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O00468

- AGRIN_HUMAN

UniProt

O00468 - AGRIN_HUMAN

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Protein

Agrin

Gene
AGRN, AGRIN
Organism
Homo sapiens (Human)
Status
Reviewed - 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 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 secreted isoform forms a bridge, after release from motor neurons, to basal lamina through binding laminin via the NtA domain.2 Publications
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.2 Publications
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.2 Publications
Isoform 3 and isoform 6: lack any 'z' insert, are muscle-specific and may be involved in endothelial cell differentiation.2 Publications
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.2 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.2 Publications

Sites

Feature keyPosition(s)LengthDescriptionGraphical viewFeature identifierActions
Sitei1102 – 11032Cleavage, alpha site; by neurotrypsin By similarity
Sitei1250 – 12501Alternative splice site to produce 'x' isoforms By similarity
Sitei1751 – 17511Alternative splice site to produce 'y' isoforms By similarity
Sitei1862 – 18621Critical for cleavage by neurotrypsin By similarity
Sitei1863 – 18642Cleavage, beta site; by neurotrypsin By similarity
Sitei1888 – 18881Alternative splice site to produce 'z' isoforms By similarity
Sitei1892 – 18921Highly important for the agrin receptor complex activity of the 'z(8)' insert By similarity

Regions

Feature keyPosition(s)LengthDescriptionGraphical viewFeature identifierActions
Calcium bindingi1940 – 200869 By similarityAdd
BLAST

GO - Molecular functioni

  1. acetylcholine receptor regulator activity Source: Ensembl
  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. laminin binding Source: UniProtKB
  7. protein binding Source: UniProtKB
  8. sialic acid binding Source: UniProtKB
  9. structural constituent of cytoskeleton Source: UniProtKB

GO - Biological processi

  1. axon guidance Source: Reactome
  2. carbohydrate metabolic process Source: Reactome
  3. chondroitin sulfate metabolic process Source: Reactome
  4. clustering of voltage-gated sodium channels Source: UniProtKB
  5. extracellular matrix organization Source: Reactome
  6. glycosaminoglycan biosynthetic process Source: Reactome
  7. glycosaminoglycan catabolic process Source: Reactome
  8. glycosaminoglycan metabolic process Source: Reactome
  9. G-protein coupled acetylcholine receptor signaling pathway Source: UniProtKB
  10. neuromuscular junction development Source: Ensembl
  11. neurotransmitter receptor metabolic process Source: Ensembl
  12. phototransduction, visible light Source: Reactome
  13. plasma membrane organization Source: Ensembl
  14. positive regulation of filopodium assembly Source: UniProtKB
  15. positive regulation of neuron apoptotic process Source: Ensembl
  16. positive regulation of Rho GTPase activity Source: UniProtKB
  17. positive regulation of synaptic growth at neuromuscular junction Source: UniProtKB
  18. positive regulation of transcription from RNA polymerase II promoter Source: UniProtKB
  19. receptor clustering Source: UniProtKB
  20. retinoid metabolic process Source: Reactome
  21. signal transduction Source: UniProtKB
  22. small molecule metabolic process Source: Reactome
  23. synapse organization Source: UniProtKB
Complete GO annotation...

Keywords - Molecular functioni

Developmental protein

Keywords - Biological processi

Differentiation

Keywords - Ligandi

Calcium

Enzyme and pathway databases

ReactomeiREACT_120752. HS-GAG degradation.
REACT_121248. HS-GAG biosynthesis.
REACT_121408. A tetrasaccharide linker sequence is required for GAG synthesis.
REACT_13552. Integrin cell surface interactions.
REACT_163874. Non-integrin membrane-ECM interactions.
REACT_163906. ECM proteoglycans.
REACT_18312. NCAM1 interactions.
REACT_24968. 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
ProteomesiUP000005640: Chromosome 1

Organism-specific databases

HGNCiHGNC:329. AGRN.

Subcellular locationi

Isoform 1 : Secretedextracellular spaceextracellular matrix
Note: Synaptic basal lamina at the neuromuscular junction By similarity.1 Publication
Isoform 2 : Cell junctionsynapse. Cell membrane; Single-pass type II membrane protein 1 Publication

GO - Cellular componenti

  1. basal lamina Source: UniProtKB
  2. cell junction Source: UniProtKB-KW
  3. cell surface Source: Ensembl
  4. cytoplasm Source: HPA
  5. extracellular matrix Source: UniProtKB
  6. extracellular region Source: Reactome
  7. extracellular space Source: Ensembl
  8. extracellular vesicular exosome Source: UniProt
  9. Golgi lumen Source: Reactome
  10. integral component of membrane Source: UniProtKB-KW
  11. lysosomal lumen Source: Reactome
  12. plasma membrane Source: HPA
  13. synapse Source: UniProtKB
Complete GO annotation...

Keywords - Cellular componenti

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

Pathology & Biotechi

Involvement in diseasei

Myasthenia, limb-girdle, familial (LGM) [MIM:254300]: A congenital myasthenic syndrome characterized by a typical 'limb girdle' pattern of muscle weakness with small, simplified neuromuscular junctions but normal acetylcholine receptor and acetylcholinesterase function.
Note: The disease is caused by mutations affecting the gene represented in this entry.2 Publications
Feature keyPosition(s)LengthDescriptionGraphical viewFeature identifierActions
Natural varianti1709 – 17091G → R in LGM; results in disruption of the neuromuscular junction architecture; does not affect phosphorylation of MUSK; does not affect AChR clustering. 1 Publication
VAR_068742
Natural varianti1727 – 17271V → F in LGM; 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 Publication
VAR_069066

Keywords - Diseasei

Congenital myasthenic syndrome, Disease mutation

Organism-specific databases

MIMi254300. phenotype.
Orphaneti98913. Postsynaptic congenital myasthenic syndromes.
PharmGKBiPA24626.

PTM / Processingi

Molecule processing

Feature keyPosition(s)LengthDescriptionGraphical viewFeature identifierActions
Signal peptidei1 – 2929 Reviewed predictionAdd
BLAST
Chaini30 – 20672038AgrinPRO_0000007471Add
BLAST
Chaini30 – 11021073Agrin N-terminal 110 kDa subunit By similarityPRO_0000421613Add
BLAST
Chaini1103 – 2067965Agrin C-terminal 110 kDa subunit By similarityPRO_0000421614Add
BLAST
Chaini1103 – 1863761Agrin C-terminal 90 kDa fragment By similarityPRO_0000421615Add
BLAST
Chaini1864 – 2067204Agrin C-terminal 22 kDa fragment By similarityPRO_0000421616Add
BLAST

Amino acid modifications

Feature keyPosition(s)LengthDescriptionGraphical viewFeature identifierActions
Disulfide bondi31 ↔ 103 By similarity
Glycosylationi135 – 1351N-linked (GlcNAc...)1 Publication
Disulfide bondi152 ↔ 177Or C-152 with C-183 By similarity
Glycosylationi250 – 2501N-linked (GlcNAc...) Reviewed prediction
Glycosylationi777 – 7771N-linked (GlcNAc...) Reviewed prediction
Disulfide bondi793 ↔ 805 By similarity
Disulfide bondi795 ↔ 812 By similarity
Disulfide bondi814 ↔ 823 By similarity
Disulfide bondi826 ↔ 844 By similarity
Disulfide bondi847 ↔ 859 By similarity
Disulfide bondi849 ↔ 866 By similarity
Disulfide bondi868 ↔ 877 By similarity
Disulfide bondi880 ↔ 891 By similarity
Glycosylationi932 – 9321N-linked (GlcNAc...) Reviewed prediction
Disulfide bondi1333 ↔ 1344 By similarity
Disulfide bondi1338 ↔ 1355 By similarity
Disulfide bondi1357 ↔ 1366 By similarity
Disulfide bondi1519 ↔ 1548 By similarity
Disulfide bondi1553 ↔ 1564 By similarity
Disulfide bondi1558 ↔ 1574 By similarity
Disulfide bondi1576 ↔ 1585 By similarity
Disulfide bondi1592 ↔ 1603 By similarity
Disulfide bondi1597 ↔ 1613 By similarity
Disulfide bondi1615 ↔ 1624 By similarity
Disulfide bondi1822 ↔ 1836 By similarity
Disulfide bondi1830 ↔ 1845 By similarity
Glycosylationi1835 – 18351O-linked (Fuc...) By similarity
Disulfide bondi1847 ↔ 1856 By similarity
Disulfide bondi2038 ↔ 2064 By 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.
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).

Keywords - PTMi

Disulfide bond, Glycoprotein, Heparan sulfate, Proteoglycan

Proteomic databases

MaxQBiO00468.
PaxDbiO00468.
PRIDEiO00468.

PTM databases

PhosphoSiteiO00468.

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

ArrayExpressiO00468.
BgeeiO00468.
CleanExiHS_AGRN.
GenevestigatoriO00468.

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.3 Publications

Binary interactionsi

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

Protein-protein interaction databases

BioGridi132000. 7 interactions.
IntActiO00468. 7 interactions.
MINTiMINT-4053526.
STRINGi9606.ENSP00000368678.

Structurei

3D structure databases

ProteinModelPortaliO00468.
SMRiO00468. Positions 36-146, 170-751, 793-921, 934-969, 1320-2067.

Family & Domainsi

Domains and Repeats

Feature keyPosition(s)LengthDescriptionGraphical viewFeature identifierActions
Domaini30 – 157128NtAAdd
BLAST
Domaini191 – 24454Kazal-like 1Add
BLAST
Domaini264 – 31956Kazal-like 2Add
BLAST
Domaini337 – 39155Kazal-like 3Add
BLAST
Domaini408 – 46356Kazal-like 4Add
BLAST
Domaini484 – 53653Kazal-like 5Add
BLAST
Domaini540 – 60162Kazal-like 6Add
BLAST
Domaini607 – 66660Kazal-like 7Add
BLAST
Domaini699 – 75254Kazal-like 8Add
BLAST
Domaini793 – 84654Laminin EGF-like 1Add
BLAST
Domaini847 – 89347Laminin EGF-like 2Add
BLAST
Domaini917 – 97155Kazal-like 9Add
BLAST
Domaini1130 – 1252123SEAAdd
BLAST
Domaini1329 – 136739EGF-like 1Add
BLAST
Domaini1372 – 1548177Laminin G-like 1Add
BLAST
Domaini1549 – 158638EGF-like 2Add
BLAST
Domaini1588 – 162538EGF-like 3Add
BLAST
Domaini1635 – 1822188Laminin G-like 2Add
BLAST
Domaini1818 – 185740EGF-like 4Add
BLAST
Domaini1868 – 2064197Laminin G-like 3Add
BLAST

Compositional bias

Feature keyPosition(s)LengthDescriptionGraphical viewFeature identifierActions
Compositional biasi671 – 6777Gly/Ser-rich
Compositional biasi974 – 1099126Ser/Thr-richAdd
BLAST
Compositional biasi1058 – 109740Gly/Ser-richAdd
BLAST
Compositional biasi1254 – 132471Ser/Thr-richAdd
BLAST

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.

Sequence similaritiesi

Contains 4 EGF-like domains.
Contains 9 Kazal-like domains.
Contains 1 SEA domain.

Keywords - Domaini

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

Phylogenomic databases

eggNOGiNOG312635.
HOGENOMiHOG000033860.
HOVERGENiHBG080471.
InParanoidiO00468.
KOiK06254.
OMAiPRCSCDR.
OrthoDBiEOG7BGHJZ.
TreeFamiTF326548.

Family and domain databases

Gene3Di2.60.120.200. 3 hits.
3.30.70.960. 1 hit.
InterProiIPR004850. Agrin_NtA.
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.
IPR008993. TIMP-like_OB-fold.
[Graphical view]
PfamiPF00008. EGF. 3 hits.
PF00050. Kazal_1. 3 hits.
PF07648. Kazal_2. 6 hits.
PF00053. Laminin_EGF. 2 hits.
PF00054. Laminin_G_1. 3 hits.
PF03146. NtA. 1 hit.
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. 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. Align

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

MAGRSHPGPL RPLLPLLVVA ACVLPGAGGT CPERALERRE EEANVVLTGT     50
VEEILNVDPV QHTYSCKVRV WRYLKGKDLV ARESLLDGGN KVVISGFGDP 100
LICDNQVSTG DTRIFFVNPA PPYLWPAHKN ELMLNSSLMR ITLRNLEEVE 150
FCVEDKPGTH FTPVPPTPPD ACRGMLCGFG AVCEPNAEGP GRASCVCKKS 200
PCPSVVAPVC GSDASTYSNE CELQRAQCSQ QRRIRLLSRG PCGSRDPCSN 250
VTCSFGSTCA RSADGLTASC LCPATCRGAP EGTVCGSDGA DYPGECQLLR 300
RACARQENVF KKFDGPCDPC QGALPDPSRS CRVNPRTRRP EMLLRPESCP 350
ARQAPVCGDD GVTYENDCVM GRSGAARGLL LQKVRSGQCQ GRDQCPEPCR 400
FNAVCLSRRG RPRCSCDRVT CDGAYRPVCA QDGRTYDSDC WRQQAECRQQ 450
RAIPSKHQGP CDQAPSPCLG VQCAFGATCA VKNGQAACEC LQACSSLYDP 500
VCGSDGVTYG SACELEATAC TLGREIQVAR KGPCDRCGQC RFGALCEAET 550
GRCVCPSECV ALAQPVCGSD GHTYPSECML HVHACTHQIS LHVASAGPCE 600
TCGDAVCAFG AVCSAGQCVC PRCEHPPPGP VCGSDGVTYG SACELREAAC 650
LQQTQIEEAR AGPCEQAECG SGGSGSGEDG DCEQELCRQR GGIWDEDSED 700
GPCVCDFSCQ SVPGSPVCGS DGVTYSTECE LKKARCESQR GLYVAAQGAC 750
RGPTFAPLPP VAPLHCAQTP YGCCQDNITA ARGVGLAGCP SACQCNPHGS 800
YGGTCDPATG QCSCRPGVGG LRCDRCEPGF WNFRGIVTDG RSGCTPCSCD 850
PQGAVRDDCE QMTGLCSCKP GVAGPKCGQC PDGRALGPAG CEADASAPAT 900
CAEMRCEFGA RCVEESGSAH CVCPMLTCPE ANATKVCGSD GVTYGNECQL 950
KTIACRQGLQ ISIQSLGPCQ EAVAPSTHPT SASVTVTTPG LLLSQALPAP 1000
PGALPLAPSS TAHSQTTPPP SSRPRTTASV PRTTVWPVLT VPPTAPSPAP 1050
SLVASAFGES GSTDGSSDEE LSGDQEASGG GSGGLEPLEG SSVATPGPPV 1100
ERASCYNSAL GCCSDGKTPS LDAEGSNCPA TKVFQGVLEL EGVEGQELFY 1150
TPEMADPKSE LFGETARSIE STLDDLFRNS DVKKDFRSVR LRDLGPGKSV 1200
RAIVDVHFDP TTAFRAPDVA RALLRQIQVS RRRSLGVRRP LQEHVRFMDF 1250
DWFPAFITGA TSGAIAAGAT ARATTASRLP SSAVTPRAPH PSHTSQPVAK 1300
TTAAPTTRRP PTTAPSRVPG RRPPAPQQPP KPCDSQPCFH GGTCQDWALG 1350
GGFTCSCPAG RGGAVCEKVL GAPVPAFEGR SFLAFPTLRA YHTLRLALEF 1400
RALEPQGLLL YNGNARGKDF LALALLDGRV QLRFDTGSGP AVLTSAVPVE 1450
PGQWHRLELS RHWRRGTLSV DGETPVLGES PSGTDGLNLD TDLFVGGVPE 1500
DQAAVALERT FVGAGLRGCI RLLDVNNQRL ELGIGPGAAT RGSGVGECGD 1550
HPCLPNPCHG GAPCQNLEAG RFHCQCPPGR VGPTCADEKS PCQPNPCHGA 1600
APCRVLPEGG AQCECPLGRE GTFCQTASGQ DGSGPFLADF NGFSHLELRG 1650
LHTFARDLGE KMALEVVFLA RGPSGLLLYN GQKTDGKGDF VSLALRDRRL 1700
EFRYDLGKGA AVIRSREPVT LGAWTRVSLE RNGRKGALRV GDGPRVLGES 1750
PKSRKVPHTV LNLKEPLYVG GAPDFSKLAR AAAVSSGFDG AIQLVSLGGR 1800
QLLTPEHVLR QVDVTSFAGH PCTRASGHPC LNGASCVPRE AAYVCLCPGG 1850
FSGPHCEKGL VEKSAGDVDT LAFDGRTFVE YLNAVTESEL ANEIPVPETL 1900
DSGALHEKAL QSNHFELSLR TEATQGLVLW SGKATERADY VALAIVDGHL 1950
QLSYNLGSQP VVLRSTVPVN TNRWLRVVAH REQREGSLQV GNEAPVTGSS 2000
PLGATQLDTD GALWLGGLPE LPVGPALPKA YGTGFVGCLR DVVVGRHPLH 2050
LLEDAVTKPE LRPCPTP 2067
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

Natural variant

Feature keyPosition(s)LengthDescriptionGraphical viewFeature identifierActions
Natural varianti23 – 231V → L.1 Publication
VAR_068724
Natural varianti58 – 581D → N.1 Publication
VAR_068725
Natural varianti105 – 1051N → I.1 Publication
VAR_068726
Natural varianti267 – 2671T → M.1 Publication
VAR_068727
Natural varianti375 – 3751A → S.1 Publication
Corresponds to variant rs138031468 [ dbSNP | Ensembl ].
VAR_068728
Natural varianti728 – 7281E → V.1 Publication
Corresponds to variant rs113288277 [ dbSNP | Ensembl ].
VAR_068729
Natural varianti852 – 8521Q → R.1 Publication
Corresponds to variant rs9697293 [ dbSNP | Ensembl ].
VAR_068730
Natural varianti984 – 9841V → M.1 Publication
VAR_068731
Natural varianti1088 – 10881L → F.1 Publication
Corresponds to variant rs150132566 [ dbSNP | Ensembl ].
VAR_068732
Natural varianti1118 – 11181T → K.1 Publication
Corresponds to variant rs149159118 [ dbSNP | Ensembl ].
VAR_068733
Natural varianti1135 – 11351Q → R.1 Publication
Corresponds to variant rs142416636 [ dbSNP | Ensembl ].
VAR_068734
Natural varianti1240 – 12401P → L.1 Publication
Corresponds to variant rs142620337 [ dbSNP | Ensembl ].
VAR_068735
Natural varianti1341 – 13411G → R.1 Publication
VAR_068736
Natural varianti1451 – 14511P → L.1 Publication
VAR_068737
Natural varianti1514 – 15141A → T.1 Publication
Corresponds to variant rs111818381 [ dbSNP | Ensembl ].
VAR_068738
Natural varianti1565 – 15651Q → H.1 Publication
Corresponds to variant rs199876002 [ dbSNP | Ensembl ].
VAR_068739
Natural varianti1666 – 16661V → I.1 Publication
Corresponds to variant rs17160775 [ dbSNP | Ensembl ].
VAR_048966
Natural varianti1671 – 16711R → Q.1 Publication
VAR_068740
Natural varianti1698 – 16981R → P.1 Publication
VAR_068741
Natural varianti1709 – 17091G → R in LGM; results in disruption of the neuromuscular junction architecture; does not affect phosphorylation of MUSK; does not affect AChR clustering. 1 Publication
VAR_068742
Natural varianti1727 – 17271V → F in LGM; 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 Publication
VAR_069066
Natural varianti1734 – 17341R → H.1 Publication
Corresponds to variant rs145444272 [ dbSNP | Ensembl ].
VAR_068743
Natural varianti1789 – 17891D → N.1 Publication
VAR_068744
Natural varianti2045 – 20451G → V.1 Publication
VAR_068745

Alternative sequence

Feature keyPosition(s)LengthDescriptionGraphical viewFeature identifierActions
Alternative sequencei1 – 104104Missing in isoform 2. VSP_045753Add
BLAST
Alternative sequencei105 – 15450NQVST…EFCVE → MPXLAVARDTRQPAGASLLV RGFMVPCNACLILLATATLG FAVLLFLNNY in isoform 2. VSP_045754Add
BLAST
Alternative sequencei1752 – 17554Missing in isoform 6 and isoform 7. VSP_045755
Alternative sequencei1889 – 190618Missing in isoform 3 and isoform 6. VSP_045756Add
BLAST
Alternative sequencei1889 – 18968Missing in isoform 4. VSP_045757
Alternative sequencei1897 – 190610Missing in isoform 5. VSP_045758

Sequence conflict

Feature keyPosition(s)LengthDescriptionGraphical viewFeature identifierActions
Sequence conflicti343 – 3431L → R in AAB52917. 1 Publication

Sequence databases

Select the link destinations:
EMBL
GenBank
DDBJ
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_005244749.1. [O00468-3]
XP_006710696.1. XM_006710633.1. [O00468-5]
UniGeneiHs.273330.
Hs.602356.

Genome annotation databases

EnsembliENST00000379370; ENSP00000368678; ENSG00000188157. [O00468-6]
GeneIDi375790.
KEGGihsa:375790.
UCSCiuc001ack.2. 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:
EMBL
GenBank
DDBJ
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 .
CCDSi CCDS30551.1. [O00468-6 ]
RefSeqi NP_940978.2. NM_198576.3. [O00468-6 ]
XP_005244806.1. XM_005244749.1. [O00468-3 ]
XP_006710696.1. XM_006710633.1. [O00468-5 ]
UniGenei Hs.273330.
Hs.602356.

3D structure databases

ProteinModelPortali O00468.
SMRi O00468. Positions 36-146, 170-751, 793-921, 934-969, 1320-2067.
ModBasei Search...
MobiDBi Search...

Protein-protein interaction databases

BioGridi 132000. 7 interactions.
IntActi O00468. 7 interactions.
MINTi MINT-4053526.
STRINGi 9606.ENSP00000368678.

PTM databases

PhosphoSitei O00468.

Proteomic databases

MaxQBi O00468.
PaxDbi O00468.
PRIDEi O00468.

Protocols and materials databases

Structural Biology Knowledgebase Search...

Genome annotation databases

Ensembli ENST00000379370 ; ENSP00000368678 ; ENSG00000188157 . [O00468-6 ]
GeneIDi 375790.
KEGGi hsa:375790.
UCSCi uc001ack.2. human. [O00468-1 ]

Organism-specific databases

CTDi 375790.
GeneCardsi GC01P000946.
GeneReviewsi AGRN.
HGNCi HGNC:329. AGRN.
HPAi HPA040090.
MIMi 103320. gene.
254300. phenotype.
neXtProti NX_O00468.
Orphaneti 98913. Postsynaptic congenital myasthenic syndromes.
PharmGKBi PA24626.
GenAtlasi Search...

Phylogenomic databases

eggNOGi NOG312635.
HOGENOMi HOG000033860.
HOVERGENi HBG080471.
InParanoidi O00468.
KOi K06254.
OMAi PRCSCDR.
OrthoDBi EOG7BGHJZ.
TreeFami TF326548.

Enzyme and pathway databases

Reactomei REACT_120752. HS-GAG degradation.
REACT_121248. HS-GAG biosynthesis.
REACT_121408. A tetrasaccharide linker sequence is required for GAG synthesis.
REACT_13552. Integrin cell surface interactions.
REACT_163874. Non-integrin membrane-ECM interactions.
REACT_163906. ECM proteoglycans.
REACT_18312. NCAM1 interactions.
REACT_24968. Retinoid metabolism and transport.
SignaLinki O00468.

Miscellaneous databases

GeneWikii Agrin.
GenomeRNAii 375790.
NextBioi 100617.
PROi O00468.
SOURCEi Search...

Gene expression databases

ArrayExpressi O00468.
Bgeei O00468.
CleanExi HS_AGRN.
Genevestigatori O00468.

Family and domain databases

Gene3Di 2.60.120.200. 3 hits.
3.30.70.960. 1 hit.
InterProi IPR004850. Agrin_NtA.
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.
IPR008993. TIMP-like_OB-fold.
[Graphical view ]
Pfami PF00008. EGF. 3 hits.
PF00050. Kazal_1. 3 hits.
PF07648. Kazal_2. 6 hits.
PF00053. Laminin_EGF. 2 hits.
PF00054. Laminin_G_1. 3 hits.
PF03146. NtA. 1 hit.
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. 4 hits.
SSF50242. SSF50242. 1 hit.
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.
PS51121. NTA. 1 hit.
PS50024. SEA. 1 hit.
[Graphical view ]
ProtoNeti Search...

Publicationsi

« Hide 'large scale' publications
  1. "Primary structure and high expression of human agrin in basement membranes of adult lung and kidney."
    Groffen A.J.A., Buskens C.A.F., Van Kuppevelt T.H., Veerkamp J.H., Monnens L.A.H., Van den Heuvel L.P.W.J.
    Eur. J. Biochem. 254:123-128(1998) [PubMed] [Europe PMC] [Abstract]
    Cited for: NUCLEOTIDE SEQUENCE [MRNA] (ISOFORM 3), TISSUE SPECIFICITY.
  2. Kato S.
    Submitted (SEP-2004) to the EMBL/GenBank/DDBJ databases
    Cited for: NUCLEOTIDE SEQUENCE [MRNA] (ISOFORM 3).
    Tissue: Retinal pigment epithelium.
  3. "The DNA sequence and biological annotation of human chromosome 1."
    Gregory S.G., Barlow K.F., McLay K.E., Kaul R., Swarbreck D., Dunham A., Scott C.E., Howe K.L., Woodfine K., Spencer C.C.A., Jones M.C., Gillson C., Searle S., Zhou Y., Kokocinski F., McDonald L., Evans R., Phillips K.
    , Atkinson A., Cooper R., Jones C., Hall R.E., Andrews T.D., Lloyd C., Ainscough R., Almeida J.P., Ambrose K.D., Anderson F., Andrew R.W., Ashwell R.I.S., Aubin K., Babbage A.K., Bagguley C.L., Bailey J., Beasley H., Bethel G., Bird C.P., Bray-Allen S., Brown J.Y., Brown A.J., Buckley D., Burton J., Bye J., Carder C., Chapman J.C., Clark S.Y., Clarke G., Clee C., Cobley V., Collier R.E., Corby N., Coville G.J., Davies J., Deadman R., Dunn M., Earthrowl M., Ellington A.G., Errington H., Frankish A., Frankland J., French L., Garner P., Garnett J., Gay L., Ghori M.R.J., Gibson R., Gilby L.M., Gillett W., Glithero R.J., Grafham D.V., Griffiths C., Griffiths-Jones S., Grocock R., Hammond S., Harrison E.S.I., Hart E., Haugen E., Heath P.D., Holmes S., Holt K., Howden P.J., Hunt A.R., Hunt S.E., Hunter G., Isherwood J., James R., Johnson C., Johnson D., Joy A., Kay M., Kershaw J.K., Kibukawa M., Kimberley A.M., King A., Knights A.J., Lad H., Laird G., Lawlor S., Leongamornlert D.A., Lloyd D.M., Loveland J., Lovell J., Lush M.J., Lyne R., Martin S., Mashreghi-Mohammadi M., Matthews L., Matthews N.S.W., McLaren S., Milne S., Mistry S., Moore M.J.F., Nickerson T., O'Dell C.N., Oliver K., Palmeiri A., Palmer S.A., Parker A., Patel D., Pearce A.V., Peck A.I., Pelan S., Phelps K., Phillimore B.J., Plumb R., Rajan J., Raymond C., Rouse G., Saenphimmachak C., Sehra H.K., Sheridan E., Shownkeen R., Sims S., Skuce C.D., Smith M., Steward C., Subramanian S., Sycamore N., Tracey A., Tromans A., Van Helmond Z., Wall M., Wallis J.M., White S., Whitehead S.L., Wilkinson J.E., Willey D.L., Williams H., Wilming L., Wray P.W., Wu Z., Coulson A., Vaudin M., Sulston J.E., Durbin R.M., Hubbard T., Wooster R., Dunham I., Carter N.P., McVean G., Ross M.T., Harrow J., Olson M.V., Beck S., Rogers J., Bentley D.R.
    Nature 441:315-321(2006) [PubMed] [Europe PMC] [Abstract]
    Cited for: NUCLEOTIDE SEQUENCE [LARGE SCALE GENOMIC DNA] (ISOFORM 3), NUCLEOTIDE SEQUENCE [LARGE SCALE GENOMIC DNA] OF 1703-1949 (ISOFORM 6).
  4. "Agrin binds to the nerve-muscle basal lamina via laminin."
    Denzer A.J., Brandenberger R., Gesemann M., Chiquet M., Ruegg M.A.
    J. Cell Biol. 137:671-683(1997) [PubMed] [Europe PMC] [Abstract]
    Cited for: NUCLEOTIDE SEQUENCE [MRNA] OF 20-172, INTERACTION WITH LAMININ.
  5. "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] OF 1558-2045.
    Tissue: Brain, Colon and Kidney.
  6. "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: IDENTIFICATION OF TRANSMEMBRANE ISOFORM (ISOFORM 2).
  7. "Identification of agrinSN isoform and muscle-specific receptor tyrosine kinase (MuSK) in sperm."
    Kumar P., Ferns M.J., Meizel S.
    Biochem. Biophys. Res. Commun. 342:522-528(2006) [PubMed] [Europe PMC] [Abstract]
    Cited for: IDENTIFICATION OF TRANSMEMBRANE ISOFORM (ISOFORM 2), ALTERNATIVE SPLICING, TISSUE SPECIFICITY.
  8. Erratum
    Kumar P., Ferns M.J., Meizel S.
    Biochem. Biophys. Res. Commun. 344:453-453(2006)
  9. "Glycoproteomics analysis of human liver tissue by combination of multiple enzyme digestion and hydrazide chemistry."
    Chen R., Jiang X., Sun D., Han G., Wang F., Ye M., Wang L., Zou H.
    J. Proteome Res. 8:651-661(2009) [PubMed] [Europe PMC] [Abstract]
    Cited for: GLYCOSYLATION [LARGE SCALE ANALYSIS] AT ASN-135.
    Tissue: Liver.
  10. "Proteomics characterization of extracellular space components in the human aorta."
    Didangelos A., Yin X., Mandal K., Baumert M., Jahangiri M., Mayr M.
    Mol. Cell. Proteomics 9:2048-2062(2010) [PubMed] [Europe PMC] [Abstract]
    Cited for: IDENTIFICATION BY MASS SPECTROMETRY, TISSUE SPECIFICITY, SUBCELLULAR LOCATION.
  11. "Agrin binds to the N-terminal region of Lrp4 protein and stimulates association between Lrp4 and the first immunoglobulin-like domain in muscle-specific kinase (MuSK)."
    Zhang W., Coldefy A.S., Hubbard S.R., Burden S.J.
    J. Biol. Chem. 286:40624-40630(2011) [PubMed] [Europe PMC] [Abstract]
    Cited for: INTERACTION WITH LRP4, FUNCTION.
  12. "C-terminal Agrin Fragment as a potential marker for sarcopenia caused by degeneration of the neuromuscular junction."
    Drey M., Sieber C.C., Bauer J.M., Uter W., Dahinden P., Fariello R.G., Vrijbloed J.W.
    Exp. Gerontol. 48:76-80(2013) [PubMed] [Europe PMC] [Abstract]
    Cited for: POTENTIAL USAGE AS A BIOMARKER FOR SARCOPENIA.
  13. Cited for: VARIANT LGM ARG-1709, VARIANTS LEU-23; ASN-58; ILE-105; MET-267; SER-375; VAL-728; ARG-852; MET-984; PHE-1088; LYS-1118; ARG-1135; LEU-1240; ARG-1341; LEU-1451; THR-1514; HIS-1565; ILE-1666; GLN-1671; PRO-1698; HIS-1734; ASN-1789 AND VAL-2045, FUNCTION, CHARACTERIZATION OF VARIANT LGM ARG-1709.
  14. "LG2 agrin mutation causing severe congenital myasthenic syndrome mimics functional characteristics of non-neural (z-) agrin."
    Maselli R.A., Fernandez J.M., Arredondo J., Navarro C., Ngo M., Beeson D., Cagney O., Williams D.C., Wollmann R.L., Yarov-Yarovoy V., Ferns M.J.
    Hum. Genet. 131:1123-1135(2012) [PubMed] [Europe PMC] [Abstract]
    Cited for: VARIANT LGM PHE-1727, INTERACTION WITH DAG1, CHARACTERIZATION OF PHE-1727.

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: September 3, 2014
This is version 138 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).

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

External Data

Dasty 3

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