Summary: Neuregulin intracellular region
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Neuregulin Edit Wikipedia article
Structure of the epidermal growth factor-like domain of heregulin-alpha, a ligand for p180erbB-4.
|SCOPe||1hrf / SUPFAM|
Neuregulins or neuroregulins are a family of four structurally related proteins that are part of the EGF family of proteins. These proteins have been shown to have diverse functions in the development of the nervous system and play multiple essential roles in vertebrate embryogenesis including: cardiac development, Schwann cell and oligodendrocyte differentiation, some aspects of neuronal development, as well as the formation of neuromuscular synapses.
Included in the family are heregulin; neu differentiation factor; acetylcholine receptor synthesis stimulator; glial growth factor; and sensory and motor-neuron derived factor. Multiple family members are generated by alternate splicing or by use of several cell type-specific transcription initiation sites. In general, they bind to and activate the erbB family of receptor tyrosine kinases (erbB2 (HER2), erbB3 (HER3), and erbB4 (HER4)), functioning both as heterodimers and homodimers.
Neuregulin family members
The neuregulin family includes:
- Neuregulin-1 (NRG1), with numerous discovered isoforms stemming from alternative splicing:
- Type I NRG1; alternative names: Heregulin, NEU differentiation factor (NDF), or acetylcholine receptor inducing activity (ARIA)
- Type II NRG1; alternative name: Glial Growth Factor-2 (GGF2);
- Type III NRG1; alternative name: Sensory and motor neuron-derived factor (SMDF);
- Type IV NRG1;
- Type V NRG1;
- Type VI NRG1; Types IV-VI are proteins with 3 novel N-terminal domains identified in 2004.
- Neuregulin-2 (NRG2);
- Neuregulin-3 (NRG3);
- Neuregulin-4 (NRG4);
The transmembrane forms of neuregulin 1 (NRG1) are present within synaptic vesicles, including those containing glutamate. After exocytosis, NRG1 is in the presynaptic membrane, where the ectodomain of NRG1 may be cleaved off. The ectodomain then migrates across the synaptic cleft and binds to and activates a member of the EGF-receptor family on the postsynaptic membrane. This has been shown to increase the expression of certain glutamate-receptor subunits. NRG1 appears to signal for glutamate-receptor subunit expression, localization, and /or phosphorylation facilitating subsequent glutamate transmission.
The NRG1 gene has been identified as a potential gene determining susceptibility to schizophrenia by a combination of genetic linkage and association approaches.
ARIA plays a role in synapse development, influencing the upregulation of acetylcholine receptor genes beneath the endplate after mammalian motor neurons have made synaptic contact with muscle fibres, hence its name ARIA = Acetylcholine Receptor Inducing Activity.
A study done on mice in early 2009 has indicated that when neuregulin-1\ErbB signalling is disrupted, the dendritic spines of neurons grow but do not fully form. This produced no immediate noticeable changes to brain development, but in adults there was a reduction of dendritic spines on neurons. Glutamatergic signalling was markedly disrupted in the mice as a result of the experiment.
In fish, birds, and earthworms
NRG-1,2,3 have been found in fish and birds.
mRNA similar to mammalian Pro-NRG2 precursor has been found in humus earthworm Lumbricidae.
- Nagata K, Kohda D, Hatanaka H, et al. (August 1994). "Solution structure of the epidermal growth factor-like domain of heregulin-alpha, a ligand for p180erbB-4". EMBO J. 13 (15): 3517â€“23. PMC 395255. PMID 8062828.
- Vartanian T, Fischbach G, Miller R (1999). "Failure of spinal cord oligodendrocyte development in mice lacking neuregulin". Proc. Natl. Acad. Sci. U.S.A. 96 (2): 731â€“5. doi:10.1073/pnas.96.2.731. PMC 15205. PMID 9892702.
- Yarden Y, Burden S (1997). "Neuregulins and their receptors: a versatile signaling module in organogenesis and oncogenesis". Neuron. 18 (6): 847â€“55. doi:10.1016/S0896-6273(00)80324-4. PMID 9208852.
- Schroering A, Carey DJ (1998). "Sensory and motor neuron-derived factor is a transmembrane heregulin that is expressed on the plasma membrane with the active domain exposed to the extracellular environment". J. Biol. Chem. 273 (46): 30643â€“50. doi:10.1074/jbc.273.46.30643. PMID 9804837.
- Steinthorsdottir V, Stefansson H, Ghosh S, Birgisdottir B, Bjornsdottir S, Fasquel AC, Olafsson O, Stefansson K, Gulcher JR (2004). "Multiple novel transcription initiation sites for NRG1". Gene. 342 (1): 97â€“105. doi:10.1016/j.gene.2004.07.029. PMID 15527969.
- Lemke G, Zhou M, Ghosh S, Harvey RP, Gulcher JR, Stefansson K, Gurney ME, Stefansson H, Sigurdsson E, Steinthorsdottir V, Bjornsdottir S, Sigmundsson T, Brynjolfsson J, Gunnarsdottir S, Ivarsson O, Chou TT, Hjaltason O, Birgisdottir B, Jonsson H, Gudnadottir VG, Gudmundsdottir E, Bjornsson A, Ingvarsson B, Ingason A, Sigfusson S, Hardardottir H, Lai D, Brunner D, Mutel V, Gonzalo A, Sainz J, Johannesson G, Andresson T, Gudbjartsson D, Manolescu A, Frigge ML, Kong A, Petursson H (2002). "Neuregulin 1 and susceptibility to schizophrenia". Am. J. Hum. Genet. 71 (4): 877â€“892. doi:10.1086/342734. PMC 378543. PMID 12145742.
- "How Microscopic Changes To Brain Cause Schizophrenic Behavior In Mice".
- Barros CS, Calabrese B, Chamero P, Roberts AJ, Korzus E, Lloyd K, Stowers L, Mayford M, Halpain S, MÃ¼ller U (February 2009). "Impaired maturation of dendritic spines without disorganization of cortical cell layers in mice lacking NRG1/ErbB signaling in the central nervous system". Proc. Natl. Acad. Sci. U.S.A. 106 (11): 4507â€“4512. doi:10.1073/pnas.0900355106. PMC 2657442. PMID 19240213.
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Neuregulin intracellular region Provide feedback
No Pfam abstract.
External database links
This tab holds annotation information from the InterPro database.
InterPro entry IPR002154
Neuregulins are a sub-family of EGF-like molecules that have been shown to play multiple essential roles in vertebrate embryogenesis including: cardiac development, Schwann cell and oligodendrocyte differentiation, some aspects of neuronal development, as well as the formation of neuromuscular synapses [PUBMED:9892702, PUBMED:9208852]. Included in the family are heregulin; neu differentiation factor; acetylcholine receptor synthesis stimulator; glial growth factor; and sensory and motor-neuron derived factor [PUBMED:9804837]. Multiple family members are generated by alternate splicing or by use of several cell type-specific transcription initiation sites. In general, they bind to and activate the erbB family of receptor tyrosine kinases (erbB2 (HER2), erbB3 (HER3), and erbB4 (HER4)), functioning both as heterodimers and homodimers.
The transmembrane forms of neuregulin 1 (NRG1) are present within synaptic vesicles, including those containing glutamate [PUBMED:12145742]. After exocytosis, NRG1 is in the presynaptic membrane, where the ectodomain of NRG1 may be cleaved off. The ectodomain then migrates across the synaptic cleft and binds to and activates a member of the EGF-receptor family on the postsynaptic membrane. This has been shown to increase the expression of certain glutamate-receptor subunits. NRG1 appears to signal for glutamate-receptor subunit expression, localisation, and /or phosphorylation facilitating subsequent glutamate transmission.
The NRG1 gene has been identified as a potential gene determining susceptibility to schizophrenia by a combination of genetic linkage and association approaches [PUBMED:12145742].
Membrane-anchored Nrg-1 isoforms consist of a variable N-terminal extracellular domain and a conserved transmembrane and C-terminal cytoplasmic domains [PUBMED:12821646]. This entry represents the C-terminal, intracellular domain.
Below is a listing of the unique domain organisations or architectures in which this domain is found. More...
The graphic that is shown by default represents the longest sequence with a given architecture. Each row contains the following information:
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We make a range of alignments for each Pfam-A family. You can see a description of each above. You can view these alignments in various ways but please note that some types of alignment are never generated while others may not be available for all families, most commonly because the alignments are too large to handle.
1Cannot generate PP/Heatmap alignments for seeds; no PP data available
Key: available, not generated, — not available.
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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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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.
|Author:||Mian N , Bateman A|
|Number in seed:||12|
|Number in full:||1001|
|Average length of the domain:||296.60 aa|
|Average identity of full alignment:||52 %|
|Average coverage of the sequence by the domain:||51.80 %|
|HMM build commands:||
build method: hmmbuild -o /dev/null HMM SEED
search method: hmmsearch -Z 47079205 -E 1000 --cpu 4 HMM pfamseq
|Family (HMM) version:||16|
|Download:||download the raw HMM for this family|
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This visualisation provides a simple graphical representation of the distribution of this family across species. You can find the original interactive tree in the More....
This chart is a modified "sunburst" visualisation of the species tree for this family. It shows each node in the tree as a separate arc, arranged radially with the superkingdoms at the centre and the species arrayed around the outermost ring.
How the sunburst is generated
The tree is built by considering the taxonomic lineage of each sequence that has a match to this family. For each node in the resulting tree, we draw an arc in the sunburst. The radius of the arc, its distance from the root node at the centre of the sunburst, shows the taxonomic level ("superkingdom", "kingdom", etc). The length of the arc represents either the number of sequences represented at a given level, or the number of species that are found beneath the node in the tree. The weighting scheme can be changed using the sunburst controls.
In order to reduce the complexity of the representation, we reduce the number of taxonomic levels that we show. We consider only the following eight major taxonomic levels:
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There are some situations that the sunburst tree cannot easily handle and for which we have work-arounds in place.
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Some species in the taxonomic tree may not have one or more of the main eight levels that we display. For example, Bos taurus is not assigned an order in the NCBI taxonomic tree. In such cases we mark the omitted level with, for example, "No order", in both the tooltip and the lineage summary.
Unmapped species names
The tree is built by looking at each sequence in the full alignment for the family. We take the name of the species given by UniProt and try to map that to the full taxonomic tree from NCBI. In some cases, the name chosen by UniProt does not map to any node in the NCBI tree, perhaps because the chosen name is listed as a synonym or a misspelling in the NCBI taxonomy.
So that these nodes are not simply omitted from the sunburst tree, we group them together in a separate branch (or segment of the sunburst tree). Since we cannot determine the lineage for these unmapped species, we show all levels between the superkingdom and the species as "uncategorised".
Since we reduce the species tree to only the eight main taxonomic levels, sequences that are mapped to the sub-species level in the tree would not normally be shown. Rather than leave out these species, we map them instead to their parent species. So, for example, for sequences belonging to one of the Vibrio cholerae sub-species in the NCBI taxonomy, we show them instead as belonging to the species Vibrio cholerae.
Too many species/sequences
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The tree shows the occurrence of this domain across different species. More...
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For all of the domain matches in a full alignment, we count the number that are found on all sequences in the alignment. This total is shown in the purple box.
We also count the number of unique sequences on which each domain is found, which is shown in green. Note that a domain may appear multiple times on the same sequence, leading to the difference between these two numbers.
Finally, we group sequences from the same organism according to the NCBI code that is assigned by UniProt, allowing us to count the number of distinct sequences on which the domain is found. This value is shown in the pink boxes.
We use the NCBI species tree to group organisms according to their taxonomy and this forms the structure of the displayed tree. Note that in some cases the trees are too large (have too many nodes) to allow us to build an interactive tree, but in most cases you can still view the tree in a plain text, non-interactive representation. Those species which are represented in the seed alignment for this domain are highlighted.
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