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The molecular basis for ribophorin I function during N-glycosylation

N-糖基化过程中核糖蛋白 I 功能的分子基础

基本信息

批准号：
BB/G000948/1
负责人：
Stephen High
金额：
$ 45.6万
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：
2008
资助国家：
英国
起止时间：
2008 至无数据
项目状态：
已结题

来源：
https://gtr.ukri.org/projects?ref=BB%2FG000948%2F1
关键词：
molecular basis ribophorin function during

项目摘要

The proteins that form the key building blocks of the cells that make up our bodies are often modified by the attachment of sugars or glycans forming so called glycoproteins. One common and important class of glycoprotein is the 'N-linked' variety, and many of these molecules are essential for life playing important roles related to development and good health. The oligosaccharyltransferase (OST) complex is the biological machine that adds N-linked glycans to proteins whilst they are being made inside the cell. Whilst the oligosaccharyltransferase of higher organisms is a large enzyme complex with a number of different components or subunits, bacteria have a much simpler enzyme with only one subunit that appears to perform a similar role. Such comparisons have led us to question the function of the various extra subunits of the human oligosaccharyltransferase machinery, and in particular to ask how one particular additional subunit, called ribophorin I, might act to alter or improve the production of glycoproteins. We recently discovered that ribophorin I acts as a non-catalytic subunit of the mammalian oligosaccharyltransferase. In practice this means that whilst ribophorin I is essential for the N-glycosylation of some proteins, may others do not need ribophorin I at all. We propose a model where the oligosaccharyltransferase complex has a central machine called the STT3 protein, and suggest that it is this component that does the actual 'work' of N-glycosylation. The role of ribophorin I would then be to assist this central machine by somehow helping unusual or difficult proteins to be delivered to the STT3 protein correctly and in a way that allows them to be efficiently glycosylated. The aim of this project is to investigate exactly what ribophorin I does and to establish how it carries out its role as part of this larger machine. To do this we will answer two fundamental questions: firstly, what are the properties of a protein that mean it needs the help of ribophorin I in order to be properly N-glycosylated; and secondly, how does ribophorin I actually assist the core STT3 subunit so that these proteins can be dealt with efficiently by the oligosaccharyltransferase complex?

构成我们身体细胞关键组成部分的蛋白质通常通过附着糖或聚糖进行修饰，形成所谓的糖蛋白。一类常见且重要的糖蛋白是“N-连接”品种，其中许多分子对于生命至关重要，在发育和健康方面发挥着重要作用。寡糖转移酶 (OST) 复合物是一种生物机器，可在细胞内制造蛋白质时将 N-连接聚糖添加到蛋白质中。高等生物的寡糖转移酶是一种具有许多不同成分或亚基的大型酶复合物，而细菌则具有一种简单得多的酶，只有一个亚基似乎发挥着类似的作用。这种比较使我们对人类寡糖转移酶机制的各种额外亚基的功能产生疑问，特别是询问一种称为核糖蛋白 I 的特定额外亚基如何发挥作用来改变或改善糖蛋白的产生。我们最近发现核糖蛋白 I 作为哺乳动物寡糖转移酶的非催化亚基。实际上，这意味着虽然核糖蛋白 I 对于某些蛋白质的 N-糖基化至关重要，但其他蛋白质可能根本不需要核糖蛋白 I。我们提出了一个模型，其中寡糖转移酶复合物有一个称为 STT3 蛋白的中央机器，并表明正是这个组件完成了 N-糖基化的实际“工作”。核糖蛋白 I 的作用就是通过某种方式帮助异常或困难的蛋白质正确地传递到 STT3 蛋白质，并以允许它们有效糖基化的方式来协助这个中央机器。该项目的目的是准确研究核糖蛋白 I 的作用，并确定它作为这个更大机器的一部分如何发挥其作用。为此，我们将回答两个基本问题：首先，蛋白质的哪些特性意味着它需要核糖蛋白 I 的帮助才能正确进行 N-糖基化？其次，核糖蛋白 I 实际上如何协助核心 STT3 亚基，以便寡糖转移酶复合物能够有效处理这些蛋白质？