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Protein

Agrin

Gene

AGRN

Organism
Homo sapiens (Human)
Status
Reviewed-Annotation score: Annotation score: 5 out of 5-Experimental evidence at protein leveli

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. 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 homeostasis in neurons, specifically by inducing an increase in cytoplasmic calcium ions. Functions differentially in the central nervous system (CNS) by inhibiting the alpha(3)-subtype of Na+/K+-ATPase and evoking depolarization at CNS synapses. This secreted isoform forms a bridge, after release from motor neurons, to basal lamina through binding laminin via the NtA domain.
Isoform 2: transmembrane form that is the predominate form in neurons of the brain, induces dendritic filopodia and synapse formation in mature hippocampal neurons in large part due to the attached glycosaminoglycan chains and the action of Rho-family GTPases.
Isoform 1, isoform 4 and isoform 5: neuron-specific (z+) isoforms that contain C-terminal insertions of 8-19 AA are potent activators of AChR clustering. Isoform 5, agrin (z+8), containing the 8-AA insert, forms a receptor complex in myotubules containing the neuronal AGRN, the muscle-specific kinase MUSK and LRP4, a member of the LDL receptor family. The splicing factors, NOVA1 and NOVA2, regulate AGRN splicing and production of the 'z' isoforms.
Isoform 3 and isoform 6: lack any 'z' insert, are muscle-specific and may be involved in endothelial cell differentiation.
Agrin N-terminal 110 kDa subunit: is involved in regulation of neurite outgrowth probably due to the presence of the glycosaminoglcan (GAG) side chains of heparan and chondroitin sulfate attached to the Ser/Thr- and Gly/Ser-rich regions. Also involved in modulation of growth factor signaling (By similarity).By similarity2 Publications
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)DescriptionActionsGraphical viewLength
Sitei1250Alternative splice site to produce 'x' isoformsBy similarity1
Sitei1751Alternative splice site to produce 'y' isoformsBy similarity1
Sitei1862Critical for cleavage by neurotrypsinBy similarity1
Sitei1888Alternative splice site to produce 'z' isoformsBy similarity1
Sitei1892Highly important for the agrin receptor complex activity of the 'z(8)' insertBy similarity1

Regions

Feature keyPosition(s)DescriptionActionsGraphical viewLength
Calcium bindingi1940 – 2008By similarityAdd BLAST69

GO - Molecular functioni

  • calcium ion binding Source: UniProtKB
  • chondroitin sulfate binding Source: UniProtKB
  • dystroglycan binding Source: UniProtKB
  • heparan sulfate proteoglycan binding Source: UniProtKB
  • laminin binding Source: UniProtKB
  • sialic acid binding Source: UniProtKB
  • structural constituent of cytoskeleton Source: UniProtKB

GO - Biological processi

Complete GO annotation...

Keywords - Molecular functioni

Developmental protein

Keywords - Biological processi

Differentiation

Keywords - Ligandi

Calcium

Enzyme and pathway databases

BioCyciZFISH:G66-33274-MONOMER.
ReactomeiR-HSA-1971475. A tetrasaccharide linker sequence is required for GAG synthesis.
R-HSA-2022928. HS-GAG biosynthesis.
R-HSA-2024096. HS-GAG degradation.
R-HSA-216083. Integrin cell surface interactions.
R-HSA-3000171. Non-integrin membrane-ECM interactions.
R-HSA-3000178. ECM proteoglycans.
R-HSA-3560783. Defective B4GALT7 causes EDS, progeroid type.
R-HSA-3560801. Defective B3GAT3 causes JDSSDHD.
R-HSA-3656237. Defective EXT2 causes exostoses 2.
R-HSA-3656253. Defective EXT1 causes exostoses 1, TRPS2 and CHDS.
R-HSA-419037. NCAM1 interactions.
R-HSA-4420332. Defective B3GALT6 causes EDSP2 and SEMDJL1.
R-HSA-975634. Retinoid metabolism and transport.
SignaLinkiO00468.

Names & Taxonomyi

Protein namesi
Recommended name:
Agrin
Cleaved into the following 4 chains:
Gene namesi
Name:AGRN
Synonyms:AGRIN
OrganismiHomo sapiens (Human)
Taxonomic identifieri9606 [NCBI]
Taxonomic lineageiEukaryotaMetazoaChordataCraniataVertebrataEuteleostomiMammaliaEutheriaEuarchontogliresPrimatesHaplorrhiniCatarrhiniHominidaeHomo
Proteomesi
  • UP000005640 Componenti: Chromosome 1

Organism-specific databases

HGNCiHGNC:329. AGRN.

Subcellular locationi

Isoform 1 :
Isoform 2 :
  • Cell junctionsynapse By similarity
  • Cell membrane By similarity; Single-pass type II membrane protein By similarity

GO - Cellular componenti

  • basal lamina Source: UniProtKB
  • cell junction Source: UniProtKB-KW
  • cytoplasm Source: HPA
  • extracellular exosome Source: UniProtKB
  • extracellular matrix Source: UniProtKB
  • extracellular region Source: Reactome
  • Golgi lumen Source: Reactome
  • integral component of membrane Source: UniProtKB-KW
  • lysosomal lumen Source: Reactome
  • plasma membrane Source: HPA
  • synapse Source: UniProtKB
Complete GO annotation...

Keywords - Cellular componenti

Cell junction, Cell membrane, Extracellular matrix, Membrane, Secreted, Synapse

Pathology & Biotechi

Involvement in diseasei

Myasthenic syndrome, congenital, 8 (CMS8)3 Publications
The disease is caused by mutations affecting the gene represented in this entry.
Disease descriptionA form of congenital myasthenic syndrome, a group of disorders characterized by failure of neuromuscular transmission, including pre-synaptic, synaptic, and post-synaptic disorders that are not of autoimmune origin. Clinical features are easy fatigability and muscle weakness. CMS8 is an autosomal recessive disease characterized by prominent defects of both the pre- and postsynaptic regions. Affected individuals have onset of muscle weakness in early childhood; the severity of the weakness and muscles affected is variable.
See also OMIM:615120
Feature keyPosition(s)DescriptionActionsGraphical viewLength
Natural variantiVAR_07136776G → S in CMS8; results in decreased AChR clustering. 1 Publication1
Natural variantiVAR_068726105N → I in CMS8; results in decreased AChR clustering. 2 Publications1
Natural variantiVAR_0687421709G → R in CMS8; results in disruption of the neuromuscular junction architecture; does not affect phosphorylation of MUSK; does not affect AChR clustering. 1 Publication1
Natural variantiVAR_0690661727V → F in CMS8; decreased AGRN-induced clustering of AChR by >100-fold and decreased phosphorylation of the MUSK receptor and AChR beta subunit by about 10-fold. Increased binding to alpha-dystroglycan. 1 Publication1
Natural variantiVAR_0713691875G → R in CMS8. 1 Publication1

Keywords - Diseasei

Congenital myasthenic syndrome, Disease mutation

Organism-specific databases

DisGeNETi375790.
MalaCardsiAGRN.
MIMi615120. phenotype.
OpenTargetsiENSG00000188157.
Orphaneti98913. Postsynaptic congenital myasthenic syndromes.
98914. Presynaptic congenital myasthenic syndromes.
PharmGKBiPA24626.

Polymorphism and mutation databases

BioMutaiAGRN.

PTM / Processingi

Molecule processing

Feature keyPosition(s)DescriptionActionsGraphical viewLength
Signal peptidei1 – 29Sequence analysisAdd BLAST29
ChainiPRO_000000747130 – 2067AgrinAdd BLAST2038
ChainiPRO_000042161330 – 1102Agrin N-terminal 110 kDa subunitBy similarityAdd BLAST1073
ChainiPRO_00004216141103 – 2067Agrin C-terminal 110 kDa subunitBy similarityAdd BLAST965
ChainiPRO_00004216151103 – 1863Agrin C-terminal 90 kDa fragmentBy similarityAdd BLAST761
ChainiPRO_00004216161864 – 2067Agrin C-terminal 22 kDa fragmentBy similarityAdd BLAST204

Amino acid modifications

Feature keyPosition(s)DescriptionActionsGraphical viewLength
Disulfide bondi31 ↔ 103By similarity
Glycosylationi135N-linked (GlcNAc...)1 Publication1
Disulfide bondi152 ↔ 177Or C-152 with C-183PROSITE-ProRule annotation
Glycosylationi250N-linked (GlcNAc...)Sequence analysis1
Modified residuei674PhosphoserineBy similarity1
Modified residuei676PhosphoserineBy similarity1
Glycosylationi777N-linked (GlcNAc...)Sequence analysis1
Disulfide bondi793 ↔ 805By similarity
Disulfide bondi795 ↔ 812By similarity
Disulfide bondi814 ↔ 823By similarity
Disulfide bondi826 ↔ 844By similarity
Disulfide bondi847 ↔ 859By similarity
Disulfide bondi849 ↔ 866By similarity
Disulfide bondi868 ↔ 877By similarity
Disulfide bondi880 ↔ 891By similarity
Glycosylationi932N-linked (GlcNAc...)Sequence analysis1
Disulfide bondi1333 ↔ 1344By similarity
Disulfide bondi1338 ↔ 1355By similarity
Disulfide bondi1357 ↔ 1366By similarity
Disulfide bondi1519 ↔ 1548By similarity
Disulfide bondi1553 ↔ 1564By similarity
Disulfide bondi1558 ↔ 1574By similarity
Disulfide bondi1576 ↔ 1585By similarity
Disulfide bondi1592 ↔ 1603By similarity
Disulfide bondi1597 ↔ 1613By similarity
Disulfide bondi1615 ↔ 1624By similarity
Disulfide bondi1822 ↔ 1836By similarity
Disulfide bondi1830 ↔ 1845By similarity
Glycosylationi1835O-linked (Fuc...)By similarity1
Disulfide bondi1847 ↔ 1856By similarity
Disulfide bondi2038 ↔ 2064By similarity

Post-translational modificationi

Contains heparan and chondroitin sulfate chains and alpha-dystroglycan as well as N-linked and O-linked oligosaccharides. Glycosaminoglycans (GAGs), present in the N-terminal 110 kDa fragment, are required for induction of filopodia in hippocampal neurons. The first cluster (Gly/Ser-rich) for GAG attachment contains heparan sulfate (HS) chains and the second cluster (Ser/Thr-rich), contains chondroitin sulfate (CS) chains. Heparin and heparin sulfate binding in the G3 domain is independent of calcium ions. Binds heparin with a stoichiometry of 2:1. Binds sialic acid with a stoichiometry of 1:1 and binding requires calcium ions (By similarity).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).

Sites

Feature keyPosition(s)DescriptionActionsGraphical viewLength
Sitei1102 – 1103Cleavage, alpha site; by neurotrypsinBy similarity2
Sitei1863 – 1864Cleavage, beta site; by neurotrypsinBy similarity2

Keywords - PTMi

Disulfide bond, Glycoprotein, Heparan sulfate, Phosphoprotein, Proteoglycan

Proteomic databases

EPDiO00468.
MaxQBiO00468.
PaxDbiO00468.
PeptideAtlasiO00468.
PRIDEiO00468.

PTM databases

iPTMnetiO00468.
PhosphoSitePlusiO00468.

Expressioni

Tissue specificityi

Expressed in basement membranes of lung and kidney. Muscle- and neuron-specific isoforms are found. Isoforms (y+) with the 4 AA insert and (z+8) isoforms with the 8 AA insert are all neuron-specific. Isoforms (z+11) are found in both neuronal and non-neuronal tissues.3 Publications

Gene expression databases

BgeeiENSG00000188157.
CleanExiHS_AGRN.
ExpressionAtlasiO00468. baseline and differential.
GenevisibleiO00468. HS.

Organism-specific databases

HPAiHPA040090.

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 (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. Interacts with DAG1; the interaction is influenced by cell surface glycosaminoglycans and by alternative splicing of AGRN.By similarity3 Publications

Binary interactionsi

WithEntry#Exp.IntActNotes
ATXN7O152652EBI-947482,EBI-708350

GO - Molecular functioni

  • dystroglycan binding Source: UniProtKB
  • laminin binding Source: UniProtKB

Protein-protein interaction databases

BioGridi132000. 15 interactors.
IntActiO00468. 8 interactors.
MINTiMINT-4053526.
STRINGi9606.ENSP00000368678.

Structurei

3D structure databases

ProteinModelPortaliO00468.
SMRiO00468.
ModBaseiSearch...
MobiDBiSearch...

Family & Domainsi

Domains and Repeats

Feature keyPosition(s)DescriptionActionsGraphical viewLength
Domaini30 – 157NtAPROSITE-ProRule annotationAdd BLAST128
Domaini191 – 244Kazal-like 1PROSITE-ProRule annotationAdd BLAST54
Domaini264 – 319Kazal-like 2PROSITE-ProRule annotationAdd BLAST56
Domaini337 – 391Kazal-like 3PROSITE-ProRule annotationAdd BLAST55
Domaini408 – 463Kazal-like 4PROSITE-ProRule annotationAdd BLAST56
Domaini484 – 536Kazal-like 5PROSITE-ProRule annotationAdd BLAST53
Domaini540 – 601Kazal-like 6PROSITE-ProRule annotationAdd BLAST62
Domaini607 – 666Kazal-like 7PROSITE-ProRule annotationAdd BLAST60
Domaini699 – 752Kazal-like 8PROSITE-ProRule annotationAdd BLAST54
Domaini793 – 846Laminin EGF-like 1PROSITE-ProRule annotationAdd BLAST54
Domaini847 – 893Laminin EGF-like 2PROSITE-ProRule annotationAdd BLAST47
Domaini917 – 971Kazal-like 9PROSITE-ProRule annotationAdd BLAST55
Domaini1130 – 1252SEAPROSITE-ProRule annotationAdd BLAST123
Domaini1329 – 1367EGF-like 1PROSITE-ProRule annotationAdd BLAST39
Domaini1372 – 1548Laminin G-like 1PROSITE-ProRule annotationAdd BLAST177
Domaini1549 – 1586EGF-like 2PROSITE-ProRule annotationAdd BLAST38
Domaini1588 – 1625EGF-like 3PROSITE-ProRule annotationAdd BLAST38
Domaini1635 – 1822Laminin G-like 2PROSITE-ProRule annotationAdd BLAST188
Domaini1818 – 1857EGF-like 4PROSITE-ProRule annotationAdd BLAST40
Domaini1868 – 2064Laminin G-like 3PROSITE-ProRule annotationAdd BLAST197

Compositional bias

Feature keyPosition(s)DescriptionActionsGraphical viewLength
Compositional biasi671 – 677Gly/Ser-rich7
Compositional biasi974 – 1099Ser/Thr-richAdd BLAST126
Compositional biasi1058 – 1097Gly/Ser-richAdd BLAST40
Compositional biasi1254 – 1324Ser/Thr-richAdd BLAST71

Domaini

The NtA domain, absent in TM-agrin, is required for binding laminin and connecting to basal lamina.
Both laminin G-like 2 (G2) and laminin G-like 3 (G3) domains are required for alpha-dystroglycan/DAG1 binding. G3 domain is required for C-terminal heparin, heparan sulfate and sialic acid binding (By similarity).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 NtA (N-terminal agrin) domain.PROSITE-ProRule annotation
Contains 1 SEA domain.PROSITE-ProRule annotation

Keywords - Domaini

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

Phylogenomic databases

eggNOGiENOG410ITSI. Eukaryota.
ENOG410YKSA. LUCA.
GeneTreeiENSGT00530000063501.
HOGENOMiHOG000033860.
HOVERGENiHBG080471.
InParanoidiO00468.
KOiK06254.
OMAiPRCSCDR.
OrthoDBiEOG091G048M.
TreeFamiTF326548.

Family and domain databases

Gene3Di2.60.120.200. 3 hits.
3.30.70.960. 1 hit.
InterProiIPR013320. ConA-like_dom.
IPR001881. EGF-like_Ca-bd_dom.
IPR013032. EGF-like_CS.
IPR000742. EGF-like_dom.
IPR003884. FacI_MAC.
IPR003645. Fol_N.
IPR002350. Kazal_dom.
IPR002049. Laminin_EGF.
IPR001791. Laminin_G.
IPR004850. NtA_dom.
IPR000082. SEA_dom.
IPR008993. TIMP-like_OB-fold.
[Graphical view]
PfamiPF00008. EGF. 2 hits.
PF00050. Kazal_1. 2 hits.
PF07648. Kazal_2. 7 hits.
PF00053. Laminin_EGF. 2 hits.
PF00054. Laminin_G_1. 3 hits.
PF03146. NtA. 1 hit.
PF01390. SEA. 1 hit.
[Graphical view]
SMARTiSM00181. EGF. 7 hits.
SM00179. EGF_CA. 3 hits.
SM00180. EGF_Lam. 2 hits.
SM00057. FIMAC. 4 hits.
SM00274. FOLN. 5 hits.
SM00280. KAZAL. 9 hits.
SM00282. LamG. 3 hits.
SM00200. SEA. 1 hit.
[Graphical view]
SUPFAMiSSF49899. SSF49899. 4 hits.
SSF50242. SSF50242. 1 hit.
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.
PS51121. NTA. 1 hit.
PS50024. SEA. 1 hit.
[Graphical view]

Sequences (7)i

Sequence statusi: Complete.

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

This entry describes 7 isoformsi produced by alternative splicing. AlignAdd to basket

Note: Many isoforms may exist depending on the occurrence and length of inserts at the x, y or z splice site. Four 'z' isoforms can be produced with inserts of 0, 8, 11 or 19 AA. Isoforms differ in their acetylcholine receptor clustering activity and tissue specificity.
Isoform 1 (identifier: O00468-1) [UniParc]FASTAAdd to basket
Also known as: Secreted agrin, LN-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

        10         20         30         40         50
MAGRSHPGPL RPLLPLLVVA ACVLPGAGGT CPERALERRE EEANVVLTGT
60 70 80 90 100
VEEILNVDPV QHTYSCKVRV WRYLKGKDLV ARESLLDGGN KVVISGFGDP
110 120 130 140 150
LICDNQVSTG DTRIFFVNPA PPYLWPAHKN ELMLNSSLMR ITLRNLEEVE
160 170 180 190 200
FCVEDKPGTH FTPVPPTPPD ACRGMLCGFG AVCEPNAEGP GRASCVCKKS
210 220 230 240 250
PCPSVVAPVC GSDASTYSNE CELQRAQCSQ QRRIRLLSRG PCGSRDPCSN
260 270 280 290 300
VTCSFGSTCA RSADGLTASC LCPATCRGAP EGTVCGSDGA DYPGECQLLR
310 320 330 340 350
RACARQENVF KKFDGPCDPC QGALPDPSRS CRVNPRTRRP EMLLRPESCP
360 370 380 390 400
ARQAPVCGDD GVTYENDCVM GRSGAARGLL LQKVRSGQCQ GRDQCPEPCR
410 420 430 440 450
FNAVCLSRRG RPRCSCDRVT CDGAYRPVCA QDGRTYDSDC WRQQAECRQQ
460 470 480 490 500
RAIPSKHQGP CDQAPSPCLG VQCAFGATCA VKNGQAACEC LQACSSLYDP
510 520 530 540 550
VCGSDGVTYG SACELEATAC TLGREIQVAR KGPCDRCGQC RFGALCEAET
560 570 580 590 600
GRCVCPSECV ALAQPVCGSD GHTYPSECML HVHACTHQIS LHVASAGPCE
610 620 630 640 650
TCGDAVCAFG AVCSAGQCVC PRCEHPPPGP VCGSDGVTYG SACELREAAC
660 670 680 690 700
LQQTQIEEAR AGPCEQAECG SGGSGSGEDG DCEQELCRQR GGIWDEDSED
710 720 730 740 750
GPCVCDFSCQ SVPGSPVCGS DGVTYSTECE LKKARCESQR GLYVAAQGAC
760 770 780 790 800
RGPTFAPLPP VAPLHCAQTP YGCCQDNITA ARGVGLAGCP SACQCNPHGS
810 820 830 840 850
YGGTCDPATG QCSCRPGVGG LRCDRCEPGF WNFRGIVTDG RSGCTPCSCD
860 870 880 890 900
PQGAVRDDCE QMTGLCSCKP GVAGPKCGQC PDGRALGPAG CEADASAPAT
910 920 930 940 950
CAEMRCEFGA RCVEESGSAH CVCPMLTCPE ANATKVCGSD GVTYGNECQL
960 970 980 990 1000
KTIACRQGLQ ISIQSLGPCQ EAVAPSTHPT SASVTVTTPG LLLSQALPAP
1010 1020 1030 1040 1050
PGALPLAPSS TAHSQTTPPP SSRPRTTASV PRTTVWPVLT VPPTAPSPAP
1060 1070 1080 1090 1100
SLVASAFGES GSTDGSSDEE LSGDQEASGG GSGGLEPLEG SSVATPGPPV
1110 1120 1130 1140 1150
ERASCYNSAL GCCSDGKTPS LDAEGSNCPA TKVFQGVLEL EGVEGQELFY
1160 1170 1180 1190 1200
TPEMADPKSE LFGETARSIE STLDDLFRNS DVKKDFRSVR LRDLGPGKSV
1210 1220 1230 1240 1250
RAIVDVHFDP TTAFRAPDVA RALLRQIQVS RRRSLGVRRP LQEHVRFMDF
1260 1270 1280 1290 1300
DWFPAFITGA TSGAIAAGAT ARATTASRLP SSAVTPRAPH PSHTSQPVAK
1310 1320 1330 1340 1350
TTAAPTTRRP PTTAPSRVPG RRPPAPQQPP KPCDSQPCFH GGTCQDWALG
1360 1370 1380 1390 1400
GGFTCSCPAG RGGAVCEKVL GAPVPAFEGR SFLAFPTLRA YHTLRLALEF
1410 1420 1430 1440 1450
RALEPQGLLL YNGNARGKDF LALALLDGRV QLRFDTGSGP AVLTSAVPVE
1460 1470 1480 1490 1500
PGQWHRLELS RHWRRGTLSV DGETPVLGES PSGTDGLNLD TDLFVGGVPE
1510 1520 1530 1540 1550
DQAAVALERT FVGAGLRGCI RLLDVNNQRL ELGIGPGAAT RGSGVGECGD
1560 1570 1580 1590 1600
HPCLPNPCHG GAPCQNLEAG RFHCQCPPGR VGPTCADEKS PCQPNPCHGA
1610 1620 1630 1640 1650
APCRVLPEGG AQCECPLGRE GTFCQTASGQ DGSGPFLADF NGFSHLELRG
1660 1670 1680 1690 1700
LHTFARDLGE KMALEVVFLA RGPSGLLLYN GQKTDGKGDF VSLALRDRRL
1710 1720 1730 1740 1750
EFRYDLGKGA AVIRSREPVT LGAWTRVSLE RNGRKGALRV GDGPRVLGES
1760 1770 1780 1790 1800
PKSRKVPHTV LNLKEPLYVG GAPDFSKLAR AAAVSSGFDG AIQLVSLGGR
1810 1820 1830 1840 1850
QLLTPEHVLR QVDVTSFAGH PCTRASGHPC LNGASCVPRE AAYVCLCPGG
1860 1870 1880 1890 1900
FSGPHCEKGL VEKSAGDVDT LAFDGRTFVE YLNAVTESEL ANEIPVPETL
1910 1920 1930 1940 1950
DSGALHEKAL QSNHFELSLR TEATQGLVLW SGKATERADY VALAIVDGHL
1960 1970 1980 1990 2000
QLSYNLGSQP VVLRSTVPVN TNRWLRVVAH REQREGSLQV GNEAPVTGSS
2010 2020 2030 2040 2050
PLGATQLDTD GALWLGGLPE LPVGPALPKA YGTGFVGCLR DVVVGRHPLH
2060
LLEDAVTKPE LRPCPTP
Length:2,067
Mass (Da):217,232
Last modified:March 6, 2013 - v5
Checksum:iE7FAAB9AFB7B8039
GO
Isoform 2 (identifier: O00468-2) [UniParc]FASTAAdd to basket
Also known as: Transmembrane agrin, TM-agrin

The sequence of this isoform differs from the canonical sequence as follows:
     1-104: Missing.
     105-154: NQVSTGDTRI...NLEEVEFCVE → MPXLAVARDT...FAVLLFLNNY

Note: Produced by usage of an alternative first exon.
Show »
Length:1,963
Mass (Da):205,544
Checksum:i8E904C7A584AE78F
GO
Isoform 3 (identifier: O00468-3) [UniParc]FASTAAdd to basket
Also known as: Agrin z(0)

The sequence of this isoform differs from the canonical sequence as follows:
     1889-1906: Missing.

Show »
Length:2,049
Mass (Da):215,345
Checksum:iC6CC67CA63060E92
GO
Isoform 4 (identifier: O00468-4) [UniParc]FASTAAdd to basket
Also known as: Agrin z(+11)

The sequence of this isoform differs from the canonical sequence as follows:
     1889-1896: Missing.

Show »
Length:2,059
Mass (Da):216,366
Checksum:i45560978CFB636D3
GO
Isoform 5 (identifier: O00468-5) [UniParc]FASTAAdd to basket
Also known as: Agrin z(+8)

The sequence of this isoform differs from the canonical sequence as follows:
     1897-1906: Missing.

Show »
Length:2,057
Mass (Da):216,211
Checksum:i099A9FB384BDE301
GO
Isoform 6 (identifier: O00468-6) [UniParc]FASTAAdd to basket
Also known as: Agrin y(0)z(0)

The sequence of this isoform differs from the canonical sequence as follows:
     1752-1755: Missing.
     1889-1906: Missing.

Show »
Length:2,045
Mass (Da):214,846
Checksum:i108BDA7146ECB94D
GO
Isoform 7 (identifier: O00468-7) [UniParc]FASTAAdd to basket
Also known as: y(0)

The sequence of this isoform differs from the canonical sequence as follows:
     1752-1755: Missing.

Show »
Length:2,063
Mass (Da):216,733
Checksum:i9E761313F0E53B1B
GO

Experimental Info

Feature keyPosition(s)DescriptionActionsGraphical viewLength
Sequence conflicti343L → R in AAB52917 (PubMed:9652404).Curated1

Natural variant

Feature keyPosition(s)DescriptionActionsGraphical viewLength
Natural variantiVAR_06872423V → L.1 Publication1
Natural variantiVAR_06872558D → N.1 Publication1
Natural variantiVAR_07136776G → S in CMS8; results in decreased AChR clustering. 1 Publication1
Natural variantiVAR_068726105N → I in CMS8; results in decreased AChR clustering. 2 Publications1
Natural variantiVAR_068727267T → M.1 Publication1
Natural variantiVAR_068728375A → S.1 PublicationCorresponds to variant rs138031468dbSNPEnsembl.1
Natural variantiVAR_068729728E → V.1 PublicationCorresponds to variant rs113288277dbSNPEnsembl.1
Natural variantiVAR_071368745A → V.1 Publication1
Natural variantiVAR_068730852Q → R.1 PublicationCorresponds to variant rs9697293dbSNPEnsembl.1
Natural variantiVAR_068731984V → M.1 Publication1
Natural variantiVAR_0687321088L → F.1 PublicationCorresponds to variant rs150132566dbSNPEnsembl.1
Natural variantiVAR_0687331118T → K.1 PublicationCorresponds to variant rs149159118dbSNPEnsembl.1
Natural variantiVAR_0687341135Q → R.1 PublicationCorresponds to variant rs142416636dbSNPEnsembl.1
Natural variantiVAR_0687351240P → L.1 PublicationCorresponds to variant rs142620337dbSNPEnsembl.1
Natural variantiVAR_0687361341G → R.1 Publication1
Natural variantiVAR_0687371451P → L.1 Publication1
Natural variantiVAR_0687381514A → T.1 PublicationCorresponds to variant rs111818381dbSNPEnsembl.1
Natural variantiVAR_0687391565Q → H.1 PublicationCorresponds to variant rs199876002dbSNPEnsembl.1
Natural variantiVAR_0489661666V → I.1 PublicationCorresponds to variant rs17160775dbSNPEnsembl.1
Natural variantiVAR_0687401671R → Q.1 Publication1
Natural variantiVAR_0687411698R → P.1 Publication1
Natural variantiVAR_0687421709G → R in CMS8; results in disruption of the neuromuscular junction architecture; does not affect phosphorylation of MUSK; does not affect AChR clustering. 1 Publication1
Natural variantiVAR_0690661727V → F in CMS8; decreased AGRN-induced clustering of AChR by >100-fold and decreased phosphorylation of the MUSK receptor and AChR beta subunit by about 10-fold. Increased binding to alpha-dystroglycan. 1 Publication1
Natural variantiVAR_0687431734R → H.1 PublicationCorresponds to variant rs145444272dbSNPEnsembl.1
Natural variantiVAR_0687441789D → N.1 Publication1
Natural variantiVAR_0713691875G → R in CMS8. 1 Publication1
Natural variantiVAR_0687452045G → V.1 Publication1

Alternative sequence

Feature keyPosition(s)DescriptionActionsGraphical viewLength
Alternative sequenceiVSP_0457531 – 104Missing in isoform 2. CuratedAdd BLAST104
Alternative sequenceiVSP_045754105 – 154NQVST…EFCVE → MPXLAVARDTRQPAGASLLV RGFMVPCNACLILLATATLG FAVLLFLNNY in isoform 2. CuratedAdd BLAST50
Alternative sequenceiVSP_0457551752 – 1755Missing in isoform 6 and isoform 7. Curated4
Alternative sequenceiVSP_0457561889 – 1906Missing in isoform 3 and isoform 6. 2 PublicationsAdd BLAST18
Alternative sequenceiVSP_0457571889 – 1896Missing in isoform 4. Curated8
Alternative sequenceiVSP_0457581897 – 1906Missing in isoform 5. Curated10

Sequence databases

Select the link destinations:
EMBLi
GenBanki
DDBJi
Links Updated
U84406 mRNA. Translation: AAB52917.1.
AB191264 mRNA. Translation: BAD52440.1.
AL645608 Genomic DNA. Translation: CAI15575.2.
AL645608 Genomic DNA. Translation: CAI15576.1.
AF016903 mRNA. Translation: AAC39776.1.
BC004220 mRNA. Translation: AAH04220.2.
BC007649 mRNA. Translation: AAH07649.1.
BC034009 mRNA. Translation: AAH34009.1.
BC063620 mRNA. Translation: AAH63620.1.
CCDSiCCDS30551.1. [O00468-6]
RefSeqiNP_940978.2. NM_198576.3. [O00468-6]
XP_005244806.1. XM_005244749.3. [O00468-3]
UniGeneiHs.273330.
Hs.602356.

Genome annotation databases

EnsembliENST00000379370; ENSP00000368678; ENSG00000188157. [O00468-6]
GeneIDi375790.
KEGGihsa:375790.
UCSCiuc001ack.3. human. [O00468-1]

Keywords - Coding sequence diversityi

Alternative splicing, Polymorphism

Cross-referencesi

Web resourcesi

The Leiden Muscular Dystrophy pages, Agrin (AGRN)

Leiden Open Variation Database (LOVD)

Sequence databases

Select the link destinations:
EMBLi
GenBanki
DDBJi
Links Updated
U84406 mRNA. Translation: AAB52917.1.
AB191264 mRNA. Translation: BAD52440.1.
AL645608 Genomic DNA. Translation: CAI15575.2.
AL645608 Genomic DNA. Translation: CAI15576.1.
AF016903 mRNA. Translation: AAC39776.1.
BC004220 mRNA. Translation: AAH04220.2.
BC007649 mRNA. Translation: AAH07649.1.
BC034009 mRNA. Translation: AAH34009.1.
BC063620 mRNA. Translation: AAH63620.1.
CCDSiCCDS30551.1. [O00468-6]
RefSeqiNP_940978.2. NM_198576.3. [O00468-6]
XP_005244806.1. XM_005244749.3. [O00468-3]
UniGeneiHs.273330.
Hs.602356.

3D structure databases

ProteinModelPortaliO00468.
SMRiO00468.
ModBaseiSearch...
MobiDBiSearch...

Protein-protein interaction databases

BioGridi132000. 15 interactors.
IntActiO00468. 8 interactors.
MINTiMINT-4053526.
STRINGi9606.ENSP00000368678.

PTM databases

iPTMnetiO00468.
PhosphoSitePlusiO00468.

Polymorphism and mutation databases

BioMutaiAGRN.

Proteomic databases

EPDiO00468.
MaxQBiO00468.
PaxDbiO00468.
PeptideAtlasiO00468.
PRIDEiO00468.

Protocols and materials databases

Structural Biology KnowledgebaseSearch...

Genome annotation databases

EnsembliENST00000379370; ENSP00000368678; ENSG00000188157. [O00468-6]
GeneIDi375790.
KEGGihsa:375790.
UCSCiuc001ack.3. human. [O00468-1]

Organism-specific databases

CTDi375790.
DisGeNETi375790.
GeneCardsiAGRN.
GeneReviewsiAGRN.
HGNCiHGNC:329. AGRN.
HPAiHPA040090.
MalaCardsiAGRN.
MIMi103320. gene.
615120. phenotype.
neXtProtiNX_O00468.
OpenTargetsiENSG00000188157.
Orphaneti98913. Postsynaptic congenital myasthenic syndromes.
98914. Presynaptic congenital myasthenic syndromes.
PharmGKBiPA24626.
GenAtlasiSearch...

Phylogenomic databases

eggNOGiENOG410ITSI. Eukaryota.
ENOG410YKSA. LUCA.
GeneTreeiENSGT00530000063501.
HOGENOMiHOG000033860.
HOVERGENiHBG080471.
InParanoidiO00468.
KOiK06254.
OMAiPRCSCDR.
OrthoDBiEOG091G048M.
TreeFamiTF326548.

Enzyme and pathway databases

BioCyciZFISH:G66-33274-MONOMER.
ReactomeiR-HSA-1971475. A tetrasaccharide linker sequence is required for GAG synthesis.
R-HSA-2022928. HS-GAG biosynthesis.
R-HSA-2024096. HS-GAG degradation.
R-HSA-216083. Integrin cell surface interactions.
R-HSA-3000171. Non-integrin membrane-ECM interactions.
R-HSA-3000178. ECM proteoglycans.
R-HSA-3560783. Defective B4GALT7 causes EDS, progeroid type.
R-HSA-3560801. Defective B3GAT3 causes JDSSDHD.
R-HSA-3656237. Defective EXT2 causes exostoses 2.
R-HSA-3656253. Defective EXT1 causes exostoses 1, TRPS2 and CHDS.
R-HSA-419037. NCAM1 interactions.
R-HSA-4420332. Defective B3GALT6 causes EDSP2 and SEMDJL1.
R-HSA-975634. Retinoid metabolism and transport.
SignaLinkiO00468.

Miscellaneous databases

ChiTaRSiAGRN. human.
GeneWikiiAgrin.
GenomeRNAii375790.
PROiO00468.
SOURCEiSearch...

Gene expression databases

BgeeiENSG00000188157.
CleanExiHS_AGRN.
ExpressionAtlasiO00468. baseline and differential.
GenevisibleiO00468. HS.

Family and domain databases

Gene3Di2.60.120.200. 3 hits.
3.30.70.960. 1 hit.
InterProiIPR013320. ConA-like_dom.
IPR001881. EGF-like_Ca-bd_dom.
IPR013032. EGF-like_CS.
IPR000742. EGF-like_dom.
IPR003884. FacI_MAC.
IPR003645. Fol_N.
IPR002350. Kazal_dom.
IPR002049. Laminin_EGF.
IPR001791. Laminin_G.
IPR004850. NtA_dom.
IPR000082. SEA_dom.
IPR008993. TIMP-like_OB-fold.
[Graphical view]
PfamiPF00008. EGF. 2 hits.
PF00050. Kazal_1. 2 hits.
PF07648. Kazal_2. 7 hits.
PF00053. Laminin_EGF. 2 hits.
PF00054. Laminin_G_1. 3 hits.
PF03146. NtA. 1 hit.
PF01390. SEA. 1 hit.
[Graphical view]
SMARTiSM00181. EGF. 7 hits.
SM00179. EGF_CA. 3 hits.
SM00180. EGF_Lam. 2 hits.
SM00057. FIMAC. 4 hits.
SM00274. FOLN. 5 hits.
SM00280. KAZAL. 9 hits.
SM00282. LamG. 3 hits.
SM00200. SEA. 1 hit.
[Graphical view]
SUPFAMiSSF49899. SSF49899. 4 hits.
SSF50242. SSF50242. 1 hit.
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.
PS51121. NTA. 1 hit.
PS50024. SEA. 1 hit.
[Graphical view]
ProtoNetiSearch...

Entry informationi

Entry nameiAGRIN_HUMAN
AccessioniPrimary (citable) accession number: O00468
Secondary accession number(s): Q5SVA1
, Q5SVA2, Q60FE1, Q7KYS8, Q8N4J5, Q96IC1, Q9BTD4
Entry historyi
Integrated into UniProtKB/Swiss-Prot: October 25, 2004
Last sequence update: March 6, 2013
Last modified: November 2, 2016
This is version 162 of the entry and version 5 of the sequence. [Complete history]
Entry statusiReviewed (UniProtKB/Swiss-Prot)
Annotation programChordata Protein Annotation Program
DisclaimerAny medical or genetic information present in this entry is provided for research, educational and informational purposes only. It is not in any way intended to be used as a substitute for professional medical advice, diagnosis, treatment or care.

Miscellaneousi

Miscellaneous

Cleaved C-terminal fragments may be used as a biomarker for sarcopenia, age-related progressive loss of skeletal muscle.1 Publication

Caution

The unknown residue 'x' in the transmembrane isoform is probably a proline residue by similarity to mouse and rat sequences.Curated

Keywords - Technical termi

Complete proteome, Reference proteome

Documents

  1. Human chromosome 1
    Human chromosome 1: entries, gene names and cross-references to MIM
  2. Human entries with polymorphisms or disease mutations
    List of human entries with polymorphisms or disease mutations
  3. Human polymorphisms and disease mutations
    Index of human polymorphisms and disease mutations
  4. MIM cross-references
    Online Mendelian Inheritance in Man (MIM) cross-references in UniProtKB/Swiss-Prot
  5. SIMILARITY comments
    Index of protein domains and families

Similar proteinsi

Links to similar proteins from the UniProt Reference Clusters (UniRef) at 100%, 90% and 50% sequence identity:
100%UniRef100 combines identical sequences and sub-fragments with 11 or more residues from any organism into one UniRef entry.
90%UniRef90 is built by clustering UniRef100 sequences that have at least 90% sequence identity to, and 80% overlap with, the longest sequence (a.k.a seed sequence).
50%UniRef50 is built by clustering UniRef90 seed sequences that have at least 50% sequence identity to, and 80% overlap with, the longest sequence in the cluster.