Neurotrophin - Function

Function

During the development of the vertebrate nervous system, many neurons become redundant (because they have died, failed to connect to target cells, etc.) and are eliminated. At the same time, developing neurons send out axon outgrowths that contact their target cells. Such cells control their degree of innervation (the number of axon connections) by the secretion of various specific neurotrophic factors that are essential for neuron survival. One of these is nerve growth factor (NGF or beta-NGF), a vertebrate protein that stimulates division and differentiation of sympathetic and embryonic sensory neurons. NGF is mostly found outside the central nervous system (CNS), but slight traces have been detected in adult CNS tissues, although a physiological role for this is unknown. It has also been found in several snake venoms.

In the peripheral and central neurons, neurotrophins are important regulators for survival, differentiation, and maintenance of nerve cells. They are small proteins that secrete into the nervous system to help keep nerve cells alive. There are two distinct classes of glycosylated receptors that can bind to neurotrophins. These two proteins are p75 (NTR), which binds to all neurotrophins, and subtypes of Trk, which are only specific for each different neurotrophins. The reported structure above is a 2.6 Å-resolution crystal structure of neurotrophin-3 (NT-3) complex to the ectodomain of glycosylated p75 (NRT), forming a symmetrical crystal structure. This is different to other studies which shows a dimer of nerve growth factor (NGF) bound to a single ectodomain of deglycosylated p75(NTR), resulting in an asymmetrical crystal structure. The crystal structure of NT-3 shows that NT-3 forms a central homodimer around which two glycosylated p75 (NRT) molecules bind symmetrically. The symmetrical binding takes place along the NT-3 interfaces, resulting in a 2:2 ligand-receptor cluster in the center. The symmetrical and asymmetrical structures show that there is a significant difference in ligand-receptor interactions and p75 (NRT) conformations. This symmetrical complex indicates that p75(NRT) activates at the cell surface. In addition, this symmetrical crystal structure provides a model for NTs-p75(NTR) recognition and signal generation, as well as insights into coordination between p75(NTR) and Trks.