Hacking the molecular logic of clathrin coat formation

每一个细胞都被它的质膜所包围。这是一个保护屏障，控制什么可以进入或离开。大分子（货物）可以通过网格蛋白介导的内吞作用进入细胞。这通常是通过细胞表面的受体抓住货物，然后在内部形成一个由称为网格蛋白的蛋白质组成的“坑”来实现的。凹坑加深，最终发芽，在细胞内形成一个微小的传递气泡，称为网格蛋白包被的囊泡。这个过程已经被科学家们研究了很多，因为它对细胞做的很多事情都非常重要：它们如何进食，分裂和移动。它也被一些病毒劫持，以便它们获得访问并感染细胞！如果我们能够控制这个过程，我们就能够做一些事情，比如将药物送入细胞，或者通过操纵内吞作用来改变细胞的运动或分裂方式。阻碍我们这么做的是谜题中缺失的一块：网格蛋白是如何组装核的。我们已经弄清楚了一种蛋白质，它提供了从受体到网格蛋白的联系，如何影响组装;我们还开发了控制这一事件的方法。然而，人类有超过10种这样的蛋白质，它们可能以不同的方式工作。在这个项目中，我们想了解这些天然蛋白质在胞吞作用中如何工作的规则。然后，我们将使用这些信息来设计一种高效的合成蛋白质。这将使我们能够尽快组装网格蛋白包被的囊泡。这种“超级内吞”系统将被用来通过改变内吞作用来操纵细胞生物学，并将外源分子送入细胞。

Every cell is enclosed by its plasma membrane. This is a protective barrier that controls what can enter or leave. Large molecules (cargo) can get into the cell using clathrin-mediated endocytosis. This works typically by a receptor on the cell surface grabbing hold of cargo and then a "pit" made of a protein called clathrin forming on the inside. The pit deepens and eventually buds off to make a tiny delivery bubble inside the cell called a clathrin-coated vesicle. This process has been studied a lot by scientists, because it is very important for lots of things that cells do: how they eat, divide and move. It is also hijacked by some viruses so that they gain access and infect the cell! If we could control this process, we would be able to do things like sending medicines into the cell or changing how cells move or divide by manipulating endocytosis. What is stopping us from doing this is a missing piece of the puzzle: how clathrin assembles the pit. We have worked out how one protein, which provides a link from the receptor to clathrin, influences the assembly; and we have also developed ways to control this event. However humans have more than ten of these proteins, and they probably work in different ways. In this project we want to understand the rules of how these natural proteins work during endocytosis. We will then use this information to design a synthetic protein that works with very high efficiency. This will allow us to assemble clathrin-coated vesicles as quickly as possible. This "super endocytosis" system will be used to manipulate cell biology by changing endocytosis and also to send foreign molecules into cells.