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

组织内细胞的行为受其所处环境的控制。细胞接收到的最重要的信号之一是来自循环中的称为生长因子的小蛋白。它们与特定的蛋白质结合，称为受体，存在于细胞表面。生长因子的结合改变了受体的形状(受体被打开)，这反过来又改变了受体与细胞内控制细胞生长和分裂的许多分子之间的相互作用模式。通过这种方式，生长因子受体充当了细胞外部和内部之间的重要桥梁，以刺激所谓的有丝分裂或生长反应。为了防止这些反应无休止地持续，这将导致不受控制的细胞分裂，必须将生长因子受体送到一个可以永久关闭的环境中。最终，它被送到细胞内的一个特殊的隔间，称为溶酶体，在那里它被摧毁。受体从细胞表面到溶酶体的运动涉及到受体被隔离到细胞表面膜的区域，这些区域内陷并被掐断，在细胞内部形成球形包或囊泡。这些囊泡首先移动到称为内小体的中间隔室，并与之结合，这很像气球。重要的是，当生长因子受体到达内体时，它们仍然是活跃的。为了确保它们停止工作，它们被封闭在迫使内体内部的小囊泡中。这是通过向内萌芽的过程发生的，就像在气球上戳进深刻的印象并想象这些印象可以被掐掉形成内部包一样。这一过程意味着有丝分裂受体现在与细胞内容物的其余部分完全分离，无法工作。这个项目的目的是了解激活的有丝分裂受体，一旦到达内吞体内，是如何被包装到隔室内部的。该项目将重点研究一组蛋白质的组成和形状，这些蛋白质组装成一个参与这一活动的“蛋白质复合体”。为了了解这种蛋白质复合体是如何工作的，找出它是如何组装的，复合体的哪些部分能够接触并抓住受体，以及那些将更多的重要蛋白质和蛋白质复合体带到受体包装位置的部分，这是至关重要的。提供有关这种蛋白质复合体如何组装的准确信息还有另一个重要原因。像许多细胞蛋白质或蛋白质复合体一样，它的一些结构特征是由参与完全不同细胞活动的蛋白质/蛋白质复合体共享的。因此，提供关于这个蛋白质复合体的非常准确的信息将有助于产生能够干扰这个并且只干扰这个蛋白质复合体的工具。当涉及到设计研究工具或临床工具时，这应该是一个真正的优势，这些工具可以选择性地调节这种复合体的活性，从而影响有丝分裂受体的寿命，但不影响其他重要的细胞过程。

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.