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Database: UniProt
Entry: A2ASQ1
LinkDB: A2ASQ1
Original site: A2ASQ1 
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   16-JAN-2019, entry version 111.
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;
OC   Mammalia; Eutheria; Euarchontoglires; Glires; Rodentia; Myomorpha;
OC   Muroidea; Muridae; 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.,
RA   She X., Bult C.J., Agarwala R., Cherry J.L., DiCuccio M., Hlavina W.,
RA   Kapustin Y., Meric P., Maglott D., Birtle Z., Marques A.C., Graves T.,
RA   Zhou S., Teague B., Potamousis K., Churas C., Place M., Herschleb J.,
RA   Runnheim R., Forrest D., Amos-Landgraf J., Schwartz D.C., Cheng Z.,
RA   Lindblad-Toh K., Eichler E.E., Ponting C.P.;
RT   "Lineage-specific biology revealed by a finished genome assembly of
RT   the 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
RT   project: 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.,
RA   Ryan T.E., Gies D.R., Shah S., Mattsson K., Burden S.J.,
RA   DiStefano P.S., 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
RT   in 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
RT   of 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,
RP   TISSUE 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:
RT   their 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.,
RA   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
RP   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.,
RA   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
RT   of perinatal death.";
RL   J. Neurosci. 27:7183-7195(2007).
RN   [12]
RP   PROTEOLYTIC PROCESSING, IDENTIFICATION OF PROTEOLYTICALLY CLEAVED
RP   FRAGMENTS BY MASS SPECTROMETRY, SUBCELLULAR LOCATION, AND TISSUE
RP   SPECIFICITY.
RX   PubMed=18230682; DOI=10.1096/fj.07-100008;
RA   Stephan A., Mateos J.M., Kozlov S.V., Cinelli P., Kistler A.D.,
RA   Hettwer S., 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
RT   filopodia 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.,
RA   Fischbach G., Burden S.J., Darnell R.B.;
RT   "Rescuing Z+ agrin splicing in Nova null mice restores synapse
RT   formation 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
RT   expression.";
RL   Cell 143:1174-1189(2010).
RN   [16]
RP   PROTEOLYTIC PROCESSING, FUNCTION, AND MOUSE MODEL OF PRECOCIOUS
RP   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
RT   of 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
RP   MODEL OF 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
RT   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
RT   domain 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
CC       that plays a central role in the formation and the maintenance of
CC       the neuromuscular junction (NMJ) and directs key events in
CC       postsynaptic differentiation. This neuron-specific (z+) isoform is
CC       a component of the AGRN-LRP4 receptor complex that induces the
CC       phosphorylation and activation of MUSK. The activation of MUSK in
CC       myotubes induces the formation of NMJ by regulating different
CC       processes including the transcription of specific genes and the
CC       clustering of AChR in the postsynaptic membrane. Calcium ions are
CC       required for maximal AChR clustering. AGRN function in neurons is
CC       highly regulated by alternative splicing, glycan binding and
CC       proteolytic processing. Modulates calcium ion homeostasis in
CC       neurons, specifically by inducing an increase in cytoplasmic
CC       calcium ions. Functions differentially in the central nervous
CC       system (CNS) by inhibiting the alpha(3)-subtype of Na+/K+-ATPase
CC       and evoking depolarization at CNS synapses. This transmembrane
CC       agrin (TM-agrin) isoform, the predominate form in neurons of the
CC       brain, induces dendritic filopodia and synapse formation in mature
CC       hippocampal neurons in large part due to the attached
CC       glycosaminoglycan chains and 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
CC       and may be involved in nervous system endothelial cell
CC       differentiation.
CC   -!- FUNCTION: Agrin N-terminal 110 kDa subunit: involved in regulation
CC       of neurite outgrowth probably due to the presence of the
CC       glycosaminoglcan (GAG) side chains of heparan and chondroitin
CC       sulfate attached to the Ser/Thr- and Gly/Ser-rich regions. Also
CC       involved in modulation of growth factor signaling (By similarity).
CC       {ECO:0000250, ECO:0000269|PubMed:10402191,
CC       ECO:0000269|PubMed:11018052, ECO:0000269|PubMed:12796478,
CC       ECO:0000269|PubMed:17611272, ECO:0000269|PubMed:19303856,
CC       ECO:0000269|PubMed:21885656, ECO:0000269|PubMed:8653787}.
CC   -!- FUNCTION: Agrin C-terminal 22 kDa fragment: this released fragment
CC       is 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)
CC       with TGF-beta family members, BMP2 AND BMP4; the interactions
CC       inhibit the activity of these growth factors. Interacts with
CC       TGFB1; the interaction enhances the activity of TGFB1. Interacts
CC       with DAG1; the interaction is influenced by cell surface
CC       glycosaminoglycans and by alternative splicing of AGRN (By
CC       similarity). Component of the AGRN-LRP4 complex that consists of a
CC       tetramer of two AGRN-LRP4 heterodimers. Interacts (via the laminin
CC       G-like 3 domain) directly with LRP4; the interaction is required
CC       for activation of MUSK and clustering of AChR and requires the
CC       'z8' insert present in the z(+8) isoforms. {ECO:0000250,
CC       ECO:0000269|PubMed:8653787}.
CC   -!- SUBCELLULAR LOCATION: Cell junction, synapse
CC       {ECO:0000269|PubMed:10402191, ECO:0000269|PubMed:12796478,
CC       ECO:0000269|PubMed:17611272, ECO:0000269|PubMed:18230682,
CC       ECO:0000269|PubMed:8653787}. Cell membrane
CC       {ECO:0000269|PubMed:11018052, ECO:0000269|PubMed:11161480};
CC       Single-pass 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
CC         length of inserts at the x, y or z splice site. There are 4 'z'
CC         isoforms produced with inserts of 0, 8, 11 or 19 AA. Isoforms
CC         differ in their acetylcholine receptor clustering activity and
CC         tissue specificity. In addition, a secreted isoform is produced
CC         by alternative usage of the 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)
CC       synapses such as in the cerebral cortex and hippocampus. Localizes
CC       to basal lamina of hippocampal blood vessels. Both (z+) and (z-)
CC       isoforms found 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
CC       present throughout muscle fiber basal laminae in neonatal animals.
CC   -!- DOMAIN: Both laminin G-like 2 (G2) and laminin G-like 3 (G3)
CC       domains are required for alpha-dystroglycan binding. G3 domain is
CC       required for C-terminal heparin, heparan sulfate and sialic acid
CC       binding (By similarity). {ECO:0000250}.
CC   -!- PTM: Contains heparan and chondroitin sulfate chains and alpha-
CC       dystroglycan as well as N-linked and O-linked oligosaccharides.
CC       Heparin and heparin sulfate binding in the G3 domain is
CC       independent of calcium ions. Binds heparin with a stoichiometry of
CC       2:1. Binds sialic acid with a stoichiometry of 1:1 and binding
CC       requires calcium ions (By similarity). Glycosaminoglycans (GAGs),
CC       present in the N-terminal 110 kDa fragment, are required for
CC       induction of filopodia in hippocampal neurons. The first cluster
CC       (Gly/Ser-rich) for GAG attachment contains heparan sulfate (HS)
CC       chains and the second cluster (Ser/Thr-rich), contains chondroitin
CC       sulfate (CS) chains. {ECO:0000250}.
CC   -!- PTM: At synaptic junctions, cleaved at two conserved sites, alpha
CC       and beta, by neurotrypsin. Cleavage at the alpha-site produces the
CC       agrin N-terminal 110-kDa subunit and the agrin C-terminal 110-kDa
CC       subunit. Further cleavage of agrin C-terminal 110-kDa subunit at
CC       the beta site produces the C-terminal fragments, agrin C-terminal
CC       90 kDa fragment and agrin C-terminal 22 kDa fragment. Excessive
CC       cleavage at the beta-site releases large amounts of the agrin C-
CC       terminal 22 kDa fragment leading to destabilization at the
CC       neuromuscular junction (NMJ). Cleavage is developmentally
CC       regulated. In developing brain, neurotrypsin-mediated cleavage
CC       occurs mainly during late fetal days and in the first postnatal
CC       week. {ECO:0000269|PubMed:18230682, ECO:0000269|PubMed:19303856,
CC       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
CC       their lungs and were never seen to move spontaneously. An
CC       intramuscular nerve is formed and axons leave the nerve and branch
CC       but do not stop and arborize. AChR clusters were fewer in number,
CC       about 30% smaller in size and lower in density. Transgenic null
CC       (Tg/Agrn -/-) mice, exhibit atrophied muscle due to denervation
CC       and are smaller than normal littermates. There is impairment of
CC       locomotory behavior and half the mice die after 50 days. There is
CC       a greatly reduced number of synapses and about 30% loss of
CC       postsynaptic spines and a decrease in the length of dendrites in
CC       cortical neurons. {ECO:0000269|PubMed:10402191,
CC       ECO:0000269|PubMed:17611272}.
CC   -!- MISCELLANEOUS: Mice that have excessive neurotrypsin-mediated
CC       agrin cleavage, exhibit pathological symptoms characteristic of
CC       precocious sarcopenia, with fragmentation and disassembly of the
CC       neuromuscular junction (NMJ). {ECO:0000305|PubMed:21885656}.
CC   -!- SEQUENCE CAUTION:
CC       Sequence=CAM14888.1; Type=Erroneous gene model prediction; Evidence={ECO:0000305};
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   RefSeq; XP_011248479.1; XM_011250177.2. [A2ASQ1-1]
DR   UniGene; Mm.273098; -.
DR   PDB; 3PVE; X-ray; 1.40 A; A/B=1510-1701.
DR   PDBsum; 3PVE; -.
DR   ProteinModelPortal; A2ASQ1; -.
DR   SMR; A2ASQ1; -.
DR   IntAct; A2ASQ1; 2.
DR   STRING; 10090.ENSMUSP00000137931; -.
DR   iPTMnet; A2ASQ1; -.
DR   PhosphoSitePlus; A2ASQ1; -.
DR   MaxQB; A2ASQ1; -.
DR   PaxDb; A2ASQ1; -.
DR   PeptideAtlas; A2ASQ1; -.
DR   PRIDE; A2ASQ1; -.
DR   Ensembl; ENSMUST00000105575; ENSMUSP00000101200; ENSMUSG00000041936. [A2ASQ1-1]
DR   GeneID; 11603; -.
DR   UCSC; uc008wgg.1; mouse. [A2ASQ1-1]
DR   CTD; 375790; -.
DR   MGI; MGI:87961; Agrn.
DR   eggNOG; ENOG410ITSI; Eukaryota.
DR   eggNOG; ENOG410YKSA; LUCA.
DR   GeneTree; ENSGT00940000158337; -.
DR   HOGENOM; HOG000033860; -.
DR   HOVERGEN; HBG080471; -.
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   ChiTaRS; Agrn; mouse.
DR   EvolutionaryTrace; A2ASQ1; -.
DR   PRO; PR:A2ASQ1; -.
DR   Proteomes; UP000000589; Chromosome 4.
DR   Bgee; ENSMUSG00000041936; Expressed in 294 organ(s), highest expression level in brain blood vessel.
DR   ExpressionAtlas; A2ASQ1; baseline and differential.
DR   Genevisible; A2ASQ1; MM.
DR   GO; GO:0044295; C:axonal growth cone; ISO:MGI.
DR   GO; GO:0005604; C:basement membrane; IDA:MGI.
DR   GO; GO:0030054; C:cell junction; IEA:UniProtKB-KW.
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:0005829; C:cytosol; ISO:MGI.
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:0005886; C:plasma membrane; ISO:MGI.
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:0005201; F:extracellular matrix structural constituent; HDA:BHF-UCL.
DR   GO; GO:0043395; F:heparan sulfate proteoglycan binding; IDA:UniProtKB.
DR   GO; GO:0044325; F:ion channel binding; IPI:BHF-UCL.
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:0007268; P:chemical synaptic transmission; IDA:MGI.
DR   GO; GO:1903277; P:negative regulation of sodium ion export across plasma membrane; IDA:BHF-UCL.
DR   GO; GO:1903407; P:negative regulation of sodium:potassium-exchanging ATPase activity; 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:0043525; P:positive regulation of 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 growth at neuromuscular junction; IMP:UniProtKB.
DR   GO; GO:0045944; P:positive regulation of transcription by RNA polymerase II; IDA:MGI.
DR   GO; GO:0051290; P:protein heterotetramerization; ISO: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   Gene3D; 3.30.70.960; -; 1.
DR   InterPro; IPR013320; ConA-like_dom_sf.
DR   InterPro; IPR001881; EGF-like_Ca-bd_dom.
DR   InterPro; IPR013032; EGF-like_CS.
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; IPR002049; Laminin_EGF.
DR   InterPro; IPR001791; Laminin_G.
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 junction;
KW   Cell membrane; Complete proteome; Developmental protein;
KW   Differentiation; Disulfide bond; EGF-like domain; Glycoprotein;
KW   Heparan sulfate; Laminin EGF-like domain; Membrane; Phosphoprotein;
KW   Polymorphism; Proteoglycan; Reference proteome; Repeat; Signal-anchor;
KW   Synapse; Transmembrane; Transmembrane helix.
FT   CHAIN         1   1950       Agrin.
FT                                /FTId=PRO_0000356178.
FT   CHAIN        48    986       Agrin N-terminal 110 kDa subunit.
FT                                /FTId=PRO_0000421617.
FT   CHAIN       987   1950       Agrin C-terminal 110 kDa subunit.
FT                                /FTId=PRO_0000421618.
FT   CHAIN       987   1745       Agrin C-terminal 90 kDa fragment.
FT                                /FTId=PRO_0000421619.
FT   CHAIN      1746   1950       Agrin C-terminal 22 kDa fragment.
FT                                /FTId=PRO_0000421620.
FT   TOPO_DOM      1     26       Cytoplasmic. {ECO:0000255}.
FT   TRANSMEM     27     47       Helical; Signal-anchor for type II
FT                                membrane protein. {ECO:0000255}.
FT   TOPO_DOM     48   1950       Extracellular. {ECO:0000255}.
FT   DOMAIN       86    139       Kazal-like 1. {ECO:0000255|PROSITE-
FT                                ProRule:PRU00798}.
FT   DOMAIN      159    214       Kazal-like 2. {ECO:0000255|PROSITE-
FT                                ProRule:PRU00798}.
FT   DOMAIN      232    286       Kazal-like 3. {ECO:0000255|PROSITE-
FT                                ProRule:PRU00798}.
FT   DOMAIN      303    358       Kazal-like 4. {ECO:0000255|PROSITE-
FT                                ProRule:PRU00798}.
FT   DOMAIN      379    431       Kazal-like 5. {ECO:0000255|PROSITE-
FT                                ProRule:PRU00798}.
FT   DOMAIN      442    496       Kazal-like 6. {ECO:0000255|PROSITE-
FT                                ProRule:PRU00798}.
FT   DOMAIN      502    561       Kazal-like 7. {ECO:0000255|PROSITE-
FT                                ProRule:PRU00798}.
FT   DOMAIN      594    647       Kazal-like 8. {ECO:0000255|PROSITE-
FT                                ProRule:PRU00798}.
FT   DOMAIN      688    741       Laminin EGF-like 1. {ECO:0000255|PROSITE-
FT                                ProRule:PRU00460}.
FT   DOMAIN      742    788       Laminin EGF-like 2. {ECO:0000255|PROSITE-
FT                                ProRule:PRU00460}.
FT   DOMAIN      812    866       Kazal-like 9. {ECO:0000255|PROSITE-
FT                                ProRule:PRU00798}.
FT   DOMAIN     1014   1136       SEA. {ECO:0000255|PROSITE-
FT                                ProRule:PRU00188}.
FT   DOMAIN     1211   1249       EGF-like 1. {ECO:0000255|PROSITE-
FT                                ProRule:PRU00076}.
FT   DOMAIN     1254   1430       Laminin G-like 1. {ECO:0000255|PROSITE-
FT                                ProRule:PRU00122}.
FT   DOMAIN     1431   1468       EGF-like 2. {ECO:0000255|PROSITE-
FT                                ProRule:PRU00076}.
FT   DOMAIN     1470   1507       EGF-like 3. {ECO:0000255|PROSITE-
FT                                ProRule:PRU00076}.
FT   DOMAIN     1517   1699       Laminin G-like 2. {ECO:0000255|PROSITE-
FT                                ProRule:PRU00122}.
FT   DOMAIN     1700   1739       EGF-like 4. {ECO:0000255|PROSITE-
FT                                ProRule:PRU00076}.
FT   DOMAIN     1775   1947       Laminin G-like 3. {ECO:0000255|PROSITE-
FT                                ProRule:PRU00122}.
FT   CA_BIND    1811   1880       {ECO:0000250}.
FT   CA_BIND    1822   1891       {ECO:0000250}.
FT   COMPBIAS    565    572       Gly/Ser-rich.
FT   COMPBIAS    900    950       Ser/Thr-rich.
FT   COMPBIAS    962    968       Gly/Ser-rich.
FT   COMPBIAS   1138   1206       Ser/Thr-rich.
FT   SITE        986    987       Cleavage, alpha site; by neurotrypsin.
FT                                {ECO:0000250}.
FT   SITE       1134   1134       Alternative splice site to produce 'x'
FT                                isoforms.
FT   SITE       1633   1633       Alternative splice site to produce 'y'
FT                                isoforms.
FT   SITE       1744   1744       Critical for cleavage by neurotrypsin.
FT                                {ECO:0000250}.
FT   SITE       1745   1746       Cleavage, beta site; by neurotrypsin.
FT                                {ECO:0000250}.
FT   SITE       1770   1770       Alternative splice site to produce 'z'
FT                                isoforms.
FT   SITE       1774   1774       Highly important for the agrin receptor
FT                                complex activity of the 'z' insert.
FT                                {ECO:0000250}.
FT   MOD_RES     569    569       Phosphoserine.
FT                                {ECO:0000244|PubMed:21183079}.
FT   MOD_RES     571    571       Phosphoserine.
FT                                {ECO:0000244|PubMed:21183079}.
FT   CARBOHYD    145    145       N-linked (GlcNAc...) asparagine.
FT                                {ECO:0000255}.
FT   CARBOHYD    672    672       N-linked (GlcNAc...) asparagine.
FT                                {ECO:0000255}.
FT   CARBOHYD    827    827       N-linked (GlcNAc...) asparagine.
FT                                {ECO:0000255}.
FT   CARBOHYD    948    948       N-linked (GlcNAc...) asparagine.
FT                                {ECO:0000255}.
FT   CARBOHYD   1717   1717       O-linked (Fuc...) serine.
FT                                {ECO:0000250|UniProtKB:P25304}.
FT   DISULFID     92    123       {ECO:0000255|PROSITE-ProRule:PRU00798}.
FT   DISULFID     97    116       {ECO:0000255|PROSITE-ProRule:PRU00798}.
FT   DISULFID    105    137       {ECO:0000255|PROSITE-ProRule:PRU00798}.
FT   DISULFID    165    198       {ECO:0000255|PROSITE-ProRule:PRU00798}.
FT   DISULFID    171    191       {ECO:0000255|PROSITE-ProRule:PRU00798}.
FT   DISULFID    180    212       {ECO:0000255|PROSITE-ProRule:PRU00798}.
FT   DISULFID    244    263       {ECO:0000255|PROSITE-ProRule:PRU00798}.
FT   DISULFID    252    284       {ECO:0000255|PROSITE-ProRule:PRU00798}.
FT   DISULFID    309    342       {ECO:0000255|PROSITE-ProRule:PRU00798}.
FT   DISULFID    316    335       {ECO:0000255|PROSITE-ProRule:PRU00798}.
FT   DISULFID    324    356       {ECO:0000255|PROSITE-ProRule:PRU00798}.
FT   DISULFID    385    415       {ECO:0000255|PROSITE-ProRule:PRU00798}.
FT   DISULFID    389    408       {ECO:0000255|PROSITE-ProRule:PRU00798}.
FT   DISULFID    397    429       {ECO:0000255|PROSITE-ProRule:PRU00798}.
FT   DISULFID    448    480       {ECO:0000255|PROSITE-ProRule:PRU00798}.
FT   DISULFID    454    473       {ECO:0000255|PROSITE-ProRule:PRU00798}.
FT   DISULFID    462    494       {ECO:0000255|PROSITE-ProRule:PRU00798}.
FT   DISULFID    508    545       {ECO:0000255|PROSITE-ProRule:PRU00798}.
FT   DISULFID    518    538       {ECO:0000255|PROSITE-ProRule:PRU00798}.
FT   DISULFID    527    559       {ECO:0000255|PROSITE-ProRule:PRU00798}.
FT   DISULFID    600    631       {ECO:0000255|PROSITE-ProRule:PRU00798}.
FT   DISULFID    604    624       {ECO:0000255|PROSITE-ProRule:PRU00798}.
FT   DISULFID    613    645       {ECO:0000255|PROSITE-ProRule:PRU00798}.
FT   DISULFID    688    700       {ECO:0000250}.
FT   DISULFID    690    707       {ECO:0000250}.
FT   DISULFID    709    718       {ECO:0000250}.
FT   DISULFID    721    739       {ECO:0000250}.
FT   DISULFID    742    754       {ECO:0000250}.
FT   DISULFID    744    761       {ECO:0000250}.
FT   DISULFID    763    772       {ECO:0000250}.
FT   DISULFID    775    786       {ECO:0000250}.
FT   DISULFID    818    850       {ECO:0000255|PROSITE-ProRule:PRU00798}.
FT   DISULFID    823    843       {ECO:0000255|PROSITE-ProRule:PRU00798}.
FT   DISULFID    832    864       {ECO:0000255|PROSITE-ProRule:PRU00798}.
FT   DISULFID   1215   1226       {ECO:0000250}.
FT   DISULFID   1220   1237       {ECO:0000250}.
FT   DISULFID   1239   1248       {ECO:0000250}.
FT   DISULFID   1401   1430       {ECO:0000250}.
FT   DISULFID   1435   1446       {ECO:0000250}.
FT   DISULFID   1440   1456       {ECO:0000250}.
FT   DISULFID   1458   1467       {ECO:0000250}.
FT   DISULFID   1474   1485       {ECO:0000250}.
FT   DISULFID   1479   1495       {ECO:0000250}.
FT   DISULFID   1497   1506       {ECO:0000250}.
FT   DISULFID   1704   1718       {ECO:0000250}.
FT   DISULFID   1712   1727       {ECO:0000250}.
FT   DISULFID   1729   1738       {ECO:0000250}.
FT   DISULFID   1921   1947       {ECO:0000250}.
FT   VAR_SEQ       1     61       Missing (in isoform 3).
FT                                {ECO:0000303|PubMed:15489334}.
FT                                /FTId=VSP_035995.
FT   VAR_SEQ    1634   1637       Missing (in isoform 2 and isoform 3).
FT                                {ECO:0000303|PubMed:15489334}.
FT                                /FTId=VSP_035996.
FT   VAR_SEQ    1771   1788       Missing (in isoform 2 and isoform 3).
FT                                {ECO:0000303|PubMed:15489334}.
FT                                /FTId=VSP_035997.
FT   VARIANT    1061   1061       F -> S (in a mutant strain; shows
FT                                symptoms similar to the motor neuron
FT                                disease, agrin-associated congenital
FT                                myasthenic syndrome (CMS) with
FT                                progressive degradation of the
FT                                neuromuscular junction, decreased
FT                                acetylcholine receptor (AChR) density and
FT                                increased subsynaptic reticulum. Synapses
FT                                eventually denervate and muscles atrophy.
FT                                There is decreased glycosylation and
FT                                proteolytic processing is altered due to
FT                                changes in sensitivity to neurotrypsin).
FT                                {ECO:0000269|PubMed:21890498}.
FT   CONFLICT   1212   1212       P -> T (in Ref. 2; AAI50704).
FT                                {ECO:0000305}.
FT   STRAND     1520   1525       {ECO:0000244|PDB:3PVE}.
FT   STRAND     1527   1530       {ECO:0000244|PDB:3PVE}.
FT   HELIX      1533   1535       {ECO:0000244|PDB:3PVE}.
FT   STRAND     1545   1555       {ECO:0000244|PDB:3PVE}.
FT   STRAND     1557   1564       {ECO:0000244|PDB:3PVE}.
FT   STRAND     1572   1578       {ECO:0000244|PDB:3PVE}.
FT   STRAND     1581   1590       {ECO:0000244|PDB:3PVE}.
FT   STRAND     1592   1596       {ECO:0000244|PDB:3PVE}.
FT   STRAND     1605   1614       {ECO:0000244|PDB:3PVE}.
FT   STRAND     1617   1622       {ECO:0000244|PDB:3PVE}.
FT   STRAND     1628   1631       {ECO:0000244|PDB:3PVE}.
FT   STRAND     1649   1652       {ECO:0000244|PDB:3PVE}.
FT   HELIX      1657   1659       {ECO:0000244|PDB:3PVE}.
FT   HELIX      1662   1664       {ECO:0000244|PDB:3PVE}.
FT   STRAND     1671   1679       {ECO:0000244|PDB:3PVE}.
FT   HELIX      1687   1689       {ECO:0000244|PDB:3PVE}.
FT   STRAND     1690   1695       {ECO:0000244|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
//
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