Inhibition of Protein Aggregation by the Curli Accessory Proteins CsgE and CsgF
Curli 辅助蛋白 CsgE 和 CsgF 对蛋白质聚集的抑制
基本信息
- 批准号:9304704
- 负责人:
- 金额:$ 33.53万
- 依托单位:
- 依托单位国家:美国
- 项目类别:
- 财政年份:2017
- 资助国家:美国
- 起止时间:2017-09-20 至 2021-08-31
- 项目状态:已结题
- 来源:
- 关键词:Alzheimer&aposs DiseaseAmyloidAmyloid beta-ProteinAreaBacteriaBehaviorBindingBiogenesisC-terminalCell surfaceCellsCenters for Disease Control and Prevention (U.S.)Cessation of lifeCircular DichroismCysteineCytosolDevelopmentDiseaseEnvironmentEscherichiaEscherichia coliFilamentFluorescence SpectroscopyGoalsHospitalizationHumanIn VitroIncidenceInfectionInvestigationLabelLaboratoriesLigand BindingLigandsMediatingMethodologyMinorMolecularMolecular ChaperonesMolecular ConformationN-terminalOutcomePlayProtein InhibitionProtein RegionProtein SubunitsProteinsPublic HealthReducing AgentsRoleSalmonellaSequence AnalysisSeriesSiteStructural ProteinStructureSurfaceTestingTherapeutic Agentsbaseextracellularfluorophorefoodborne illnessislet amyloid polypeptidemutantnovelnovel therapeuticspathogenpathogenic bacteriapolypeptidepreventprotein aggregateprotein aggregationresponse
项目摘要
Illness due to pathogenic bacteria such Salmonella and E. Coli pose a significant public health problem. The
Centers for Disease Control estimates that every year Salmonella alone causes one million foodborne illnesses
leading to 19,000 hospitalizations, and 380 deaths. Compounds that are able to mitigate the infectivity of
pathogenic bacteria, such as Salmonella and E. Coli, could play an important role in our ability to prevent, or at
least reduce the incidence of, food borne illness. Curli are a class of cell surface filaments found in Escherichia
and Salmonella spp. Curli, comprised mainly of the oligomerized protein subunit CsgA, are thought to facilitate
bacterial surface colonization, long-term survival, and bacterial cell-cell association, and appear to play a vital
role in host infection. Given its apparent role in bacterial survival, inhibition of CsgA oligomerization to form curli
is thought to be a promising avenue for the development of novel agents that reduce bacterial viability and
infection. However, our ability to exploit curli biogenesis in the development of novel therapeutic agents is limited
due to scant mechanistic information available on curli assembly. The overall goal of our investigations in our
laboratory is to determine the mechanism of curli biogenesis. Curli formation is thought to be mediated by at
least six different proteins: CsgA, CagB, CsgC, CsgE, CsgF, and CsgG. CsgA and CsgB are the structural
subunits of curli with CsgA present as the major, and CsgB the minor, protein components. Although CsgA and
CsgB are synthesized in the cytosol, the assembly of these proteins into curli occurs on the cell surface. It has
been postulated that two proteins, CsgE and CsgF act as chaperones to prevent the improper aggregation of
CsgA and/or CsgB until these proteins are properly localized on the extracellular surface where they form curli.
Based on sequence analysis, and circular dichroism, we found that CsgE and CsgF contain significant regions
that lack defined secondary structure, and posited that the two proteins may be intrinsically disordered with the
disordered regions serving as sites of protein interaction. In the studies proposed herein we aim determine the
details of the interaction between the curli assembly chaperon proteins, CsgE and CsgF, and the curli structural
proteins CsgA and CsgB. Determining the molecular details of CsgA assembly may help us elucidate the details
of curli formation and, in the long-term, aid in the development of novel, fimbriae based, therapies to reduce
long-term pathogen survival and persistence.
沙门氏菌和大肠杆菌等致病细菌引起的疾病是一个重大的公共卫生问题。这个
疾病控制中心估计,每年仅沙门氏菌一项就导致100万人食源性疾病
导致19,000人住院,380人死亡。能够减轻细菌感染性的化合物
致病细菌,如沙门氏菌和大肠埃希氏菌,可能在我们预防或预防
将食源性疾病的发病率降至最低。卷曲是在大肠杆菌中发现的一类细胞表面细丝
和沙门氏菌属。Curli主要由寡聚化的蛋白质亚单位CsgA组成,被认为有助于
细菌表面定植、长期存活和细菌细胞间的相互作用,似乎起着至关重要的作用
在宿主感染中的作用。鉴于CsgA在细菌存活中的明显作用,抑制CsgA齐聚形成卷曲
被认为是开发降低细菌生存能力的新型药物的一条很有前途的途径
感染。然而,我们在开发新的治疗药物中利用卷曲生物发生的能力是有限的。
由于缺乏关于卷曲组件的机械信息。我们在调查中的总体目标是
实验室是为了确定卷曲的生物发生机制。卷曲的形成被认为是由at介导的。
至少六种不同的蛋白质:CsgA、CagB、CsgC、CsgE、CsgF和CsgG。CsgA和CsgB是结构
卷曲的亚基以CsgA为主,CsgB为次要的蛋白质组分。虽然CsgA和
CsgB是在胞浆中合成的,这些蛋白在细胞表面组装成卷曲。它有
据推测,CsgE和CsgF这两种蛋白质是作为伴侣来防止不适当的聚集。
CsgA和/或CsgB,直到这些蛋白质正确地定位在它们形成卷曲的细胞外表面。
基于序列分析和圆二色谱,我们发现CsgE和CsgF含有显著区域
缺乏明确的二级结构,并推测这两种蛋白质可能本质上是无序的
作为蛋白质相互作用场所的无序区域。在这里提出的研究中,我们的目标是确定
Curli组装伴侣蛋白CsgE和CsgF与Curli结构相互作用的细节
蛋白质CsgA和CsgB。确定CsgA组装的分子细节可能有助于我们阐明细节
卷曲的形成,从长远来看,有助于开发以菌毛为基础的新疗法,以减少
病原体的长期存活和持久性。
项目成果
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