Summary: Agrin NtA domain
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Agrin Edit Wikipedia article
|, CMS8, CMSPPD, agrin|
|Agrin NtA domain|
|SCOPe||1jc7 / SUPFAM|
Agrin is a large proteoglycan whose best-characterised role is in the development of the neuromuscular junction during embryogenesis. Agrin is named based on its involvement in the aggregation of acetylcholine receptors during synaptogenesis. In humans, this protein is encoded by the AGRN gene.
This protein has nine domains homologous to protease inhibitors. It may also have functions in other tissues and during other stages of development. It is a major proteoglycan component in the glomerular basement membrane and may play a role in the renal filtration and cell-matrix interactions.
Agrin was first identified by the U.J. McMahan laboratory, Stanford University.
Mechanism of action
During development in humans, the growing end of motor neuron axons secrete a protein called agrin. When secreted, agrin binds to several receptors on the surface of skeletal muscle. The receptor which appears to be required for the formation of the neuromuscular junction (NMJ) is called the MuSK receptor (Muscle specific kinase). MuSK is a receptor tyrosine kinase - meaning that it induces cellular signaling by causing the addition of phosphate molecules to particular tyrosines on itself and on proteins that bind the cytoplasmic domain of the receptor.
The requirement for Agrin and MuSK in the formation of the NMJ was demonstrated primarily by knockout mouse studies. In mice that are deficient for either protein, the neuromuscular junction does not form. Many other proteins also comprise the NMJ, and are required to maintain its integrity. For example, MuSK also binds a protein called "dishevelled" (Dvl), which is in the Wnt signalling pathway. Dvl is additionally required for MuSK-mediated clustering of AChRs, since inhibition of Dvl blocks clustering.
The nerve secretes agrin, resulting in phosphorylation of the MuSK receptor.
A protein called rapsyn is then recruited to the primary MuSK scaffold, to induce the additional clustering of acetylcholine receptors (AChR). This is thought of as the secondary scaffold. A protein called Dok-7 has shown to be additionally required for the formation of the secondary scaffold; it is apparently recruited after MuSK phosphorylation and before acetylcholine receptors are clustered.
There are three potential heparan sulfate (HS) attachment sites within the primary structure of agrin, but it is thought that only two of these actually carry HS chains when the protein is expressed.
In fact, one study concluded that at least two attachment sites are necessary by inducing synthetic agents. Since agrin fragments induce acetylcholine receptor aggregation as well as phosphorylation of the MuSK receptor, researchers spliced them and found that the variant did not trigger phosphorylation. It has also been shown that the G3 domain of agrin is very plastic, meaning it can discriminate between binding partners for a better fit.
Heparan sulfate glycosaminoglycans covalently linked to the agrin protein have been shown to play a role in the clustering of AChR. Interference in the correct formation of heparan sulfate through the addition of chlorate to skeletal muscle cell culture results in a decrease in the frequency of spontaneous acetylcholine receptor (AChR) clustering. It may be that rather than solely binding directly to the agrin protein core a number of components of the secondary scaffold may also interact with its heparan sulfate side-chains.
- GRCh38: Ensembl release 89: ENSG00000188157 - Ensembl, May 2017
- GRCm38: Ensembl release 89: ENSMUSG00000041936 - Ensembl, May 2017
- "Human PubMed Reference:". National Center for Biotechnology Information, U.S. National Library of Medicine.
- "Mouse PubMed Reference:". National Center for Biotechnology Information, U.S. National Library of Medicine.
- Rupp F, Payan DG, Magill-Solc C, Cowan DM, Scheller RH (May 1991). "Structure and expression of a rat agrin". Neuron. 6 (5): 811â€“23. doi:10.1016/0896-6273(91)90177-2. PMID 1851019.
- KrÃ¶ger S, SchrÃ¶der JE (October 2002). "Agrin in the developing CNS: new roles for a synapse organizer". News Physiol. Sci. 17 (5): 207â€“12. doi:10.1152/nips.01390.2002. PMID 12270958.
- Groffen AJ, Buskens CA, van Kuppevelt TH, Veerkamp JH, Monnens LA, van den Heuvel LP (May 1998). "Primary structure and high expression of human agrin in basement membranes of adult lung and kidney". Eur. J. Biochem. 254 (1): 123â€“8. doi:10.1046/j.1432-1327.1998.2540123.x. PMID 9652404.
- Tsen G, Halfter W, KrÃ¶ger S, Cole GJ (1995). "Agrin is a heparan sulfate proteoglycan". J Biol Chem. 270 (7): 3392â€“3399. doi:10.1074/jbc.270.7.3392. PMID 7852425.
- Groffen AJ, Ruegg MA, Dijkman H, van de Velden TJ, Buskens CA, van den Born J, Assmann KJ, Monnens LA, Veerkamp JH, van den Heuvel LP (1998). "Agrin is a major heparan sulfate proteoglycan in the human glomerular basement membrane". J Histochem Cytochem. 46 (1): 19â€“27. doi:10.1177/002215549804600104. PMID 9405491.
- Magill C, Reist NE, Fallon JR, Nitkin RM, Wallace BG, McMahan UJ (1987). "Agrin". Prog. Brain Res. Progress in Brain Research. 71: 391â€“6. doi:10.1016/S0079-6123(08)61840-3. ISBN 978-0-444-80814-1. PMID 3035610.
- Sanes JR, Lichtman JW (November 2001). "Induction, assembly, maturation and maintenance of a postsynaptic apparatus". Nat. Rev. Neurosci. 2 (11): 791â€“805. doi:10.1038/35097557. PMID 11715056.
- Glass DJ, Bowen DC, Stitt TN, Radziejewski C, Bruno J, Ryan TE, Gies DR, Shah S, Mattsson K, Burden SJ, DiStefano PS, Valenzuela DM, DeChiara TM, Yancopoulos GD (May 1996). "Agrin acts via a MuSK receptor complex". Cell. 85 (4): 513â€“23. doi:10.1016/S0092-8674(00)81252-0. PMID 8653787.
- Sanes JR, Apel ED, Gautam M, Glass D, Grady RM, Martin PT, Nichol MC, Yancopoulos GD (May 1998). "Agrin receptors at the skeletal neuromuscular junction". Ann. N. Y. Acad. Sci. 841: 1â€“13. doi:10.1111/j.1749-6632.1998.tb10905.x. PMID 9668217.
- Gautam M, Noakes PG, Moscoso L, Rupp F, Scheller RH, Merlie JP, Sanes JR (May 1996). "Defective neuromuscular synaptogenesis in agrin-deficient mutant mice". Cell. 85 (4): 525â€“35. doi:10.1016/S0092-8674(00)81253-2. PMID 8653788.
- Cheusova T, Khan MA, Schubert SW, Gavin AC, Buchou T, Jacob G, Sticht H, Allende J, Boldyreff B, Brenner HR, Hashemolhosseini S (July 2006). "Casein kinase 2-dependent serine phosphorylation of MuSK regulates acetylcholine receptor aggregation at the neuromuscular junction". Genes Dev. 20 (13): 1800â€“16. doi:10.1101/gad.375206. PMC 1522076. PMID 16818610.
- doi:10.1016/j.str.2004.02.001. PMID 15016366. ; Stetefeld, J.; Alexandrescu, A.T.; Maciejewski, M.W.; Jenny, M.; Rathgeb-Szabo, K.; Schulthess, T.; Landwehr, R.; Frank, S.; Ruegg, M.A.; Kammerer, R.A. (2004). "Modulation of agrin function by alternative splicing and Ca2+ binding". Structure. 12: 503â€“515.
- McDonnell KM, Grow WA (2004). "Reduced glycosaminoglycan sulfation diminishes the agrin signal transduction pathway". Dev. Neurosci. 26 (1): 1â€“10. doi:10.1159/000080706. PMID 15509893.
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Agrin NtA domain Provide feedback
Agrin is a multidomain heparan sulphate proteoglycan, that is a key organiser for the induction of postsynaptic specialisations at the neuromuscular junction. Binding of agrin to basement membranes requires the amino terminal (NtA) domain . This region mediates high affinity interaction with the coiled-coil domain of laminins. The binding of agrin to laminins via the NtA domain is subject to tissue-specific regulation. The NtA domain-containing form of agrin is expressed in non-neuronal cells or in neurons that project to non-neuronal cell such as motor neurons. The structure of this domain is an OB-fold .
Stetefeld J, Jenny M, Schulthess T, Landwehr R, Schumacher B, Frank S, Ruegg MA, Engel J, Kammerer RA; , Nat Struct Biol 2001;8:705-709.: The laminin-binding domain of agrin is structurally related to N-TIMP-1. PUBMED:11473262 EPMC:11473262
Denzer AJ, Hauser DM, Gesemann M, Ruegg MA; , Cell Tissue Res 1997;290:357-365.: Synaptic differentiation: the role of agrin in the formation and maintenance of the neuromuscular junction. PUBMED:9321698 EPMC:9321698
External database links
This tab holds annotation information from the InterPro database.
InterPro entry IPR004850
Agrin is a multidomain heparan sulphate proteoglycan, that is a key organiser for the induction of postsynaptic specializations at the neuromuscular junction. Binding of agrin to basement membranes requires the amino terminal (NtA) domain [PUBMED:9321698]. This region mediates high affinity interaction with the coiled-coil domain of laminins. The binding of agrin to laminins via the NtA domain is subject to tissue-specific regulation. The NtA domain-containing form of agrin is expressed in non-neuronal cells or in neurons that project to non-neuronal cell such as motor neurons. The NtA domain forms the most N-terminal part, followed by 9 Kazal-like domains and 2 LE domains. The C-terminal part consists of a SEA domain, 4 EGF-like domains and 3 Laminin G domains, responsible for the clustering of acetylcholine receptors [PUBMED:11473262].
Tertiairy structures show that the NtA domain folds as a beta-barrel core flanked by N- and C-terminal helical regions. The core of the domain consists of 5 beta-strands that form 2 beta-sheets. The structure belongs to the OB fold family and shows similarity with the protease inhibition domain of TIMP-1, suggesting alternative functions for agrin in addition to synaptogenic activity [PUBMED:11473262]. Residues Leu 117 and Val 124 in helix 3 of the NtA domain are essential for binding to the laminin gamma1 chain [PUBMED:12554653].
The mapping between Pfam and Gene Ontology is provided by InterPro. If you use this data please cite InterPro.
|Molecular function||laminin binding (GO:0043236)|
|Biological process||receptor clustering (GO:0043113)|
|G-protein coupled acetylcholine receptor signaling pathway (GO:0007213)|
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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This example describes an architecture with one
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This superfamily consists of the C-terminal domains of netrins, complement proteins C3, C4, C5, secreted frizzled-related proteins, and type I procollagen C-proteinase enhancer proteins, as well as the homologous N-terminal domains of tissue inhibitors of metalloproteinases (TIMPs).
The clan contains the following 3 members:NtA NTR TIMP
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1Cannot generate PP/Heatmap alignments for seeds; no PP data available
Key: available, not generated, — not available.
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|Number in seed:||10|
|Number in full:||182|
|Average length of the domain:||104.00 aa|
|Average identity of full alignment:||51 %|
|Average coverage of the sequence by the domain:||8.58 %|
|HMM build commands:||
build method: hmmbuild -o /dev/null HMM SEED
search method: hmmsearch -Z 45638612 -E 1000 --cpu 4 HMM pfamseq
|Family (HMM) version:||15|
|Download:||download the raw HMM for this family|
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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.
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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.
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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 NtA domain has been found. There are 4 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 sequence.
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