Clathrin assembly regulation of glucose metabolism

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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.