Controlling Bacterial Amyloid Formation and the Influence of Curli Subunits on Pathogenic Alpha-synuclein Aggregation
控制细菌淀粉样蛋白的形成以及 Curli 亚基对致病性 α-突触核蛋白聚集的影响
基本信息
- 批准号:10586077
- 负责人:
- 金额:$ 30.43万
- 依托单位:
- 依托单位国家:美国
- 项目类别:
- 财政年份:2016
- 资助国家:美国
- 起止时间:2016-04-01 至 2025-03-31
- 项目状态:未结题
- 来源:
- 关键词:AccelerationAdoptedAmyloidAmyloid beta-Protein PrecursorAmyloid fibersAntimicrobial ResistanceBacteriaBehavioralBindingBiochemicalBiogenesisBiological AssayBiological ProcessBrainCell surfaceChemicalsCollaborationsDiseaseEnsureEnterobacteriaceaeEscherichia coliExtracellular MatrixFiberFluorescence MicroscopyGenesGeneticGenomeGram-Negative BacteriaGrantHomologous GeneHumanHuman MicrobiomeIn VitroKnowledgeLearningLifeLinkMembraneMicrobial BiofilmsMinorModelingMolecular ChaperonesMusNerve DegenerationNeurodegenerative DisordersOutcomeParkinson DiseasePathogenesisPathogenicityPathway interactionsPolymersPropertyProtein SubunitsProteinsSpecificitySymptomsSystemTherapeuticTimeToxic effectUropathogenic E. coliVariantWorkalpha synucleinamyloid formationassociated symptombiophysical propertiescytotoxicexperimental studyextracellulargut bacteriagut microbiotahost colonizationhuman diseasemicrobialmutantnovel therapeuticsperiplasmpolymerizationpreventprotein foldingprotein misfoldingsynuclein
项目摘要
Escherichia coli (E.coli) and other enteric bacteria are a major cause of human diseases. Biofilm formation
contributes greatly to bacterial persistence and antimicrobial resistance in the host. Many Enterobacteriaceae,
such as E. coli, produce functional amyloid fibers called curli as a major proteinaceous component of their
extracellular matrix. It is now clear that functional amyloids are widespread, with examples found throughout
cellular life. The curli system in E. coli provides a rich and high throughput genetic and biochemical toolbox for
the study of amyloid formation. The work has contributed to a curli assembly model where the main fiber
component CsgA and the minor subunit CsgB are secreted through the outer membrane-located CsgG. CsgB
attaches to the surface of the cell and templates the folding of CsgA into an amyloid fiber. CsgA subunits that
inappropriately polymerize in the periplasm are inhibited from amyloid accumulation via CsgC. The exquisitely-
controlled curli biogenesis system ensures that E. coli is not exposed to the potentially cytotoxic outcomes of
amyloid formation.
Uncontrolled or inappropriate amyloid formation results in several neurodegenerative diseases, including
Parkinson’s. The hallmark of Parkinson’s disease is the amyloid aggregation of alpha-synuclein, although it is
unknown how amyloid formation is initiated. Colonization of mice with curli amyloid producing bacteria results
in alpha-synuclein amyloid formation and Parkinson’s like symptoms. Furthermore, purified CsgA protein can
accelerate alpha-synuclein amyloid formation in vitro. Therefore, it is imperative to learn how E. coli controls
curli amyloid formation and how CsgA can accelerate alpha-synuclein amyloid formation. Interestingly, CsgC
from E. coli can inhibit CsgA and alpha-synuclein amyloid formation. Knowledge gained from the following
experiments will have implications for microbial pathogenesis, general protein folding, and amyloid biogenesis,
thus paving the way for new therapies that rationally target these critical biological processes. In Aim 1 The
mechanism and specificity of CsgC will be revealed, including how CsgC functions to inhibit CsgA and alpha-
synuclein polymerization at low stoichiometric ratios. In Aim 2 The relationship between the intrinsic ability of
CsgA to form amyloid and its ability to accelerate alpha-synuclein amyloid formation will be assessed. Finally,
in Aim 3 CsgA and CsgC-like proteins in the sequenced genomes of the human gut microbiota will be
identified and biochemically characterized. Together the successful completion of these aims will give an
overall understanding of the mechanism of amyloid inhibitory activity and the interactions between bacterial
amyloid formation and neurodegenerative diseases.
大肠杆菌(E.coli)和其他肠道细菌是人类疾病的主要原因。生物膜形成
极大地促进宿主中的细菌持久性和抗微生物剂抗性。许多肠杆菌科,
如大肠大肠杆菌,产生功能性淀粉样纤维称为卷曲作为其主要的蛋白质成分,
细胞外基质现在很清楚,功能性淀粉样蛋白是广泛存在的,
细胞生命在E.大肠杆菌提供了一个丰富的和高通量的遗传和生化工具箱,
淀粉样蛋白形成的研究。这项工作有助于建立一个curli组装模型,其中主纤维
组分CsgA和次要亚基CsgB通过位于外膜的CsgG分泌。CsgB
它附着在细胞表面,并作为模板将CsgA折叠成淀粉样纤维。CsgA亚基,
通过CsgC抑制周质中不适当的淀粉样蛋白积聚。精致的-
控制curli生物发生系统保证了E.大肠杆菌不会暴露于潜在的细胞毒性结果
淀粉样蛋白形成。
不受控制或不适当的淀粉样蛋白形成导致几种神经退行性疾病,包括
帕金森等帕金森病的标志是α-突触核蛋白的淀粉样蛋白聚集,尽管它是
淀粉样蛋白是如何形成的尚不清楚。产生卷曲淀粉样蛋白的细菌在小鼠中的定殖结果
在α-突触核蛋白淀粉样蛋白形成和帕金森样症状中的作用。此外,纯化的CsgA蛋白可
加速体外α-突触核蛋白淀粉样蛋白形成。因此,了解E.大肠杆菌对照
卷曲淀粉样蛋白的形成以及CsgA如何加速α-突触核蛋白淀粉样蛋白的形成。有趣的是,CsgC
来自大肠大肠杆菌能抑制CsgA和α-突触核蛋白淀粉样蛋白的形成。从以下方面获得的知识
实验将对微生物发病机理、一般蛋白质折叠和淀粉样蛋白生物发生产生影响,
从而为合理地靶向这些关键生物过程的新疗法铺平道路。在目标1
CsgC的机制和特异性将被揭示,包括CsgC如何发挥作用,抑制CsgA和α-
在低化学计量比下的突触核蛋白聚合。目标2:人的内在能力
将评估CsgA形成淀粉样蛋白的能力及其加速α-突触核蛋白淀粉样蛋白形成的能力。最后,
在目标3中,人类肠道微生物群的测序基因组中的CsgA和CsgC样蛋白将被
鉴定和生化特征。这些目标的成功实现将为
全面了解淀粉样蛋白抑制活性的机制和细菌之间的相互作用,
淀粉样蛋白形成和神经变性疾病。
项目成果
期刊论文数量(20)
专著数量(0)
科研奖励数量(0)
会议论文数量(0)
专利数量(0)
Bacterial amyloids.
细菌淀粉样蛋白。
- DOI:10.1007/978-1-61779-551-0_21
- 发表时间:2012
- 期刊:
- 影响因子:0
- 作者:Zhou,Yizhou;Blanco,LuzP;Smith,DanielR;Chapman,MatthewR
- 通讯作者:Chapman,MatthewR
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Matthew Richard Chapman其他文献
Matthew Richard Chapman的其他文献
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{{ truncateString('Matthew Richard Chapman', 18)}}的其他基金
Controlling Bacterial Amyloid Formation and the Influence of Curli Subunits on Pathogenic Alpha-synuclein Aggregation
控制细菌淀粉样蛋白的形成以及 Curli 亚基对致病性 α-突触核蛋白聚集的影响
- 批准号:
9973388 - 财政年份:2016
- 资助金额:
$ 30.43万 - 项目类别:
Controlling Bacterial Amyloid Formation and the Influence of Curli Subunits on Pathogenic Alpha-synuclein Aggregation
控制细菌淀粉样蛋白的形成以及 Curli 亚基对致病性 α-突触核蛋白聚集的影响
- 批准号:
10369667 - 财政年份:2016
- 资助金额:
$ 30.43万 - 项目类别:
Protein and Chemical Modulation of Curli Amyloid Biogenesis
Curli 淀粉样蛋白生物发生的蛋白质和化学调节
- 批准号:
9078907 - 财政年份:2016
- 资助金额:
$ 30.43万 - 项目类别:
FASEB SRC on Molecular Mechanisms and Physiological Consequences of Protein Aggregation
FASEB SRC 关于蛋白质聚集的分子机制和生理后果
- 批准号:
8910849 - 财政年份:2015
- 资助金额:
$ 30.43万 - 项目类别:
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