase enzymes DsbA and DsbB. In contrast, little is known about oxidative protein folding in single- membrane Gram-positive bacteria, which are not considered to have periplasms. Specifically, how protein precursors translocated across the cytoplasmic membrane by the general secretion Sec translocon in an unfolded state manage to fold correctly is poorly understood. Recent findings of oxidoreductase-encoding genes in the genome of actinobacteria and Vitamin K epoxide reductase in Mycobacterium tuberculosis, considered as a functional homolog of Escherichia coli DsbB, offer some clue to an oxidative folding mechanism in these organisms. Therefore, our laboratory recently began to investigate this fundamental problem using an experimental model in Actinomyces oris, an actinobacterium known to play an important role in the formation of oral biofilms or dental plaque. By structural analysis, we identified disulfide bonds in FimA of A. oris. FimA is the fimbrial shaft required for biofilm formation and interspecies interactions. We demonstrated that the C-terminal disulfide bond of FimA is essential for fimbrial assembly and biofilm formation. More recently, we revealed that disruption of a disulfide bond in coaggregation factor CafA eliminates A. oris coaggregation with Streptococcus oralis. To find additional factors that affect interspecies interactions, we performed a large-scale screen with a Tn5 transposon mutant library in A. oris and identified coaggregation- defective mutants mapped to genes potentially encoding various components of an oxidative protein folding pathway. By using a multidisciplinary approach that combines genetics, biophysics, biochemistry, crystallography, mass spectrometry, cell-based assays, and models of dental caries and bacterial infection, we aim to elucidate the mechanism of oxidative protein folding in A. oris, to determine the conservation of this pathway in other actinobacteria, and to explore preventive strategies for dental caries and bacterial infections.
描述(由申请人提供):正确的蛋白质折叠对细胞功能至关重要。促进蛋白质正确折叠的二硫键形成机器在真核生物和革兰氏阴性细菌中得到了很好的认可。二硫键的形成有助于整个蛋白质折叠过程,稳定结构并防止降解。在革兰氏阴性菌中,该过程发生在氧化周质空间中,并且需要一对氧化还原酶DsbA和DsbB。相比之下,对单膜革兰氏阳性细菌中的氧化蛋白折叠知之甚少,其不被认为具有周膜性。具体而言,蛋白质前体如何通过一般分泌Sec易位子在未折叠状态下跨细胞质膜易位,以正确地折叠是知之甚少的。氧化还原酶编码基因的放线菌和维生素K环氧化物还原酶在结核分枝杆菌,被认为是大肠杆菌DsbB的功能同源基因的基因组中的最新发现,提供了一些线索,在这些生物体中的氧化折叠机制。因此,我们的实验室最近开始使用口腔放线菌的实验模型来研究这个基本问题,口腔放线菌是一种已知在口腔生物膜或牙菌斑形成中起重要作用的放线菌。通过结构分析,我们确定了A.奥里斯。FimA是生物膜形成和种间相互作用所需的菌毛轴。我们证明了FimA的C-末端二硫键对于菌毛组装和生物膜形成是必不可少的。最近,我们发现,破坏共聚集因子CafA中的二硫键可以消除A。口腔链球菌与口腔链球菌共聚集。为了寻找影响种间相互作用的其他因素,我们在A. oris和鉴定的共聚集缺陷突变体定位于可能编码氧化蛋白折叠途径的各种组分的基因。通过使用多学科的方法,结合遗传学,生物物理学,生物化学,晶体学,质谱,基于细胞的测定,以及龋齿和细菌感染的模型,我们的目标是阐明A. oris,以确定该途径在其他放线菌中的保守性,并探索龋齿和细菌感染的预防策略。
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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10440483 - 财政年份:2021
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10270286 - 财政年份:2021
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10440538 - 财政年份:2021
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$ 27.79万 - 项目类别:
UCLA Dentist-Scientist and Oral Health-Researcher Training Program
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10655274 - 财政年份:2021
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$ 27.79万 - 项目类别:
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