In-depth structural characterization of the tetraspanin CD81
四跨膜蛋白 CD81 的深入结构表征
基本信息
- 批准号:BB/N007417/1
- 负责人:
- 金额:$ 44.5万
- 依托单位:
- 依托单位国家:英国
- 项目类别:Research Grant
- 财政年份:2016
- 资助国家:英国
- 起止时间:2016 至 无数据
- 项目状态:已结题
- 来源:
- 关键词:
项目摘要
Every human cell is encased by a cell membrane that separates the cell contents from its surroundings. Proteins embedded in this membrane act as gates to allow molecules to enter and exit cells; they also mediate the interactions that occur between a cell and its environment. This means that membrane proteins are involved in many of the most fundamental processes in normal cell function; when these processes fail, diseases result. It is no surprise, then, that the top ten best-selling small molecule drugs of all time all target membrane proteins.There are many different membrane proteins in any given cell, grouped into over 1,500 families, each with many members. In order to study any of them in detail, it is important to understand their three-dimensional structures. Central to this is a technique called X-ray crystallography that allows scientists to obtain a detailed view of how the atoms within a protein are arranged, providing a framework for further study. Scientists use this framework to investigate how the protein functions, bringing new levels of understanding to how cells work in health and disease, and providing knowledge to develop new drugs.Tetraspanins are membrane proteins that function by interacting with a wide range of other membrane and soluble proteins, thereby affecting how cells signal, interact, change shape and move. Remarkably, tetraspanins are also involved in the process of infection for a wide range of diseases. However, because there is no known structure of any full-length tetraspanin family member, the mode of action of tetraspanins in these essential processes is not understood, leaving a major gap in our knowledge of cell biology.Obtaining the structure of any membrane protein is a major scientific challenge: It is necessary to remove the protein from the cell membrane which often results in the protein becoming so unstable that it cannot be used to make the crystals required to perform X-ray crystallography. Consequently, we know very little about many membrane protein families with important biological functions. We have now overcome this crystallization challenge for the tetraspanin, CD81.Human CD81 is one of the best understood tetraspanin family members and is the subject of our proposed research. It has well-established roles in how cells interact with each other, the immune response and fertilization. Notably CD81 is a receptor for some very important human pathogens including influenza, human immunodeficiency virus, the malarial parasite, T-cell lymphotropic virus type 1 and hepatitis C virus (HCV). It may also be a tumour promoter. Central to CD81 function (and to that of all tetraspanins) is its ability to form extensive interactions with itself and other proteins; however, we don't know what these structures look like and therefore lack the framework for further study, mentioned above.The first aim of the research outlined in our proposal is to solve the three-dimensional structure of CD81. We have made excellent progress towards this goal, having crystallized CD81 and collected X-ray diffraction data.We have also teamed up with scientists in France who can make soluble forms of the HCV protein, E2, that binds CD81. The second aim of our project is to make an HCV-E2/CD81 complex so we can characterize it and solve its structure; this will allow us to learn more about how CD81 interacts with other proteins. We believe we are the only team in the world that has all the tools to take on this challenge.Brand new developments in structural biology (e.g. high-resolution electron microscopy) have enabled us to devise a third aim, which is to look at these structures in the cell membrane (by electron tomography), linking our atomic level structural data to what is actually happening in the cell.Studying the structure of CD81 at this level of detail will allow us to begin to understand how tetraspanins work in health and disease.
每个人类细胞都被一层细胞膜包裹着,细胞膜将细胞内容物与周围环境隔开。嵌入在细胞膜中的蛋白质充当大门,允许分子进入和离开细胞;它们还调节细胞与其环境之间发生的相互作用。这意味着膜蛋白参与了许多正常细胞功能中最基本的过程;当这些过程失败时,疾病就会发生。因此,有史以来最畅销的十种小分子药物都以膜蛋白为靶标也就不足为奇了。在任何给定的细胞中,都有许多不同的膜蛋白,分为1500多个家族,每个家族都有许多成员。为了详细研究它们中的任何一个,了解它们的三维结构是很重要的。这项研究的核心是一种名为X射线结晶学的技术,它使科学家能够详细了解蛋白质中的原子是如何排列的,为进一步研究提供了一个框架。科学家们使用这个框架来研究这种蛋白质的功能,为了解细胞在健康和疾病中的工作方式带来了新的水平,并为开发新药提供了知识。Tetraspanins是一种膜蛋白,通过与广泛的其他膜蛋白和可溶性蛋白相互作用来发挥功能,从而影响细胞的信号、相互作用、改变形状和移动的方式。值得注意的是,Tetraspanins还参与了多种疾病的感染过程。然而,由于目前还没有已知的全长Tetraspanin家族成员的结构,所以Tetraspanins在这些重要过程中的作用方式还不清楚,这给我们的细胞生物学知识留下了一个巨大的空白。获得任何膜蛋白的结构都是一个重大的科学挑战:必须将蛋白质从细胞膜上移除,这往往会导致蛋白质变得非常不稳定,以至于它不能用于制造进行X射线结晶学所需的晶体。因此,我们对许多具有重要生物学功能的膜蛋白家族知之甚少。我们现在已经克服了Tetraspanin CD81的结晶挑战。人CD81是Tetraspanin家族中最被理解的成员之一,也是我们拟议的研究的主题。它在细胞如何相互作用、免疫反应和受精方面发挥着既定的作用。值得注意的是,CD81是一些非常重要的人类病原体的受体,包括流感、人类免疫缺陷病毒、疟疾寄生虫、T细胞嗜淋巴病毒1型和丙型肝炎病毒。它也可能是肿瘤的促进剂。CD81功能的核心(以及所有Tetraspanins的功能)是它与自身和其他蛋白质形成广泛相互作用的能力;然而,我们不知道这些结构是什么样子,因此缺乏进一步研究的框架,如上所述。我们提案中概述的研究的第一个目的是解决CD81的三维结构。我们已经朝着这个目标取得了很好的进展,已经结晶了CD81并收集了X射线衍射数据。我们还与法国的科学家合作,他们可以制造出结合CD81的丙型肝炎病毒蛋白E2的可溶性形式。我们项目的第二个目标是制作一个丙型肝炎病毒-E2/CD81复合体,这样我们就可以表征它并解决它的结构;这将使我们能够更多地了解CD81如何与其他蛋白质相互作用。我们相信我们是世界上唯一一个拥有所有工具来应对这一挑战的团队。结构生物学(例如高分辨率电子显微镜)的全新发展使我们能够设计第三个目标,即(通过电子断层扫描)观察细胞膜中的这些结构,将我们的原子级结构数据与细胞中实际发生的事情联系起来。在这种细节水平上研究CD81的结构将使我们能够开始了解河豚毒素如何在健康和疾病中发挥作用。
项目成果
期刊论文数量(8)
专著数量(0)
科研奖励数量(0)
会议论文数量(0)
专利数量(0)
The synthesis of recombinant membrane proteins in yeast for structural studies.
- DOI:10.1016/j.ymeth.2015.09.027
- 发表时间:2016-02
- 期刊:
- 影响因子:4.8
- 作者:S. Routledge;Lina Mikaliunaite;Anjana Patel;Michelle Clare;Stephanie P. Cartwright;Z. Bawa;Martin D B Wilks;F. Low;D. Hardy;A. Rothnie;R. Bill
- 通讯作者:S. Routledge;Lina Mikaliunaite;Anjana Patel;Michelle Clare;Stephanie P. Cartwright;Z. Bawa;Martin D B Wilks;F. Low;D. Hardy;A. Rothnie;R. Bill
A new panel of epitope mapped monoclonal antibodies recognising the prototypical tetraspanin CD81.
- DOI:10.12688/wellcomeopenres.12058.1
- 发表时间:2017
- 期刊:
- 影响因子:0
- 作者:Grove J;Hu K;Farquhar MJ;Goodall M;Walker L;Jamshad M;Drummer HE;Bill RM;Balfe P;McKeating JA
- 通讯作者:McKeating JA
Membrane Protein Production in the Yeast P. pastoris.
毕赤酵母中的膜蛋白生产。
- DOI:10.1007/978-1-0716-2368-8_10
- 发表时间:2022
- 期刊:
- 影响因子:0
- 作者:Ayub H
- 通讯作者:Ayub H
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Roslyn Bill其他文献
Evaluation of antifoams in the expression of a recombinant FC fusion protein in shake flask cultures of Saccharomyces cerevisiae &Pichia pastoris
- DOI:
10.1186/1475-2859-5-s1-p30 - 发表时间:
2006-01-01 - 期刊:
- 影响因子:4.900
- 作者:
William Holmes;Rodney Smith;Roslyn Bill - 通讯作者:
Roslyn Bill
Characterising the surface activity of recombinant pulmonary surfactant proteins SP-B and SP-C together with synthetic analogues: Potential tear film supplements
- DOI:
10.1016/j.clae.2018.03.025 - 发表时间:
2018-06-01 - 期刊:
- 影响因子:
- 作者:
Val Franklin;Aiman Gulamhussein;Anjana Patel;Alice Rothnie;Brian Tighe;Roslyn Bill - 通讯作者:
Roslyn Bill
Progress towards recombinant synthesis of pulmonary surfactant proteins SP-B and SP-C
- DOI:
10.1016/j.clae.2018.04.096 - 发表时间:
2018-06-01 - 期刊:
- 影响因子:
- 作者:
Anjana Patel;Roslyn Bill;Brian Tighe - 通讯作者:
Brian Tighe
Roslyn Bill的其他文献
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{{ truncateString('Roslyn Bill', 18)}}的其他基金
FORTIFY - From Molecular Physiology to Biophysics of the Glymphatic System: a Regulatory Role for Aquaporin-4
FORTIFY - 从类淋巴系统的分子生理学到生物物理学:Aquaporin-4 的调节作用
- 批准号:
EP/Y023684/1 - 财政年份:2024
- 资助金额:
$ 44.5万 - 项目类别:
Research Grant
Setting up a core facility for the production and purification of recombinant membrane proteins as a service to research institutions and industry
建立重组膜蛋白生产和纯化的核心设施,为研究机构和工业界提供服务
- 批准号:
BB/S004696/1 - 财政年份:2018
- 资助金额:
$ 44.5万 - 项目类别:
Research Grant
Canada: Membrane protein technologies for drug discovery
加拿大:用于药物发现的膜蛋白技术
- 批准号:
BB/P025927/1 - 财政年份:2017
- 资助金额:
$ 44.5万 - 项目类别:
Research Grant
Cascade processes for integrated bio-refining of agricultural waste in India and Vietnam
印度和越南农业废弃物综合生物精炼级联工艺
- 批准号:
BB/P022685/1 - 财政年份:2017
- 资助金额:
$ 44.5万 - 项目类别:
Research Grant
The expression, modification and enhancement of protein therapeutics
蛋白质疗法的表达、修饰和增强
- 批准号:
DT/F00270X/1 - 财政年份:2008
- 资助金额:
$ 44.5万 - 项目类别:
Research Grant
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