Characterisation of GLUT4 glycan-lectin interactions

A major action of insulin is to increase the rate of glucose transport into fat and muscle. This is achieved through regulated trafficking of the facilitative glucose transporter GLUT4, and is defective in individuals suffering from insulin-resistance and Type-2 diabetes. Understanding the molecular mechanisms that underlie GLUT4 trafficking therefore represents an important step in the development of rational therapies for these disease states. Research in this area has focused on information contained within the protein sequence of GLUT4 with far less attention being paid to the role of post translational modifications received by the transporter, in particular the single N-linked carbohydrate moiety carried by GLUT4. This represents an important knowledge gap as clinical studies have implicated a role for circulating serum lectins (glycan-binding proteins) in the development of insulin-resistance. This project builds on our recent exciting discovery that GLUT4’s glycan contains an unusual monosaccharide. This holds great potential as a therapeutic target to modulate surface levels of GLUT4 as a mechanism to ameliorate insulin-resistance. To unlock this potential we propose to investigate the structure of GLUT4’s glycan and how this is used by various lectins to regulate levels of GLUT4 at the cell surface.