Structural characterization of MCE transport systems from Mycobacterium tuberculosis
结核分枝杆菌 MCE 转运系统的结构表征
基本信息
- 批准号:10681871
- 负责人:
- 金额:$ 81.68万
- 依托单位:
- 依托单位国家:美国
- 项目类别:
- 财政年份:2023
- 资助国家:美国
- 起止时间:2023-02-03 至 2028-01-31
- 项目状态:未结题
- 来源:
- 关键词:AntibioticsArchitectureBacteriaBindingBiochemicalBiological AssayCause of DeathCellsCellular MembraneCholesterolCommunicable DiseasesComplexComplex AnalysisCryoelectron MicroscopyDevelopmentDrug resistanceEnvironmentEscherichia coliFatty AcidsGenesGenus MycobacteriumGram-Negative BacteriaGrowthHydrophobicityImmune responseImmune systemIn VitroIndividualLearningLinkLipidsLungMacrophageMaintenanceMammalian CellMass Spectrum AnalysisMembraneModelingMultiprotein ComplexesMutationMycobacterium smegmatisMycobacterium tuberculosisNutrientOperonPathogenesisPhagosomesPlanetsPlayProtein FamilyProtein SubunitsProteinsProteomicsRoleStructureSystemTestingTimeTuberculosisVirulenceVirulence FactorsWorkcell envelopecombatdesigngene productinsightlipid transportmembrane biogenesismycobacterialparticlepathogenpolypeptideprotein complexprotein functionprotein protein interactionprotein structureprotein transportresistant strainstructural biologytrafficking
项目摘要
Project Summary/Abstract
Mycobacterium tuberculosis (Mtb), the causative agent of tuberculosis (TB), is one of the deadliest pathogens
on the planet, and for decades, TB has been the leading cause of death due to infectious disease. The cell
envelope of Mtb forms a notoriously tough barrier around the cell, protecting the bacterium from harsh agents
in the environment such as antibiotics and host immune responses. At the same time, Mtb imports nutrients
from the host cell, such as cholesterol, across the cell envelope. Transport of lipids, metabolites and nutrients
across the cell envelope, between the inner and outer membranes is critical for building and maintaining the
cell envelope itself, and for import of key factors required for bacterial growth. Therefore, the transport systems
that facilitate this trafficking are critical for allowing Mtb to survive and thrive in its intracellular niche, most
typically macrophages in the lungs.
The MCE (Mammalian Cell Entry) family of proteins are transport systems that have been implicated as
virulence factors in Mtb, and are an expanded protein family in mycobacteria compared with other
double-membraned bacteria. In Mtb, several lines of evidence suggest that MCE systems are important for
importing nutrients such as cholesterol and fatty acids. Recent work on E. coli MCE systems has shown that
these are multi-protein complexes anchored in the inner membrane of double-membraned bacteria, and may
play an important role in the maintenance of outer membrane integrity, raising the possibility that this may also
be a role that MCE proteins play in Mtb. The structure and mechanisms of the highly complex MCE systems in
Mtb remain unknown, and studying these is critical for understanding how MCE systems work, what their
substrates are, and how they may be linked to virulence.
This proposal is focused on biochemical and structural characterization of MCE transport systems from
Mtb and the non-pathogenic model, Mycobacterium smegmatis. Using single particle cryo-EM, mass
spectrometry, biochemical and functional assays, we aim to study the structure and function of endogenous
Mtb MCE systems, decipher which protein subunits come together to form complexes and define
protein-protein interactions that are important for the systems to assemble and function. The results of this
work will provide important insights into the structure and function of the large, multi-protein MCE complexes in
the Mtb cell envelope, and how they influence replication and virulence in the host.
项目总结/摘要
结核分枝杆菌(Mycobacterium tuberculosis,Mtb)是结核病的病原体,是最致命的病原体之一
几十年来,结核病一直是传染病导致死亡的主要原因。细胞
结核分枝杆菌的包膜在细胞周围形成了一个众所周知的坚韧屏障,保护细菌免受苛刻的试剂
例如抗生素和宿主免疫反应。与此同时,结核病进口营养素
从宿主细胞,如胆固醇,穿过细胞膜。脂质、代谢物和营养物质的运输
穿过细胞膜,在内外膜之间,对于建立和维持细胞膜是至关重要的。
细胞包膜本身,以及细菌生长所需的关键因子的输入。因此,运输系统
促进这种贩运对于允许结核分枝杆菌在其细胞内生态位中生存和繁荣至关重要,
通常是肺部的巨噬细胞
MCE(哺乳动物细胞进入)蛋白质家族是转运系统,其被认为是
Mtb中的毒力因子,并且与其他毒力因子相比,是分枝杆菌中扩展的蛋白质家族。
双膜细菌在结核分枝杆菌中,几条证据表明MCE系统对于
输入胆固醇和脂肪酸等营养素。E. coli MCE系统已经表明,
它们是锚定在双膜细菌内膜上的多蛋白复合物,
在维持外膜完整性方面起着重要作用,这也提高了这可能
是MCE蛋白在结核分枝杆菌中发挥的作用。本文研究了高复杂MCE系统的结构和机理,
结核分枝杆菌仍然是未知的,研究这些对于了解MCE系统如何工作,
底物是什么,以及它们如何与毒力联系在一起。
该建议的重点是从MCE运输系统的生化和结构表征
结核分枝杆菌和非致病性模型,耻垢分枝杆菌。使用单粒子冷冻EM,质量
光谱,生化和功能测定,我们的目的是研究内源性的结构和功能
Mtb MCE系统,破译哪些蛋白质亚基聚集在一起形成复合物,并定义
蛋白质-蛋白质相互作用对系统的组装和功能很重要。的结果
这项工作将提供重要的见解的结构和功能的大型,多蛋白质MCE复合物,
Mtb细胞包膜,以及它们如何影响宿主中的复制和毒力。
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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{{ truncateString('Gira Bhabha', 18)}}的其他基金
Structural basis of the polar tube invasion machinery from microsporidia parasites
微孢子虫寄生虫极管入侵机制的结构基础
- 批准号:
10349551 - 财政年份:2020
- 资助金额:
$ 81.68万 - 项目类别:
Structural basis of the polar tube invasion machinery from microsporidia parasites
微孢子虫寄生虫极管入侵机制的结构基础
- 批准号:
10563182 - 财政年份:2020
- 资助金额:
$ 81.68万 - 项目类别:
Structural basis of the polar tube invasion machinery from microsporidia parasites
微孢子虫寄生虫极管入侵机制的结构基础
- 批准号:
9913209 - 财政年份:2020
- 资助金额:
$ 81.68万 - 项目类别:
Structure and mechanism of cytoplasmic and axonemal dyneins
细胞质和轴丝动力蛋白的结构和机制
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9521385 - 财政年份:2015
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Structure and mechanism of cytoplasmic and axonemal dyneins
细胞质和轴丝动力蛋白的结构和机制
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8804578 - 财政年份:2015
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