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High-risk research

18 July 2003

Dr Paula Booth, in the Department of Biochemistry, recently won a Leverhulme Prize for her groundbreaking research. Part of that work was funded by a Wellcome Trust 'Showcase' grant, given specifically for innovative, high-risk research.

Proteins are the ‘worker’ molecules in all life forms, so an understanding of how proteins work is essential in the fight against disease. But certain kinds of proteins – ‘membrane’ proteins – are very difficult to study since it is almost impossible to replicate in the laboratory the conditions in which they exist in the body. If a protein normally lives in water, you can take it out of the cell and put it into water in a test tube in order to study it. As a result, we know the structure of thousands of water-soluble proteins, whereas our knowledge of the structure of membrane proteins is limited to about ten.

Membranes surround cells and subdivide them into compartments, to ensure that the right reactions happen at the right time. Membranes are made up of lipid (fatty) molecules and cholesterol. Embedded in the membranes, acting as communication channels between cells, are proteins which allow information and matter to pass across the membranes. But although membrane proteins represent some 30% of all proteins in our body – our nervous system, our heart rate, our vision are all controlled by them – we know very little about how they behave.

By devising such a simple ‘model’ membrane, Booth has overcome one of the major barriers to studying membrane proteins – a problem others have worked on for years

The membrane is a two-dimensional environment with water on either side. However, the salt concentration and other things in the water are different on each side. Furthermore, the part of the protein inside the membrane is surrounded by lipids and cholesterol. Clearly membrane proteins live in a very non-homogeneous environment and it is this that is so difficult to mimic outside the cell. But if the environment in which these proteins exist cannot be replicated, then it is impossible to study the protein itself outside the cell.

To address this dilemma, Booth devised some ground rules by approaching the problem in a very controlled way, using very simple systems. She asked the question: ‘What are the minimum components of a natural membrane that we can replicate in the lab?’ After months of hard work it appears that the deceptively simple answer was ‘two lipids’, into which she was able to insert a membrane protein. This highly simplified system has allowed her to control the behaviour of the membrane which will, in turn, control the behaviour of the protein.

By devising such a simple ‘model’ membrane, Booth has overcome one of the major barriers to studying membrane proteins – a problem others have worked on for years. Having proved the method on ‘model’ proteins from bacteria, her next objective is to extend this approach to proteins from our bodies that participate in controlling vision and heart rate – these particularly delicate proteins have proved very difficult to work with in the past. Ultimately this work will be of immense value in under-standing and preventing disease.

Dr Paula Booth / Department of Biochemistry

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