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How does the cytosol reduce non-native disulfides formed in the endoplasmic reticulum?

细胞质如何减少内质网中形成的非天然二硫化物？

基本信息

批准号：
BB/P017665/1
负责人：
Neil Bulleid
金额：
$ 53.02万
依托单位：
University of Glasgow
依托单位国家：
英国
项目类别：
Research Grant
财政年份：
2017
资助国家：
英国
起止时间：
2017 至无数据
项目状态：
已结题

来源：
https://gtr.ukri.org/projects?ref=BB%2FP017665%2F1
关键词：
How does cytosol reduce non

项目摘要

The ability of cells to correctly fold and assemble proteins is the final stage in protein synthesis. Protein folding requires a subset of proteins able to either catalyse folding reactions or act as molecular chaperones preventing non-productive protein aggregation and cell stress. The inability of cells to carry out the folding process results in cell death and consequently some of the most catastrophic disease pathologies such as diabetes, Alzheimer's and Parkinson's.For cells and tissues to remain healthy they must be able to make proteins and the proteins they make must be able to function correctly. The cell has complex machinery for ensuring that when new proteins are made they are functional and are transported to the correct location, be it within the cell or outside. This project will determine one crucial process that allows proteins to be made efficiently and be delivered outside the cell and, in particular, how this process breaks down during disease. The production and delivery of proteins can be summarised into two key stages: i) ensuring proteins are made correctly and adopt the correct shape, ii) transport of the proteins from the inside to the outside of the cell.Proteins are made as a string of amino acids which coil-up or fold to adopt a characteristic shape or three-dimensional structure. Only one such shape is functional and the cell ensures that this shape is adopted by providing helper proteins or chaperones to aid this process. If cells are unable to correctly fold proteins then disease results. For the secreted proteins to function they need to be robust and to ensure this is the case they form links within the protein to tie the protein together. These links are called disulfide bonds. Without these bonds the proteins would not function and would not be secreted. We know very little about how incorrect linkages are removed. This project will investigate how the correct bonds are formed. Our group wants to understand in detail how cells provide the correct environment to allow proteins to fold and to form the correct disulfide bonds to ensure their stability. To understand how cells fold and assemble proteins we are studying this process in mammalian cells using a combination of cell biological and biochemical techniques.

细胞正确折叠和组装蛋白质的能力是蛋白质合成的最后阶段。蛋白质折叠需要能够催化折叠反应或作为分子伴侣防止非生产性蛋白质聚集和细胞应激的蛋白质子集。细胞无法进行折叠过程导致细胞死亡，从而导致一些最灾难性的疾病病理，如糖尿病，阿尔茨海默氏症和帕金森氏症。细胞和组织要保持健康，它们必须能够制造蛋白质，并且它们制造的蛋白质必须能够正确发挥作用。细胞具有复杂的机制，以确保当新蛋白质产生时，它们是功能性的，并被运送到正确的位置，无论是在细胞内还是细胞外。该项目将确定一个关键的过程，使蛋白质能够有效地制造并在细胞外传递，特别是在疾病期间这个过程如何分解。蛋白质的生产和输送可以概括为两个关键阶段：i）确保蛋白质正确地合成并采用正确的形状，ii）将蛋白质从细胞内部运输到细胞外部。蛋白质是由一串氨基酸组成，这些氨基酸卷曲或折叠以采用特征形状或三维结构。只有一个这样的形状是功能性的，细胞通过提供辅助蛋白或伴侣蛋白来帮助这一过程，以确保这种形状被采用。如果细胞不能正确折叠蛋白质，就会导致疾病。为了使分泌的蛋白质发挥作用，它们需要是稳健的，并且为了确保这一点，它们在蛋白质内形成连接以将蛋白质连接在一起。这些连接被称为二硫键。如果没有这些键，蛋白质将无法发挥功能，也无法分泌。我们对如何消除不正确的联系知之甚少。本项目将研究如何形成正确的债券。我们的团队希望详细了解细胞如何提供正确的环境，使蛋白质折叠并形成正确的二硫键，以确保其稳定性。为了了解细胞如何折叠和组装蛋白质，我们正在使用细胞生物学和生物化学技术相结合的方法研究哺乳动物细胞中的这一过程。

项目成果

期刊论文数量（10）

专著数量（0）

科研奖励数量（0）

会议论文数量（0）

专利数量（0）

How Are Proteins Reduced in the Endoplasmic Reticulum?

DOI：
10.1016/j.tibs.2017.10.006
发表时间：
2018-01
期刊：
Trends in biochemical sciences
影响因子：
13.8
作者：
Ellgaard L;Sevier CS;Bulleid NJ
通讯作者：
Bulleid NJ

Methionine sulfoxide reductase B3 requires resolving cysteine residues for full activity and can act as a stereospecific methionine oxidase.

蛋氨酸亚氧化亚氧化物还原酶B3需要解决半胱氨酸残基以进行全活性，并且可以作为立体特异性蛋氨酸氧化酶。

DOI：
10.1042/bcj20170929
发表时间：
2018-02-28
期刊：
The Biochemical journal
影响因子：
0
作者：
Cao Z;Mitchell L;Hsia O;Scarpa M;Caldwell ST;Alfred AD;Gennaris A;Collet JF;Hartley RC;Bulleid NJ
通讯作者：
Bulleid NJ

The Mammalian Cytosolic Thioredoxin Reductase Pathway Acts via a Membrane Protein to Reduce ER-localised Proteins

哺乳动物细胞质硫氧还蛋白还原酶途径通过膜蛋白减少内质网定位蛋白