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24  structures 2066  species 2  interactions 3765  sequences 4  architectures

Family: NGF (PF00243)

Summary: Nerve growth factor family

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This is the Wikipedia entry entitled "Neurotrophin". More...

Neurotrophin Edit Wikipedia article

Neurotrophin
3BUK.pdb.png
Identifiers
Symbol NGF
Pfam PF00243
InterPro IPR002072
PROSITE PDOC00221
SCOP 1bet
SUPERFAMILY 1bet

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 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 each specific for different neurotrophins. The reported structure above is a 2.6 Å-resolution crystal structure of neurotrophin-3 (NT-3) complexed to the ectodomain of glycosylated p75 (NRT), forming a symmetrical crystal structure.

Receptors

There are two classes of receptors for neurotrophins: p75 and the "Trk" family of Tyrosine kinases receptors.[10]

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

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. Exercise has been shown to increase the amount of BDNF and therefore serve as a vehicle for neuroplasticity.[11]

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

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. 
  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. 
  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. 
  4. ^ Neurotrophins at the US National Library of Medicine Medical Subject Headings (MeSH)
  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. 
  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. ^ 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. 
  11. ^ Exercise builds brain health: key roles of growth factor cascades and inflammation by Carl W. Cotman, Nicole C. Berchtold and Lori-Ann Christie http://scholar.google.com/scholar?cluster=11830727319998892361&hl=en&as_sdt=0,10
  12. ^ "Entrez database entry for NT-4/5". NCBI. 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'
  • Neurotrophins at the US National Library of Medicine Medical Subject Headings (MeSH)
  • [1] - Neurotrophin-3 image

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

This page is based on a Wikipedia article. The text is available under the Creative Commons Attribution/Share-Alike License.

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Nerve growth factor family Provide feedback

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External database links

This tab holds annotation information from the InterPro database.

InterPro entry IPR002072

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:

                                    +------------------------+
                                    |                        |
                                    |                        |
        xxxxxxCxxxxxxxxxxxxxxxxxxxxxCxxxxCxxxxxCxxxxxxxxxxxxxCxCxxxx
              |                          |     |               |
              +--------------------------|-----+               |
                                         +---------------------+
'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].

Gene Ontology

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Domain organisation

Below is a listing of the unique domain organisations or architectures in which this domain is found. More...

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Pfam Clan

This family is a member of clan Cystine-knot (CL0079), which has the following description:

The cytokine families in this clan have the cystine-knot fold. In this 6 cysteines form three disulphide bridges that are interlinked.

The clan contains the following 9 members:

Coagulin Cys_knot DAN Hormone_6 NGF Noggin PDGF Sclerostin TGF_beta

Alignments

We store a range of different sequence alignments for families. As well as the seed alignment from which the family is built, we provide the full alignment, generated by searching the sequence database using the family HMM. We also generate alignments using four representative proteomes (RP) sets, the NCBI sequence database, and our metagenomics sequence database. More...

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  Seed
(7)
Full
(3765)
Representative proteomes NCBI
(2860)
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(0)
RP15
(12)
RP35
(21)
RP55
(45)
RP75
(107)
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Format an alignment

  Seed
(7)
Full
(3765)
Representative proteomes NCBI
(2860)
Meta
(0)
RP15
(12)
RP35
(21)
RP55
(45)
RP75
(107)
Alignment:
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  Seed
(7)
Full
(3765)
Representative proteomes NCBI
(2860)
Meta
(0)
RP15
(12)
RP35
(21)
RP55
(45)
RP75
(107)
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Gzipped Download   Download   Download   Download   Download   Download   Download    

You can also download a FASTA format file containing the full-length sequences for all sequences in the full alignment.

External links

MyHits provides a collection of tools to handle multiple sequence alignments. For example, one can refine a seed alignment (sequence addition or removal, re-alignment or manual edition) and then search databases for remote homologs using HMMER3.

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Trees

This page displays the phylogenetic tree for this family's seed alignment. We use FastTree to calculate neighbour join trees with a local bootstrap based on 100 resamples (shown next to the tree nodes). FastTree calculates approximately-maximum-likelihood phylogenetic trees from our seed alignment.

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Curation and family details

This section shows the detailed information about the Pfam family. You can see the definitions of many of the terms in this section in the glossary and a fuller explanation of the scoring system that we use in the scores section of the help pages.

Curation View help on the curation process

Seed source: Prosite
Previous IDs: none
Type: Domain
Author: Finn RD
Number in seed: 7
Number in full: 3765
Average length of the domain: 90.40 aa
Average identity of full alignment: 67 %
Average coverage of the sequence by the domain: 44.04 %

HMM information View help on HMM parameters

HMM build commands:
build method: hmmbuild -o /dev/null HMM SEED
search method: hmmsearch -Z 23193494 -E 1000 --cpu 4 HMM pfamseq
Model details:
Parameter Sequence Domain
Gathering cut-off 21.3 21.3
Trusted cut-off 21.3 21.7
Noise cut-off 21.0 20.5
Model length: 116
Family (HMM) version: 13
Download: download the raw HMM for this family

Species distribution

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Interactions

There are 2 interactions for this family. More...

TNFR_c6 NGF

Structures

For those sequences which have a structure in the Protein DataBank, we use the mapping between UniProt, PDB and Pfam coordinate systems from the PDBe group, to allow us to map Pfam domains onto UniProt sequences and three-dimensional protein structures. The table below shows the structures on which the NGF domain has been found. There are 24 instances of this domain found in the PDB. Note that there may be multiple copies of the domain in a single PDB structure, since many structures contain multiple copies of the same protein seqence.

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