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4  structures 29  species 0  interactions 48  sequences 18  architectures

Family: NtA (PF03146)

Summary: Agrin NtA domain

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Agrin Edit Wikipedia article


Crystallographic structure of chicken agrin.[1]
Symbols AGRN; FLJ45064
External IDs OMIM103320 MGI87961 HomoloGene27907 GeneCards: AGRN Gene
Species Human Mouse
Entrez 375790 11603
Ensembl ENSG00000188157 ENSMUSG00000041936
UniProt O00468 A2ASQ1
RefSeq (mRNA) NM_198576 NM_021604
RefSeq (protein) NP_940978 NP_067617
Location (UCSC) Chr 1:
0.96 – 0.99 Mb
Chr 4:
156.17 – 156.2 Mb
PubMed search [1] [2]
Agrin NtA domain
Symbol NtA
Pfam PF03146
InterPro IPR004850
SCOP 1jc7

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.[2][3][4]

This protein has nine domains homologous to protease inhibitors.[5] 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.[6]


Agrin was first identified by the U.J. McMahan laboratory, Stanford University.[7]

Mechanism of action[edit]

During development, the growing end of motor neuron axons secrete a protein called agrin.[8] This protein binds to several receptors on the surface of skeletal muscle. The receptor that seems to be required for formation of the neuromuscular junction (NMJ) is called the MuSK receptor (Muscle specific kinase).[9][10] 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.

In addition to MuSK, agrin binds several other proteins on the surface of muscle, including dystroglycan and laminin. It is seen that these additional binding steps are required to stabilize the NMJ.

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.[11] 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.

It seems that the MuSK receptor recruits casein kinase 2, which is required for clustering.[12]

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.[1]

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.[13]

A role in the retention of anionic macromolecules within the vasculature has also been suggested for agrin-linked HS at the glomerular or alveolar basement membrane.


  1. ^ a b PDB 1PZ7; 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: 503–515. doi:10.2210/pdb1pz7/pdb. PMID 15016366. 
  2. ^ Rupp F, Payan DG, Magill-Solc C, Cowan DM, Scheller RH (May 1991). "Structure and expression of a rat agrin". Neuron 6 (5): 811–23. doi:10.1016/0896-6273(91)90177-2. PMID 1851019. 
  3. ^ Kröger S, Schröder JE (October 2002). "Agrin in the developing CNS: new roles for a synapse organizer". News Physiol. Sci. 17 (5): 207–12. doi:10.1152/nips.01390.2002 (inactive 2010-08-28). PMID 12270958. 
  4. ^ 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): 123–8. doi:10.1046/j.1432-1327.1998.2540123.x. PMID 9652404. 
  5. ^ Tsen G, Halfter W, Kröger S, Cole GJ. (1995). "Agrin is a heparan sulfate proteoglycan". J Biol Chem 270 (7): 3392–3399. doi:10.1074/jbc.270.7.3392. PMID 7852425. 
  6. ^ 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): 19–27. doi:10.1177/002215549804600104. PMID 9405491. 
  7. ^ Magill C, Reist NE, Fallon JR, Nitkin RM, Wallace BG, McMahan UJ (1987). "Agrin". Prog. Brain Res. Progress in Brain Research 71: 391–6. doi:10.1016/S0079-6123(08)61840-3. ISBN 978-0-444-80814-1. PMID 3035610. 
  8. ^ Sanes JR, Lichtman JW (November 2001). "Induction, assembly, maturation and maintenance of a postsynaptic apparatus". Nat. Rev. Neurosci. 2 (11): 791–805. doi:10.1038/35097557. PMID 11715056. 
  9. ^ 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): 513–23. doi:10.1016/S0092-8674(00)81252-0. PMID 8653787. 
  10. ^ 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: 1–13. doi:10.1111/j.1749-6632.1998.tb10905.x. PMID 9668217. 
  11. ^ 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): 525–35. doi:10.1016/S0092-8674(00)81253-2. PMID 8653788. 
  12. ^ 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): 1800–16. doi:10.1101/gad.375206. PMC 1522076. PMID 16818610. 
  13. ^ McDonnell KM, Grow WA (2004). "Reduced glycosaminoglycan sulfation diminishes the agrin signal transduction pathway". Dev. Neurosci. 26 (1): 1–10. doi:10.1159/000080706. PMID 15509893. 

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This tab holds the annotation information that is stored in the Pfam database. As we move to using Wikipedia as our main source of annotation, the contents of this tab will be gradually replaced by the Wikipedia tab.

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 [2]. 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 [1].

Literature references

  1. 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

  2. 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].

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Domain organisation

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Seed source: [1]
Previous IDs: none
Type: Domain
Author: Bateman A
Number in seed: 2
Number in full: 48
Average length of the domain: 116.40 aa
Average identity of full alignment: 73 %
Average coverage of the sequence by the domain: 11.37 %

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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 20.8 20.8
Trusted cut-off 20.8 22.8
Noise cut-off 20.0 19.9
Model length: 128
Family (HMM) version: 10
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Species distribution

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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 seqence.

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