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Protein

Agrin

Gene

Agrn

Organism
Rattus norvegicus (Rat)
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. 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 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 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 1, isoform 4, isoform 5 and isoform 6: 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.
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 similarity8 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)LengthDescriptionGraphical viewFeature identifierActions
Sitei1143 – 11431Alternative splice site to produce 'x' isoforms
Sitei1642 – 16421Alternative splice site to produce 'y' isoforms
Sitei1753 – 17531Critical for cleavage by neurotrypsin
Sitei1779 – 17791Alternative splice site to produce 'z' isoforms
Sitei1783 – 17831Highly important for the agrin receptor complex activity of the 'z(8)' insert

Regions

Feature keyPosition(s)LengthDescriptionGraphical viewFeature identifierActions
Calcium bindingi1831 – 190070Add
BLAST

GO - Molecular functioni

  • BMP binding Source: RGD
  • calcium ion binding Source: UniProtKB
  • chondroitin sulfate binding Source: UniProtKB
  • dystroglycan binding Source: UniProtKB
  • heparan sulfate proteoglycan binding Source: UniProtKB
  • sialic acid binding Source: UniProtKB
  • transforming growth factor beta binding Source: RGD

GO - Biological processi

  • neuromuscular junction development Source: RGD
  • positive regulation of filopodium assembly Source: UniProtKB
  • positive regulation of GTPase activity Source: UniProtKB
  • positive regulation of peptidyl-tyrosine phosphorylation Source: UniProtKB
  • positive regulation of protein phosphorylation Source: UniProtKB
  • positive regulation of synaptic growth at neuromuscular junction Source: UniProtKB
  • positive regulation of transcription from RNA polymerase II promoter Source: UniProtKB
  • protein heterotetramerization Source: UniProtKB
  • receptor clustering Source: UniProtKB
  • regulation of axon guidance Source: RGD
  • regulation of microtubule cytoskeleton organization Source: RGD
  • regulation of protein phosphorylation Source: UniProtKB
  • skeletal muscle acetylcholine-gated channel clustering Source: UniProtKB
  • synapse assembly Source: RGD
  • synaptic transmission Source: RGD
Complete GO annotation...

Keywords - Molecular functioni

Developmental protein

Keywords - Biological processi

Differentiation

Keywords - Ligandi

Calcium

Names & Taxonomyi

Protein namesi
Recommended name:
Agrin
Cleaved into the following 4 chains:
Gene namesi
Name:Agrn
Synonyms:Agrin
OrganismiRattus norvegicus (Rat)
Taxonomic identifieri10116 [NCBI]
Taxonomic lineageiEukaryotaMetazoaChordataCraniataVertebrataEuteleostomiMammaliaEutheriaEuarchontogliresGliresRodentiaSciurognathiMuroideaMuridaeMurinaeRattus
Proteomesi
  • UP000002494 Componenti: Unplaced

Organism-specific databases

RGDi2067. Agrn.

Subcellular locationi

Topology

Feature keyPosition(s)LengthDescriptionGraphical viewFeature identifierActions
Topological domaini1 – 2626CytoplasmicSequence analysisAdd
BLAST
Transmembranei27 – 4721Helical; Signal-anchor for type II membrane proteinSequence analysisAdd
BLAST
Topological domaini48 – 19591912ExtracellularSequence analysisAdd
BLAST

GO - Cellular componenti

  • axonal growth cone Source: RGD
  • basal lamina Source: UniProtKB
  • basement membrane Source: RGD
  • cell junction Source: UniProtKB-KW
  • extracellular region Source: Reactome
  • integral component of membrane Source: UniProtKB-KW
  • plasma membrane Source: UniProtKB-SubCell
  • proteinaceous extracellular matrix Source: RGD
  • synapse Source: UniProtKB
Complete GO annotation...

Keywords - Cellular componenti

Cell junction, Cell membrane, Membrane, Synapse

Pathology & Biotechi

Mutagenesis

Feature keyPosition(s)LengthDescriptionGraphical viewFeature identifierActions
Mutagenesisi566 – 5716SGGSGS → AGGAGA: Abolishes heparan sulfate (HS) binding, greatly reduced branched retraction fiber (BRF) formation, filopodia formation reduced by about 50% and lowered RAC1 and CDK1 activation. No chondroitin sulfate (CS) nor heparan sulfate attachment, almost no branched retraction fiber (BRF) formation, filopodia formation reduced by about 60% and lowered RAC1 and CDK1 activation; when associated with 953-AGA-955.
Mutagenesisi953 – 9553SGS → AGA: Abolishes chondroitin sulfate (CS) binding, greatly reduced branched retraction fiber (BRF) formation, filopodia formation reduced by about 50% and lowered RAC1 and CDK1 activation. No chondroitin sulfate (CS) nor heparan sulfate (HS) binding almost no retraction fiber (BRF) formation, filopodia formation reduced by about 60% lowered RAC1 and CDK1 activation; when associated with 566-AGGAGA-571.
Mutagenesisi991 – 9911P → A: About 13% reduction in cleavage by neurotrypsin. 1 Publication
Mutagenesisi992 – 9921P → A: About 64% reduction in cleavage by neurotrypsin. 1 Publication
Mutagenesisi993 – 9931I → A: About 60% reduction in cleavage by neurotrypsin. 1 Publication
Mutagenesisi994 – 9941E → A: Almost completely abolishes cleavage by neurotrypsin. 1 Publication
Mutagenesisi995 – 9951R → A: Completely abolishes cleavage by neurotrypsin. 1 Publication
Mutagenesisi995 – 9951R → K: About 30% reduction in cleavage by neurotrypsin. 1 Publication
Mutagenesisi1726 – 17261S → A: Abolishes fucosylation of muscle agrin. Stimulates MUSK phosphorylation and increases AChR clustering. 1 Publication
Mutagenesisi1751 – 17511L → A: About 23% reduction in cleavage by neurotrypsin. Reduces cleavage by neurotrypsin by about 90%; when associated with A-1752. Completely abolishes cleavage by neurotrypsin; when associated with A-1753. 1 Publication
Mutagenesisi1752 – 17521V → A: About 41% reduction in cleavage by neurotrypsin. Reduces cleavage by neurotrypsin by about 90%; when associated with A-1751. Completely abolishes cleavage by neurotrypsin; when associated with A-1753. 1 Publication
Mutagenesisi1753 – 17531E → A or K: Almost completely abolishes cleavage by neurotrypsin. Completely abolishes cleavage by neurotrypsin; when associated with A-1751 or A-1752. 1 Publication
Mutagenesisi1753 – 17531E → D, L or Q: About 20% reduction in cleavage by neurotrypsin. 1 Publication
Mutagenesisi1754 – 17541K → A: Completely abolishes cleavage by neurotrypsin. 1 Publication
Mutagenesisi1754 – 17541K → R: About 55% reduction in cleavage by neurotrypsin. 1 Publication
Mutagenesisi1755 – 17551S → A: About 62% reduction in cleavage by neurotrypsin. 1 Publication
Mutagenesisi1756 – 17561V → A: Slight reduction in cleavage by neurotrypsin. 1 Publication
Mutagenesisi1757 – 17571G → A: Slight reduction in cleavage by neurotrypsin. 1 Publication
Mutagenesisi1780 – 17801E → A: Slight reduction in AChR clustering ability. 1 Publication
Mutagenesisi1781 – 17811L → A: Slight reduction in AChR clustering ability. Slight reduction in AChR clustering ability. 1 Publication
Mutagenesisi1782 – 17821T → A: Slight reduction in AChR clustering ability. 1 Publication
Mutagenesisi1783 – 17831N → A: Abolishes formation of AGRN-LRP4 complex and MUSK activation. No AChR clustering activity. 2 Publications
Mutagenesisi1784 – 17841E → A: Significant reduction in AChR clustering ability. 1 Publication
Mutagenesisi1785 – 17851I → A: Significant reduction in AChR clustering ability. 2 Publications
Mutagenesisi1785 – 17851I → S: Abolishes formation of AGRN-LRP4 complex and MUSK activation. 2 Publications
Mutagenesisi1786 – 17861P → A: Significant reduction in AChR clustering ability. 1 Publication
Mutagenesisi1806 – 18061H → L: No effect on formation of AGRN-LRP4 complex nor on MUSK activation. 1 Publication
Mutagenesisi1831 – 18311D → A: Abolishes calcium binding, lowering of binding to myotubes and some loss of AChR clustering activity; when associated with A-1900. 1 Publication
Mutagenesisi1876 – 18761R → E: No effect formation of AGRN-LRP4 complex nor on MUSK activation. 1 Publication
Mutagenesisi1900 – 19001D → A: Abolishes calcium binding, lowering of binding to myotubes and some loss of AChR clustering activity; when associated with A-1831. 1 Publication
Mutagenesisi1938 – 19381H → L: No effect formation of AGRN-LRP4 complex nor on MUSK activation. 1 Publication

PTM / Processingi

Molecule processing

Feature keyPosition(s)LengthDescriptionGraphical viewFeature identifierActions
Chaini1 – 19591959AgrinPRO_0000007472Add
BLAST
Chaini27 – 995969Agrin N-terminal 110 kDa subunitPRO_0000421621Add
BLAST
Chaini996 – 1959964Agrin C-terminal 110 kDa subunitPRO_0000421622Add
BLAST
Chaini996 – 1754759Agrin C-terminal 90 kDa fragmentPRO_0000421623Add
BLAST
Chaini1755 – 1959205Agrin C-terminal 22 kDa fragmentPRO_0000421624Add
BLAST

Amino acid modifications

Feature keyPosition(s)LengthDescriptionGraphical viewFeature identifierActions
Disulfide bondi97 ↔ 116Sequence analysis
Disulfide bondi105 ↔ 137Sequence analysis
Glycosylationi145 – 1451N-linked (GlcNAc...)Sequence analysis
Disulfide bondi171 ↔ 191Sequence analysis
Disulfide bondi180 ↔ 212Sequence analysis
Disulfide bondi244 ↔ 263Sequence analysis
Disulfide bondi252 ↔ 284Sequence analysis
Disulfide bondi316 ↔ 335Sequence analysis
Disulfide bondi324 ↔ 356Sequence analysis
Disulfide bondi389 ↔ 408Sequence analysis
Disulfide bondi397 ↔ 429Sequence analysis
Disulfide bondi454 ↔ 473Sequence analysis
Disulfide bondi462 ↔ 494Sequence analysis
Disulfide bondi518 ↔ 538Sequence analysis
Disulfide bondi527 ↔ 559Sequence analysis
Modified residuei569 – 5691PhosphoserineBy similarity
Modified residuei571 – 5711PhosphoserineBy similarity
Disulfide bondi604 ↔ 624Sequence analysis
Disulfide bondi613 ↔ 645Sequence analysis
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 ↔ 843Sequence analysis
Glycosylationi827 – 8271N-linked (GlcNAc...)Sequence analysis
Disulfide bondi832 ↔ 864Sequence analysis
Glycosylationi957 – 9571N-linked (GlcNAc...)Sequence analysis
Disulfide bondi1224 ↔ 1235By similarity
Disulfide bondi1229 ↔ 1246By similarity
Disulfide bondi1248 ↔ 1257By similarity
Disulfide bondi1410 ↔ 1439By similarity
Disulfide bondi1444 ↔ 1455Sequence analysis
Disulfide bondi1449 ↔ 1465Sequence analysis
Disulfide bondi1467 ↔ 1476Sequence analysis
Disulfide bondi1483 ↔ 1494By similarity
Disulfide bondi1488 ↔ 1504By similarity
Disulfide bondi1506 ↔ 1515By similarity
Disulfide bondi1713 ↔ 1727By similarity
Disulfide bondi1721 ↔ 1736By similarity
Disulfide bondi1738 ↔ 1747By similarity
Disulfide bondi1930 ↔ 1956By 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 agrin 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 doamin 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.2 Publications
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).2 Publications

Sites

Feature keyPosition(s)LengthDescriptionGraphical viewFeature identifierActions
Sitei995 – 9962Cleavage, alpha site; by neurotrypsin
Sitei1754 – 17552Cleavage, beta site; by neurotrypsin

Keywords - PTMi

Disulfide bond, Glycoprotein, Heparan sulfate, Phosphoprotein, Proteoglycan

Proteomic databases

PaxDbiP25304.
PRIDEiP25304.

PTM databases

iPTMnetiP25304.
SwissPalmiP25304.

Expressioni

Tissue specificityi

Embryonic nervous system and muscle.2 Publications

Developmental stagei

More abundant early in development. At E13, highly expressed in the developing nervous system. Isoform y(+4)z(0), containing the 'y' insert but no 'z' insert, is the most prevelant at this stage with pronounced expression in developing spinal and sympathetic ganglia. Isoforms with no 'y' insert (y0) localized to peripheral tissue. At E15, y(+4) isoform continues to be highly expressed in neural tissue predominantly in the spinal column and developing brain. The y0 isoform is weakly expressed in capillaries and meninges and the y0(z0) in non-neural tissues, predominantly in epithelial cells lining the developing lung bronchioles and kidney tubules. Isoforms Z(+8) and z(+19) are highly expressed in ventral motor columns and facial nerve with weaker expression throughout spinal cord tissue. At later stages of development, isoform y(4)z(0) is the most prominent form in developing cortex, corpus striatum, hippocampus and cerebellum. Isoform y(0)z(0) expression is still detected in brain capillaries at stage P1. The z(+19) isoform is most highly expressed from E15 to E18 and declines slightly to P1. Isoforms y14z0 and y(+4)z(+8) are still expressed in adulthood, the former scattered throughout the spinal cord gray matter and, the latter, in motor neurons of the ventral spinal cord.2 Publications

Interactioni

Subunit structurei

Monomer. 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 (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.4 Publications

Binary interactionsi

WithEntry#Exp.IntActNotes
Lrp4Q8VI563EBI-2106099,EBI-2106160From a different organism.

GO - Molecular functioni

  • BMP binding Source: RGD
  • dystroglycan binding Source: UniProtKB
  • heparan sulfate proteoglycan binding Source: UniProtKB
  • transforming growth factor beta binding Source: RGD

Protein-protein interaction databases

IntActiP25304. 2 interactions.
STRINGi10116.ENSRNOP00000050623.

Structurei

Secondary structure

1
1959
Legend: HelixTurnBeta strand
Show more details
Feature keyPosition(s)LengthDescriptionGraphical viewFeature identifierActions
Beta strandi1761 – 17677Combined sources
Beta strandi1770 – 17734Combined sources
Helixi1779 – 17824Combined sources
Beta strandi1800 – 181213Combined sources
Beta strandi1816 – 18249Combined sources
Beta strandi1826 – 18294Combined sources
Beta strandi1832 – 18387Combined sources
Beta strandi1841 – 185010Combined sources
Beta strandi1853 – 18608Combined sources
Beta strandi1863 – 18653Combined sources
Beta strandi1867 – 18748Combined sources
Beta strandi1877 – 18826Combined sources
Beta strandi1888 – 18914Combined sources
Beta strandi1899 – 19013Combined sources
Beta strandi1903 – 19086Combined sources
Helixi1921 – 19233Combined sources
Beta strandi1928 – 19369Combined sources
Turni1943 – 19464Combined sources

3D structure databases

Select the link destinations:
PDBei
RCSB PDBi
PDBji
Links Updated
EntryMethodResolution (Å)ChainPositionsPDBsum
3V64X-ray2.85A/B1759-1959[»]
3V65X-ray3.30A/C1759-1959[»]
ProteinModelPortaliP25304.
SMRiP25304. Positions 1748-1956.
ModBaseiSearch...
MobiDBiSearch...

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
Domaini810 – 86657Kazal-like 9PROSITE-ProRule annotationAdd
BLAST
Domaini1023 – 1145123SEAPROSITE-ProRule annotationAdd
BLAST
Domaini1220 – 125839EGF-like 1PROSITE-ProRule annotationAdd
BLAST
Domaini1263 – 1439177Laminin G-like 1PROSITE-ProRule annotationAdd
BLAST
Domaini1440 – 147738EGF-like 2PROSITE-ProRule annotationAdd
BLAST
Domaini1479 – 151638EGF-like 3PROSITE-ProRule annotationAdd
BLAST
Domaini1526 – 1708183Laminin G-like 2PROSITE-ProRule annotationAdd
BLAST
Domaini1709 – 174840EGF-like 4PROSITE-ProRule annotationAdd
BLAST
Domaini1784 – 1956173Laminin G-like 3PROSITE-ProRule annotationAdd
BLAST

Compositional bias

Feature keyPosition(s)LengthDescriptionGraphical viewFeature identifierActions
Compositional biasi565 – 5728Gly/Ser-rich
Compositional biasi857 – 94892Ser/Thr-richAdd
BLAST
Compositional biasi953 – 9608Gly/Ser-rich
Compositional biasi971 – 9777Gly/Ser-rich
Compositional biasi1147 – 121468Ser/Thr-richAdd
BLAST
Compositional biasi1676 – 169015Gly/Ser-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.

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

eggNOGiENOG410ITSI. Eukaryota.
ENOG410YKSA. LUCA.
HOGENOMiHOG000033860.
HOVERGENiHBG080471.
InParanoidiP25304.
KOiK06254.
PhylomeDBiP25304.

Family and domain databases

Gene3Di2.60.120.200. 4 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.
IPR000082. SEA_dom.
[Graphical view]
PfamiPF00008. EGF. 3 hits.
PF00050. Kazal_1. 1 hit.
PF07648. Kazal_2. 8 hits.
PF00053. Laminin_EGF. 2 hits.
PF00054. Laminin_G_1. 3 hits.
PF01390. SEA. 1 hit.
[Graphical view]
SMARTiSM00181. EGF. 6 hits.
SM00179. EGF_CA. 3 hits.
SM00180. EGF_Lam. 2 hits.
SM00057. FIMAC. 3 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 (6)i

Sequence statusi: Complete.

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

This entry describes 6 isoformsi produced by alternative splicing. AlignAdd to basket

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 may be produced by alternative usage of the first exon.

Isoform 1 (identifier: P25304-1) [UniParc]FASTAAdd to basket

Also known as: Transmembrane agrin, TM-agrin, Agrin z(+19)

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
MPPLPLEHRP RQEPGASMLV RYFMIPCNIC LILLATSTLG FAVLLFLSNY
60 70 80 90 100
KPGIHFTPAP PTPPDVCRGM LCGFGAVCEP SVEDPGRASC VCKKNACPAT
110 120 130 140 150
VAPVCGSDAS TYSNECELQR AQCNQQRRIR LLRQGPCGSR DPCANVTCSF
160 170 180 190 200
GSTCVPSADG QTASCLCPTT CFGAPDGTVC GSDGVDYPSE CQLLSHACAS
210 220 230 240 250
QEHIFKKFNG PCDPCQGSMS DLNHICRVNP RTRHPEMLLR PENCPAQHTP
260 270 280 290 300
ICGDDGVTYE NDCVMSRIGA TRGLLLQKVR SGQCQTRDQC PETCQFNSVC
310 320 330 340 350
LSRRGRPHCS CDRVTCDGSY RPVCAQDGHT YNNDCWRQQA ECRQQRAIPP
360 370 380 390 400
KHQGPCDQTP SPCHGVQCAF GAVCTVKNGK AECECQRVCS GIYDPVCGSD
410 420 430 440 450
GVTYGSVCEL ESMACTLGRE IQVARRGPCD PCGQCRFGSL CEVETGRCVC
460 470 480 490 500
PSECVESAQP VCGSDGHTYA SECELHVHAC THQISLYVAS AGHCQTCGEK
510 520 530 540 550
VCTFGAVCSA GQCVCPRCEH PPPGPVCGSD GVTYLSACEL REAACQQQVQ
560 570 580 590 600
IEEAHAGPCE PAECGSGGSG SGEDDECEQE LCRQRGGIWD EDSEDGPCVC
610 620 630 640 650
DFSCQSVPRS PVCGSDGVTY GTECDLKKAR CESQQELYVA AQGACRGPTL
660 670 680 690 700
APLLPVAFPH CAQTPYGCCQ DNFTAAQGVG LAGCPSTCHC NPHGSYSGTC
710 720 730 740 750
DPATGQCSCR PGVGGLRCDR CEPGFWNFRG IVTDGHSGCT PCSCDPRGAV
760 770 780 790 800
RDDCEQMTGL CSCRPGVAGP KCGQCPDGQV LGHLGCEADP MTPVTCVEIH
810 820 830 840 850
CEFGASCVEK AGFAQCICPT LTCPEANSTK VCGSDGVTYG NECQLKAIAC
860 870 880 890 900
RQRLDISTQS LGPCQESVTP GASPTSASMT TPRHILSKTL PFPHNSLPLS
910 920 930 940 950
PGSTTHDWPT PLPISPHTTV SIPRSTAWPV LTVPPTAAAS DVTSLATSIF
960 970 980 990 1000
SESGSANGSG DEELSGDEEA SGGGSGGLEP PVGSIVVTHG PPIERASCYN
1010 1020 1030 1040 1050
SPLGCCSDGK TPSLDSEGSN CPATKAFQGV LELEGVEGQE LFYTPEMADP
1060 1070 1080 1090 1100
KSELFGETAR SIESTLDDLF RNSDVKKDFW SVRLRELGPG KLVRAIVDVH
1110 1120 1130 1140 1150
FDPTTAFQAS DVGQALLRQI QVSRPWALAV RRPLQEHVRF LDFDWFPTFF
1160 1170 1180 1190 1200
TGAATGTTAA MATARATTVS RLPASSVTPR VYPSHTSRPV GRTTAPPTTR
1210 1220 1230 1240 1250
RPPTTATNMD RPRTPGHQQP SKSCDSQPCL HGGTCQDQDS GKGFTCSCTA
1260 1270 1280 1290 1300
GRGGSVCEKV QPPSMPAFKG HSFLAFPTLR AYHTLRLALE FRALETEGLL
1310 1320 1330 1340 1350
LYNGNARGKD FLALALLDGR VQFRFDTGSG PAVLTSLVPV EPGRWHRLEL
1360 1370 1380 1390 1400
SRHWRQGTLS VDGETPVVGE SPSGTDGLNL DTNLYVGGIP EEQVAMVLDR
1410 1420 1430 1440 1450
TSVGVGLKGC IRMLDINNQQ LELSDWQRAA VQSSGVGECG DHPCLPNPCH
1460 1470 1480 1490 1500
GGALCQALEA GMFLCQCPPG RFGPTCADEK SPCQPNPCHG AAPCRVLSSG
1510 1520 1530 1540 1550
GAKCECPLGR SGTFCQTVLE TAGSRPFLAD FNGFSYLELK GLHTFERDLG
1560 1570 1580 1590 1600
EKMALEMVFL ARGPSGLLLY NGQKTDGKGD FVSLALHNRH LEFCYDLGKG
1610 1620 1630 1640 1650
AAVIRSKEPI ALGTWVRVFL ERNGRKGALQ VGDGPRVLGE SPKSRKVPHT
1660 1670 1680 1690 1700
MLNLKEPLYI GGAPDFSKLA RGAAVSSGFS GVIQLVSLRG HQLLTQEHVL
1710 1720 1730 1740 1750
RAVDVSPFAD HPCTQALGNP CLNGGSCVPR EATYECLCPG GFSGLHCEKG
1760 1770 1780 1790 1800
LVEKSVGDLE TLAFDGRTYI EYLNAVIESE LTNEIPAPET LDSRALFSEK
1810 1820 1830 1840 1850
ALQSNHFELS LRTEATQGLV LWIGKAAERA DYMALAIVDG HLQLSYDLGS
1860 1870 1880 1890 1900
QPVVLRSTVK VNTNRWLRIR AHREHREGSL QVGNEAPVTG SSPLGATQLD
1910 1920 1930 1940 1950
TDGALWLGGL QKLPVGQALP KAYGTGFVGC LRDVVVGHRQ LHLLEDAVTK

PELRPCPTP
Length:1,959
Mass (Da):208,646
Last modified:July 1, 1993 - v2
Checksum:i7FEFDFDAFF89CC31
GO
Isoform 2 (identifier: P25304-2) [UniParc]FASTAAdd to basket

Also known as: Agrin x(0)

The sequence of this isoform differs from the canonical sequence as follows:
     1144-1152: Missing.

Show »
Length:1,950
Mass (Da):207,547
Checksum:iDA0C31258A7BE9E7
GO
Isoform 3 (identifier: P25304-3) [UniParc]FASTAAdd to basket

Also known as: Agrin z(0)

The sequence of this isoform differs from the canonical sequence as follows:
     1780-1798: Missing.

Show »
Length:1,940
Mass (Da):206,561
Checksum:i47D7E361C3169B25
GO
Isoform 4 (identifier: P25304-4) [UniParc]FASTAAdd to basket

Also known as: Agrin z(+11)

The sequence of this isoform differs from the canonical sequence as follows:
     1788-1798: Missing.

Show »
Length:1,948
Mass (Da):207,429
Checksum:i69C99FF177D5B036
GO
Isoform 5 (identifier: P25304-5) [UniParc]FASTAAdd to basket

Also known as: Agrin z(+8)

The sequence of this isoform differs from the canonical sequence as follows:
     1780-1787: Missing.

Show »
Length:1,951
Mass (Da):207,778
Checksum:i3BC18F7BCCE34FC2
GO
Isoform 6 (identifier: P25304-6) [UniParc]FASTAAdd to basket

Also known as: Agrin y(0)

The sequence of this isoform differs from the canonical sequence as follows:
     1643-1646: Missing.

Show »
Length:1,955
Mass (Da):208,146
Checksum:i8A100E409BFEEB51
GO

Experimental Info

Feature keyPosition(s)LengthDescriptionGraphical viewFeature identifierActions
Sequence conflicti315 – 3173Missing in AAA40702 (PubMed:1851019).Curated

Alternative sequence

Feature keyPosition(s)LengthDescriptionGraphical viewFeature identifierActions
Alternative sequencei1144 – 11529Missing in isoform 2. 1 PublicationVSP_001365
Alternative sequencei1643 – 16464Missing in isoform 6. CuratedVSP_045759
Alternative sequencei1780 – 179819Missing in isoform 3. 2 PublicationsVSP_001366Add
BLAST
Alternative sequencei1780 – 17878Missing in isoform 5. 1 PublicationVSP_001368
Alternative sequencei1788 – 179811Missing in isoform 4. 1 PublicationVSP_001367Add
BLAST

Sequence databases

Select the link destinations:
EMBLi
GenBanki
DDBJi
Links Updated
M64780 mRNA. Translation: AAA40702.1.
M64780 mRNA. Translation: AAA40703.1.
S44194 mRNA. Translation: AAB23326.1.
PIRiJH0399. AGRT.
RefSeqiNP_786930.1. NM_175754.1. [P25304-3]
UniGeneiRn.2163.

Genome annotation databases

GeneIDi25592.
KEGGirno:25592.

Keywords - Coding sequence diversityi

Alternative splicing

Cross-referencesi

Sequence databases

Select the link destinations:
EMBLi
GenBanki
DDBJi
Links Updated
M64780 mRNA. Translation: AAA40702.1.
M64780 mRNA. Translation: AAA40703.1.
S44194 mRNA. Translation: AAB23326.1.
PIRiJH0399. AGRT.
RefSeqiNP_786930.1. NM_175754.1. [P25304-3]
UniGeneiRn.2163.

3D structure databases

Select the link destinations:
PDBei
RCSB PDBi
PDBji
Links Updated
EntryMethodResolution (Å)ChainPositionsPDBsum
3V64X-ray2.85A/B1759-1959[»]
3V65X-ray3.30A/C1759-1959[»]
ProteinModelPortaliP25304.
SMRiP25304. Positions 1748-1956.
ModBaseiSearch...
MobiDBiSearch...

Protein-protein interaction databases

IntActiP25304. 2 interactions.
STRINGi10116.ENSRNOP00000050623.

PTM databases

iPTMnetiP25304.
SwissPalmiP25304.

Proteomic databases

PaxDbiP25304.
PRIDEiP25304.

Protocols and materials databases

Structural Biology KnowledgebaseSearch...

Genome annotation databases

GeneIDi25592.
KEGGirno:25592.

Organism-specific databases

CTDi375790.
RGDi2067. Agrn.

Phylogenomic databases

eggNOGiENOG410ITSI. Eukaryota.
ENOG410YKSA. LUCA.
HOGENOMiHOG000033860.
HOVERGENiHBG080471.
InParanoidiP25304.
KOiK06254.
PhylomeDBiP25304.

Miscellaneous databases

PROiP25304.

Family and domain databases

Gene3Di2.60.120.200. 4 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.
IPR000082. SEA_dom.
[Graphical view]
PfamiPF00008. EGF. 3 hits.
PF00050. Kazal_1. 1 hit.
PF07648. Kazal_2. 8 hits.
PF00053. Laminin_EGF. 2 hits.
PF00054. Laminin_G_1. 3 hits.
PF01390. SEA. 1 hit.
[Graphical view]
SMARTiSM00181. EGF. 6 hits.
SM00179. EGF_CA. 3 hits.
SM00180. EGF_Lam. 2 hits.
SM00057. FIMAC. 3 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]
ProtoNetiSearch...

Publicationsi

  1. Cited for: NUCLEOTIDE SEQUENCE [MRNA] (ISOFORM 3), TISSUE SPECIFICITY.
    Tissue: Embryonic spinal cord.
  2. "Structure and chromosomal localization of the mammalian agrin gene."
    Rupp F., Oezcelik T., Linial M., Peterson K., Francke U., Scheller R.H.
    J. Neurosci. 12:3535-3544(1992) [PubMed] [Europe PMC] [Abstract]
    Cited for: NUCLEOTIDE SEQUENCE [MRNA] (ISOFORMS 1; 2; 3; 4 AND 5), DEVELOPMENTAL STAGE.
  3. "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: NUCLEOTIDE SEQUENCE [MRNA] OF 1-60 (ISOFORM 1), ALTERNATIVE PROMOTER USAGE, SUBCELLULAR LOCATION.
  4. "The ability of agrin to cluster AChRs depends on alternative splicing and on cell surface proteoglycans."
    Ferns M.J., Campanelli J.T., Hoch W., Scheller R.H., Hall Z.
    Neuron 11:491-502(1993) [PubMed] [Europe PMC] [Abstract]
    Cited for: ALTERNATING SPLICING, TISSUE SPECIFICITY, GLYCOSYLATION, FUNCTION.
  5. "Tissue- and age-specific expression patterns of alternatively spliced agrin mRNA transcripts in embryonic rat suggest novel developmental roles."
    Stone D.M., Nikolics K.
    J. Neurosci. 15:6767-6778(1995) [PubMed] [Europe PMC] [Abstract]
    Cited for: ALTERNATIVE SPLICING, DEVELOPMENTAL STAGE.
  6. Cited for: FUNCTION IN NEUROMUSCULAR JUNCTION DEVELOPMENT, SUBCELLULAR LOCATION, FUNCTION IN PHOSPHORYLATION OF MUSK, INTERACTION WITH LRP4.
  7. "Alternative splicing of agrin regulates its binding to heparin, alpha-dystroglycan, and the cell surface."
    O'Toole J.J., Deyst K.A., Bowe M.A., Nastuk M.A., McKechnie B.A., Fallon J.R.
    Proc. Natl. Acad. Sci. U.S.A. 93:7369-7374(1996) [PubMed] [Europe PMC] [Abstract]
    Cited for: ALTERNATIVE SPLICING, INTERACTION WITH DAG1, HEPARIN BINDING, FUNCTION.
  8. "Specific cleavage of agrin by neurotrypsin, a synaptic protease linked to mental retardation."
    Reif R., Sales S., Hettwer S., Dreier B., Gisler C., Wolfel J., Luscher D., Zurlinden A., Stephan A., Ahmed S., Baici A., Ledermann B., Kunz B., Sonderegger P.
    FASEB J. 21:3468-3478(2007) [PubMed] [Europe PMC] [Abstract]
    Cited for: PROTEOLYTIC PROCESSING, IDENTIFICATION OF PROTEOLYTICALLY CLEAVED PRODUCTS BY MASS SPECTROMETRY, MUTAGENESIS OF PRO-991; PRO-992; ILE-993; GLU-994; ARG-995; LEU-1751; VAL-1752; GLU-1753; LYS-1754; SER-1755; VAL-1756 AND GLY-1757.
  9. "O-fucosylation of muscle agrin determines its ability to cluster acetylcholine receptors."
    Kim M.L., Chandrasekharan K., Glass M., Shi S., Stahl M.C., Kaspar B., Stanley P., Martin P.T.
    Mol. Cell. Neurosci. 39:452-464(2008) [PubMed] [Europe PMC] [Abstract]
    Cited for: GLYCOSYLATION AT SER-1726, FUNCTION, MUTAGENESIS OF SER-1726.
  10. "Transmembrane agrin regulates dendritic filopodia and synapse formation in mature hippocampal neuron cultures."
    McCroskery S., Bailey A., Lin L., Daniels M.P.
    Neuroscience 163:168-179(2009) [PubMed] [Europe PMC] [Abstract]
    Cited for: FUNCTION.
  11. "Induction of filopodia-like protrusions by transmembrane agrin: role of agrin glycosaminoglycan chains and Rho-family GTPases."
    Lin L., McCroskery S., Ross J.M., Chak Y., Neuhuber B., Daniels M.P.
    Exp. Cell Res. 316:2260-2277(2010) [PubMed] [Europe PMC] [Abstract]
    Cited for: FUNCTION, HEPARAN SULFATE BINDING, CHONDROITIN SULFATE BINDING.
  12. "Asparagine of z8 insert is critical for the affinity, conformation, and acetylcholine receptor-clustering activity of neural agrin."
    Tseng C.N., Zhang L., Wu S.L., Wang W.F., Wang Z.Z., Cascio M.
    J. Biol. Chem. 285:27641-27651(2010) [PubMed] [Europe PMC] [Abstract]
    Cited for: FUNCTION, CALCIUM-BINDING, MUTAGENESIS OF GLU-1780; LEU-1781; THR-1782; ASN-1783; GLU-1784; ILE-1785; PRO-1786; ASP-1831 AND ASP-1900.
  13. Cited for: PROTEOLYTIC PROCESSING.
  14. Cited for: INTERACTION WITH BMP2; BMP4 AND TGFB1, FUNCTION.
  15. Cited for: X-RAY CRYSTALLOGRAPHY (2.85 ANGSTROMS) OF 1759-1959 IN COMPLEX WITH LRP4, SUBUNIT, MUTAGENESIS OF ASN-1783; ILE-1785; HIS-1806; ARG-1876 AND HIS-1938.

Entry informationi

Entry nameiAGRIN_RAT
AccessioniPrimary (citable) accession number: P25304
Secondary accession number(s): Q63034
Entry historyi
Integrated into UniProtKB/Swiss-Prot: May 1, 1992
Last sequence update: July 1, 1993
Last modified: June 8, 2016
This is version 152 of the entry and version 2 of the sequence. [Complete history]
Entry statusiReviewed (UniProtKB/Swiss-Prot)
Annotation programChordata Protein Annotation Program

Miscellaneousi

Keywords - Technical termi

3D-structure, Complete proteome, Reference proteome

Documents

  1. PDB cross-references
    Index of Protein Data Bank (PDB) cross-references
  2. 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.