Bacterial outer membrane biogenesis through a novel periplasmic protein that recognizes and traffics phospholipids
通过识别和运输磷脂的新型周质蛋白进行细菌外膜生物发生
基本信息
- 批准号:RGPIN-2018-04994
- 负责人:
- 金额:$ 7.29万
- 依托单位:
- 依托单位国家:加拿大
- 项目类别:Discovery Grants Program - Individual
- 财政年份:2022
- 资助国家:加拿大
- 起止时间:2022-01-01 至 2023-12-31
- 项目状态:已结题
- 来源:
- 关键词:
项目摘要
The overall aim of this project is to determine how bacteria recognize and organize lipids in their outer membrane. The challenge we are tackling here is best described by Bruce Alberts, Editor of Science, who stated "I am painfully aware of the huge gap that remains in our understanding of even the simplest cells. Consider, for example, the common bacterium E. coli, which served as a predominant model organism in the early years of molecular biology. It is very sobering to report that more than 50 years later, nearly a quarter of the more than 4000 proteins encoded by its genome have functions that remain unknown. Might some new functional classes of biological molecules, common to all cells, be discovered by a focus on such proteins?"We will address this gap by elucidating the mechanism of an E. coli protein called YraP. There are at least 7000 proteins with similarity to YraP which have been found in a range of bacteria including various pathogens, and hence there are implications for infectious diseases. Moreover, as a unique gene product that is expressed in response to stress, YraP could offer opportunities for the design of antimicrobial agents once its structure, function and screening assays are available. The evolutionary relatives of YraP includes hemolysins, mechanosensitive channels, the membrane-pore forming protein Secretin, and a variety of eukaryotic proteins. We propose that they share a common function based on lipid recognition. Our focus is on understanding the cellular function, molecular interactions and 3D structures of YraP. We will reveal how this lipoprotein engages the phospholipids found in the membrane that surrounds all Gram negative bacteria. The outer membrane's role is to form a semi-permeable layer that controls the entry and exit of nutrients and other materials including drug molecules. The proteins inserted into this membrane include pores, channels and antigens that act as targets of immune responses. We propose that they all depend on YraP to deliver a specific lipid to the outer membrane. We will investigate how YraP recognizes and organizes this lipid, and how it traffics lipid from inside the cell. We will use methods including magnetic resonance spectroscopy to visualize the atoms of the structures and binding interfaces to expose the specific roles of its amino acid residues and lipids they contact. The resulting principles of ligand recognition and membrane biogenesis will inform the discovery of inhibitors, vaccines and antimicrobial agents. This project is collaborative, involving detailed structure-function analysis of a novel target by researchers at Canada's national NMR facility and the UK-based Institute of Microbiology and Infection. We will capitalize on our joint discovery of the role of YraP in lipid trafficking, along with a new NMR system geared to elucidate how this superfamily of proteins recognizes lipids, shapes membranes and protect cells.
该项目的总体目标是确定细菌如何识别和组织其外膜中的脂质。 《科学》杂志编辑布鲁斯·阿尔伯特 (Bruce Alberts) 最好地描述了我们在此应对的挑战,他表示:“我痛苦地意识到,即使是最简单的细胞,我们的理解仍然存在巨大差距。以常见的细菌大肠杆菌为例,它是分子生物学早期的主要模式生物。令人震惊的是,50 多年后,其基因组编码的 4000 多种蛋白质中,有近四分之一的蛋白质已经被研究出来了。” 具有仍未知的功能。通过关注这些蛋白质,是否可以发现一些所有细胞共有的新功能类别的生物分子?”我们将通过阐明一种名为 YraP 的大肠杆菌蛋白质的机制来解决这一空白。在包括各种病原体在内的一系列细菌中发现了至少 7000 种与 YraP 相似的蛋白质,因此对传染病具有重要意义。此外,作为一种在应激反应中表达的独特基因产物,一旦其结构、功能和筛选分析可用,YraP 就可以为抗菌药物的设计提供机会。 YraP 的进化亲属包括溶血素、机械敏感通道、膜孔形成蛋白促胰液素和多种真核蛋白。我们认为它们具有基于脂质识别的共同功能。我们的重点是了解 YraP 的细胞功能、分子相互作用和 3D 结构。我们将揭示这种脂蛋白如何与所有革兰氏阴性细菌周围的膜中发现的磷脂结合。外膜的作用是形成半透层,控制营养物质和其他材料(包括药物分子)的进出。插入该膜的蛋白质包括作为免疫反应目标的孔、通道和抗原。我们认为它们都依赖于 YraP 将特定的脂质传递到外膜。我们将研究 YraP 如何识别和组织这种脂质,以及它如何从细胞内部运输脂质。我们将使用包括磁共振光谱在内的方法来可视化结构的原子和结合界面,以揭示其所接触的氨基酸残基和脂质的特定作用。由此产生的配体识别和膜生物发生原理将为抑制剂、疫苗和抗菌剂的发现提供信息。该项目是合作项目,涉及加拿大国家核磁共振设施和英国微生物与感染研究所的研究人员对新靶点进行详细的结构功能分析。我们将利用我们对 YraP 在脂质运输中的作用的共同发现,以及一个新的 NMR 系统,该系统旨在阐明这个蛋白质超家族如何识别脂质、塑造膜和保护细胞。
项目成果
期刊论文数量(0)
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专利数量(0)
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Overduin, Michael其他文献
Binding of the periplakin linker requires vimentin acidic residues D176 and E187
- DOI:
10.1038/s42003-020-0810-y - 发表时间:
2020-02-21 - 期刊:
- 影响因子:5.9
- 作者:
Odintsova, Elena;Mohammed, Fiyaz;Overduin, Michael - 通讯作者:
Overduin, Michael
Structural Basis of Ligand Interactions of the Large Extracellular Domain of Tetraspanin CD81
- DOI:
10.1128/jvi.00559-12 - 发表时间:
2012-09-01 - 期刊:
- 影响因子:5.4
- 作者:
Rajesh, Sundaresan;Sridhar, Pooja;Overduin, Michael - 通讯作者:
Overduin, Michael
Structural biology of endogenous membrane protein assemblies in native nanodiscs
- DOI:
10.1016/j.sbi.2021.03.008 - 发表时间:
2021-08-01 - 期刊:
- 影响因子:6.8
- 作者:
Brown, Chanelle J.;Trieber, Catharine;Overduin, Michael - 通讯作者:
Overduin, Michael
Ambidextrous binding of cell and membrane bilayers by soluble matrix metalloproteinase-12.
- DOI:
10.1038/ncomms6552 - 发表时间:
2014-11-21 - 期刊:
- 影响因子:16.6
- 作者:
Koppisetti, Rama K.;Fulcher, Yan G.;Jurkevich, Alexander;Prior, Stephen H.;Xu, Jia;Lenoir, Marc;Overduin, Michael;Van Doren, Steven R. - 通讯作者:
Van Doren, Steven R.
Advancing membrane biology with poly(styrene-co-maleic acid)-based native nanodiscs
- DOI:
10.1016/j.eurpolymj.2018.11.015 - 发表时间:
2019-01-01 - 期刊:
- 影响因子:6
- 作者:
Overduin, Michael;Klumperman, Bert - 通讯作者:
Klumperman, Bert
Overduin, Michael的其他文献
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{{ truncateString('Overduin, Michael', 18)}}的其他基金
Bacterial outer membrane biogenesis through a novel periplasmic protein that recognizes and traffics phospholipids
通过识别和运输磷脂的新型周质蛋白进行细菌外膜生物发生
- 批准号:
RGPIN-2018-04994 - 财政年份:2021
- 资助金额:
$ 7.29万 - 项目类别:
Discovery Grants Program - Individual
Functional Derivatives of Maleic Acid copolymers and Native Nanodisc Technology (FUNDEMANNT) [Phase 1]
马来酸共聚物的功能衍生物和天然纳米圆盘技术 (FUNDEMANNT) [第 1 阶段]
- 批准号:
548807-2020 - 财政年份:2020
- 资助金额:
$ 7.29万 - 项目类别:
Idea to Innovation
Bacterial outer membrane biogenesis through a novel periplasmic protein that recognizes and traffics phospholipids
通过识别和运输磷脂的新型周质蛋白进行细菌外膜生物发生
- 批准号:
RGPIN-2018-04994 - 财政年份:2020
- 资助金额:
$ 7.29万 - 项目类别:
Discovery Grants Program - Individual
Bacterial outer membrane biogenesis through a novel periplasmic protein that recognizes and traffics phospholipids
通过识别和运输磷脂的新型周质蛋白进行细菌外膜生物发生
- 批准号:
RGPIN-2018-04994 - 财政年份:2019
- 资助金额:
$ 7.29万 - 项目类别:
Discovery Grants Program - Individual
Bacterial outer membrane biogenesis through a novel periplasmic protein that recognizes and traffics phospholipids
通过识别和运输磷脂的新型周质蛋白进行细菌外膜生物发生
- 批准号:
RGPIN-2018-04994 - 财政年份:2018
- 资助金额:
$ 7.29万 - 项目类别:
Discovery Grants Program - Individual
System for Resolving Native Membrane Nanodiscs and Protein Assemblies
用于解析天然膜纳米圆盘和蛋白质组件的系统
- 批准号:
RTI-2018-00620 - 财政年份:2017
- 资助金额:
$ 7.29万 - 项目类别:
Research Tools and Instruments
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