Nerve growth factor in complex with its receptor, p75
Homo sapiens (human)
The development of the nervous system begins with the generation of specialized cells called neurons. A neuron is an extended cell with a long axon and branching dendrites that extend from its cell body. Axons and dendrites form profuse synapses of connections with other remote cells. The neurons communicate with these cells by sending signals through the synapses. Axons and dendrites grow out from neurons via growth cones. Growth cones follow specific pathways to their target tissues helped by various signal molecules along the way. On reaching the target tissue, only some of the neurons survive. The surviving number of neurons and their type is decided by the growth factors secreted by the target tissue. Neurotrophins are a family of secreted growth factors that are crucial for the development and maintenance of the vertebrate nervous system. Nerve growth factor (NGF) is one such neurotrophin. The presence of NGF results in the survival of sympathetic neurons and those that have originated from the neural crest. NGF also regulates the outgrowth of axons and dendrites, promoting or preventing their extensive growth depending on its presence or absence, respectively. NGF is known to function by binding two different neural cell surface receptors, the p75 receptor and Trk tyrosine kinase receptors.
The structure above is that of an NGF dimer bound to a p75 receptor. The extracellular domain of p75 is seen as the long thin protein, into whose concave space, the smaller NGF dimer binds. An NGF dimer has 2 symmetrical p75 binding sites. However, the NGF homodimer binds a single p75 asymmetrically causing a conformational change in the other p75 binding site thus preventing the dimerization of the p75 receptors. The authors suggest that neurotrophin signaling through p75 could occur through the disassembly of p75 dimers as a result of the formation of 2:1 neurotrophin/p75 complexes. They also suggest the possibility of the 2:1 neurotrophin/p75 complex binding to a Trk receptor, thus forming a trimolecular signaling complex.
Protein Data Bank (PDB)
He, X.L. Garcia, K.C.; "Structure of nerve growth factor complexed with the shared neurotrophin receptor p75"; Science; (2004) 304:870-875 PubMed:15131306.
author: Ashwini Patil