Mechanisms of membrane pore formation

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The amino acid sequence of a protein, determined by its genetic code, defines the structure and function of the protein. Usually, the native (correct) protein structure is unique, and is the most stable form for that particular protein. There are two distinct environments in which proteins are stable: water-soluble proteins are found in solution in cells and tissues, but membrane proteins are found in the oil-like layers of cellular membranes. Soluble proteins are much easier to work with and are much better understood than membrane proteins. Although membrane proteins play important roles in many key cellular functions such as detection and response to signals from the environment, communication between cells, and uptake of nutrients, only a tiny number of three-dimensional structures of membrane proteins are known in comparison to those of soluble proteins. The surface properties of soluble and membrane proteins are very different. A very interesting class of proteins break the general rule that proteins are either water-soluble or inserted into membranes. The bacterial toxins and certain proteins of the immune system are synthesised as individual, water-soluble proteins but in the course of their function, they assemble into rings that penetrate cell membranes and puncture holes through their target membranes. In the case of bacterial toxins, the role of such toxins is to release nutrients for the bacteria, incidentally killing the host cell. In the immune system, pore forming proteins are secreted in the course of immune surveillance when infected or cancerous cells are detected, in order to kill them. Thus, pore-forming proteins have evolved as part of the 'armaments race' between organisms and their pathogens. In this project, we are studying the structures of the pores formed by the bacterial toxin pneumolysin, an important factor in pneumonia and other diseases, and also by the immune system protein perforin, essential for the immune response to maintain the health of the organism. The pores are bound to model membranes, and we can study them by recording images of rapidly frozen suspensions of these membranes in an electron microscope. With suitable computer image processing we can determine their three-dimensional structures, which will give us an understanding of how these proteins change their shape and properties so dramatically, and how the membrane is punctured.