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Clathrin assembly regulation of glucose metabolism

网格蛋白组装调节葡萄糖代谢

基本信息

批准号：
BB/V001221/1
负责人：
Frances Martha Brodsky
金额：
$ 66.33万
依托单位：
University College London
依托单位国家：
英国
项目类别：
Research Grant
财政年份：
2021
资助国家：
英国
起止时间：
2021 至无数据
项目状态：
未结题

来源：
https://gtr.ukri.org/projects?ref=BB%2FV001221%2F1
关键词：
Clathrin assembly regulation glucose metabolism

项目摘要

Organs and tissues are made up of cells that must be able to respond to their environment in order to carry out many tasks, including regulating growth, fighting infection and controlling nutrition. A critical step in nutritional regulation is the ability to maintain blood sugar levels after eating. The body does this by moving a protein called GLUT4 in fat and muscle cells from within the cell to the cell's surface in response to insulin, which is released when blood sugar levels are high. GLUT4 acts to shuttle glucose (the form of sugar in the blood) into the cell, thereby reducing blood sugar levels. As such, in a fasting state, GLUT4 is retained inside the cell to prevent blood sugar levels becoming dangerously low, but is moved to the cell surface in response to the insulin released after you eat to prevent blood sugar levels becoming dangerously high. The GLUT4 is then moved back inside the cell when blood sugar levels have returned to normal. Disruption of this ability to control blood sugar levels can lead to diabetes. Key to controlling blood sugar levels, therefore, is the ability to move GLUT4 from its specialised storage site to the cell surface in response to insulin, and then remove it from the cell surface after enough glucose has been removed from the blood. For this, a protein called clathrin is critical. Named for its clathrate (lattice-like) structure, clathrin acts to ensure that a huge range of proteins are in the right place in the cell at any time. Multiple molecules of clathrin self-assemble into basket-like coats that form and wrap around 'vesicles' that pinch off from membranes and are then transported to another part of the cell, in a mechanism known as 'membrane trafficking'. There are two forms of clathrin. The originally discovered form, referred to as CHC17, is best known for a stage in membrane traffic called 'endocytosis', the process by which proteins are moved from the cell surface to the interior of the cell. More recently, a second form of clathrin, CHC22, has been identified and been shown to be involved in a separate process. Instead of functioning at the cell surface, CHC22 operates entirely within the cell to move GLUT4 to its storage compartment, from where it is able to respond to insulin. Therefore, both forms of clathrin are critical to ensure that GLUT4 is trafficked properly in response to changing blood sugar levels. Recently, it has been discovered that humans have evolved two different forms of CHC22, and these two variants change how individuals are able to respond to blood glucose levels.A key step in understanding clathrin function is to understand how clathrin self-assembles into coats. Here, two laboratories that have studied clathrin biology for many years are joined by two other experts in analysing the structures and interactions of proteins to answer this question. Thanks to exciting recent advances in the structural knowledge of clathrin led by one of the investigators collaborating here, detailed structures of CHC17 assemblies, including many key interacting points, are now known for the first time. This work aims to build on this knowledge to compare the contacts that are critical to assemblies of CHC17 and CHC22, and test how these contact points affect assembly rates of both clathrins. The structure of CHC22 assemblies is less well known than that of CHC17. This work aims to rectify that, and will determine the structures of the two major CHC22 variants. We will use this information to investigate how the regulation of clathrin assembly affects GLUT4 trafficking in response to insulin in cells. Therefore, this work will help to understand the mechanisms by which clathrin functions, which could in turn aid in the development of therapeutic strategies to help alter blood glucose clearance, for instance in diabetic patients.

器官和组织是由细胞组成的，细胞必须能够对环境做出反应，才能完成许多任务，包括调节生长、抵抗感染和控制营养。营养调节的关键一步是在进食后维持血糖水平的能力。身体通过将脂肪和肌肉细胞中的一种叫做GLUT4的蛋白质从细胞内部移动到细胞表面来响应胰岛素，当血糖水平高时，胰岛素就会释放出来。GLUT4的作用是将葡萄糖（血液中糖的一种形式）运送到细胞中，从而降低血糖水平。因此，在禁食状态下，GLUT4被保留在细胞内，以防止血糖水平降到危险的低水平，但在你吃东西后释放胰岛素，GLUT4被转移到细胞表面，以防止血糖水平降到危险的高水平。当血糖水平恢复正常时，GLUT4会被移回细胞内。这种控制血糖水平的能力被破坏会导致糖尿病。因此，控制血糖水平的关键是将GLUT4从其专门的储存位置移动到细胞表面以响应胰岛素的能力，然后在足够的葡萄糖从血液中移除后将其从细胞表面移除。为此，一种叫做网格蛋白的蛋白质至关重要。网格蛋白以其笼形（晶格状）结构而命名，其作用是确保大量蛋白质在任何时候都处于细胞中的正确位置。网格蛋白的多个分子自组装成篮状的外壳，形成并包裹在“囊泡”周围，这些囊泡从细胞膜上挤压下来，然后被运送到细胞的另一部分，这种机制被称为“膜运输”。网格蛋白有两种形式。最初发现的形式被称为CHC17，最著名的是在膜交通的一个阶段被称为“内吞作用”，蛋白质从细胞表面移动到细胞内部的过程。最近，第二种形式的网格蛋白CHC22被发现并被证明参与了一个单独的过程。CHC22不是在细胞表面起作用，而是完全在细胞内起作用，将GLUT4移动到它的储存室，从那里它能够对胰岛素作出反应。因此，这两种形式的网格蛋白对于确保GLUT4在血糖水平变化的情况下正常运输至关重要。最近，人们发现人类进化出了两种不同形式的CHC22，这两种变体改变了个体对血糖水平的反应。了解网格蛋白功能的关键一步是了解网格蛋白如何自组装成衣层。在这里，两个研究网格蛋白生物学多年的实验室与另外两位专家一起分析蛋白质的结构和相互作用来回答这个问题。由于其中一位研究人员在网格蛋白结构知识方面取得了令人兴奋的最新进展，CHC17组装体的详细结构，包括许多关键的相互作用点，现在首次为人所知。这项工作旨在建立在这些知识的基础上，比较对CHC17和CHC22组装至关重要的接触点，并测试这些接触点如何影响两种网格蛋白的组装率。与CHC17相比，CHC22的结构鲜为人知。这项工作旨在纠正这一点，并将确定两个主要CHC22变体的结构。我们将利用这些信息来研究网格蛋白组装的调节如何影响GLUT4运输以响应胰岛素在细胞中的作用。因此，这项工作将有助于了解网格蛋白的功能机制，从而有助于开发治疗策略，以帮助改变血糖清除，例如糖尿病患者。