Macromolecular structures of receptor -ligand complexes from developmental neurobiology and cancer biology.

摘要

Growth factors play a critical role in the development, maturation, maintenance, and programmed cell death of most cells. For the developing nervous system, one family that bears these responsibilities is the neurotrophins. How the neurotrophins orchestrate these activities depends on the receptor proteins with which they interact. One major aim of my research is to better understand the activation process of the neurotrophins and their receptors by studying their atomic structures. I investigated the neurotrophin called neurotrophin-3, which plays a major role in the development of the peripheral nervous system and neural crest cells.;One process triggered by growth factors is remodeling the shape of the cell, for example to grow in a certain direction. This process appears to be controlled by a cell surface molecule called the urokinase receptor (uPAR). Like other receptors, uPAR sends a signal when activated by a ligand, in this case a protease called urokinase; this signal then informs the cell to reshape itself and migrate. Urokinase is a protease that can cut basement membrane and extracellular matrix, especially when restrained to the surface of a cell by uPAR. Cancerous cells appear to maliciously use these mechanisms to invade into blood vessels and metastasize.;Using X-ray crystallography, I solved the structure of neurotrophin-3 (NT-3) to 2.4 A. The structure can be compared to those of other neurotrophins to clarify how NT-3 interacts specifically with its receptor. I also determined the low-resolution structure of uPAR with urokinase, which helps us understand how cells make use of this signaling system.