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Details on Person UniProt:O00468 AGRN
| Class:Id | ReferenceGeneProduct:143911 |
|---|---|
| _chainChangeLog | signal peptide:1-29 added on Fri February 6 2015;chain:30-2067 added on Fri February 6 2015;chain:30-1102 added on Fri February 6 2015;chain:1103-2067 added on Fri February 6 2015;chain:1103-1863 added on Fri February 6 2015;chain:1864-2067 added on Fri February 6 2015 |
| _displayName | UniProt:O00468 AGRN |
| _timestamp | 2026-02-20 21:36:53 |
| chain | signal peptide:1-29 chain:30-2068 chain:30-1102 chain:1103-2068 chain:1103-1863 chain:1864-2068 |
| checksum | 8B3E3D0FF65517F0 |
| comment | FUNCTION Depending on alternative splicing and post-translational modifications, it has a role in different processes, including neuromuscular junction formation and maintenance, and regulation of neurite outgrowth (By similarity). Also involved in positive regulation of cartilage formation through alpha-dystroglycan binding and up-regulation of SOX9 (PubMed:26290588).FUNCTION Heparan sulfate basal lamina glycoprotein that plays a central role in the formation and the maintenance of the neuromuscular junction (NMJ) and directs key events in postsynaptic differentiation. Component of the AGRN-LRP4 receptor complex that induces the phosphorylation and activation of MUSK (PubMed:21969364). The activation of MUSK in myotubes induces the formation of NMJ by regulating different processes including the transcription of specific genes and the clustering of AChR in the postsynaptic membrane. Calcium ions are required for maximal AChR clustering. AGRN function in neurons is highly regulated by alternative splicing, glycan binding and proteolytic processing. Modulates calcium ion homeostasis in neurons, specifically by inducing an increase in cytoplasmic calcium ions. Functions differentially in the central nervous system (CNS) by inhibiting the alpha(3)-subtype of Na+/K+-ATPase and evoking depolarization at CNS synapses. This secreted isoform forms a bridge, after release from motor neurons, to basal lamina through binding laminin via the NtA domain.FUNCTION Transmembrane form that is the predominate form in neurons of the brain, induces dendritic filopodia and synapse formation in mature hippocampal neurons in large part due to the attached glycosaminoglycan chains and the action of Rho-family GTPases.FUNCTION Isoform 1, isoform 4 and isoform 5: neuron-specific (z+) isoforms that contain C-terminal insertions of 8-19 AA are potent activators of AChR clustering. Isoform 5, agrin (z+8), containing the 8-AA insert, forms a receptor complex in myotubules containing the neuronal AGRN, the muscle-specific kinase MUSK and LRP4, a member of the LDL receptor family. The splicing factors, NOVA1 and NOVA2, regulate AGRN splicing and production of the 'z' isoforms.FUNCTION Muscle-specific isoform, probably involved in endothelial cell differentiation.FUNCTION Involved in the positive regulation of cartilage formation, acting through alpha-dystroglycan binding and up-regulation of SOX9, a transcription factor that plays a key role in chondrocytes differentiation.FUNCTION Is involved in regulation of neurite outgrowth probably due to the presence of the glycosaminoglcan (GAG) side chains of heparan and chondroitin sulfate attached to the Ser/Thr- and Gly/Ser-rich regions. Also involved in modulation of growth factor signaling (By similarity).FUNCTION This released fragment is important for agrin signaling and to exert a maximal dendritic filopodia-inducing effect. All 'z' splice variants (z+) of this fragment also show an increase in the number of filopodia.SUBUNIT Monomer (By similarity). Interacts (N-terminal subunit) with TGF-beta family members, BMP2 and BMP4; the interactions inhibit the activity of these growth factors. Interacts with TGFB1; the interaction enhances the activity of TGFB1 (By similarity). Component of the AGRN-LRP4 complex that consists of a tetramer of two AGRN-LRP4 heterodimers (PubMed:21969364). Interacts (via the laminin G-like 3 domain) directly with LRP4; the interaction is required for activation of MUSK and clustering of AChR and requires the 'z8' insert present in the z(+8) isoforms (PubMed:21969364). Interacts with DAG1; the interaction is influenced by cell surface glycosaminoglycans and by alternative splicing of AGRN, and is required for up-regulation of SOX9 and cartilage formation (PubMed:22205389, PubMed:26290588).INTERACTION Synaptic basal lamina at the neuromuscular junction.SUBCELLULAR LOCATION Many isoforms may exist depending on the occurrence and length of inserts at the x, y or z splice site. Four 'z' isoforms can be produced with inserts of 0, 8, 11 or 19 AA. Isoform 3 and isoform 6 lack any 'z' insert. Isoforms differ in their acetylcholine receptor clustering activity and tissue specificity.TISSUE SPECIFICITY Expressed in basement membranes of lung and kidney. Muscle- and neuron-specific isoforms are found. Isoforms (y+) with the 4 AA insert and (z+8) isoforms with the 8 AA insert are all neuron-specific. Isoforms (z+11) are found in both neuronal and non-neuronal tissues.TISSUE SPECIFICITY Expressed in articular cartilage.DOMAIN The NtA domain, absent in TM-agrin, is required for binding laminin and connecting to basal lamina.DOMAIN Both laminin G-like 2 (G2) and laminin G-like 3 (G3) domains are required for alpha-dystroglycan/DAG1 binding. G3 domain is required for C-terminal heparin, heparan sulfate and sialic acid binding (By similarity).PTM Contains heparan and chondroitin sulfate chains and alpha-dystroglycan as well as N-linked and O-linked oligosaccharides. Glycosaminoglycans (GAGs), present in the N-terminal 110 kDa fragment, are required for induction of filopodia in hippocampal neurons. The first cluster (Gly/Ser-rich) for GAG attachment contains heparan sulfate (HS) chains and the second cluster (Ser/Thr-rich), contains chondroitin sulfate (CS) chains. Heparin and heparin sulfate binding in the G3 domain is independent of calcium ions. Binds heparin with a stoichiometry of 2:1. Binds sialic acid with a stoichiometry of 1:1 and binding requires calcium ions (By similarity).PTM At synaptic junctions, cleaved at two conserved sites, alpha and beta, by neurotrypsin. Cleavage at the alpha-site produces the agrin N-terminal 110-kDa subunit and the agrin C-terminal 110-kDa subunit. Further cleavage of agrin C-terminal 110-kDa subunit at the beta site produces the C-terminal fragments, agrin C-terminal 90 kDa fragment and agrin C-terminal 22 kDa fragment. Excessive cleavage at the beta-site releases large amounts of the agrin C-terminal 22 kDa fragment leading to destabilization at the neuromuscular junction (NMJ).DISEASE The disease is caused by variants affecting the gene represented in this entry.MISCELLANEOUS Cleaved C-terminal fragments may be used as a biomarker for sarcopenia, age-related progressive loss of skeletal muscle.MISCELLANEOUS Produced by usage of an alternative first exon.CAUTION The unknown residue 'x' in the transmembrane isoform is probably a proline residue by similarity to mouse and rat sequences.ONLINE INFORMATION Leiden Open Variation Database (LOVD) |
| created | [InstanceEdit:143527] Schmidt, EE, 2004-11-12 07:45:10 |
| description | recommendedName: Agrin component recommendedName: Agrin N-terminal 110 kDa subunit /component component recommendedName: Agrin C-terminal 110 kDa subunit /component component recommendedName: Agrin C-terminal 90 kDa fragment shortName: C90 /component component recommendedName: Agrin C-terminal 22 kDa fragment shortName: C22 /component |
| geneName | AGRN AGRIN |
| identifier | O00468 |
| isSequenceChanged | FALSE |
| keyword | 3D-structure Alternative splicing Calcium Cell membrane Congenital myasthenic syndrome Developmental protein Differentiation Disease variant Disulfide bond EGF-like domain Extracellular matrix Glycoprotein Heparan sulfate Laminin EGF-like domain Membrane Metal-binding Phosphoprotein Proteoglycan Proteomics identification Reference proteome Repeat Secreted Signal Synapse Transmembrane Transmembrane helix |
| modified | [InstanceEdit:9836292] Weiser, Joel, 2023-05-25 [InstanceEdit:9852000] Weiser, Joel, 2023-11-03 [InstanceEdit:9926675] Weiser, Joel, 2024-11-03 [InstanceEdit:9983091] Weiser, Joel, 2026-02-20 |
| name | AGRN |
| referenceDatabase | [ReferenceDatabase:2] UniProt |
| referenceGene | [ReferenceDNASequence:8988258] ENSEMBL:ENSG00000188157 AGRN [Homo sapiens] |
| secondaryIdentifier | AGRIN_HUMAN Q5SVA1 Q5SVA2 Q60FE1 Q7KYS8 Q8N4J5 Q96IC1 Q9BTD4 |
| sequenceLength | 2068 |
| species | [Species:48887] Homo sapiens |
| (isoformParent) | [ReferenceIsoform:8968648] UniProt:O00468-1 AGRN [Homo sapiens] [ReferenceIsoform:8968649] UniProt:O00468-2 AGRN [Homo sapiens] [ReferenceIsoform:8968650] UniProt:O00468-3 AGRN [Homo sapiens] [ReferenceIsoform:8968651] UniProt:O00468-4 AGRN [Homo sapiens] [ReferenceIsoform:8968652] UniProt:O00468-5 AGRN [Homo sapiens] [ReferenceIsoform:8968653] UniProt:O00468-6 AGRN [Homo sapiens] [ReferenceIsoform:8968654] UniProt:O00468-7 AGRN [Homo sapiens] |
| (referenceEntity) | [EntityWithAccessionedSequence:375056] AGRN(30-2068) [extracellular region] [Homo sapiens] [EntityWithAccessionedSequence:2054104] AGRN(30-2068) [Golgi lumen] [Homo sapiens] [EntityWithAccessionedSequence:2064040] Gal-Gal-Xyl-AGRN [Golgi lumen] [Homo sapiens] [EntityWithAccessionedSequence:2064130] Gal-Xyl-AGRN [Golgi lumen] [Homo sapiens] [EntityWithAccessionedSequence:2064200] GlcA-Gal-Gal-Xyl-AGRN [Golgi lumen] [Homo sapiens] [EntityWithAccessionedSequence:2064220] XylS-AGRN(30-2068) [Golgi lumen] [Homo sapiens] [EntityWithAccessionedSequence:2076300] Heparan(4)-AGRN [Golgi lumen] [Homo sapiens] [EntityWithAccessionedSequence:2076301] Heparan(2)-AGRN [Golgi lumen] [Homo sapiens] [EntityWithAccessionedSequence:2076317] Heparan(1)-AGRN [Golgi lumen] [Homo sapiens] [EntityWithAccessionedSequence:2076337] HS(4)-AGRN [Golgi lumen] [Homo sapiens] |
| (referenceSequence) | [GroupModifiedResidue:2064063] O-xylosyl-L-serine (O3-(4-β-D-galactosyl-β-D-xylosyl)-L-serine residue) at unknown position [GroupModifiedResidue:2064181] O-xylosyl-L-serine (3-O-(β-D-glucuronosyl-(1→3)-β-D-galactosyl-(1→3)-β-D-galactosyl-(1→4)-β-D-xylosyl)-L-serine residue) at unknown position [ModifiedResidue:2064184] O-xylosyl-L-serine at unknown position [GroupModifiedResidue:2064238] O-xylosyl-L-serine (O3-(β-D-galactosyl-(1→3)-β-D-galactosyl-(1→4)-β-D-xylosyl)-L-serine residue) at unknown position [GroupModifiedResidue:2076299] O-xylosyl-L-serine (beta-D-IdoA-(1->4)-alpha-D-GlcNS-(1->4)-beta-D-IdoA2S-(1->4)-alpha-D-GlcNS3S-(1->4)-beta-D-GlcA-(1->3)-beta-D-Gal-(1->3)-beta-D-Gal-(1->4)-beta-D-Xyl-yl group) at unknown position [GroupModifiedResidue:2076312] O-xylosyl-L-serine (ChEBI:63652) at unknown position [GroupModifiedResidue:2076347] O-xylosyl-L-serine (ChEBI:63654) at unknown position [GroupModifiedResidue:2076386] O-xylosyl-L-serine (ChEBI:63657) at unknown position [GroupModifiedResidue:2076390] O-xylosyl-L-serine (ChEBI:63648) at unknown position [GroupModifiedResidue:2076464] O-xylosyl-L-serine (ChEBI:63651) at unknown position |
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No pathways have been reviewed or authored by UniProt:O00468 AGRN (143911)
