A novel protein export chaperone of Mycobacterium tuberculosis
A novel protein export chaperone of Mycobacterium tuberculosis
批准号:
9892319
负责人:
Miriam S. Braunstein
金额:
$59.87万
依托单位国家:
美国
项目类别:
财政年份:
2020
资助国家:
美国
项目状态:
已结题
起止时间:
2020-01-03 至 2024-12-31
关键词:
AntigensAntitubercular AgentsAttenuated Live Virus VaccineBacterial PhysiologyBacterial ProteinsBinding SitesBiochemicalBiochemical GeneticsBiologyCategoriesCessation of lifeComplexCrystallizationCytoplasmDataDevelopmentEngineeringEnvironmentEpidemicExhibitsFutureGenetic StructuresGenus MycobacteriumGoalsGrowthHealthHydrophobicityImmune responseInfectionInterdisciplinary StudyKnowledgeLabelLaboratoriesLeadLengthLipidsMeasuresMolecularMolecular BiologyMolecular ChaperonesMycobacterium tuberculosisPathogenesisPathway interactionsPeptidesPhagosomesPhosphoric Monoester HydrolasesPlayProtein Export PathwayProteinsProteomicsResearch PersonnelRoentgen RaysRoleStructureSubstrate SpecificityTestingTuberculosisVirulenceWorld Healthbiological systemsbiophysical analysiscell envelopedrug developmentextracellularimprovedmacrophagemycobacterialnovelnovel strategiesnovel therapeuticspathogenic bacteriapreventstoichiometrytooltuberculosis treatmentvaccine development
中文摘要
结核分枝杆菌(Mtb)是结核病(TB)的病原体,代表着严重的世界健康。
危机(每天有4000人死于结核病)。更好地了解结核分枝杆菌的生物学和发病机制将推动发展
控制结核病流行的新战略。在细菌病原体中,如结核分枝杆菌,许多蛋白质被输出到
细菌的细胞膜或细胞外环境,以便在细菌中执行关键功能
生理、毒性或免疫反应。因此,输出蛋白质的Mtb途径可能是靶点或
被开发用于开发新的抗结核病控制措施。然而,在我们的国家中存在着显著的差距
了解结核分枝杆菌蛋白出口。
本研究旨在探讨我们发现的一种新的蛋白质输出伴侣蛋白--饱和脂肪酸的作用机制
在Mtb。Sts是由专门的SecA2蛋白质出口输出的蛋白质子集的伴侣
在巨噬细胞中,结核分枝杆菌的细胞内生长需要SATS。然而,SAT并不共享
与任何以前表征的蛋白质的序列或结构相似,并且SATS的机制是
完全未知。底物专一性和SATS底物的范围也是未知的。目标1
建议确定SATS在蛋白质出口中作用的机制细节。目标2是确定
SAT的结构以及与底物的多肽形成的复合物的结构。目标3是确定与SAT的结合
以确定更多的SATS底物。通过实现这些目标,我们将确定
小卫星对结核分枝杆菌蛋白输出和生物学的作用机制和贡献。更广泛地说,这些研究将
提高我们对细菌输出蛋白质的策略和分子多样性的理解
生物系统中的伴侣。从长远来看,这一结果可能导致抑制蛋白质的策略
EXPORT作为一种新的抗结核病疗法。或者,可以将所获得的知识用于工程设计
分枝杆菌菌株具有更好的输出蛋白质作为实验工具或活的能力,
加强抗原输出的减毒疫苗。
英文摘要
Mycobacterium tuberculosis (Mtb), the causative agent of tuberculosis (TB), represents a severe world health
crisis (4,000 TB deaths daily). A better understanding of Mtb biology and pathogenesis will drive development
of novel strategies to control the TB epidemic. In bacterial pathogens, like Mtb, many proteins are exported to
the bacterial cell envelope or the extracellular environment in order to carry out critical functions in bacterial
physiology, virulence or immune responses. Thus, Mtb pathways that export proteins could be targeted or
exploited for the development of novel anti-TB control measures. However, significant gaps exist in our
understanding of Mtb protein export.
This proposal is to determine the mechanism of SatS, a novel protein export chaperone we discovered
in Mtb. SatS is a chaperone for a subset of proteins that are exported by the specialized SecA2 protein export
pathway, and SatS is required for intracellular growth of Mtb in macrophages. However, SatS shares no
sequence or structural similarity with any previously characterized proteins and the mechanism of SatS is
completely unknown. Substrate specificity and the scope of SatS substrates are also unknown. Aim 1 of this
proposal is to determine the mechanistic details of SatS function in protein export. Aim 2 is to determine the
structures of SatS and that of SatS in complex with peptides of substrates. Aim 3 is to identify SatS-binding
sites in substrates and to identify additional SatS substrates. By completing these Aims, we will determine the
mechanism and contribution of SatS to Mtb protein export and biology. More broadly, these studies will
improve our understanding of bacterial strategies for exporting proteins and of the diversity of molecular
chaperones across biological systems. Long-term, the results could lead to strategies for inhibiting protein
export as a novel anti-TB therapy. Alternatively, the knowledge gained could be harnessed to engineer
mycobacterial strains with improved capacity to export proteins for use as experimental tools or as live,
attenuated vaccines with enhanced antigen export.
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会议论文
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依托单位:
Developing High-Throughput Assays for M. tuberculosis Tat Pathway Inhibitors
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财政年份:2012
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负责人:Miriam S. Braunstein
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依托单位:
Developing High-Throughput Assays for M. tuberculosis Tat Pathway Inhibitors
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批准号:8434858
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资助金额:$34.78万
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财政年份:2012
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负责人:Miriam S. Braunstein
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依托单位:
Developing High-Throughput Assays for M. tuberculosis Tat Pathway Inhibitors
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批准号:8284652
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项目类别:
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资助金额:$37.0万
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财政年份:2012
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依托单位:
Innate Immune Responses to Pro-Apoptotic BCG
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批准号:7652144
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资助金额:$10.0万
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财政年份:2008
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负责人:Miriam S. Braunstein
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依托单位:
A Reporter Transposon for Studying Exported Proteins of M. tuberculosis
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依托单位:
A Reporter Transposon for Studying Exported Proteins of M. tuberculosis
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财政年份:2007
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依托单位:
Identification of M. tuberculosis Protein Secreted During Growth in Macrophages
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Protein Secretion Pathways of Mycobacterium tuberculosis
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批准号:8509569
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依托单位:
海外基金