Probing the interplay of substrate and lipid interactions in the mechanism of a transporter family linked to age-related metabolic diseases and cancer

点击翻译按钮获取中文摘要

Advances in healthcare practices and technology have increased human lifespan, but increased longevity correlates with an increase in age-related diseases, including diabetes, obesity and cancer. These chronic diseases have life-changing effects on patients and are an enormous burden on our health services.Age-related diseases such as those named above are closely linked with cellular metabolism. In fact, symptoms can often be alleviated by reducing the number of calories consumed in the diet (termed caloric restriction). Caloric restriction has been shown to reverse age-related diseases and prolong the life of many different species, including primates, suggesting these benefits could also be extended to humans. For the human body to use nutrients from the diet, the nutrients have to be transported from the bloodstream into cells, where they are processed for energy production and the synthesis of cellular components. Nutrient uptake is performed by proteins called transporters that exist in the cell membrane, which is the greasy, oil-like barrier between the inside of the cell and the environment. Transporters are miniature molecular machines that "pump" chemicals across the cell membrane using an energy source provided by the cell. As with any pump, cutting it off from its energy source or jamming up the mechanism will stop it from functioning.Citrate is a key nutrient for normal metabolism and fat production in humans, and is transported into cells by a protein called INDY, which stands for I'm not dead yet because disruption of INDY function in fruitflies doubles their lifespan. In mice, disrupting INDY protects them from diabetes and obesity. Therefore, drugs that stop human INDY transporter proteins from functioning properly could be used to treat age-related metabolic diseases and promote healthy ageing.The aim of this study is to understand how INDY transporters are able recognise different chemical compounds, and how they harness an energy source to power movement of these chemicals across the cell membrane. In understanding how they work, we can design chemical inhibitors that could cut off the energy supply or act as molecular spanners in the works of these molecular machines. To develop drugs that target INDY proteins we need to know what these proteins look like, how they recognise the nutrients they transport, how the energy source is harnessed, and how the natural environment, i.e. the oil-like membrane, influences the activity of these transporters. Using a wide variety of complementary experimental approaches, we will address these gaps in our knowledge, which will give us a profound understanding of how these proteins work at a fundamental level, and will lay the foundation for the development of INDY specific drugs in the future.