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 [ (PUBMED:2369898) ]. 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 [ (PUBMED:3589669) (PUBMED:8488558) ]. 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 [ (PUBMED:2369898) ]; it has also been found in several snake venoms [ (PUBMED:1477101) (PUBMED:1995338) ].
NGF is a protein of about 120 residues that is cleaved from a larger precursor molecule. It contains six cysteines all involved in intrachain disulphide bonds. A schematic representation of the structure of NGF is shown below:
'C': conserved cysteine involved in a disulphide bond.
This entry also contains NGF-related proteins such as neutrophin 3, which promotes the survival of visceral and proprioceptive sensory neurons, and brain-derived neurotrophin, which promotes the survival of neuronal populations that are located either in the central nervous system or directly connected to it [ (PUBMED:2236018) (PUBMED:8527932) ].
Nerve growth factor: from neurotrophin to neurokine.
Trends Neurosci. 1996; 19: 514-20
Display abstract
Nerve growth factor (NGF) is largely known as a target-derived factor responsible for the survival and maintenance of the phenotype of specific subsets of peripheral neurones and basal forebrain cholinergic nuclei during development and maturation. However, NGF also exerts a modulatory role on sensory, nociceptive nerve physiology during adulthood that appears to correlate with hyperalgesic phenomena occurring in tissue inflammation. Other NGF-responsive cells are now recognized as belonging to the haemopoietic-immune system and to populations in the brain involved in neuroendocrine functions. The concentration of NGF is elevated in a number of inflammatory and autoimmune states in conjunction with an increased accumulation of mast cells. Mast cells and NGF appear to be involved in neuroimmune interactions and tissue inflammation, with NGF acting as a general 'alert' molecule capable of recruiting and priming tissue defence processes following insult as well as systemic defensive mechanisms. Moreover, mast cells themselves produce NGF, suggesting that alterations in normal mast cell behaviours can provoke maladaptive neuroimmune tissue responses whose consequences could have profound implications in inflammatory disease states. This review discusses recent discoveries involving novel and diverse biological activities of this fascinating molecule.
Nerve growth factor (NGF), which has a tertiary structure based on a cluster of 3 cystine disulfides and 2 very extended, but distorted beta-hairpins, is the prototype of a larger family of neurotrophins. Prior to the availability of cloning techniques, the mouse submandibular gland was the richest source of NGF and provided sufficient material to enable its biochemical characterization. It binds as a dimer to at least 2 cell-surface receptor types expressed in a variety of neuronal and non-neuronal cells. Residues involved in these interactions and in the maintenance of tertiary and quaternary structure have been identified by chemical modification and site-directed mutagenesis, and this information can be related to their location in the 3-dimensional structure. For example, interactions between aromatic residues contribute to the stability of the NGF dimer, and specific surface lysine residues participate in receptor contacts. The conclusion from these studies is that receptor interactions involve broad surface regions, which may be composed of residues from both promoters in the dimer.
Recent studies on nerve growth factor have revealed important new insights into the structure, function and evolution of this prototypical neurotrophic factor. Some of its features are (1) it has a unique three-dimensional fold that has since been found in two other growth factors, (2) it uses the trk proto-oncogene product, which has a tyrosine kinase, as a receptor and (3) it shares homology with at least three other factors, now collectively called neurotrophins, which have a spectrum of target cells.
Topological similarities in TGF-beta 2, PDGF-BB and NGF define a superfamily of polypeptide growth factors.
Structure. 1993; 1: 153-9
Display abstract
BACKGROUND: The development of functional diversity through gene duplication and subsequent divergent evolution can give rise to proteins that have little or no sequence similarity, but retain similar topologies. RESULTS: The crystal structures of nerve growth factor, transforming growth factor-beta 2 and platelet-derived growth factor-BB show that all three are based on a cystine-knot plus beta-strands topology. There is very little sequence identity between the three proteins and the relationship between the structures had not been deduced from sequence comparisons. Each growth factor is usually active as a dimer; each exists as a dimer in the crystal, but the relative orientations of the protomers are different in each case. CONCLUSION: The structural motif of disulphide bonds and hydrogen-bonded beta-strands unexpectedly found in these three growth factors acts as a stable framework for elaboration of loops of low sequence similarity that contain the specificity for receptor interaction.
This information is based on mapping of SMART genomic protein database to KEGG orthologous groups. Percentage points are related to the number of proteins with NGF domain which could be assigned to a KEGG orthologous group, and not all proteins containing NGF domain. Please note that proteins can be included in multiple pathways, ie. the numbers above will not always add up to 100%.
