Regulation of SsrA-mediated proteolysis of S. aureus
SsrA 介导的金黄色葡萄球菌蛋白水解的调节
基本信息
- 批准号:8951755
- 负责人:
- 金额:$ 20.25万
- 依托单位:
- 依托单位国家:美国
- 项目类别:
- 财政年份:2015
- 资助国家:美国
- 起止时间:2015-06-15 至 2017-05-31
- 项目状态:已结题
- 来源:
- 关键词:ATP-Dependent ProteasesAdultAffectAmino Acid SequenceAmino AcidsAnterior naresBacteriaBorrelia burgdorferiC-terminalCandidate Disease GeneCarbonClothingCommunitiesDNA-Binding ProteinsDataDiamideEnvironmentEscherichia coliExposure toFluorescenceFrequenciesFutureGenesGoalsGrowthHeatingHomologous GeneHospitalsHumanHybridsIndividualInfectionKnowledgeLeadLengthLibrariesListeriaLocationMediatingMediator of activation proteinMessenger RNAMicrobeMindMolecular ChaperonesMonitorMutationOpen Reading FramesOrganismOxidative StressParentsPathway interactionsPatternPeptide HydrolasesPlasmidsPopulationProcessProkaryotic CellsProteinsProteolysisProteomePublishingQuality ControlReading FramesRegulationRegulation of ProteolysisResistanceRibosomesSignal TransductionSiteSourceStaphylococcus aureusStarvationStressSulfhydryl CompoundsSurfaceSystemTherapeutic InterventionTimeTranscriptTranscriptional RegulationTransfer RNATranslationsVariantVenusbiological adaptation to stresscell motilitymutantnovelpathogenprotein degradationpublic health relevancetmRNAtransmission process
项目摘要
DESCRIPTION (provided by applicant): Proteolytic regulation of the SsrA degradation motif in the human pathogen Staphylococcus aureus occurs through a seemingly unique pathway as compared to other prokaryotes. In most cases, the ATP- dependent protease ClpP recognizes and degrades SsrA-tagged proteins following recognition by either the chaperone ClpX or ClpA. S. aureus instead uses the chaperone ClpC and the adaptor TrfA to assist ClpP in SsrA degradation. This novel mechanism is further enhanced by the observation that SsrA breakdown continues to occur during thiol or oxidative stress in strains lacking TrfA, suggesting an additional layer of proteolytic regulation beyond ClpPC/TrfA. To fully characterize the regulation of SsrA-tagged protein levels in S. aureus, our first aim is to uncover additional regulators and adaptors of the SsrA degradation motif in S. aureus and determine their interplay with the known SsrA regulator TrfA. A sequence-defined transposon mutant library of S. aureus USA300 LAC JE2 will be transformed with a plasmid capable of expressing the rapidly maturing Venus protein that is C-terminally tagged with SsrA. To cast the widest net in this search, fluorescence patterns from strains exposed to a variety of stress conditions (e.g. diamide, starvation, etc.) will be obtained. Most strains in these populations will demonstrate low levels o fluorescence due to their persistent degradation of SsrA- tagged Venus. However, a small number will have mutations that affect SsrA degradation, which when compared to patterns from strains lacking clpC or trfA, will allow initial categorization into various control pathways.
Subsequent strains doubly disrupted for each candidate gene and trfA will be created to further guide this process, as well as downstream complementation with each identified gene to hone a hierarchy of SsrA regulation in S. aureus. The use of ClpPC/TrfA in S. aureus as mediators of SsrA proteolysis suggests that the established motifs in SsrA used by other microbes may not be valid for S. aureus. Therefore, the S. aureus SsrA sequence may contain novel degradation signals, and our second aim will be to identify novel motifs in the SsrA tag, and to evaluate the importance of various residues in these motifs. Individual and groups of the eleven amino acids of SsrA appended to Venus will be altered to identify critical regions for proteolytic regulation. The resulting changes will be evaluated by monitoring fluorescence over time and during exposure to various stresses. Ultimately, unraveling how S. aureus regulates SsrA-tagged proteins provides an opportunity to better understand how this bacteria adjusts its proteome to challenging environments, and can provide S. aureus- specific targets for treating infections.
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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Ambrose Lin Yau Cheung其他文献
Ambrose Lin Yau Cheung的其他文献
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{{ truncateString('Ambrose Lin Yau Cheung', 18)}}的其他基金
Membrane-active quinoline and quinazoline antibacterials that target Gram positive pathogens
针对革兰氏阳性病原体的膜活性喹啉和喹唑啉抗菌剂
- 批准号:
9973439 - 财政年份:2020
- 资助金额:
$ 20.25万 - 项目类别:
Membrane-active quinoline and quinazoline antibacterials that target Gram positive pathogens
针对革兰氏阳性病原体的膜活性喹啉和喹唑啉抗菌剂
- 批准号:
10563142 - 财政年份:2020
- 资助金额:
$ 20.25万 - 项目类别:
Membrane-active quinoline and quinazoline antibacterials that target Gram positive pathogens
针对革兰氏阳性病原体的膜活性喹啉和喹唑啉抗菌剂
- 批准号:
10331864 - 财政年份:2020
- 资助金额:
$ 20.25万 - 项目类别:
Membrane-active quinoline and quinazoline antibacterials that target Gram positive pathogens
针对革兰氏阳性病原体的膜活性喹啉和喹唑啉抗菌剂
- 批准号:
10117071 - 财政年份:2020
- 资助金额:
$ 20.25万 - 项目类别:
Optimization of a novel compound that enhances the activity of beta-lactams against Gram+ bacteria
增强 β-内酰胺抗革兰氏菌活性的新型化合物的优化
- 批准号:
9296686 - 财政年份:2017
- 资助金额:
$ 20.25万 - 项目类别:
Bypassing the restriction barrier to improve transformation in S. epidermidis
绕过限制性屏障以改善表皮葡萄球菌的转化
- 批准号:
9386188 - 财政年份:2017
- 资助金额:
$ 20.25万 - 项目类别:
Regulation of SsrA-mediated proteolysis of S. aureus
SsrA 介导的金黄色葡萄球菌蛋白水解的调节
- 批准号:
9089861 - 财政年份:2015
- 资助金额:
$ 20.25万 - 项目类别:
The role of CshA and CshB in selective mRNA protection in S. aureus
CshA 和 CshB 在金黄色葡萄球菌选择性 mRNA 保护中的作用
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8665389 - 财政年份:2013
- 资助金额:
$ 20.25万 - 项目类别:
The role of CshA and CshB in selective mRNA protection in S. aureus
CshA 和 CshB 在金黄色葡萄球菌选择性 mRNA 保护中的作用
- 批准号:
8830428 - 财政年份:2013
- 资助金额:
$ 20.25万 - 项目类别:
The role of CshA and CshB in selective mRNA protection in S. aureus
CshA 和 CshB 在金黄色葡萄球菌选择性 mRNA 保护中的作用
- 批准号:
8557227 - 财政年份:2013
- 资助金额:
$ 20.25万 - 项目类别:
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