Defining the architecture of the endosome-specific ESCRT-I complex

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The behaviour of cells within a tissue is controlled by their environment. Amongst the most important signals that cells receive are from circulating small proteins called growth factors. These bind to specific proteins, called receptors, which are found on the surface of cells. Binding of growth factors alters the shape of receptors (the receptor is turned 'on'), and this in turn changes the pattern of interactions between receptors and many molecules inside the cell that control cell growth and division. In this way growth factor receptors act as essential bridges between the cell exterior and interior to stimulate so-called mitogenic, or growth, responses. In order to prevent these responses continuing endlessly, which would lead to uncontrolled cell division, the growth factor receptor must be sent to an environment where it can be permanently turned 'off'. Ultimately, it is sent to a specialised compartment within the cell, called the lysosome, where it is destroyed. Movement of the receptor from the cell surface to the lysosome involves the receptor being sequestered into regions of the cell surface membrane that invaginate and pinch off to form spherical packages, or vesicles, within the cell interior. These vesicles first move to and coalesce with an intermediate compartment called the endosome, which is rather like a balloon. Importantly, the growth factor receptors are still active when they reach the endosome. To ensure they are stopped from working, they are enclosed within little vesicles that are forced within the inside of the endosome. This occurs by a process of inward budding, rather like poking deep impressions into a balloon and imagining these could pinch off to form internal packets. This process means that the mitogenic receptors are now completely separated away from the rest of the cell contents and unable to work. The endosome, along with these internal packages, is then sent to the lysosome.The aim of this project is to understand how activated mitogenic receptors, once they reach the endosome, are packaged into the interior of the compartment. The project will focus on examining the composition and shape of a group of proteins which assemble into a 'protein complex' that take part in this event. It is crucial, in order to understand how this protein complex works, to find out how it is assembled and which parts of the complex are able to reach out and grab the receptors, as well as those parts that bring additional important proteins and protein complexes to the site of receptor packaging. There is one additional important reason for providing accurate information about how this protein complex is assembled. Like many cellular proteins or protein complexes, several of its structural features are shared by proteins/protein complexes that are involved in completely different cellular activities. Therefore, providing very accurate information about what this protein complex looks like will help generate tools that can interfere with this and only this protein complex. This should be a real advantage when it comes to designing research tools or clinical tools that selectively modulate the activity of this complex and therefore influence mitogenic receptor lifetime but not other important cellular processes.