Neurotrophin

Neurotrophin
Identifiers
Symbol	NGF
Pfam	PF00243
InterPro	IPR002072
PROSITE	PDOC00221
SCOP	1bet
Available protein structures: Pfam structures PDB RCSB PDB; PDBe PDBsum structure summary

Neurotrophins are a family of proteins that induce the survival,^[1] development, and function^[2] of neurons.

They belong to a class of growth factors, secreted proteins that are capable of signaling particular cells to survive, differentiate, or grow.^[3] Growth factors such as neurotrophins that promote the survival of neurons are known as neurotrophic factors. Neurotrophic factors are secreted by target tissue and act by preventing the associated neuron from initiating programmed cell death - thus allowing the neurons to survive. Neurotrophins also induce differentiation of progenitor cells, to form neurons.

Although the vast majority of neurons in the mammalian brain are formed prenatally, parts of the adult brain (for example, the hippocampus) retain the ability to grow new neurons from neural stem cells^{[citation needed]}, a process known as neurogenesis. Neurotrophins are chemicals that help to stimulate and control neurogenesis.

Terminology

The term neurotrophin may be used as a synonym for neurotrophic factor,^[4] but the term neurotrophin is more generally reserved for four structurally related factors: nerve growth factor (NGF), brain-derived neurotrophic factor (BDNF), neurotrophin-3 (NT-3), and neurotrophin-4 (NT-4), with neurotrophic factor additionally referring to the GDNF family of ligands and ciliary neurotrophic factor (CNTF).^{[citation needed]}

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.^[5] 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.^[6][7] 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.^[5] It has also been found in several snake venoms.^[8][9]

In the peripheral and central neurons, neurotrophins are important regulators for suvival, 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.^[10]

Structure

NGF is a protein of about 120 residues that is cleaved from a larger precursor molecule. It contains six cysteines all involved in intrachain disulfide bonds. A schematic representation of the structure of NGF is shown below:

                                   +------------------------+
                                   |                        |
                                   |                        |
       xxxxxxCxxxxxxxxxxxxxxxxxxxxxCxxxxCxxxxxCxxxxxxxxxxxxxCxCxxxx
             |                          |     |               |
             +--------------------------|-----+               |
                                        +---------------------+

where 'C': conserved cysteine involved in a disulfide bond.

Receptors

Main article: Nerve growth factor receptor

There are two classes of receptors for neurotrophins: p75 and the "Trk" family of Tyrosine kinases receptors.^[11]

Types

Nerve growth factor

Main article: Nerve growth factor

Nerve growth factor (NGF), the prototypical growth factor, is a protein secreted by a neuron's target cell. NGF is critical for the survival and maintenance of sympathetic and sensory neurons. NGF is released from the target cells, binds to and activates its high affinity receptor TrkA on the neuron, and is internalized into the responsive neuron. The NGF/TrkA complex is subsequently trafficked back to the neuron's cell body. This movement of NGF from axon tip to soma is thought to be involved in the long-distance signaling of neurons^{[citation needed]}.

Brain-derived neurotrophic factor

Main article: Brain-derived neurotrophic factor

Brain-derived neurotrophic factor (BDNF) is a neurotrophic factor found originally in the brain, but also found in the periphery. To be specific, it is a protein that has activity on certain neurons of the central nervous system and the peripheral nervous system; it helps to support the survival of existing neurons, and encourage the growth and differentiation of new neurons and synapses through axonal and dendritic sprouting. In the brain, it is active in the hippocampus, cortex, cerebellum, and basal forebrain — areas vital to learning, memory, and higher thinking. BDNF is the second neurotrophic factor to be characterized, after NGF and before neurotrophin-3.

BDNF is one of the most active substances to stimulate neurogenesis. Mice born without the ability to make BDNF suffer developmental defects in the brain and sensory nervous system, and usually die soon after birth, suggesting that BDNF plays an important role in normal neural development.

Despite its name, BDNF is actually found in a range of tissue and cell types, not just the brain. Expression can be seen in the retina, the CNS, motor neurons, the kidneys, and the prostate.

Neurotrophin-3

Main article: Neurotrophin-3

Neurotrophin-3, or NT-3, is a neurotrophic factor, in the NGF-family of neurotrophins. It is a protein growth factor that has activity on certain neurons of the peripheral and central nervous system; it helps to support the survival and differentiation of existing neurons, and encourages the growth and differentiation of new neurons and synapses. NT-3 is the third neurotrophic factor to be characterized, after NGF and BDNF.

NT-3 is unique among the neurotrophins in the number of neurons it has potential to stimulate, given its ability to activate two of the receptor tyrosine kinase neurotrophin receptors (TrkC and TrkB). Mice born without the ability to make NT-3 have loss of proprioceptive and subsets of mechanoreceptive sensory neurons.

Neurotrophin-4

Main article: Neurotrophin-4

Neurotrophin-4 (NT-4) is a neurotrophic factor that signals predominantly through the TrkB receptor tyrosine kinase. It is also known as NT4, NT5, NTF4, and NT-4/5.^[12]

See also

• Neurotrophic electrode

References

1. ^ Hempstead BL (February 2006). "Dissecting the diverse actions of pro- and mature neurotrophins". Curr Alzheimer Res 3 (1): 19–24. doi:10.2174/156720506775697061. PMID 16472198. http://www.bentham-direct.org/pages/content.php?CAR/2006/00000003/00000001/005AT.SGM. 
2. ^ Reichardt LF (September 2006). "Neurotrophin-regulated signalling pathways". Philos. Trans. R. Soc. Lond., B, Biol. Sci. 361 (1473): 1545–64. doi:10.1098/rstb.2006.1894. PMC 1664664. PMID 16939974. http://journals.royalsociety.org/openurl.asp?genre=article&doi=10.1098/rstb.2006.1894. 
3. ^ Allen SJ, Dawbarn D (February 2006). "Clinical relevance of the neurotrophins and their receptors". Clin. Sci. 110 (2): 175–91. doi:10.1042/CS20050161. PMID 16411894. http://www.clinsci.org/cs/110/0175/cs1100175.htm. 
4. ^ MeSH Neurotrophins
5. ^ ^{a b} Hofer M, Pagliusi SR, Hohn A, Leibrock J, Barde YA (1990). "Regional distribution of brain-derived neurotrophic factor mRNA in the adult mouse brain". EMBO J. 9 (8): 2459–2464. PMC 552273. PMID 2369898. http://www.pubmedcentral.nih.gov/articlerender.fcgi?tool=pmcentrez&artid=552273. 
6. ^ Piatigorsky J, Wistow G (1987). "Recruitment of enzymes as lens structural proteins". Science 236 (4808): 1554–1556. doi:10.1126/science.3589669. PMID 3589669. 
7. ^ McDonald NQ, Blundell TL, Lapatto R, Murray-Rust J, Bradshaw RA (1993). "Nerve growth factor revisited". Trends Biochem. Sci. 18 (2): 48–52. doi:10.1016/0968-0004(93)90052-O. PMID 8488558. 
8. ^ Inoue S, Ikeda K, Hayashi K, Koyama J (1992). "Purification and amino-acid sequence of a nerve growth factor from the venom of Vipera russelli russelli". Biochim. Biophys. Acta 1160 (3): 287–292. doi:10.1016/0167-4838(92)90090-Z. PMID 1477101. 
9. ^ Oda T, Inoue S, Ikeda K, Hayashi K, Koyama J (1991). "Amino acid sequences of nerve growth factors derived from cobra venoms". FEBS Lett. 279 (1): 38–40. doi:10.1016/0014-5793(91)80244-W. PMID 1995338. 
10. ^ Gong Y, Cao P, Yu HJ, Jiang T (August 2008). "Crystal structure of the neurotrophin-3 and p75NTR symmetrical complex". Nature 454 (7205): 789–93. doi:10.1038/nature07089. PMID 18596692. 
11. ^ Arévalo JC, Wu SH (July 2006). "Neurotrophin signaling: many exciting surprises!". Cell. Mol. Life Sci. 63 (13): 1523–37. doi:10.1007/s00018-006-6010-1. PMID 16699811. 
12. ^ "Entrez database entry for NT-4/5". NCBI. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=gene&cmd=retrieve&dopt=default&list_uids=4909&rn=1. Retrieved 2007-05-07. 

External links

• DevBio.com - 'Neurotrophin Receptors: The neurotrophin family consists of four members: nerve growth factor (NGF), brain derived neurotrophic factor (BDNF), neurotrophin 3 (NT-3), and neurotrophin 4 (NT-4)' (April 4, 2003)
• Dr.Koop.com - 'New Clues to Neurological Diseases Discovered: Findings could lead to new treatments, two studies suggest', Steven Reinberg, HealthDay (July 5, 2006)
• Helsinki.fi - 'Neurotrophic factors'
• MeSH Neurotrophins
• [1] - Neurotrophin-3 image

This article includes text from the public domain Pfam and InterPro IPR002072