Grant: Project Grant

Dependence receptors are cell surface receptors that determine cell fate dependent on the availability of their extracellular ligand, called Netrin-1 (NET1). Know functions of NET1 include cell guidance, adhesion and regulation of cell survival. We focus on the structure and function of NET1 and how it orchestrates its unique interactions with individual dependence receptors, such as UNC5 and DCC. Most remarkably, if the NET1-dependence receptor complex is interrupted- a programmed cell death is triggered. However, to date it is not known how NET1 orchestrates on a molecular level this complex set of signals. We aim to perform an integrated structural biology approach, combining protein X-ray crystallography in conjunction with SAXS, AUC/DLS/SEC-MALS and in-depth biochemical and functional assays. When combined, these tools create a detailed molecular understanding of how NET1 acts on its receptors, and how the activated receptors together work to influence the cell physiology. This research proposal aims to define the molecular basis of NET1-UNC5 and NET1-UNC5-DCC complex interactions and to unravel the structural basis for relevant signaling pathways. In these studies we will seek to develop new therapeutic targets with the overall goal to interrupt NET1-mediated dependence receptor complexes and thereby causing apoptosis in tumor cells.