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Defining the architecture of the endosome-specific ESCRT-I complex

定义内体特异性 ESCRT-I 复合物的结构

基本信息

批准号：
BB/K008773/1
负责人：
Philip Woodman
金额：
$ 50.86万
依托单位：
University of Manchester
依托单位国家：
英国
项目类别：
Research Grant
财政年份：
2013
资助国家：
英国
起止时间：
2013 至无数据
项目状态：
已结题

来源：
https://gtr.ukri.org/projects?ref=BB%2FK008773%2F1
关键词：
Defining architecture endosome specific ESCRT

项目摘要

The behaviour of cells within a tissue is controlled by their environment. Amongst the most important signals that cells receive are from circulating small proteins called growth factors. These bind to specific proteins, called receptors, which are found on the surface of cells. Binding of growth factors alters the shape of receptors (the receptor is turned 'on'), and this in turn changes the pattern of interactions between receptors and many molecules inside the cell that control cell growth and division. In this way growth factor receptors act as essential bridges between the cell exterior and interior to stimulate so-called mitogenic, or growth, responses. In order to prevent these responses continuing endlessly, which would lead to uncontrolled cell division, the growth factor receptor must be sent to an environment where it can be permanently turned 'off'. Ultimately, it is sent to a specialised compartment within the cell, called the lysosome, where it is destroyed. Movement of the receptor from the cell surface to the lysosome involves the receptor being sequestered into regions of the cell surface membrane that invaginate and pinch off to form spherical packages, or vesicles, within the cell interior. These vesicles first move to and coalesce with an intermediate compartment called the endosome, which is rather like a balloon. Importantly, the growth factor receptors are still active when they reach the endosome. To ensure they are stopped from working, they are enclosed within little vesicles that are forced within the inside of the endosome. This occurs by a process of inward budding, rather like poking deep impressions into a balloon and imagining these could pinch off to form internal packets. This process means that the mitogenic receptors are now completely separated away from the rest of the cell contents and unable to work. The endosome, along with these internal packages, is then sent to the lysosome.The aim of this project is to understand how activated mitogenic receptors, once they reach the endosome, are packaged into the interior of the compartment. The project will focus on examining the composition and shape of a group of proteins which assemble into a 'protein complex' that take part in this event. It is crucial, in order to understand how this protein complex works, to find out how it is assembled and which parts of the complex are able to reach out and grab the receptors, as well as those parts that bring additional important proteins and protein complexes to the site of receptor packaging. There is one additional important reason for providing accurate information about how this protein complex is assembled. Like many cellular proteins or protein complexes, several of its structural features are shared by proteins/protein complexes that are involved in completely different cellular activities. Therefore, providing very accurate information about what this protein complex looks like will help generate tools that can interfere with this and only this protein complex. This should be a real advantage when it comes to designing research tools or clinical tools that selectively modulate the activity of this complex and therefore influence mitogenic receptor lifetime but not other important cellular processes.

组织内细胞的行为受其环境控制。细胞接收的最重要的信号来自循环中的小蛋白质，称为生长因子。它们与细胞表面的特定蛋白质（称为受体）结合。生长因子的结合改变了受体的形状（受体被“打开”），这反过来又改变了受体与细胞内控制细胞生长和分裂的许多分子之间的相互作用模式。生长因子受体以这种方式充当细胞外部和内部之间的重要桥梁，以刺激所谓的促有丝分裂或生长反应。为了防止这些反应无休止地继续下去，这将导致不受控制的细胞分裂，生长因子受体必须被送到一个环境中，在那里它可以被永久关闭。最终，它被送到细胞内的一个专门的隔间，称为溶酶体，在那里它被破坏。受体从细胞表面到溶酶体的移动涉及受体被隔离到细胞表面膜的区域中，这些区域内陷并夹断以在细胞内部形成球形包装或囊泡。这些囊泡首先移动到一个叫做内体的中间室并与之结合，内体很像气球。重要的是，生长因子受体在到达内体时仍然是活性的。为了确保它们停止工作，它们被封闭在小泡内，这些小泡被迫进入内体内部。这是通过一个向内发芽的过程发生的，就像把深深的印象戳进气球里，想象这些印象可以收缩形成内部的包。这个过程意味着促有丝分裂受体现在完全与细胞内容物的其余部分分离，并且无法工作。内体，沿着这些内部包装，然后被送到溶酶体。这个项目的目的是了解激活的促有丝分裂受体，一旦他们到达内体，是如何包装到内部的隔室。该项目将重点研究一组蛋白质的组成和形状，这些蛋白质组装成参与这一事件的“蛋白质复合物”。为了了解这种蛋白质复合物是如何工作的，找出它是如何组装的，复合物的哪些部分能够伸出并抓住受体，以及那些将额外的重要蛋白质和蛋白质复合物带到受体包装部位的部分是至关重要的。还有一个重要的原因是提供关于这种蛋白质复合物如何组装的准确信息。像许多细胞蛋白质或蛋白质复合物一样，它的几个结构特征是由参与完全不同细胞活动的蛋白质/蛋白质复合物共享的。因此，提供关于这种蛋白质复合物外观的非常准确的信息将有助于生成可以干扰这种且仅干扰这种蛋白质复合物的工具。这应该是一个真实的优势，当涉及到设计的研究工具或临床工具，选择性地调节这种复合物的活性，因此影响促有丝分裂受体的寿命，但不影响其他重要的细胞过程。

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）

Dissecting the role of His domain protein tyrosine phosphatase/PTPN23 and ESCRTs in sorting activated epidermal growth factor receptor to the multivesicular body.

DOI：
10.1042/bst20170443
发表时间：
2018-10-19
期刊：
Biochemical Society transactions
影响因子：
3.9
作者：
Tabernero L;Woodman P
通讯作者：
Woodman P

The open architecture of HD-PTP phosphatase provides new insights into the mechanism of regulation of ESCRT function.

HD-PTP磷酸酶的开放结构为ESCRT功能调节机理提供了新的见解。

DOI：
10.1038/s41598-017-09467-9
发表时间：
2017-08-22
期刊：
Scientific reports
影响因子：
4.6
作者：
Gahloth D;Heaven G;Jowitt TA;Mould AP;Bella J;Baldock C;Woodman P;Tabernero L
通讯作者：
Tabernero L

Structural Basis for Selective Interaction between the ESCRT Regulator HD-PTP and UBAP1.

DOI：
10.1016/j.str.2016.10.006
发表时间：
2016-12-06
期刊：
STRUCTURE
影响因子：
5.7
作者：
Gahloth, Deepankar;Levy, Colin;Heaven, Graham;Stefani, Flavia;Wunderley, Lydia;Mould, Paul;Cliff, Matthew J.;Bella, Jordi;Fielding, Alistair J.;Woodman, Philip;Tabernero, Lydia
通讯作者：
Tabernero, Lydia

The molecular basis for selective assembly of the UBAP1-containing endosome-specific ESCRT-I complex.