MEMSUGAR · Mechanism of Sugar Transporters involved in Human Health and Disease

From molds to mammals, glucose is the most important fuel for life on earth. The rate-limiting step for the utilization of glucose is its uptake into cells. Mammals have fourteen different sugar transporters belonging to the SLC2A family, referred to as GLUTs. GLUT1-14 transporters have varied tissue expression and kinetics, and their activities must be synchronized and regulated for the appropriate whole-organism-wide distribution of glucose and other sugars. Even at the most basic level, we still do not know the physiological substrates for a number of GLUT isoforms and if, or how, some members use proton-gradients to energize transport. Although GLUT transport activity is thought to be regulated through the binding of accessory factors, e.g., thioredoxin-interacting protein, we still have no molecular details for such interactions of high medical importance. Moreover, a major determinant of insulin resistance leading to type-2-diabetes is the impairment of insulin-stimulated GLUT4 trafficking. Despite extensive investigation, we still do not know what GLUT4 storage vesicles (GSVs) look like at the molecular level and how their composition changes in insulin resistance. Here, we will combine state-of-the-art methods to establish the physiological substrates for all GLUTs and develop tool compounds specific to each GLUT isoform to aid structural studies and for better assessing their contribution to metabolic reprogramming in cancer. We will combine NMR with cryo EM structures and computational and biochemical approaches to establish how protein dynamics dictates substrate specificity and proton coupling. We will resolve native-like structures of GLUT transporters directly from membranes and image GSVs using in situ cryo EM to build transport models beyond the individual transporters. By uncovering novel insight into a fundamental mechanism for life we will aid the development of drugs targeting GLUTs and other SLC transporters in general.