Structure/function studies of a cyclomodulin

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Proteins are a biological molecules encoded by a gene, and they are the molecular machines of life. Proteins form a complex 3-dimensional structure that frequently determines their function. A protein's function is usually dependent on interaction with another molecule and this interaction leads to an effect. The experiments described in this proposal aim to investigate the structure and function of a protein from pathogenic bacteria that is able to change the properties of the host cell during infection. Specifically this protein, called 'Cif' interferes with progression of the host cell cycle (process of growth and division), irreversibly stopping it in its tracks. Although it is not currently understood why, this presumably has some benefit for the invading bacteria. Studying proteins such as this is important for both understanding host-pathogen interactions (the molecular causes of disease) and the host cell processes themselves. For instance, a deregulated cell cycle is often linked to development of cancer, and proteins that regulate the cell cycle are one of the most targeted set of molecules by the pharmaceutical industry. How Cif actually brings about its effect in host cells is not currently understood. One powerful approach to determining how this protein functions is to look at its structure. This can be visualised using a technique called X-ray crystallography followed by reconstruction of a model using computer graphics. Once the structure is known alterations to the protein can be designed to further investigate protein function in host cells. Also important for understanding Cif function is identifying the protein's molecular targets within host cells (most likely other proteins), characterising the interaction (how strongly do they bind to each other?), and ultimately determining the structure of molecules together. This would generate a picture of a bacterial protein interacting with a host cell protein, and a complex responsible for transducing an effect ultimately leading to host cell cycle arrest. Understanding the nature of these interactions for Cif has long-term applications for development of novel therapeutics targeting host-pathogen interactions and also carcinogenesis.