Phosphodependent helix switches in cellular signalling

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Cells must be able to respond to changes in the human body. They grow, divide, change their shape and sometimes even die as the body requires. The millions of individual molecules that make up a cell contribute to the cell's response, and their individual actions are coordinated through an intricate cellular messaging system. One of the most common types of message is chemical modification of proteins, the presence of which may affect the location, stability or activity of that protein. The modification can also be detected by other proteins, which can then pass on the message. By analogy with written messages, the protein that carries out the modification is called a 'writer' and the protein that detects modification is called a 'reader'. Perhaps the most common modification is phosphorylation, which is written by a family of proteins called kinases, of which there are more than 500 in humans. Phosphorylation is commonly used to pass on the message that a cell is prepared to reproduce, and reaches a peak as a cell is just about to divide. Several different reader proteins are known to read the phosphorylation message. They recognize the shape and electrical charge of the phosphate group and the features of a region of the protein surrounding it. Alternatively, phosphorylation can alter the shape of the protein, and this new shape is then recognized by a reader. We recently discovered an example that works through a simple mechanism: a protein that has a fluctuating, undefined shape becomes a helix when it is phosphorylated. The helix is a rigid shape that fits into the groove of a specific reader protein. Strikingly, the molecular and structural features of the protein that are involved in helix formation are also required for the kinase to bind and phosphorylate it. Analysis of other proteins that are subject to phosphorylation suggests that this might cause many of them to form a helix. We now aim to clarify the details of what features of a protein are needed for phosphorylation to switch it from a dynamic shape to a defined helical shape. Based on this analysis, we will predict which other proteins are most likely to be switched, carry out experiments to test the predictions, and identify how they are read. Finally, we will use these insights to develop chemicals that block the interaction of the phosphorylated protein and its reader (chemical inhibitors). This will help us to understand what happens to cancer cells when the binding is blocked - in other words when the message is not passed on. If the interaction is essential for cancer cells to divide, the chemical inhibitors could be studied further for development into new cancer therapies.