AGRIN_MOUSE
ID AGRIN_MOUSE Reviewed; 1950 AA.
AC A2ASQ1; A2ASP9; A2ASQ0; B2RWU1;
DT 16-DEC-2008, integrated into UniProtKB/Swiss-Prot.
DT 20-FEB-2007, sequence version 1.
DT 03-AUG-2022, entry version 131.
DE RecName: Full=Agrin;
DE Contains:
DE RecName: Full=Agrin N-terminal 110 kDa subunit;
DE Contains:
DE RecName: Full=Agrin C-terminal 110 kDa subunit;
DE Contains:
DE RecName: Full=Agrin C-terminal 90 kDa fragment;
DE Short=C90;
DE Contains:
DE RecName: Full=Agrin C-terminal 22 kDa fragment;
DE Short=C22;
GN Name=Agrn; Synonyms=Agrin;
OS Mus musculus (Mouse).
OC Eukaryota; Metazoa; Chordata; Craniata; Vertebrata; Euteleostomi; Mammalia;
OC Eutheria; Euarchontoglires; Glires; Rodentia; Myomorpha; Muroidea; Muridae;
OC Murinae; Mus; Mus.
OX NCBI_TaxID=10090;
RN [1]
RP NUCLEOTIDE SEQUENCE [LARGE SCALE GENOMIC DNA].
RC STRAIN=C57BL/6J;
RX PubMed=19468303; DOI=10.1371/journal.pbio.1000112;
RA Church D.M., Goodstadt L., Hillier L.W., Zody M.C., Goldstein S., She X.,
RA Bult C.J., Agarwala R., Cherry J.L., DiCuccio M., Hlavina W., Kapustin Y.,
RA Meric P., Maglott D., Birtle Z., Marques A.C., Graves T., Zhou S.,
RA Teague B., Potamousis K., Churas C., Place M., Herschleb J., Runnheim R.,
RA Forrest D., Amos-Landgraf J., Schwartz D.C., Cheng Z., Lindblad-Toh K.,
RA Eichler E.E., Ponting C.P.;
RT "Lineage-specific biology revealed by a finished genome assembly of the
RT mouse.";
RL PLoS Biol. 7:E1000112-E1000112(2009).
RN [2]
RP NUCLEOTIDE SEQUENCE [LARGE SCALE MRNA] (ISOFORM 3).
RC TISSUE=Brain;
RX PubMed=15489334; DOI=10.1101/gr.2596504;
RG The MGC Project Team;
RT "The status, quality, and expansion of the NIH full-length cDNA project:
RT the Mammalian Gene Collection (MGC).";
RL Genome Res. 14:2121-2127(2004).
RN [3]
RP FUNCTION IN NEUROMUSCULAR JUNCTION DEVELOPMENT, SUBCELLULAR LOCATION,
RP FUNCTION IN PHOSPHORYLATION OF MUSK, AND INTERACTION WITH LRP4.
RX PubMed=8653787; DOI=10.1016/s0092-8674(00)81252-0;
RA Glass D.J., Bowen D.C., Stitt T.N., Radziejewski C., Bruno J., Ryan T.E.,
RA Gies D.R., Shah S., Mattsson K., Burden S.J., DiStefano P.S.,
RA Valenzuela D.M., DeChiara T.M., Yancopoulos G.D.;
RT "Agrin acts via a MuSK receptor complex.";
RL Cell 85:513-523(1996).
RN [4]
RP REGULATION OF ALTERNATIVE SPLICING.
RX PubMed=9188458; DOI=10.1074/jbc.272.25.15675;
RA Smith M.A., Fanger G.R., O'Connor L.T., Bridle P., Maue R.A.;
RT "Selective regulation of agrin mRNA induction and alternative splicing in
RT PC12 cells by Ras-dependent actions of nerve growth factor.";
RL J. Biol. Chem. 272:15675-15681(1997).
RN [5]
RP LAMININ BINDING.
RX PubMed=10581249; DOI=10.1093/emboj/18.23.6762;
RA Kammerer R.A., Schulthess T., Landwehr R., Schumacher B., Lustig A.,
RA Yurchenco P.D., Ruegg M.A., Engel J., Denzer A.J.;
RT "Interaction of agrin with laminin requires a coiled-coil conformation of
RT the agrin-binding site within the laminin gamma1 chain.";
RL EMBO J. 18:6762-6770(1999).
RN [6]
RP ALTERNATIVE SPLICING, SUBCELLULAR LOCATION, DISRUPTION PHENOTYPE, TISSUE
RP SPECIFICITY, AND FUNCTION.
RX PubMed=10402191; DOI=10.1016/s0896-6273(00)80751-5;
RA Burgess R.W., Nguyen Q.T., Son Y.J., Lichtman J.W., Sanes J.R.;
RT "Alternatively spliced isoforms of nerve- and muscle-derived agrin: their
RT roles at the neuromuscular junction.";
RL Neuron 23:33-44(1999).
RN [7]
RP ALTERNATIVE SPLICING, SUBCELLULAR LOCATION, TISSUE SPECIFICITY, AND
RP FUNCTION.
RX PubMed=11018052; DOI=10.1083/jcb.151.1.41;
RA Burgess R.W., Skarnes W.C., Sanes J.R.;
RT "Agrin isoforms with distinct amino termini: differential expression,
RT localization, and function.";
RL J. Cell Biol. 151:41-52(2000).
RN [8]
RP ALTERNATIVE SPLICING, AND SUBCELLULAR LOCATION.
RX PubMed=11161480; DOI=10.1006/mcne.2000.0932;
RA Neumann F.R., Bittcher G., Annies M., Schumacher B., Kroger S., Ruegg M.A.;
RT "An alternative amino-terminus expressed in the central nervous system
RT converts agrin to a type II transmembrane protein.";
RL Mol. Cell. Neurosci. 17:208-225(2001).
RN [9]
RP FUNCTION OF AGRIN C-TERMINAL 22 KDA FRAGMENT, AND SUBCELLULAR LOCATION.
RX PubMed=12796478; DOI=10.1083/jcb.200301013;
RA Hoover C.L., Hilgenberg L.G., Smith M.A.;
RT "The COOH-terminal domain of agrin signals via a synaptic receptor in
RT central nervous system neurons.";
RL J. Cell Biol. 161:923-932(2003).
RN [10]
RP IDENTIFICATION BY MASS SPECTROMETRY [LARGE SCALE ANALYSIS].
RC TISSUE=Brain;
RX PubMed=16452087; DOI=10.1074/mcp.t500041-mcp200;
RA Trinidad J.C., Specht C.G., Thalhammer A., Schoepfer R., Burlingame A.L.;
RT "Comprehensive identification of phosphorylation sites in postsynaptic
RT density preparations.";
RL Mol. Cell. Proteomics 5:914-922(2006).
RN [11]
RP DISRUPTION PHENOTYPE, TISSUE SPECIFICITY, SUBCELLULAR LOCATION, AND
RP FUNCTION.
RX PubMed=17611272; DOI=10.1523/jneurosci.1609-07.2007;
RA Ksiazek I., Burkhardt C., Lin S., Seddik R., Maj M., Bezakova G.,
RA Jucker M., Arber S., Caroni P., Sanes J.R., Bettler B., Ruegg M.A.;
RT "Synapse loss in cortex of agrin-deficient mice after genetic rescue of
RT perinatal death.";
RL J. Neurosci. 27:7183-7195(2007).
RN [12]
RP PROTEOLYTIC PROCESSING, IDENTIFICATION OF PROTEOLYTICALLY CLEAVED FRAGMENTS
RP BY MASS SPECTROMETRY, SUBCELLULAR LOCATION, AND TISSUE SPECIFICITY.
RX PubMed=18230682; DOI=10.1096/fj.07-100008;
RA Stephan A., Mateos J.M., Kozlov S.V., Cinelli P., Kistler A.D., Hettwer S.,
RA Rulicke T., Streit P., Kunz B., Sonderegger P.;
RT "Neurotrypsin cleaves agrin locally at the synapse.";
RL FASEB J. 22:1861-1873(2008).
RN [13]
RP PROTEOLYTIC PROCESSING, AND FUNCTION.
RX PubMed=19303856; DOI=10.1016/j.cell.2009.02.034;
RA Matsumoto-Miyai K., Sokolowska E., Zurlinden A., Gee C.E., Luscher D.,
RA Hettwer S., Wolfel J., Ladner A.P., Ster J., Gerber U., Rulicke T.,
RA Kunz B., Sonderegger P.;
RT "Coincident pre- and postsynaptic activation induces dendritic filopodia
RT via neurotrypsin-dependent agrin cleavage.";
RL Cell 136:1161-1171(2009).
RN [14]
RP REGULATION OF ALTERNATIVE SPLICING AT THE Z SITE.
RX PubMed=19221030; DOI=10.1073/pnas.0813112106;
RA Ruggiu M., Herbst R., Kim N., Jevsek M., Fak J.J., Mann M.A., Fischbach G.,
RA Burden S.J., Darnell R.B.;
RT "Rescuing Z+ agrin splicing in Nova null mice restores synapse formation
RT and unmasks a physiologic defect in motor neuron firing.";
RL Proc. Natl. Acad. Sci. U.S.A. 106:3513-3518(2009).
RN [15]
RP PHOSPHORYLATION [LARGE SCALE ANALYSIS] AT SER-569 AND SER-571, AND
RP IDENTIFICATION BY MASS SPECTROMETRY [LARGE SCALE ANALYSIS].
RC TISSUE=Brain, Brown adipose tissue, Heart, Kidney, Liver, Lung, and
RC Pancreas;
RX PubMed=21183079; DOI=10.1016/j.cell.2010.12.001;
RA Huttlin E.L., Jedrychowski M.P., Elias J.E., Goswami T., Rad R.,
RA Beausoleil S.A., Villen J., Haas W., Sowa M.E., Gygi S.P.;
RT "A tissue-specific atlas of mouse protein phosphorylation and expression.";
RL Cell 143:1174-1189(2010).
RN [16]
RP PROTEOLYTIC PROCESSING, FUNCTION, AND MOUSE MODEL OF PRECOCIOUS SARCOPENIA.
RX PubMed=21885656; DOI=10.1096/fj.11-191262;
RA Butikofer L., Zurlinden A., Bolliger M.F., Kunz B., Sonderegger P.;
RT "Destabilization of the neuromuscular junction by proteolytic cleavage of
RT agrin results in precocious sarcopenia.";
RL FASEB J. 25:4378-4393(2011).
RN [17]
RP VARIANT A MUTANT STRAIN SER-1061, AND CHARACTERIZATION OF A MOUSE MODEL OF
RP AGRIN-ASSOCIATED CONGENITAL MYASTHENIC SYNDROME.
RX PubMed=21890498; DOI=10.1093/hmg/ddr396;
RA Bogdanik L.P., Burgess R.W.;
RT "A valid mouse model of AGRIN-associated congenital myasthenic syndrome.";
RL Hum. Mol. Genet. 20:4617-4633(2011).
RN [18]
RP STRUCTURAL CHARACTERISTICS OF LAMININ G3 DOMAIN.
RX PubMed=21037280; DOI=10.1093/protein/gzq082;
RA Tidow H., Mattle D., Nissen P.;
RT "Structural and biophysical characterisation of agrin laminin G3 domain
RT constructs.";
RL Protein Eng. Des. Sel. 24:219-224(2011).
RN [19]
RP X-RAY CRYSTALLOGRAPHY (1.4 ANGSTROMS) OF 1510-1701.
RG New York structural genomix research consortium (NYSGXRC);
RT "Crystal structure of the g2 domain of agrin from Mus musculus.";
RL Submitted (JAN-2011) to the PDB data bank.
CC -!- FUNCTION: [Isoform 1]: Heparan sulfate basal lamina glycoprotein that
CC plays a central role in the formation and the maintenance of the
CC neuromuscular junction (NMJ) and directs key events in postsynaptic
CC differentiation. This neuron-specific (z+) isoform is a component of
CC the AGRN-LRP4 receptor complex that induces the phosphorylation and
CC activation of MUSK. The activation of MUSK in myotubes induces the
CC formation of NMJ by regulating different processes including the
CC transcription of specific genes and the clustering of AChR in the
CC postsynaptic membrane. Calcium ions are required for maximal AChR
CC clustering. AGRN function in neurons is highly regulated by alternative
CC splicing, glycan binding and proteolytic processing. Modulates calcium
CC ion homeostasis in neurons, specifically by inducing an increase in
CC cytoplasmic calcium ions. Functions differentially in the central
CC nervous system (CNS) by inhibiting the alpha(3)-subtype of Na+/K+-
CC ATPase and evoking depolarization at CNS synapses. This transmembrane
CC agrin (TM-agrin) isoform, the predominate form in neurons of the brain,
CC induces dendritic filopodia and synapse formation in mature hippocampal
CC neurons in large part due to the attached glycosaminoglycan chains and
CC the action of Rho-family GTPases.
CC -!- FUNCTION: Isoform 2 and isoform 3: these isoforms lacking the 'z'
CC insert (z0) are muscle-specific, have no AChR clustering ability and
CC may be involved in nervous system endothelial cell differentiation.
CC -!- FUNCTION: [Agrin N-terminal 110 kDa subunit]: Involved in regulation of
CC neurite outgrowth probably due to the presence of the glycosaminoglcan
CC (GAG) side chains of heparan and chondroitin sulfate attached to the
CC Ser/Thr- and Gly/Ser-rich regions. Also involved in modulation of
CC growth factor signaling (By similarity). {ECO:0000250,
CC ECO:0000269|PubMed:10402191, ECO:0000269|PubMed:11018052,
CC ECO:0000269|PubMed:12796478, ECO:0000269|PubMed:17611272,
CC ECO:0000269|PubMed:19303856, ECO:0000269|PubMed:21885656,
CC ECO:0000269|PubMed:8653787}.
CC -!- FUNCTION: [Agrin C-terminal 22 kDa fragment]: This released fragment is
CC important for agrin signaling and to exert a maximal dendritic
CC filopodia-inducing effect. All 'z' splice variants (z+) of this
CC fragment also show an increase in the number of filopodia.
CC -!- SUBUNIT: Monomer (By similarity). Interacts (N-terminal subunit) with
CC TGF-beta family members, BMP2 AND BMP4; the interactions inhibit the
CC activity of these growth factors. Interacts with TGFB1; the interaction
CC enhances the activity of TGFB1. Interacts with DAG1; the interaction is
CC influenced by cell surface glycosaminoglycans and by alternative
CC splicing of AGRN (By similarity). Component of the AGRN-LRP4 complex
CC that consists of a tetramer of two AGRN-LRP4 heterodimers. Interacts
CC (via the laminin G-like 3 domain) directly with LRP4; the interaction
CC is required for activation of MUSK and clustering of AChR and requires
CC the 'z8' insert present in the z(+8) isoforms. {ECO:0000250,
CC ECO:0000269|PubMed:8653787}.
CC -!- SUBCELLULAR LOCATION: Synapse {ECO:0000269|PubMed:10402191,
CC ECO:0000269|PubMed:12796478, ECO:0000269|PubMed:17611272,
CC ECO:0000269|PubMed:18230682, ECO:0000269|PubMed:8653787}. Cell membrane
CC {ECO:0000269|PubMed:11018052, ECO:0000269|PubMed:11161480}; Single-pass
CC type II membrane protein {ECO:0000269|PubMed:11018052,
CC ECO:0000269|PubMed:11161480}.
CC -!- ALTERNATIVE PRODUCTS:
CC Event=Alternative splicing; Named isoforms=3;
CC Comment=Many isoforms exist depending on the occurrence and length of
CC inserts at the x, y or z splice site. There are 4 'z' isoforms
CC produced with inserts of 0, 8, 11 or 19 AA. Isoforms differ in their
CC acetylcholine receptor clustering activity and tissue specificity. In
CC addition, a secreted isoform is produced by alternative usage of the
CC first exon.;
CC Name=1; Synonyms=Transmembrane agrin, TM-agrin;
CC IsoId=A2ASQ1-1; Sequence=Displayed;
CC Name=2;
CC IsoId=A2ASQ1-2; Sequence=VSP_035996, VSP_035997;
CC Name=3;
CC IsoId=A2ASQ1-3; Sequence=VSP_035995, VSP_035996, VSP_035997;
CC -!- TISSUE SPECIFICITY: Expressed in central nervous system (CNS) synapses
CC such as in the cerebral cortex and hippocampus. Localizes to basal
CC lamina of hippocampal blood vessels. Both (z+) and (z-) isoforms found
CC in kidney, heart and cerebral vasculature.
CC {ECO:0000269|PubMed:10402191, ECO:0000269|PubMed:11018052,
CC ECO:0000269|PubMed:17611272, ECO:0000269|PubMed:18230682}.
CC -!- DEVELOPMENTAL STAGE: All (z+), (z-), (y+) and (y-) isoforms present
CC throughout muscle fiber basal laminae in neonatal animals.
CC -!- DOMAIN: Both laminin G-like 2 (G2) and laminin G-like 3 (G3) domains
CC are required for alpha-dystroglycan binding. G3 domain is required for
CC C-terminal heparin, heparan sulfate and sialic acid binding (By
CC similarity). {ECO:0000250}.
CC -!- PTM: Contains heparan and chondroitin sulfate chains and alpha-
CC dystroglycan as well as N-linked and O-linked oligosaccharides. Heparin
CC and heparin sulfate binding in the G3 domain is independent of calcium
CC ions. Binds heparin with a stoichiometry of 2:1. Binds sialic acid with
CC a stoichiometry of 1:1 and binding requires calcium ions (By
CC similarity). Glycosaminoglycans (GAGs), present in the N-terminal 110
CC kDa fragment, are required for induction of filopodia in hippocampal
CC neurons. The first cluster (Gly/Ser-rich) for GAG attachment contains
CC heparan sulfate (HS) chains and the second cluster (Ser/Thr-rich),
CC contains chondroitin sulfate (CS) chains. {ECO:0000250}.
CC -!- PTM: At synaptic junctions, cleaved at two conserved sites, alpha and
CC beta, by neurotrypsin. Cleavage at the alpha-site produces the agrin N-
CC terminal 110-kDa subunit and the agrin C-terminal 110-kDa subunit.
CC Further cleavage of agrin C-terminal 110-kDa subunit at the beta site
CC produces the C-terminal fragments, agrin C-terminal 90 kDa fragment and
CC agrin C-terminal 22 kDa fragment. Excessive cleavage at the beta-site
CC releases large amounts of the agrin C-terminal 22 kDa fragment leading
CC to destabilization at the neuromuscular junction (NMJ). Cleavage is
CC developmentally regulated. In developing brain, neurotrypsin-mediated
CC cleavage occurs mainly during late fetal days and in the first
CC postnatal week. {ECO:0000269|PubMed:18230682,
CC ECO:0000269|PubMed:19303856, ECO:0000269|PubMed:21885656}.
CC -!- DISRUPTION PHENOTYPE: Z(-)/z(-) mice lacking the 'z' insert are
CC stillborn or die immediately after birth. They did not inflate their
CC lungs and were never seen to move spontaneously. An intramuscular nerve
CC is formed and axons leave the nerve and branch but do not stop and
CC arborize. AChR clusters were fewer in number, about 30% smaller in size
CC and lower in density. Transgenic null (Tg/Agrn -/-) mice, exhibit
CC atrophied muscle due to denervation and are smaller than normal
CC littermates. There is impairment of locomotory behavior and half the
CC mice die after 50 days. There is a greatly reduced number of synapses
CC and about 30% loss of postsynaptic spines and a decrease in the length
CC of dendrites in cortical neurons. {ECO:0000269|PubMed:10402191,
CC ECO:0000269|PubMed:17611272}.
CC -!- MISCELLANEOUS: Mice that have excessive neurotrypsin-mediated agrin
CC cleavage, exhibit pathological symptoms characteristic of precocious
CC sarcopenia, with fragmentation and disassembly of the neuromuscular
CC junction (NMJ). {ECO:0000305|PubMed:21885656}.
CC -!- SEQUENCE CAUTION:
CC Sequence=CAM14888.1; Type=Erroneous gene model prediction; Evidence={ECO:0000305};
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DR EMBL; AL928667; CAM14888.1; ALT_SEQ; Genomic_DNA.
DR EMBL; AL928667; CAM14889.1; -; Genomic_DNA.
DR EMBL; AL928667; CAM14890.1; -; Genomic_DNA.
DR EMBL; BC150703; AAI50704.1; -; mRNA.
DR CCDS; CCDS89874.1; -. [A2ASQ1-1]
DR RefSeq; XP_011248479.1; XM_011250177.2.
DR PDB; 3PVE; X-ray; 1.40 A; A/B=1510-1701.
DR PDBsum; 3PVE; -.
DR AlphaFoldDB; A2ASQ1; -.
DR SMR; A2ASQ1; -.
DR IntAct; A2ASQ1; 2.
DR STRING; 10090.ENSMUSP00000137931; -.
DR GlyGen; A2ASQ1; 5 sites.
DR iPTMnet; A2ASQ1; -.
DR PhosphoSitePlus; A2ASQ1; -.
DR MaxQB; A2ASQ1; -.
DR PaxDb; A2ASQ1; -.
DR PeptideAtlas; A2ASQ1; -.
DR PRIDE; A2ASQ1; -.
DR ProteomicsDB; 296138; -. [A2ASQ1-1]
DR ProteomicsDB; 296139; -. [A2ASQ1-2]
DR ProteomicsDB; 296140; -. [A2ASQ1-3]
DR Antibodypedia; 12009; 221 antibodies from 27 providers.
DR Ensembl; ENSMUST00000105575; ENSMUSP00000101200; ENSMUSG00000041936. [A2ASQ1-1]
DR UCSC; uc008wgg.1; mouse. [A2ASQ1-1]
DR MGI; MGI:87961; Agrn.
DR VEuPathDB; HostDB:ENSMUSG00000041936; -.
DR eggNOG; KOG3509; Eukaryota.
DR GeneTree; ENSGT00940000158337; -.
DR InParanoid; A2ASQ1; -.
DR OrthoDB; 414294at2759; -.
DR PhylomeDB; A2ASQ1; -.
DR TreeFam; TF326548; -.
DR Reactome; R-MMU-1971475; A tetrasaccharide linker sequence is required for GAG synthesis.
DR Reactome; R-MMU-2022928; HS-GAG biosynthesis.
DR Reactome; R-MMU-2024096; HS-GAG degradation.
DR Reactome; R-MMU-3000178; ECM proteoglycans.
DR Reactome; R-MMU-975634; Retinoid metabolism and transport.
DR BioGRID-ORCS; 11603; 3 hits in 73 CRISPR screens.
DR ChiTaRS; Agrn; mouse.
DR EvolutionaryTrace; A2ASQ1; -.
DR PRO; PR:A2ASQ1; -.
DR Proteomes; UP000000589; Chromosome 4.
DR RNAct; A2ASQ1; protein.
DR Bgee; ENSMUSG00000041936; Expressed in metanephric proximal tubule and 260 other tissues.
DR ExpressionAtlas; A2ASQ1; baseline and differential.
DR Genevisible; A2ASQ1; MM.
DR GO; GO:0070161; C:anchoring junction; IEA:UniProtKB-KW.
DR GO; GO:0044295; C:axonal growth cone; ISO:MGI.
DR GO; GO:0005604; C:basement membrane; IDA:MGI.
DR GO; GO:0009986; C:cell surface; IDA:BHF-UCL.
DR GO; GO:0062023; C:collagen-containing extracellular matrix; HDA:BHF-UCL.
DR GO; GO:0005576; C:extracellular region; TAS:Reactome.
DR GO; GO:0005615; C:extracellular space; IDA:MGI.
DR GO; GO:0098978; C:glutamatergic synapse; ISO:MGI.
DR GO; GO:0005796; C:Golgi lumen; TAS:Reactome.
DR GO; GO:0016021; C:integral component of membrane; IEA:UniProtKB-KW.
DR GO; GO:0042383; C:sarcolemma; IDA:BHF-UCL.
DR GO; GO:0045202; C:synapse; IDA:MGI.
DR GO; GO:0043083; C:synaptic cleft; IDA:SynGO.
DR GO; GO:0030548; F:acetylcholine receptor regulator activity; IDA:MGI.
DR GO; GO:0042030; F:ATPase inhibitor activity; IDA:BHF-UCL.
DR GO; GO:0036122; F:BMP binding; ISO:MGI.
DR GO; GO:0005509; F:calcium ion binding; ISS:UniProtKB.
DR GO; GO:0035374; F:chondroitin sulfate binding; IDA:UniProtKB.
DR GO; GO:0002162; F:dystroglycan binding; ISS:UniProtKB.
DR GO; GO:0043395; F:heparan sulfate proteoglycan binding; IDA:UniProtKB.
DR GO; GO:0033691; F:sialic acid binding; ISS:UniProtKB.
DR GO; GO:0050431; F:transforming growth factor beta binding; ISO:MGI.
DR GO; GO:0044325; F:transmembrane transporter binding; IPI:BHF-UCL.
DR GO; GO:0009887; P:animal organ morphogenesis; IBA:GO_Central.
DR GO; GO:0030154; P:cell differentiation; IEA:UniProtKB-KW.
DR GO; GO:0007268; P:chemical synaptic transmission; IDA:MGI.
DR GO; GO:0097049; P:motor neuron apoptotic process; IMP:MGI.
DR GO; GO:1903407; P:negative regulation of P-type sodium:potassium-exchanging transporter activity; IDA:BHF-UCL.
DR GO; GO:1903277; P:negative regulation of sodium ion export across plasma membrane; IDA:BHF-UCL.
DR GO; GO:0007528; P:neuromuscular junction development; IGI:MGI.
DR GO; GO:0045213; P:neurotransmitter receptor metabolic process; IDA:MGI.
DR GO; GO:0007009; P:plasma membrane organization; IMP:MGI.
DR GO; GO:0051491; P:positive regulation of filopodium assembly; ISS:UniProtKB.
DR GO; GO:0043547; P:positive regulation of GTPase activity; ISS:UniProtKB.
DR GO; GO:2000673; P:positive regulation of motor neuron apoptotic process; IMP:MGI.
DR GO; GO:0050731; P:positive regulation of peptidyl-tyrosine phosphorylation; ISO:MGI.
DR GO; GO:0032092; P:positive regulation of protein binding; IDA:UniProtKB.
DR GO; GO:2000541; P:positive regulation of protein geranylgeranylation; IMP:UniProtKB.
DR GO; GO:0001934; P:positive regulation of protein phosphorylation; IDA:UniProtKB.
DR GO; GO:0061098; P:positive regulation of protein tyrosine kinase activity; IDA:BHF-UCL.
DR GO; GO:0045887; P:positive regulation of synaptic assembly at neuromuscular junction; IMP:UniProtKB.
DR GO; GO:0045944; P:positive regulation of transcription by RNA polymerase II; IDA:MGI.
DR GO; GO:0043113; P:receptor clustering; IDA:MGI.
DR GO; GO:1902667; P:regulation of axon guidance; ISO:MGI.
DR GO; GO:0086036; P:regulation of cardiac muscle cell membrane potential; IDA:BHF-UCL.
DR GO; GO:0055117; P:regulation of cardiac muscle contraction; IDA:BHF-UCL.
DR GO; GO:0043087; P:regulation of GTPase activity; IDA:UniProtKB.
DR GO; GO:0070507; P:regulation of microtubule cytoskeleton organization; ISO:MGI.
DR GO; GO:0001932; P:regulation of protein phosphorylation; ISO:MGI.
DR GO; GO:0050807; P:regulation of synapse organization; ISO:MGI.
DR GO; GO:0071340; P:skeletal muscle acetylcholine-gated channel clustering; ISO:MGI.
DR GO; GO:0007416; P:synapse assembly; ISO:MGI.
DR GO; GO:0009888; P:tissue development; IBA:GO_Central.
DR CDD; cd00055; EGF_Lam; 2.
DR CDD; cd00110; LamG; 3.
DR Gene3D; 3.30.70.960; -; 1.
DR InterPro; IPR013320; ConA-like_dom_sf.
DR InterPro; IPR001881; EGF-like_Ca-bd_dom.
DR InterPro; IPR000742; EGF-like_dom.
DR InterPro; IPR003884; FacI_MAC.
DR InterPro; IPR003645; Fol_N.
DR InterPro; IPR002350; Kazal_dom.
DR InterPro; IPR036058; Kazal_dom_sf.
DR InterPro; IPR001791; Laminin_G.
DR InterPro; IPR002049; LE_dom.
DR InterPro; IPR000082; SEA_dom.
DR InterPro; IPR036364; SEA_dom_sf.
DR Pfam; PF00008; EGF; 3.
DR Pfam; PF00050; Kazal_1; 1.
DR Pfam; PF07648; Kazal_2; 8.
DR Pfam; PF00053; Laminin_EGF; 2.
DR Pfam; PF00054; Laminin_G_1; 3.
DR Pfam; PF01390; SEA; 1.
DR SMART; SM00181; EGF; 6.
DR SMART; SM00179; EGF_CA; 3.
DR SMART; SM00180; EGF_Lam; 2.
DR SMART; SM00057; FIMAC; 3.
DR SMART; SM00274; FOLN; 5.
DR SMART; SM00280; KAZAL; 9.
DR SMART; SM00282; LamG; 3.
DR SMART; SM00200; SEA; 1.
DR SUPFAM; SSF100895; SSF100895; 9.
DR SUPFAM; SSF49899; SSF49899; 3.
DR SUPFAM; SSF82671; SSF82671; 1.
DR PROSITE; PS00022; EGF_1; 6.
DR PROSITE; PS01186; EGF_2; 1.
DR PROSITE; PS50026; EGF_3; 4.
DR PROSITE; PS01248; EGF_LAM_1; 1.
DR PROSITE; PS50027; EGF_LAM_2; 2.
DR PROSITE; PS51465; KAZAL_2; 9.
DR PROSITE; PS50025; LAM_G_DOMAIN; 3.
DR PROSITE; PS50024; SEA; 1.
PE 1: Evidence at protein level;
KW 3D-structure; Alternative splicing; Calcium; Cell membrane;
KW Developmental protein; Differentiation; Disulfide bond; EGF-like domain;
KW Glycoprotein; Heparan sulfate; Laminin EGF-like domain; Membrane;
KW Metal-binding; Phosphoprotein; Proteoglycan; Reference proteome; Repeat;
KW Signal-anchor; Synapse; Transmembrane; Transmembrane helix.
FT CHAIN 1..1950
FT /note="Agrin"
FT /id="PRO_0000356178"
FT CHAIN 48..986
FT /note="Agrin N-terminal 110 kDa subunit"
FT /id="PRO_0000421617"
FT CHAIN 987..1950
FT /note="Agrin C-terminal 110 kDa subunit"
FT /id="PRO_0000421618"
FT CHAIN 987..1745
FT /note="Agrin C-terminal 90 kDa fragment"
FT /id="PRO_0000421619"
FT CHAIN 1746..1950
FT /note="Agrin C-terminal 22 kDa fragment"
FT /id="PRO_0000421620"
FT TOPO_DOM 1..26
FT /note="Cytoplasmic"
FT /evidence="ECO:0000255"
FT TRANSMEM 27..47
FT /note="Helical; Signal-anchor for type II membrane protein"
FT /evidence="ECO:0000255"
FT TOPO_DOM 48..1950
FT /note="Extracellular"
FT /evidence="ECO:0000255"
FT DOMAIN 86..139
FT /note="Kazal-like 1"
FT /evidence="ECO:0000255|PROSITE-ProRule:PRU00798"
FT DOMAIN 159..214
FT /note="Kazal-like 2"
FT /evidence="ECO:0000255|PROSITE-ProRule:PRU00798"
FT DOMAIN 232..286
FT /note="Kazal-like 3"
FT /evidence="ECO:0000255|PROSITE-ProRule:PRU00798"
FT DOMAIN 303..358
FT /note="Kazal-like 4"
FT /evidence="ECO:0000255|PROSITE-ProRule:PRU00798"
FT DOMAIN 379..431
FT /note="Kazal-like 5"
FT /evidence="ECO:0000255|PROSITE-ProRule:PRU00798"
FT DOMAIN 442..496
FT /note="Kazal-like 6"
FT /evidence="ECO:0000255|PROSITE-ProRule:PRU00798"
FT DOMAIN 502..561
FT /note="Kazal-like 7"
FT /evidence="ECO:0000255|PROSITE-ProRule:PRU00798"
FT DOMAIN 594..647
FT /note="Kazal-like 8"
FT /evidence="ECO:0000255|PROSITE-ProRule:PRU00798"
FT DOMAIN 688..741
FT /note="Laminin EGF-like 1"
FT /evidence="ECO:0000255|PROSITE-ProRule:PRU00460"
FT DOMAIN 742..788
FT /note="Laminin EGF-like 2"
FT /evidence="ECO:0000255|PROSITE-ProRule:PRU00460"
FT DOMAIN 812..866
FT /note="Kazal-like 9"
FT /evidence="ECO:0000255|PROSITE-ProRule:PRU00798"
FT DOMAIN 1014..1136
FT /note="SEA"
FT /evidence="ECO:0000255|PROSITE-ProRule:PRU00188"
FT DOMAIN 1211..1249
FT /note="EGF-like 1"
FT /evidence="ECO:0000255|PROSITE-ProRule:PRU00076"
FT DOMAIN 1254..1430
FT /note="Laminin G-like 1"
FT /evidence="ECO:0000255|PROSITE-ProRule:PRU00122"
FT DOMAIN 1431..1468
FT /note="EGF-like 2"
FT /evidence="ECO:0000255|PROSITE-ProRule:PRU00076"
FT DOMAIN 1470..1507
FT /note="EGF-like 3"
FT /evidence="ECO:0000255|PROSITE-ProRule:PRU00076"
FT DOMAIN 1517..1699
FT /note="Laminin G-like 2"
FT /evidence="ECO:0000255|PROSITE-ProRule:PRU00122"
FT DOMAIN 1700..1739
FT /note="EGF-like 4"
FT /evidence="ECO:0000255|PROSITE-ProRule:PRU00076"
FT DOMAIN 1775..1947
FT /note="Laminin G-like 3"
FT /evidence="ECO:0000255|PROSITE-ProRule:PRU00122"
FT REGION 892..971
FT /note="Disordered"
FT /evidence="ECO:0000256|SAM:MobiDB-lite"
FT REGION 1174..1217
FT /note="Disordered"
FT /evidence="ECO:0000256|SAM:MobiDB-lite"
FT COMPBIAS 892..933
FT /note="Polar residues"
FT /evidence="ECO:0000256|SAM:MobiDB-lite"
FT COMPBIAS 1174..1203
FT /note="Polar residues"
FT /evidence="ECO:0000256|SAM:MobiDB-lite"
FT BINDING 1822
FT /ligand="Ca(2+)"
FT /ligand_id="ChEBI:CHEBI:29108"
FT /evidence="ECO:0000250|UniProtKB:P25304"
FT BINDING 1839
FT /ligand="Ca(2+)"
FT /ligand_id="ChEBI:CHEBI:29108"
FT /evidence="ECO:0000250|UniProtKB:P25304"
FT BINDING 1889
FT /ligand="Ca(2+)"
FT /ligand_id="ChEBI:CHEBI:29108"
FT /evidence="ECO:0000250|UniProtKB:P25304"
FT BINDING 1891
FT /ligand="Ca(2+)"
FT /ligand_id="ChEBI:CHEBI:29108"
FT /evidence="ECO:0000250|UniProtKB:P25304"
FT SITE 986..987
FT /note="Cleavage, alpha site; by neurotrypsin"
FT /evidence="ECO:0000250"
FT SITE 1134
FT /note="Alternative splice site to produce 'x' isoforms"
FT SITE 1633
FT /note="Alternative splice site to produce 'y' isoforms"
FT SITE 1744
FT /note="Critical for cleavage by neurotrypsin"
FT /evidence="ECO:0000250"
FT SITE 1745..1746
FT /note="Cleavage, beta site; by neurotrypsin"
FT /evidence="ECO:0000250"
FT SITE 1770
FT /note="Alternative splice site to produce 'z' isoforms"
FT SITE 1774
FT /note="Highly important for the agrin receptor complex
FT activity of the 'z' insert"
FT /evidence="ECO:0000250"
FT MOD_RES 569
FT /note="Phosphoserine"
FT /evidence="ECO:0007744|PubMed:21183079"
FT MOD_RES 571
FT /note="Phosphoserine"
FT /evidence="ECO:0007744|PubMed:21183079"
FT CARBOHYD 145
FT /note="N-linked (GlcNAc...) asparagine"
FT /evidence="ECO:0000255"
FT CARBOHYD 672
FT /note="N-linked (GlcNAc...) asparagine"
FT /evidence="ECO:0000255"
FT CARBOHYD 827
FT /note="N-linked (GlcNAc...) asparagine"
FT /evidence="ECO:0000255"
FT CARBOHYD 948
FT /note="N-linked (GlcNAc...) asparagine"
FT /evidence="ECO:0000255"
FT CARBOHYD 1717
FT /note="O-linked (Fuc...) serine"
FT /evidence="ECO:0000250|UniProtKB:P25304"
FT DISULFID 92..123
FT /evidence="ECO:0000255|PROSITE-ProRule:PRU00798"
FT DISULFID 97..116
FT /evidence="ECO:0000255|PROSITE-ProRule:PRU00798"
FT DISULFID 105..137
FT /evidence="ECO:0000255|PROSITE-ProRule:PRU00798"
FT DISULFID 165..198
FT /evidence="ECO:0000255|PROSITE-ProRule:PRU00798"
FT DISULFID 171..191
FT /evidence="ECO:0000255|PROSITE-ProRule:PRU00798"
FT DISULFID 180..212
FT /evidence="ECO:0000255|PROSITE-ProRule:PRU00798"
FT DISULFID 244..263
FT /evidence="ECO:0000255|PROSITE-ProRule:PRU00798"
FT DISULFID 252..284
FT /evidence="ECO:0000255|PROSITE-ProRule:PRU00798"
FT DISULFID 309..342
FT /evidence="ECO:0000255|PROSITE-ProRule:PRU00798"
FT DISULFID 316..335
FT /evidence="ECO:0000255|PROSITE-ProRule:PRU00798"
FT DISULFID 324..356
FT /evidence="ECO:0000255|PROSITE-ProRule:PRU00798"
FT DISULFID 385..415
FT /evidence="ECO:0000255|PROSITE-ProRule:PRU00798"
FT DISULFID 389..408
FT /evidence="ECO:0000255|PROSITE-ProRule:PRU00798"
FT DISULFID 397..429
FT /evidence="ECO:0000255|PROSITE-ProRule:PRU00798"
FT DISULFID 448..480
FT /evidence="ECO:0000255|PROSITE-ProRule:PRU00798"
FT DISULFID 454..473
FT /evidence="ECO:0000255|PROSITE-ProRule:PRU00798"
FT DISULFID 462..494
FT /evidence="ECO:0000255|PROSITE-ProRule:PRU00798"
FT DISULFID 508..545
FT /evidence="ECO:0000255|PROSITE-ProRule:PRU00798"
FT DISULFID 518..538
FT /evidence="ECO:0000255|PROSITE-ProRule:PRU00798"
FT DISULFID 527..559
FT /evidence="ECO:0000255|PROSITE-ProRule:PRU00798"
FT DISULFID 600..631
FT /evidence="ECO:0000255|PROSITE-ProRule:PRU00798"
FT DISULFID 604..624
FT /evidence="ECO:0000255|PROSITE-ProRule:PRU00798"
FT DISULFID 613..645
FT /evidence="ECO:0000255|PROSITE-ProRule:PRU00798"
FT DISULFID 688..700
FT /evidence="ECO:0000250"
FT DISULFID 690..707
FT /evidence="ECO:0000250"
FT DISULFID 709..718
FT /evidence="ECO:0000250"
FT DISULFID 721..739
FT /evidence="ECO:0000250"
FT DISULFID 742..754
FT /evidence="ECO:0000250"
FT DISULFID 744..761
FT /evidence="ECO:0000250"
FT DISULFID 763..772
FT /evidence="ECO:0000250"
FT DISULFID 775..786
FT /evidence="ECO:0000250"
FT DISULFID 818..850
FT /evidence="ECO:0000255|PROSITE-ProRule:PRU00798"
FT DISULFID 823..843
FT /evidence="ECO:0000255|PROSITE-ProRule:PRU00798"
FT DISULFID 832..864
FT /evidence="ECO:0000255|PROSITE-ProRule:PRU00798"
FT DISULFID 1215..1226
FT /evidence="ECO:0000250"
FT DISULFID 1220..1237
FT /evidence="ECO:0000250"
FT DISULFID 1239..1248
FT /evidence="ECO:0000250"
FT DISULFID 1401..1430
FT /evidence="ECO:0000250"
FT DISULFID 1435..1446
FT /evidence="ECO:0000250"
FT DISULFID 1440..1456
FT /evidence="ECO:0000250"
FT DISULFID 1458..1467
FT /evidence="ECO:0000250"
FT DISULFID 1474..1485
FT /evidence="ECO:0000250"
FT DISULFID 1479..1495
FT /evidence="ECO:0000250"
FT DISULFID 1497..1506
FT /evidence="ECO:0000250"
FT DISULFID 1704..1718
FT /evidence="ECO:0000250"
FT DISULFID 1712..1727
FT /evidence="ECO:0000250"
FT DISULFID 1729..1738
FT /evidence="ECO:0000250"
FT DISULFID 1921..1947
FT /evidence="ECO:0000250"
FT VAR_SEQ 1..61
FT /note="Missing (in isoform 3)"
FT /evidence="ECO:0000303|PubMed:15489334"
FT /id="VSP_035995"
FT VAR_SEQ 1634..1637
FT /note="Missing (in isoform 2 and isoform 3)"
FT /evidence="ECO:0000303|PubMed:15489334"
FT /id="VSP_035996"
FT VAR_SEQ 1771..1788
FT /note="Missing (in isoform 2 and isoform 3)"
FT /evidence="ECO:0000303|PubMed:15489334"
FT /id="VSP_035997"
FT VARIANT 1061
FT /note="F -> S (in a mutant strain; shows symptoms similar
FT to the motor neuron disease, agrin-associated congenital
FT myasthenic syndrome (CMS) with progressive degradation of
FT the neuromuscular junction, decreased acetylcholine
FT receptor (AChR) density and increased subsynaptic
FT reticulum. Synapses eventually denervate and muscles
FT atrophy. There is decreased glycosylation and proteolytic
FT processing is altered due to changes in sensitivity to
FT neurotrypsin)"
FT /evidence="ECO:0000269|PubMed:21890498"
FT CONFLICT 1212
FT /note="P -> T (in Ref. 2; AAI50704)"
FT /evidence="ECO:0000305"
FT STRAND 1520..1525
FT /evidence="ECO:0007829|PDB:3PVE"
FT STRAND 1527..1530
FT /evidence="ECO:0007829|PDB:3PVE"
FT HELIX 1533..1535
FT /evidence="ECO:0007829|PDB:3PVE"
FT STRAND 1545..1555
FT /evidence="ECO:0007829|PDB:3PVE"
FT STRAND 1557..1564
FT /evidence="ECO:0007829|PDB:3PVE"
FT STRAND 1572..1578
FT /evidence="ECO:0007829|PDB:3PVE"
FT STRAND 1581..1590
FT /evidence="ECO:0007829|PDB:3PVE"
FT STRAND 1592..1596
FT /evidence="ECO:0007829|PDB:3PVE"
FT STRAND 1605..1614
FT /evidence="ECO:0007829|PDB:3PVE"
FT STRAND 1617..1622
FT /evidence="ECO:0007829|PDB:3PVE"
FT STRAND 1628..1631
FT /evidence="ECO:0007829|PDB:3PVE"
FT STRAND 1649..1652
FT /evidence="ECO:0007829|PDB:3PVE"
FT HELIX 1657..1659
FT /evidence="ECO:0007829|PDB:3PVE"
FT HELIX 1662..1664
FT /evidence="ECO:0007829|PDB:3PVE"
FT STRAND 1671..1679
FT /evidence="ECO:0007829|PDB:3PVE"
FT HELIX 1687..1689
FT /evidence="ECO:0007829|PDB:3PVE"
FT STRAND 1690..1695
FT /evidence="ECO:0007829|PDB:3PVE"
SQ SEQUENCE 1950 AA; 207539 MW; 0679A3F6D8BD1286 CRC64;
MPPLPLEHRP RQQPGASVLV RYFMIPCNIC LILLATSTLG FAVLLFLSNY KPGIHFTAAP
SMPPDVCRGM LCGFGAVCEP SVEDPGRASC VCKKNVCPAM VAPVCGSDAS TYSNECELQR
AQCNQQRRIR LLRQGPCGSR DPCANVTCSF GSTCVPSADG QTASCLCPTT CFGAPDGTVC
GSDGVDYPSE CQLLRHACAN QEHIFKKFDG PCDPCQGSMS DLNHICRVNP RTRHPEMLLR
PENCPAQHTP ICGDDGVTYE NDCVMSRIGA ARGLLLQKVR SGQCQTRDQC PETCQFNSVC
LSRRGRPHCS CDRVTCDGAY RPVCAQDGHT YDNDCWRQQA ECRQQQTIPP KHQGPCDQTP
SPCRGAQCAF GATCTVKNGK AVCECQRVCS GGYDPVCGSD GVTYGSVCEL ESMACTLGRE
IRVARRGPCD RCGQCRFGSL CEVETGRCVC PSECVESAQP VCGSDGHTYA SECELHVHAC
THQISLYVAS AGHCQTCGET VCTFGAVCSA GQCVCPRCEH PPPGPVCGSD GVTYLSACEL
REAACQQQVQ IEEARAGPCE PAECGSGGSG SGEDNACEQE LCRQHGGVWD EDSEDGPCVC
DFSCQSVLKS PVCGSDGVTY STECHLKKAR CEARQELYVA AQGACRGPTL APLLPMASPH
CAQTPYGCCQ DNVTAAQGVG LAGCPSTCHC NPHGSYSGTC DPVTGQCSCR PGVGGLRCDR
CEPGFWNFRG IVTDGHSGCT PCSCDPRGAV RDDCEQMTGL CSCRPGVAGP KCGQCPDGQA
LGHLGCEADP TTPVTCVEMH CEFGASCVEE AGFAQCVCPT LTCPEANSTK VCGSDGVTYG
NECQLKTIAC RQRLDISIQS LGPCRESVAP GVSPTSASMT TPRHILSRTL ASPHSSLPLS
PSTTAHDWPT PLPTSPQTVV GTPRSTAATP SDVASLATAI FRESGSTNGS GDEELSGDEE
ASGGGSGGLE PPVGSVVVTH GPPIERASCY NSPLGCCSDG KTPSLDSEGS NCPATKAFQG
VLELEGVEGQ ELFYTPEMAD PKSELFGETA RSIESTLDDL FRNSDVKKDF WSIRLRELGP
GKLVRAIVDV HFDPTTAFQA PDVGQALLQQ IQVSRPWALA VRRPLREHVR FLDFDWFPTF
FTGAATGTTA AVATARATTV SRLSASSVTP RVYPSYTSRP VGRTTAPLTT RRPPTTTASI
DRPRTPGPQR PPKSCDSQPC LHGGTCQDLD SGKGFSCSCT AGRAGTVCEK VQLPSVPAFK
GHSFLAFPTL RAYHTLRLAL EFRALETEGL LLYNGNARGK DFLALALLDG HVQFRFDTGS
GPAVLTSLVP VEPGRWHRLE LSRHWRQGTL SVDGEAPVVG ESPSGTDGLN LDTKLYVGGL
PEEQVATVLD RTSVGIGLKG CIRMLDINNQ QLELSDWQRA VVQSSGVGEC GDHPCSPNPC
HGGALCQALE AGVFLCQCPP GRFGPTCADE KNPCQPNPCH GSAPCHVLSR GGAKCACPLG
RSGSFCETVL ENAGSRPFLA DFNGFSYLEL KGLHTFERDL GEKMALEMVF LARGPSGLLL
YNGQKTDGKG DFVSLALHNR HLEFRYDLGK GAAIIRSKEP IALGTWVRVF LERNGRKGAL
QVGDGPRVLG ESPKSRKVPH TMLNLKEPLY VGGAPDFSKL ARGAAVASGF DGAIQLVSLR
GHQLLTQEHV LRAVDVAPFA GHPCTQAVDN PCLNGGSCIP REATYECLCP GGFSGLHCEK
GIVEKSVGDL ETLAFDGRTY IEYLNAVTES ELTNEIPAPE TLDSRALFSE KALQSNHFEL
SLRTEATQGL VLWIGKVGER ADYMALAIVD GHLQLSYDLG SQPVVLRSTV KVNTNRWLRV
RAHREHREGS LQVGNEAPVT GSSPLGATQL DTDGALWLGG LQKLPVGQAL PKAYGTGFVG
CLRDVVVGHR QLHLLEDAVT KPELRPCPTL
