| ABC (ATP binding cassette) transporters catalyze the transport of a wide variety of molecules across lipid bilayers into or out of cells and organelles. Knowledge of their structure and mechanism is important not only from a basic point of view, but also because they have a huge impact on human health. Various genetic diseases are caused by defective ABC transporters (e.g. cystic fibrosis). Other ABC transporters pump drugs out of cells and are responsible for multidrug resistance of cancer cells and pathogenic bacteria. Here, I propose to study the structure and mechanism of a new type of ABC transporter, which transports vitamins and other compounds needed in trace amounts, into cells. The proteins have an exceptional design and require a novel type of integral membrane protein to bind their substrates. For each substrate a different substrate-binding protein is required, but the same translocator may be used. The unusual design will allow the study mechanistic details (such as lateral gating) that are difficult to study in classical ABC transporters, and will help to answer outstanding fundamental questions about their molecular mechanism. A combination of microbiological, biochemical and biophysical methods (including crystallography) is proposed to characterize the new and unconventional vitamin uptake systems. The work is expected to lead to a better understanding of the mechanism of ABC transporters in general. Furthermore, the new family of transporters is found in prokaryotes only, and is particularly abundant in pathogenic organisms. Because transport of vitamins is often essential in these organisms the proteins may be targets for antibiotics development. |
