Hacking the molecular logic of clathrin coat formation

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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.