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Defining factors that ensure unidirectionality of endocytosis

确保胞吞作用单向性的定义因素

基本信息

批准号：
BB/J017094/1
负责人：
Kathryn Ayscough
金额：
$ 62.03万
依托单位：
University of Sheffield
依托单位国家：
英国
项目类别：
Research Grant
财政年份：
2012
资助国家：
英国
起止时间：
2012 至无数据
项目状态：
已结题

来源：
https://gtr.ukri.org/projects?ref=BB%2FJ017094%2F1
关键词：
Defining factors ensure unidirectionality endocytosis

项目摘要

Cells are the basic unit of life and all organisms are composed of one or more cells. These cells are covered in proteins that are embedded in their cell surface. This protein coat helps cells to perform certain functions such as responding to chemical messages. The coat also lets other cells recognise it. An analogy would be recognising groups of people according to the clothes they wear. However, sometimes a message that a cell receives tells it to behave differently. It therefore needs to remove elements of its protein coat. One of the ways that many cells do this is by a process of internalising some of the proteins from the coat. This protein internalisation is achieved by a process called endocytosis. The surface of the cell folds inwards in small portions and then pinches off inside the cell. This forms a small vesicle that can then carry the protein away inside the cell. Often the proteins get broken down and their most basic parts are released for re-use by the cell. In this way the parts of the coat that are not needed can be removed. At the same time, this process is often balanced by the addition of new proteins, which respond to different messages, to the cell surface. If the proteins are not removed properly because endocytosis is not functioning correctly, the cell could have proteins at the surface that send conflicting messages that may be detrimental to the well-being of the cell. Several diseases have been associated with defective endocytosis including Alzheimers, Huntingtons and cancer. In addition, several pathogens and toxins exploit the endocytic pathway to gain entry to cells. This project aims to use a simple system to understand how cells can take-up proteins from their surface. We are using a model organism called yeast because the molecules involved in the endocytic process are very similar to those in more complex human cells, but the yeast cells are much easier to manipulate to investigate the processes we are interested in. In particular we are trying to determine the mechanisms that ensure that once the internalisation process has begun, that it continues to completion. We know that the endocytosis process involves more than 50 proteins. Many of them form groups or complexes with one another, and then components of these groups interact with a single factor that is called Las17/WASP. We aim to test the idea that this particular protein acts as a ratchet in the endocytic process. By closely regulating the interactions of this one protein, the cell can ensure that interactions take place sequentially. Overall, we think that this might be the mechanism that ensures key stages of endocytosis proceed in a linear fashion rather than starting and then reversing or aborting before the invagination has completed and the membrane has pinched off inside the cell. We will use a wide range of techniques both inside and outside of the cell environment to investigate the interactions of Las17/WASP and to determine how these interactions are regulated to ensure endocytosis functions correctly.

细胞是生命的基本单位，所有生物体都是由一个或多个细胞组成的。这些细胞被嵌入其细胞表面的蛋白质覆盖。这种蛋白质外壳帮助细胞执行某些功能，例如对化学信息做出反应。这件外套也让其他细胞识别它，一个类比是根据人们穿的衣服来识别人群。然而，有时细胞收到的信息会告诉它采取不同的行为。因此，它需要去除其蛋白质外壳的元素。许多细胞这样做的方法之一是通过内化一些来自外壳的蛋白质。这种蛋白质的内化是通过一种称为内吞作用的过程实现的。细胞的表面向内折叠成小部分，然后在细胞内部夹断。这形成了一个小囊泡，然后可以将蛋白质带入细胞内。通常蛋白质被分解，它们最基本的部分被释放出来，供细胞重新使用。这样就可以去除不需要的部分。与此同时，这一过程通常通过向细胞表面添加新的蛋白质来平衡，这些蛋白质对不同的信息做出反应。如果由于内吞作用不能正常发挥作用而不能正确去除蛋白质，则细胞表面可能有蛋白质，这些蛋白质会发送可能对细胞健康有害的相互冲突的信息。有几种疾病与内吞作用缺陷有关，包括阿尔茨海默病、亨廷顿病和癌症。此外，一些病原体和毒素利用内吞途径进入细胞。该项目旨在使用一个简单的系统来了解细胞如何从其表面吸收蛋白质。我们正在使用一种称为酵母的模式生物，因为参与内吞过程的分子与更复杂的人类细胞中的分子非常相似，但酵母细胞更容易操纵，以研究我们感兴趣的过程。特别是，我们正在努力确定机制，以确保一旦内部化过程已经开始，它将继续完成。我们知道内吞过程涉及50多种蛋白质。它们中的许多彼此形成群体或复合体，然后这些群体的组成部分与称为Las 17/WASP的单一因素相互作用。我们的目标是测试这种特殊的蛋白质在内吞过程中充当棘轮的想法。通过密切调节这一蛋白质的相互作用，细胞可以确保相互作用顺序发生。总的来说，我们认为这可能是确保内吞作用的关键阶段以线性方式进行的机制，而不是在内陷完成和细胞膜在细胞内被夹断之前开始然后逆转或中止。我们将在细胞环境内外使用广泛的技术来研究Las 17/WASP的相互作用，并确定这些相互作用是如何调节的，以确保内吞功能正确。

项目成果

期刊论文数量（9）

专著数量（0）

科研奖励数量（0）

会议论文数量（0）

专利数量（0）

Distinct Actin and Lipid Binding Sites in Ysc84 Are Required during Early Stages of Yeast Endocytosis.

DOI：
10.1371/journal.pone.0136732
发表时间：
2015
期刊：
PloS one
影响因子：
3.7
作者：
Urbanek AN;Allwood EG;Smith AP;Booth WI;Ayscough KR
通讯作者：
Ayscough KR

Forty years on: clathrin-coated pits continue to fascinate.

DOI：
10.1091/mbc.e16-04-0213
发表时间：
2017-04-01
期刊：
Molecular biology of the cell
影响因子：
3.3
作者：
Maib H;Smythe E;Ayscough K
通讯作者：
Ayscough K

Elucidating Key Motifs Required for Arp2/3-Dependent and Independent Actin Nucleation by Las17/WASP.

DOI：
10.1371/journal.pone.0163177
发表时间：
2016
期刊：
PloS one
影响因子：
3.7
作者：
Allwood EG;Tyler JJ;Urbanek AN;Smaczynska-de Rooij II;Ayscough KR
通讯作者：
Ayscough KR

Yeast endocytic adaptor AP-2 binds the stress sensor Mid2 and functions in polarized cell responses.

DOI：
10.1111/tra.12155
发表时间：
2014-05
期刊：
Traffic (Copenhagen, Denmark)
影响因子：
0
作者：
Chapa-y-Lazo B;Allwood EG;Smaczynska-de Rooij II;Snape ML;Ayscough KR
通讯作者：
Ayscough KR

A dynamin-actin interaction is required for vesicle scission during endocytosis in yeast.

DOI：
10.1016/j.cub.2015.01.061
发表时间：
2015-03-30
期刊：
CURRENT BIOLOGY
影响因子：
9.2
作者：
Palmer, Sarah E.;Smaczynska-de Rooij, Iwona I.;Marklew, Christopher J.;Allwood, Ellen G.;Mishra, Ritu;Johnson, Simeon;Goldberg, Martin W.;Ayscough, Kathryn R.
通讯作者：
Ayscough, Kathryn R.