THE PHYSIOLOGICAL ROLE OF CLATHRIN LIGHT CHAIN DIVERSITY IN VERTEBRATES. (360G-Wellcome-107858_Z_15_Z)

Cells respond to their environment in tissues and blood using proteins on their surfaces called receptors. Through binding extracellular molecules, receptors send internal signals that control whether a cell should multiply, absorb nutrients and/or produce hormones. This research defines molecular properties of an intracellular protein, clathrin, which forms a network to capture receptors from the cell surface for removal into the cell interior. This process regulates cellular metabolism and gro wth, as well as immune and nerve cell function through influencing how the cell receives signals from the outside. Clathrin is formed by two components called clathrin heavy chain (CHC) and clathrin light chain (CLC). In vertebrates, including humans, multiple types (isoforms) of CLCs combine with one type of CHC to form different types of clathrin in tissues that have specific isoforms. CLCs regulate formation and strength of the clathrin network. Using protein chemistry, cell biology and mouse genetics, we will define the differential contributions of CLC isoforms to these clathrin properties and their influence on which receptors are selected as cargo for clearance from the surface of different tissues. These studies define physiological functions of clathrin relevant to such diseases as diabetes, cancer, hypercholesterolemia, neurological or developmental defects, and infection.