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A2ASQ1

- AGRIN_MOUSE

UniProt

A2ASQ1 - AGRIN_MOUSE

Protein

Agrin

Gene

Agrn

Organism
Mus musculus (Mouse)
Status
Reviewed - Annotation score: 5 out of 5- Experimental evidence at protein leveli
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    • History
      Entry version 73 (01 Oct 2014)
      Sequence version 1 (20 Feb 2007)
      Previous versions | rss
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    Functioni

    Isoform 1: 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. This neuron-specific (z+) isoform is a component of the AGRN-LRP4 receptor complex that induces the phosphorylation and activation of MUSK. 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 homestasis 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 transmembrane agrin (TM-agrin) isoform, 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.
    Isoform 2 and isoform 3: these isoforms lacking the 'z' insert (z0) are muscle-specific, have no AChR clustering ability and may be involved in nervous system endothelial cell differentiation.
    Agrin N-terminal 110 kDa subunit: 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.By similarity
    Agrin C-terminal 22 kDa fragment: 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.

    Sites

    Feature keyPosition(s)LengthDescriptionGraphical viewFeature identifierActions
    Sitei986 – 9872Cleavage, alpha site; by neurotrypsinBy similarity
    Sitei1134 – 11341Alternative splice site to produce 'x' isoforms
    Sitei1633 – 16331Alternative splice site to produce 'y' isoforms
    Sitei1744 – 17441Critical for cleavage by neurotrypsinBy similarity
    Sitei1745 – 17462Cleavage, beta site; by neurotrypsinBy similarity
    Sitei1770 – 17701Alternative splice site to produce 'z' isoforms
    Sitei1774 – 17741Highly important for the agrin receptor complex activity of the 'z' insertBy similarity

    Regions

    Feature keyPosition(s)LengthDescriptionGraphical viewFeature identifierActions
    Calcium bindingi1811 – 188070By similarityAdd
    BLAST
    Calcium bindingi1822 – 189170By similarityAdd
    BLAST

    GO - Molecular functioni

    1. acetylcholine receptor regulator activity Source: MGI
    2. calcium ion binding Source: UniProtKB
    3. chondroitin sulfate binding Source: UniProtKB
    4. dystroglycan binding Source: UniProtKB
    5. heparan sulfate proteoglycan binding Source: UniProtKB
    6. protein binding Source: UniProt
    7. sialic acid binding Source: UniProtKB

    GO - Biological processi

    1. cell differentiation Source: UniProtKB-KW
    2. multicellular organismal development Source: UniProtKB-KW
    3. neuromuscular junction development Source: MGI
    4. neurotransmitter receptor metabolic process Source: MGI
    5. plasma membrane organization Source: MGI
    6. positive regulation of filopodium assembly Source: UniProtKB
    7. positive regulation of neuron apoptotic process Source: MGI
    8. positive regulation of protein binding Source: UniProt
    9. positive regulation of protein geranylgeranylation Source: UniProtKB
    10. positive regulation of protein phosphorylation Source: UniProtKB
    11. positive regulation of Rho GTPase activity Source: UniProtKB
    12. positive regulation of synaptic growth at neuromuscular junction Source: UniProtKB
    13. positive regulation of transcription from RNA polymerase II promoter Source: MGI
    14. receptor clustering Source: MGI
    15. regulation of Rac GTPase activity Source: UniProtKB
    16. regulation of receptor activity Source: GOC
    17. regulation of synaptic growth at neuromuscular junction Source: MGI
    18. synaptic transmission Source: MGI

    Keywords - Molecular functioni

    Developmental protein

    Keywords - Biological processi

    Differentiation

    Keywords - Ligandi

    Calcium

    Enzyme and pathway databases

    ReactomeiREACT_196489. A tetrasaccharide linker sequence is required for GAG synthesis.
    REACT_196606. ECM proteoglycans.
    REACT_196607. Non-integrin membrane-ECM interactions.
    REACT_198569. Retinoid metabolism and transport.
    REACT_198654. HS-GAG biosynthesis.
    REACT_198967. HS-GAG degradation.
    REACT_216309. Integrin cell surface interactions.

    Names & Taxonomyi

    Protein namesi
    Recommended name:
    Agrin
    Cleaved into the following 4 chains:
    Gene namesi
    Name:Agrn
    Synonyms:Agrin
    OrganismiMus musculus (Mouse)
    Taxonomic identifieri10090 [NCBI]
    Taxonomic lineageiEukaryotaMetazoaChordataCraniataVertebrataEuteleostomiMammaliaEutheriaEuarchontogliresGliresRodentiaSciurognathiMuroideaMuridaeMurinaeMusMus
    ProteomesiUP000000589: Chromosome 4

    Organism-specific databases

    MGIiMGI:87961. Agrn.

    Subcellular locationi

    GO - Cellular componenti

    1. basal lamina Source: MGI
    2. basement membrane Source: MGI
    3. cell junction Source: UniProtKB-KW
    4. cell surface Source: MGI
    5. extracellular region Source: Reactome
    6. extracellular space Source: MGI
    7. Golgi lumen Source: Reactome
    8. integral component of membrane Source: UniProtKB-KW
    9. plasma membrane Source: UniProtKB-SubCell
    10. synapse Source: MGI

    Keywords - Cellular componenti

    Cell junction, Cell membrane, Membrane, Synapse

    Pathology & Biotechi

    Disruption phenotypei

    Z-/z- mice lacking the 'z' insert are stillborn or die immediately after birth. They did not inflate their lungs and were never seen to move spontaneously. An intramuscular nerve is formed and axons leave the nerve and branch but do not stop and arborize. AChR clusters were fewer in number, about 30% smaller in size and lower in density. Transgenic null (Tg/Agrn -/-) mice, exhibit atrophied muscle due to denervation and are smaller than normal littermates. There is impairment of locomotory behavior and half the mice die after 50 days. There is a greatly reduced number of synapses and about 30% loss of postsynaptic spines and a decrease in the length of dendrites in cortical neurons.2 Publications

    PTM / Processingi

    Molecule processing

    Feature keyPosition(s)LengthDescriptionGraphical viewFeature identifierActions
    Chaini1 – 19501950AgrinPRO_0000356178Add
    BLAST
    Chaini48 – 986939Agrin N-terminal 110 kDa subunitPRO_0000421617Add
    BLAST
    Chaini987 – 1950964Agrin C-terminal 110 kDa subunitPRO_0000421618Add
    BLAST
    Chaini987 – 1745759Agrin C-terminal 90 kDa fragmentPRO_0000421619Add
    BLAST
    Chaini1746 – 1950205Agrin C-terminal 22 kDa fragmentPRO_0000421620Add
    BLAST

    Amino acid modifications

    Feature keyPosition(s)LengthDescriptionGraphical viewFeature identifierActions
    Disulfide bondi97 ↔ 116By similarity
    Disulfide bondi105 ↔ 137By similarity
    Glycosylationi145 – 1451N-linked (GlcNAc...)Sequence Analysis
    Disulfide bondi171 ↔ 191By similarity
    Disulfide bondi180 ↔ 212By similarity
    Disulfide bondi244 ↔ 263By similarity
    Disulfide bondi252 ↔ 284By similarity
    Disulfide bondi316 ↔ 335By similarity
    Disulfide bondi324 ↔ 356By similarity
    Disulfide bondi389 ↔ 408By similarity
    Disulfide bondi397 ↔ 429By similarity
    Disulfide bondi454 ↔ 473By similarity
    Disulfide bondi462 ↔ 494By similarity
    Disulfide bondi518 ↔ 538By similarity
    Disulfide bondi527 ↔ 559By similarity
    Disulfide bondi604 ↔ 624By similarity
    Disulfide bondi613 ↔ 645By similarity
    Glycosylationi672 – 6721N-linked (GlcNAc...)Sequence Analysis
    Disulfide bondi688 ↔ 700By similarity
    Disulfide bondi690 ↔ 707By similarity
    Disulfide bondi709 ↔ 718By similarity
    Disulfide bondi721 ↔ 739By similarity
    Disulfide bondi742 ↔ 754By similarity
    Disulfide bondi744 ↔ 761By similarity
    Disulfide bondi763 ↔ 772By similarity
    Disulfide bondi775 ↔ 786By similarity
    Disulfide bondi823 ↔ 843By similarity
    Glycosylationi827 – 8271N-linked (GlcNAc...)Sequence Analysis
    Disulfide bondi832 ↔ 864By similarity
    Glycosylationi948 – 9481N-linked (GlcNAc...)Sequence Analysis
    Disulfide bondi1215 ↔ 1226By similarity
    Disulfide bondi1220 ↔ 1237By similarity
    Disulfide bondi1239 ↔ 1248By similarity
    Disulfide bondi1401 ↔ 1430By similarity
    Disulfide bondi1435 ↔ 1446By similarity
    Disulfide bondi1440 ↔ 1456By similarity
    Disulfide bondi1458 ↔ 1467By similarity
    Disulfide bondi1474 ↔ 1485By similarity
    Disulfide bondi1479 ↔ 1495By similarity
    Disulfide bondi1497 ↔ 1506By similarity
    Disulfide bondi1704 ↔ 1718By similarity
    Disulfide bondi1712 ↔ 1727By similarity
    Disulfide bondi1729 ↔ 1738By similarity
    Disulfide bondi1921 ↔ 1947By similarity

    Post-translational modificationi

    Contains heparan and chondroitin sulfate chains and alpha-dystroglycan as well as N-linked and O-linked oligosaccharides. 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. 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.By similarity
    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). Cleavage is developmentally regulated. In developing brain, neurotrypsin-mediated cleavage occurs mainly during late fetal days and in the first postnatal week.3 Publications

    Keywords - PTMi

    Disulfide bond, Glycoprotein, Heparan sulfate, Proteoglycan

    Proteomic databases

    MaxQBiA2ASQ1.
    PaxDbiA2ASQ1.
    PRIDEiA2ASQ1.

    Expressioni

    Tissue specificityi

    Expressed in central nervous system (CNS) synapses such as in the cerebral cortex and hippocampus. Localizes to basal lamina of hippocampal blood vessels. Both (z+) and (z-) isoforms found in kidney, heart and cerebral vasculature.4 Publications

    Developmental stagei

    All (z+), (z-), (y+) and (y-) isoforms present throughout muscle fiber basal laminae in neonatal animals.

    Gene expression databases

    ArrayExpressiA2ASQ1.
    BgeeiA2ASQ1.
    GenevestigatoriA2ASQ1.

    Interactioni

    Subunit structurei

    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. Interacts with DAG1; the interaction is influenced by cell surface glycosaminoglycans and by alternative splicing of AGRN By similarity. Component of the AGRN-LRP4 complex that consists of a tetramer of two AGRN-LRP4 heterodimers. 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.By similarity1 Publication

    Structurei

    Secondary structure

    1
    1950
    Legend: HelixTurnBeta strand
    Show more details
    Feature keyPosition(s)LengthDescriptionGraphical viewFeature identifierActions
    Beta strandi1520 – 15256
    Beta strandi1527 – 15304
    Helixi1533 – 15353
    Beta strandi1545 – 155511
    Beta strandi1557 – 15648
    Beta strandi1572 – 15787
    Beta strandi1581 – 159010
    Beta strandi1592 – 15965
    Beta strandi1605 – 161410
    Beta strandi1617 – 16226
    Beta strandi1628 – 16314
    Beta strandi1649 – 16524
    Helixi1657 – 16593
    Helixi1662 – 16643
    Beta strandi1671 – 16799
    Helixi1687 – 16893
    Beta strandi1690 – 16956

    3D structure databases

    Select the link destinations:
    PDBe
    RCSB PDB
    PDBj
    Links Updated
    EntryMethodResolution (Å)ChainPositionsPDBsum
    3PVEX-ray1.40A/B1510-1701[»]
    ProteinModelPortaliA2ASQ1.
    SMRiA2ASQ1. Positions 67-646, 688-774, 1198-1949.
    ModBaseiSearch...
    MobiDBiSearch...

    Miscellaneous databases

    EvolutionaryTraceiA2ASQ1.

    Topological domain

    Feature keyPosition(s)LengthDescriptionGraphical viewFeature identifierActions
    Topological domaini1 – 2626CytoplasmicSequence AnalysisAdd
    BLAST
    Topological domaini48 – 19501903ExtracellularSequence AnalysisAdd
    BLAST

    Transmembrane

    Feature keyPosition(s)LengthDescriptionGraphical viewFeature identifierActions
    Transmembranei27 – 4721Helical; Signal-anchor for type II membrane proteinSequence AnalysisAdd
    BLAST

    Family & Domainsi

    Domains and Repeats

    Feature keyPosition(s)LengthDescriptionGraphical viewFeature identifierActions
    Domaini86 – 13954Kazal-like 1PROSITE-ProRule annotationAdd
    BLAST
    Domaini159 – 21456Kazal-like 2PROSITE-ProRule annotationAdd
    BLAST
    Domaini232 – 28655Kazal-like 3PROSITE-ProRule annotationAdd
    BLAST
    Domaini303 – 35856Kazal-like 4PROSITE-ProRule annotationAdd
    BLAST
    Domaini379 – 43153Kazal-like 5PROSITE-ProRule annotationAdd
    BLAST
    Domaini442 – 49655Kazal-like 6PROSITE-ProRule annotationAdd
    BLAST
    Domaini502 – 56160Kazal-like 7PROSITE-ProRule annotationAdd
    BLAST
    Domaini594 – 64754Kazal-like 8PROSITE-ProRule annotationAdd
    BLAST
    Domaini688 – 74154Laminin EGF-like 1PROSITE-ProRule annotationAdd
    BLAST
    Domaini742 – 78847Laminin EGF-like 2PROSITE-ProRule annotationAdd
    BLAST
    Domaini812 – 86655Kazal-like 9PROSITE-ProRule annotationAdd
    BLAST
    Domaini1014 – 1136123SEAPROSITE-ProRule annotationAdd
    BLAST
    Domaini1211 – 124939EGF-like 1PROSITE-ProRule annotationAdd
    BLAST
    Domaini1254 – 1430177Laminin G-like 1PROSITE-ProRule annotationAdd
    BLAST
    Domaini1431 – 146838EGF-like 2PROSITE-ProRule annotationAdd
    BLAST
    Domaini1470 – 150738EGF-like 3PROSITE-ProRule annotationAdd
    BLAST
    Domaini1517 – 1699183Laminin G-like 2PROSITE-ProRule annotationAdd
    BLAST
    Domaini1700 – 173940EGF-like 4PROSITE-ProRule annotationAdd
    BLAST
    Domaini1775 – 1947173Laminin G-like 3PROSITE-ProRule annotationAdd
    BLAST

    Compositional bias

    Feature keyPosition(s)LengthDescriptionGraphical viewFeature identifierActions
    Compositional biasi565 – 5728Gly/Ser-rich
    Compositional biasi900 – 95051Ser/Thr-richAdd
    BLAST
    Compositional biasi962 – 9687Gly/Ser-rich
    Compositional biasi1138 – 120669Ser/Thr-richAdd
    BLAST

    Domaini

    Both laminin G-like 2 (G2) and laminin G-like 3 (G3) domains are required for alpha-dystroglycan binding. G3 domain is required for C-terminal heparin, heparan sulfate and sialic acid binding By similarity.By similarity

    Sequence similaritiesi

    Contains 4 EGF-like domains.PROSITE-ProRule annotation
    Contains 9 Kazal-like domains.PROSITE-ProRule annotation
    Contains 2 laminin EGF-like domains.PROSITE-ProRule annotation
    Contains 3 laminin G-like domains.PROSITE-ProRule annotation
    Contains 1 SEA domain.PROSITE-ProRule annotation

    Keywords - Domaini

    EGF-like domain, Laminin EGF-like domain, Repeat, Signal-anchor, Transmembrane, Transmembrane helix

    Phylogenomic databases

    eggNOGiNOG312635.
    GeneTreeiENSGT00530000063501.
    HOGENOMiHOG000033860.
    HOVERGENiHBG080471.
    InParanoidiA2ASQ1.
    OrthoDBiEOG7BGHJZ.
    PhylomeDBiA2ASQ1.
    TreeFamiTF326548.

    Family and domain databases

    Gene3Di2.60.120.200. 4 hits.
    3.30.70.960. 1 hit.
    InterProiIPR008985. ConA-like_lec_gl_sf.
    IPR013320. ConA-like_subgrp.
    IPR000742. EG-like_dom.
    IPR013032. EGF-like_CS.
    IPR002049. EGF_laminin.
    IPR003645. Fol_N.
    IPR002350. Kazal_dom.
    IPR001791. Laminin_G.
    IPR000082. SEA_dom.
    [Graphical view]
    PfamiPF00008. EGF. 3 hits.
    PF00050. Kazal_1. 4 hits.
    PF07648. Kazal_2. 5 hits.
    PF00053. Laminin_EGF. 2 hits.
    PF00054. Laminin_G_1. 3 hits.
    PF01390. SEA. 1 hit.
    [Graphical view]
    SMARTiSM00181. EGF. 4 hits.
    SM00180. EGF_Lam. 2 hits.
    SM00274. FOLN. 5 hits.
    SM00280. KAZAL. 9 hits.
    SM00282. LamG. 3 hits.
    SM00200. SEA. 1 hit.
    [Graphical view]
    SUPFAMiSSF49899. SSF49899. 3 hits.
    SSF82671. SSF82671. 1 hit.
    PROSITEiPS00022. EGF_1. 6 hits.
    PS01186. EGF_2. 1 hit.
    PS50026. EGF_3. 4 hits.
    PS01248. EGF_LAM_1. 1 hit.
    PS50027. EGF_LAM_2. 2 hits.
    PS51465. KAZAL_2. 9 hits.
    PS50025. LAM_G_DOMAIN. 3 hits.
    PS50024. SEA. 1 hit.
    [Graphical view]

    Sequences (3)i

    Sequence statusi: Complete.

    Sequence processingi: The displayed sequence is further processed into a mature form.

    This entry describes 3 isoformsi produced by alternative splicing. Align

    Note: Many isoforms exist depending on the occurrence and length of inserts at the x, y or z splice site. There are 4 'z' isoforms produced with inserts of 0, 8, 11 or 19 AA. Isoforms differ in their acetylcholine receptor clustering activity and tissue specificity. In addition, a secreted isoform is produced by alternative usage of the first exon.

    Isoform 1 (identifier: A2ASQ1-1) [UniParc]FASTAAdd to Basket

    Also known as: Transmembrane agrin, TM-agrin

    This isoform has been chosen as the 'canonical' sequence. All positional information in this entry refers to it. This is also the sequence that appears in the downloadable versions of the entry.

    « Hide

    MPPLPLEHRP RQQPGASVLV RYFMIPCNIC LILLATSTLG FAVLLFLSNY     50
    KPGIHFTAAP SMPPDVCRGM LCGFGAVCEP SVEDPGRASC VCKKNVCPAM 100
    VAPVCGSDAS TYSNECELQR AQCNQQRRIR LLRQGPCGSR DPCANVTCSF 150
    GSTCVPSADG QTASCLCPTT CFGAPDGTVC GSDGVDYPSE CQLLRHACAN 200
    QEHIFKKFDG PCDPCQGSMS DLNHICRVNP RTRHPEMLLR PENCPAQHTP 250
    ICGDDGVTYE NDCVMSRIGA ARGLLLQKVR SGQCQTRDQC PETCQFNSVC 300
    LSRRGRPHCS CDRVTCDGAY RPVCAQDGHT YDNDCWRQQA ECRQQQTIPP 350
    KHQGPCDQTP SPCRGAQCAF GATCTVKNGK AVCECQRVCS GGYDPVCGSD 400
    GVTYGSVCEL ESMACTLGRE IRVARRGPCD RCGQCRFGSL CEVETGRCVC 450
    PSECVESAQP VCGSDGHTYA SECELHVHAC THQISLYVAS AGHCQTCGET 500
    VCTFGAVCSA GQCVCPRCEH PPPGPVCGSD GVTYLSACEL REAACQQQVQ 550
    IEEARAGPCE PAECGSGGSG SGEDNACEQE LCRQHGGVWD EDSEDGPCVC 600
    DFSCQSVLKS PVCGSDGVTY STECHLKKAR CEARQELYVA AQGACRGPTL 650
    APLLPMASPH CAQTPYGCCQ DNVTAAQGVG LAGCPSTCHC NPHGSYSGTC 700
    DPVTGQCSCR PGVGGLRCDR CEPGFWNFRG IVTDGHSGCT PCSCDPRGAV 750
    RDDCEQMTGL CSCRPGVAGP KCGQCPDGQA LGHLGCEADP TTPVTCVEMH 800
    CEFGASCVEE AGFAQCVCPT LTCPEANSTK VCGSDGVTYG NECQLKTIAC 850
    RQRLDISIQS LGPCRESVAP GVSPTSASMT TPRHILSRTL ASPHSSLPLS 900
    PSTTAHDWPT PLPTSPQTVV GTPRSTAATP SDVASLATAI FRESGSTNGS 950
    GDEELSGDEE ASGGGSGGLE PPVGSVVVTH GPPIERASCY NSPLGCCSDG 1000
    KTPSLDSEGS NCPATKAFQG VLELEGVEGQ ELFYTPEMAD PKSELFGETA 1050
    RSIESTLDDL FRNSDVKKDF WSIRLRELGP GKLVRAIVDV HFDPTTAFQA 1100
    PDVGQALLQQ IQVSRPWALA VRRPLREHVR FLDFDWFPTF FTGAATGTTA 1150
    AVATARATTV SRLSASSVTP RVYPSYTSRP VGRTTAPLTT RRPPTTTASI 1200
    DRPRTPGPQR PPKSCDSQPC LHGGTCQDLD SGKGFSCSCT AGRAGTVCEK 1250
    VQLPSVPAFK GHSFLAFPTL RAYHTLRLAL EFRALETEGL LLYNGNARGK 1300
    DFLALALLDG HVQFRFDTGS GPAVLTSLVP VEPGRWHRLE LSRHWRQGTL 1350
    SVDGEAPVVG ESPSGTDGLN LDTKLYVGGL PEEQVATVLD RTSVGIGLKG 1400
    CIRMLDINNQ QLELSDWQRA VVQSSGVGEC GDHPCSPNPC HGGALCQALE 1450
    AGVFLCQCPP GRFGPTCADE KNPCQPNPCH GSAPCHVLSR GGAKCACPLG 1500
    RSGSFCETVL ENAGSRPFLA DFNGFSYLEL KGLHTFERDL GEKMALEMVF 1550
    LARGPSGLLL YNGQKTDGKG DFVSLALHNR HLEFRYDLGK GAAIIRSKEP 1600
    IALGTWVRVF LERNGRKGAL QVGDGPRVLG ESPKSRKVPH TMLNLKEPLY 1650
    VGGAPDFSKL ARGAAVASGF DGAIQLVSLR GHQLLTQEHV LRAVDVAPFA 1700
    GHPCTQAVDN PCLNGGSCIP REATYECLCP GGFSGLHCEK GIVEKSVGDL 1750
    ETLAFDGRTY IEYLNAVTES ELTNEIPAPE TLDSRALFSE KALQSNHFEL 1800
    SLRTEATQGL VLWIGKVGER ADYMALAIVD GHLQLSYDLG SQPVVLRSTV 1850
    KVNTNRWLRV RAHREHREGS LQVGNEAPVT GSSPLGATQL DTDGALWLGG 1900
    LQKLPVGQAL PKAYGTGFVG CLRDVVVGHR QLHLLEDAVT KPELRPCPTL 1950
    Length:1,950
    Mass (Da):207,539
    Last modified:February 20, 2007 - v1
    Checksum:i0679A3F6D8BD1286
    GO
    Isoform 2 (identifier: A2ASQ1-2) [UniParc]FASTAAdd to Basket

    The sequence of this isoform differs from the canonical sequence as follows:
         1634-1637: Missing.
         1771-1788: Missing.

    Show »
    Length:1,928
    Mass (Da):205,041
    Checksum:i8D720587D8FCA978
    GO
    Isoform 3 (identifier: A2ASQ1-3) [UniParc]FASTAAdd to Basket

    The sequence of this isoform differs from the canonical sequence as follows:
         1-61: Missing.
         1634-1637: Missing.
         1771-1788: Missing.

    Show »
    Length:1,867
    Mass (Da):198,336
    Checksum:iD3CCD34419F1FE14
    GO

    Sequence cautioni

    The sequence CAM14888.1 differs from that shown. Reason: Erroneous gene model prediction.

    Experimental Info

    Feature keyPosition(s)LengthDescriptionGraphical viewFeature identifierActions
    Sequence conflicti1212 – 12121P → T in AAI50704. (PubMed:15489334)Curated

    Natural variant

    Feature keyPosition(s)LengthDescriptionGraphical viewFeature identifierActions
    Natural varianti1061 – 10611F → S in a mutant strain; shows symptoms similar to the motor neuron disease, agrin-associated congenital myasthenic syndrome (CMS) with progressive degradation of the neuromuscular junction, decreased acetylcholine receptor (AChR) density and increased subsynaptic reticulum. Synapses eventually denervate and muscles atrophy. There is decreased glycosylation and proteolytic processing is altered due to changes in sensitivity to neurotrypsin. 1 Publication

    Alternative sequence

    Feature keyPosition(s)LengthDescriptionGraphical viewFeature identifierActions
    Alternative sequencei1 – 6161Missing in isoform 3. 1 PublicationVSP_035995Add
    BLAST
    Alternative sequencei1634 – 16374Missing in isoform 2 and isoform 3. 1 PublicationVSP_035996
    Alternative sequencei1771 – 178818Missing in isoform 2 and isoform 3. 1 PublicationVSP_035997Add
    BLAST

    Sequence databases

    Select the link destinations:
    EMBL
    GenBank
    DDBJ
    Links Updated
    AL928667 Genomic DNA. Translation: CAM14888.1. Sequence problems.
    AL928667 Genomic DNA. Translation: CAM14889.1.
    AL928667 Genomic DNA. Translation: CAM14890.1.
    BC150703 mRNA. Translation: AAI50704.1.
    UniGeneiMm.273098.

    Genome annotation databases

    EnsembliENSMUST00000105575; ENSMUSP00000101200; ENSMUSG00000041936. [A2ASQ1-1]
    UCSCiuc008wgf.2. mouse. [A2ASQ1-2]
    uc008wgg.1. mouse. [A2ASQ1-1]

    Keywords - Coding sequence diversityi

    Alternative splicing, Polymorphism

    Cross-referencesi

    Sequence databases

    Select the link destinations:
    EMBL
    GenBank
    DDBJ
    Links Updated
    AL928667 Genomic DNA. Translation: CAM14888.1 . Sequence problems.
    AL928667 Genomic DNA. Translation: CAM14889.1 .
    AL928667 Genomic DNA. Translation: CAM14890.1 .
    BC150703 mRNA. Translation: AAI50704.1 .
    UniGenei Mm.273098.

    3D structure databases

    Select the link destinations:
    PDBe
    RCSB PDB
    PDBj
    Links Updated
    Entry Method Resolution (Å) Chain Positions PDBsum
    3PVE X-ray 1.40 A/B 1510-1701 [» ]
    ProteinModelPortali A2ASQ1.
    SMRi A2ASQ1. Positions 67-646, 688-774, 1198-1949.
    ModBasei Search...
    MobiDBi Search...

    Proteomic databases

    MaxQBi A2ASQ1.
    PaxDbi A2ASQ1.
    PRIDEi A2ASQ1.

    Protocols and materials databases

    Structural Biology Knowledgebase Search...

    Genome annotation databases

    Ensembli ENSMUST00000105575 ; ENSMUSP00000101200 ; ENSMUSG00000041936 . [A2ASQ1-1 ]
    UCSCi uc008wgf.2. mouse. [A2ASQ1-2 ]
    uc008wgg.1. mouse. [A2ASQ1-1 ]

    Organism-specific databases

    MGIi MGI:87961. Agrn.

    Phylogenomic databases

    eggNOGi NOG312635.
    GeneTreei ENSGT00530000063501.
    HOGENOMi HOG000033860.
    HOVERGENi HBG080471.
    InParanoidi A2ASQ1.
    OrthoDBi EOG7BGHJZ.
    PhylomeDBi A2ASQ1.
    TreeFami TF326548.

    Enzyme and pathway databases

    Reactomei REACT_196489. A tetrasaccharide linker sequence is required for GAG synthesis.
    REACT_196606. ECM proteoglycans.
    REACT_196607. Non-integrin membrane-ECM interactions.
    REACT_198569. Retinoid metabolism and transport.
    REACT_198654. HS-GAG biosynthesis.
    REACT_198967. HS-GAG degradation.
    REACT_216309. Integrin cell surface interactions.

    Miscellaneous databases

    ChiTaRSi AGRN. mouse.
    EvolutionaryTracei A2ASQ1.
    PROi A2ASQ1.
    SOURCEi Search...

    Gene expression databases

    ArrayExpressi A2ASQ1.
    Bgeei A2ASQ1.
    Genevestigatori A2ASQ1.

    Family and domain databases

    Gene3Di 2.60.120.200. 4 hits.
    3.30.70.960. 1 hit.
    InterProi IPR008985. ConA-like_lec_gl_sf.
    IPR013320. ConA-like_subgrp.
    IPR000742. EG-like_dom.
    IPR013032. EGF-like_CS.
    IPR002049. EGF_laminin.
    IPR003645. Fol_N.
    IPR002350. Kazal_dom.
    IPR001791. Laminin_G.
    IPR000082. SEA_dom.
    [Graphical view ]
    Pfami PF00008. EGF. 3 hits.
    PF00050. Kazal_1. 4 hits.
    PF07648. Kazal_2. 5 hits.
    PF00053. Laminin_EGF. 2 hits.
    PF00054. Laminin_G_1. 3 hits.
    PF01390. SEA. 1 hit.
    [Graphical view ]
    SMARTi SM00181. EGF. 4 hits.
    SM00180. EGF_Lam. 2 hits.
    SM00274. FOLN. 5 hits.
    SM00280. KAZAL. 9 hits.
    SM00282. LamG. 3 hits.
    SM00200. SEA. 1 hit.
    [Graphical view ]
    SUPFAMi SSF49899. SSF49899. 3 hits.
    SSF82671. SSF82671. 1 hit.
    PROSITEi PS00022. EGF_1. 6 hits.
    PS01186. EGF_2. 1 hit.
    PS50026. EGF_3. 4 hits.
    PS01248. EGF_LAM_1. 1 hit.
    PS50027. EGF_LAM_2. 2 hits.
    PS51465. KAZAL_2. 9 hits.
    PS50025. LAM_G_DOMAIN. 3 hits.
    PS50024. SEA. 1 hit.
    [Graphical view ]
    ProtoNeti Search...

    Publicationsi

    1. Cited for: NUCLEOTIDE SEQUENCE [LARGE SCALE GENOMIC DNA].
      Strain: C57BL/6J.
    2. "The status, quality, and expansion of the NIH full-length cDNA project: the Mammalian Gene Collection (MGC)."
      The MGC Project Team
      Genome Res. 14:2121-2127(2004) [PubMed] [Europe PMC] [Abstract]
      Cited for: NUCLEOTIDE SEQUENCE [LARGE SCALE MRNA] (ISOFORM 3).
      Tissue: Brain.
    3. Cited for: FUNCTION IN NEUROMUSCULAR JUNCTION DEVELOPMENT, SUBCELLULAR LOCATION, FUNCTION IN PHOSPHORYLATION OF MUSK, INTERACTION WITH LRP4.
    4. "Selective regulation of agrin mRNA induction and alternative splicing in PC12 cells by Ras-dependent actions of nerve growth factor."
      Smith M.A., Fanger G.R., O'Connor L.T., Bridle P., Maue R.A.
      J. Biol. Chem. 272:15675-15681(1997) [PubMed] [Europe PMC] [Abstract]
      Cited for: REGULATION OF ALTERNATIVE SPLICING.
    5. "Interaction of agrin with laminin requires a coiled-coil conformation of the agrin-binding site within the laminin gamma1 chain."
      Kammerer R.A., Schulthess T., Landwehr R., Schumacher B., Lustig A., Yurchenco P.D., Ruegg M.A., Engel J., Denzer A.J.
      EMBO J. 18:6762-6770(1999) [PubMed] [Europe PMC] [Abstract]
      Cited for: LAMININ BINDING.
    6. "Alternatively spliced isoforms of nerve- and muscle-derived agrin: their roles at the neuromuscular junction."
      Burgess R.W., Nguyen Q.T., Son Y.J., Lichtman J.W., Sanes J.R.
      Neuron 23:33-44(1999) [PubMed] [Europe PMC] [Abstract]
      Cited for: ALTERNATIVE SPLICING, SUBCELLULAR LOCATION, DISRUPTION PHENOTYPE, TISSUE SPECIFICITY, FUNCTION.
    7. "Agrin isoforms with distinct amino termini: differential expression, localization, and function."
      Burgess R.W., Skarnes W.C., Sanes J.R.
      J. Cell Biol. 151:41-52(2000) [PubMed] [Europe PMC] [Abstract]
      Cited for: ALTERNATIVE SPLICING, SUBCELLULAR LOCATION, TISSUE SPECIFICITY, FUNCTION.
    8. "An alternative amino-terminus expressed in the central nervous system converts agrin to a type II transmembrane protein."
      Neumann F.R., Bittcher G., Annies M., Schumacher B., Kroger S., Ruegg M.A.
      Mol. Cell. Neurosci. 17:208-225(2001) [PubMed] [Europe PMC] [Abstract]
      Cited for: ALTERNATIVE SPLICING, SUBCELLULAR LOCATION.
    9. "The COOH-terminal domain of agrin signals via a synaptic receptor in central nervous system neurons."
      Hoover C.L., Hilgenberg L.G., Smith M.A.
      J. Cell Biol. 161:923-932(2003) [PubMed] [Europe PMC] [Abstract]
      Cited for: FUNCTION OF AGRIN C-TERMINAL 22 KDA FRAGMENT, SUBCELLULAR LOCATION.
    10. "Comprehensive identification of phosphorylation sites in postsynaptic density preparations."
      Trinidad J.C., Specht C.G., Thalhammer A., Schoepfer R., Burlingame A.L.
      Mol. Cell. Proteomics 5:914-922(2006) [PubMed] [Europe PMC] [Abstract]
      Cited for: IDENTIFICATION BY MASS SPECTROMETRY [LARGE SCALE ANALYSIS].
      Tissue: Brain.
    11. "Synapse loss in cortex of agrin-deficient mice after genetic rescue of perinatal death."
      Ksiazek I., Burkhardt C., Lin S., Seddik R., Maj M., Bezakova G., Jucker M., Arber S., Caroni P., Sanes J.R., Bettler B., Ruegg M.A.
      J. Neurosci. 27:7183-7195(2007) [PubMed] [Europe PMC] [Abstract]
      Cited for: DISRUPTION PHENOTYPE, TISSUE SPECIFICITY, SUBCELLULAR LOCATION, FUNCTION.
    12. Cited for: PROTEOLYTIC PROCESSING, IDENTIFICATION OF PROTEOLYTICALLY CLEAVED FRAGMENTS BY MASS SPECTROMETRY, SUBCELLULAR LOCATION, TISSUE SPECIFICITY.
    13. "Coincident pre- and postsynaptic activation induces dendritic filopodia via neurotrypsin-dependent agrin cleavage."
      Matsumoto-Miyai K., Sokolowska E., Zurlinden A., Gee C.E., Luscher D., Hettwer S., Wolfel J., Ladner A.P., Ster J., Gerber U., Rulicke T., Kunz B., Sonderegger P.
      Cell 136:1161-1171(2009) [PubMed] [Europe PMC] [Abstract]
      Cited for: PROTEOLYTIC PROCESSING, FUNCTION.
    14. "Rescuing Z+ agrin splicing in Nova null mice restores synapse formation and unmasks a physiologic defect in motor neuron firing."
      Ruggiu M., Herbst R., Kim N., Jevsek M., Fak J.J., Mann M.A., Fischbach G., Burden S.J., Darnell R.B.
      Proc. Natl. Acad. Sci. U.S.A. 106:3513-3518(2009) [PubMed] [Europe PMC] [Abstract]
      Cited for: REGULATION OF ALTERNATIVE SPLICING AT THE Z SITE.
    15. "Destabilization of the neuromuscular junction by proteolytic cleavage of agrin results in precocious sarcopenia."
      Butikofer L., Zurlinden A., Bolliger M.F., Kunz B., Sonderegger P.
      FASEB J. 25:4378-4393(2011) [PubMed] [Europe PMC] [Abstract]
      Cited for: PROTEOLYTIC PROCESSING, FUNCTION, MOUSE MODEL OF PRECOCIOUS SARCOPENIA.
    16. "A valid mouse model of AGRIN-associated congenital myasthenic syndrome."
      Bogdanik L.P., Burgess R.W.
      Hum. Mol. Genet. 20:4617-4633(2011) [PubMed] [Europe PMC] [Abstract]
      Cited for: VARIANT A MUTANT STRAIN SER-1061, CHARACTERIZATION OF A MOUSE MODEL OF AGRIN-ASSOCIATED CONGENITAL MYASTHENIC SYNDROME.
    17. "Structural and biophysical characterisation of agrin laminin G3 domain constructs."
      Tidow H., Mattle D., Nissen P.
      Protein Eng. Des. Sel. 24:219-224(2011) [PubMed] [Europe PMC] [Abstract]
      Cited for: STRUCTURAL CHARACTERISTICS OF LAMININ G3 DOMAIN.
    18. "Crystal structure of the g2 domain of agrin from Mus musculus."
      New York structural genomix research consortium (NYSGXRC)
      Submitted (JAN-2011) to the PDB data bank
      Cited for: X-RAY CRYSTALLOGRAPHY (1.4 ANGSTROMS) OF 1510-1701.

    Entry informationi

    Entry nameiAGRIN_MOUSE
    AccessioniPrimary (citable) accession number: A2ASQ1
    Secondary accession number(s): A2ASP9, A2ASQ0, B2RWU1
    Entry historyi
    Integrated into UniProtKB/Swiss-Prot: December 16, 2008
    Last sequence update: February 20, 2007
    Last modified: October 1, 2014
    This is version 73 of the entry and version 1 of the sequence. [Complete history]
    Entry statusiReviewed (UniProtKB/Swiss-Prot)
    Annotation programChordata Protein Annotation Program

    Miscellaneousi

    Miscellaneous

    Mice that have excessive neurotrypsin-mediated agrin cleavage, exhibit pathological symptoms characteristic of precocious sarcopenia, with fragmentation and disassembly of the neuromuscular junction (NMJ).1 Publication

    Keywords - Technical termi

    3D-structure, Complete proteome, Reference proteome

    Documents

    1. MGD cross-references
      Mouse Genome Database (MGD) cross-references in UniProtKB/Swiss-Prot
    2. PDB cross-references
      Index of Protein Data Bank (PDB) cross-references
    3. SIMILARITY comments
      Index of protein domains and families

    External Data

    Dasty 3