AGRIN_RAT
ID AGRIN_RAT Reviewed; 1959 AA.
AC P25304; Q63034;
DT 01-MAY-1992, integrated into UniProtKB/Swiss-Prot.
DT 01-JUL-1993, sequence version 2.
DT 03-AUG-2022, entry version 189.
DE RecName: Full=Agrin;
DE Contains:
DE RecName: Full=Agrin N-terminal 110 kDa subunit;
DE Contains:
DE RecName: Full=Agrin C-terminal 110 kDa subunit;
DE Contains:
DE RecName: Full=Agrin C-terminal 90 kDa fragment;
DE Short=C90;
DE Contains:
DE RecName: Full=Agrin C-terminal 22 kDa fragment;
DE Short=C22;
GN Name=Agrn; Synonyms=Agrin;
OS Rattus norvegicus (Rat).
OC Eukaryota; Metazoa; Chordata; Craniata; Vertebrata; Euteleostomi; Mammalia;
OC Eutheria; Euarchontoglires; Glires; Rodentia; Myomorpha; Muroidea; Muridae;
OC Murinae; Rattus.
OX NCBI_TaxID=10116;
RN [1]
RP NUCLEOTIDE SEQUENCE [MRNA] (ISOFORM 3), AND TISSUE SPECIFICITY.
RC TISSUE=Embryonic spinal cord;
RX PubMed=1851019; DOI=10.1016/0896-6273(91)90177-2;
RA Rupp F., Payan D.G., Magill-Solc C., Cowan D.M., Scheller R.H.;
RT "Structure and expression of a rat agrin.";
RL Neuron 6:811-823(1991).
RN [2]
RP NUCLEOTIDE SEQUENCE [MRNA] (ISOFORMS 1; 2; 3; 4 AND 5), AND DEVELOPMENTAL
RP STAGE.
RX PubMed=1326608; DOI=10.1523/jneurosci.12-09-03535.1992;
RA Rupp F., Oezcelik T., Linial M., Peterson K., Francke U., Scheller R.H.;
RT "Structure and chromosomal localization of the mammalian agrin gene.";
RL J. Neurosci. 12:3535-3544(1992).
RN [3]
RP NUCLEOTIDE SEQUENCE [MRNA] OF 1-60 (ISOFORM 1), ALTERNATIVE PROMOTER USAGE,
RP AND SUBCELLULAR LOCATION.
RX PubMed=11161480; DOI=10.1006/mcne.2000.0932;
RA Neumann F.R., Bittcher G., Annies M., Schumacher B., Kroger S., Ruegg M.A.;
RT "An alternative amino-terminus expressed in the central nervous system
RT converts agrin to a type II transmembrane protein.";
RL Mol. Cell. Neurosci. 17:208-225(2001).
RN [4]
RP ALTERNATING SPLICING, TISSUE SPECIFICITY, GLYCOSYLATION, AND FUNCTION.
RX PubMed=8398142; DOI=10.1016/0896-6273(93)90153-i;
RA Ferns M.J., Campanelli J.T., Hoch W., Scheller R.H., Hall Z.;
RT "The ability of agrin to cluster AChRs depends on alternative splicing and
RT on cell surface proteoglycans.";
RL Neuron 11:491-502(1993).
RN [5]
RP ALTERNATIVE SPLICING, AND DEVELOPMENTAL STAGE.
RX PubMed=7472435; DOI=10.1523/jneurosci.15-10-06767.1995;
RA Stone D.M., Nikolics K.;
RT "Tissue- and age-specific expression patterns of alternatively spliced
RT agrin mRNA transcripts in embryonic rat suggest novel developmental
RT roles.";
RL J. Neurosci. 15:6767-6778(1995).
RN [6]
RP FUNCTION IN NEUROMUSCULAR JUNCTION DEVELOPMENT, SUBCELLULAR LOCATION,
RP FUNCTION IN PHOSPHORYLATION OF MUSK, AND INTERACTION WITH LRP4.
RX PubMed=8653787; DOI=10.1016/s0092-8674(00)81252-0;
RA Glass D.J., Bowen D.C., Stitt T.N., Radziejewski C., Bruno J., Ryan T.E.,
RA Gies D.R., Shah S., Mattsson K., Burden S.J., DiStefano P.S.,
RA Valenzuela D.M., DeChiara T.M., Yancopoulos G.D.;
RT "Agrin acts via a MuSK receptor complex.";
RL Cell 85:513-523(1996).
RN [7]
RP ALTERNATIVE SPLICING, INTERACTION WITH DAG1, HEPARIN BINDING, AND FUNCTION.
RX PubMed=8693000; DOI=10.1073/pnas.93.14.7369;
RA O'Toole J.J., Deyst K.A., Bowe M.A., Nastuk M.A., McKechnie B.A.,
RA Fallon J.R.;
RT "Alternative splicing of agrin regulates its binding to heparin, alpha-
RT dystroglycan, and the cell surface.";
RL Proc. Natl. Acad. Sci. U.S.A. 93:7369-7374(1996).
RN [8]
RP PROTEOLYTIC PROCESSING, IDENTIFICATION OF PROTEOLYTICALLY CLEAVED PRODUCTS
RP BY MASS SPECTROMETRY, AND MUTAGENESIS OF PRO-991; PRO-992; ILE-993;
RP GLU-994; ARG-995; LEU-1751; VAL-1752; GLU-1753; LYS-1754; SER-1755;
RP VAL-1756 AND GLY-1757.
RX PubMed=17586728; DOI=10.1096/fj.07-8800com;
RA Reif R., Sales S., Hettwer S., Dreier B., Gisler C., Wolfel J., Luscher D.,
RA Zurlinden A., Stephan A., Ahmed S., Baici A., Ledermann B., Kunz B.,
RA Sonderegger P.;
RT "Specific cleavage of agrin by neurotrypsin, a synaptic protease linked to
RT mental retardation.";
RL FASEB J. 21:3468-3478(2007).
RN [9]
RP GLYCOSYLATION AT SER-1726, FUNCTION, AND MUTAGENESIS OF SER-1726.
RX PubMed=18775496; DOI=10.1016/j.mcn.2008.07.026;
RA Kim M.L., Chandrasekharan K., Glass M., Shi S., Stahl M.C., Kaspar B.,
RA Stanley P., Martin P.T.;
RT "O-fucosylation of muscle agrin determines its ability to cluster
RT acetylcholine receptors.";
RL Mol. Cell. Neurosci. 39:452-464(2008).
RN [10]
RP FUNCTION.
RX PubMed=19524020; DOI=10.1016/j.neuroscience.2009.06.012;
RA McCroskery S., Bailey A., Lin L., Daniels M.P.;
RT "Transmembrane agrin regulates dendritic filopodia and synapse formation in
RT mature hippocampal neuron cultures.";
RL Neuroscience 163:168-179(2009).
RN [11]
RP FUNCTION, HEPARAN SULFATE BINDING, AND CHONDROITIN SULFATE BINDING.
RX PubMed=20471381; DOI=10.1016/j.yexcr.2010.05.006;
RA Lin L., McCroskery S., Ross J.M., Chak Y., Neuhuber B., Daniels M.P.;
RT "Induction of filopodia-like protrusions by transmembrane agrin: role of
RT agrin glycosaminoglycan chains and Rho-family GTPases.";
RL Exp. Cell Res. 316:2260-2277(2010).
RN [12]
RP FUNCTION, CALCIUM-BINDING, AND MUTAGENESIS OF GLU-1780; LEU-1781; THR-1782;
RP ASN-1783; GLU-1784; ILE-1785; PRO-1786; ASP-1831 AND ASP-1900.
RX PubMed=20566625; DOI=10.1074/jbc.m110.130625;
RA Tseng C.N., Zhang L., Wu S.L., Wang W.F., Wang Z.Z., Cascio M.;
RT "Asparagine of z8 insert is critical for the affinity, conformation, and
RT acetylcholine receptor-clustering activity of neural agrin.";
RL J. Biol. Chem. 285:27641-27651(2010).
RN [13]
RP PROTEOLYTIC PROCESSING.
RX PubMed=20980386; DOI=10.1242/jcs.072090;
RA Bolliger M.F., Zurlinden A., Luscher D., Butikofer L., Shakhova O.,
RA Francolini M., Kozlov S.V., Cinelli P., Stephan A., Kistler A.D.,
RA Rulicke T., Pelczar P., Ledermann B., Fumagalli G., Gloor S.M., Kunz B.,
RA Sonderegger P.;
RT "Specific proteolytic cleavage of agrin regulates maturation of the
RT neuromuscular junction.";
RL J. Cell Sci. 123:3944-3955(2010).
RN [14]
RP INTERACTION WITH BMP2; BMP4 AND TGFB1, AND FUNCTION.
RX PubMed=20505824; DOI=10.1371/journal.pone.0010758;
RA Banyai L., Sonderegger P., Patthy L.;
RT "Agrin binds BMP2, BMP4 and TGFbeta1.";
RL PLoS ONE 5:E10758-E10758(2010).
RN [15] {ECO:0007744|PDB:3V64, ECO:0007744|PDB:3V65}
RP X-RAY CRYSTALLOGRAPHY (2.85 ANGSTROMS) OF 1759-1959 IN COMPLEX WITH LRP4
RP AND CALCIUM, SUBUNIT, AND MUTAGENESIS OF ASN-1783; ILE-1785; HIS-1806;
RP ARG-1876 AND HIS-1938.
RX PubMed=22302937; DOI=10.1101/gad.180885.111;
RA Zong Y., Zhang B., Gu S., Lee K., Zhou J., Yao G., Figueiredo D., Perry K.,
RA Mei L., Jin R.;
RT "Structural basis of agrin-LRP4-MuSK signaling.";
RL Genes Dev. 26:247-258(2012).
CC -!- FUNCTION: [Isoform 1]: Heparan sulfate basal lamina glycoprotein that
CC plays a central role in the formation and the maintenance of the
CC neuromuscular junction (NMJ) and directs key events in postsynaptic
CC differentiation. This neuron-specific (z+) isoform is a component of
CC the AGRN-LRP4 receptor complex that induces the phosphorylation and
CC activation of MUSK. The activation of MUSK in myotubes induces the
CC formation of NMJ by regulating different processes including the
CC transcription of specific genes and the clustering of AChR in the
CC postsynaptic membrane. Calcium ions are required for maximal AChR
CC clustering. AGRN function in neurons is highly regulated by alternative
CC splicing, glycan binding and proteolytic processing. Modulates calcium
CC ion homeostasis in neurons, specifically by inducing an increase in
CC cytoplasmic calcium ions. Functions differentially in the central
CC nervous system (CNS) by inhibiting the alpha(3)-subtype of Na+/K+-
CC ATPase and evoking depolarization at CNS synapses. This transmembrane
CC agrin (TM-agrin) isoform, the predominate form in neurons of the brain,
CC induces dendritic filopodia and synapse formation in mature hippocampal
CC neurons in large part due to the attached glycosaminoglycan chains and
CC the action of Rho-family GTPases.
CC -!- FUNCTION: Isoform 1, isoform 4, isoform 5 and isoform 6: neuron-
CC specific (z+) isoforms that contain C-terminal insertions of 8-19 AA
CC are potent activators of AChR clustering. Isoform 5, agrin (z+8),
CC containing the 8-AA insert, forms a receptor complex in myotubules
CC containing the neuronal AGRN, the muscle-specific kinase MUSK and LRP4,
CC a member of the LDL receptor family. The splicing factors, NOVA1 and
CC NOVA2, regulate AGRN splicing and production of the 'z' isoforms.
CC -!- FUNCTION: [Agrin N-terminal 110 kDa subunit]: Is involved in regulation
CC of neurite outgrowth probably due to the presence of the
CC glycosaminoglcan (GAG) side chains of heparan and chondroitin sulfate
CC attached to the Ser/Thr- and Gly/Ser-rich regions. Also involved in
CC modulation of growth factor signaling (By similarity). {ECO:0000250,
CC ECO:0000269|PubMed:18775496, ECO:0000269|PubMed:19524020,
CC ECO:0000269|PubMed:20471381, ECO:0000269|PubMed:20505824,
CC ECO:0000269|PubMed:20566625, ECO:0000269|PubMed:8398142,
CC ECO:0000269|PubMed:8653787, ECO:0000269|PubMed:8693000}.
CC -!- FUNCTION: [Agrin C-terminal 22 kDa fragment]: This released fragment is
CC important for agrin signaling and to exert a maximal dendritic
CC filopodia-inducing effect. All 'z' splice variants (z+) of this
CC fragment also show an increase in the number of filopodia.
CC -!- SUBUNIT: Monomer. Component of the AGRN-LRP4 complex that consists of a
CC tetramer of two AGRN-LRP4 heterodimers. Interacts (via the laminin G-
CC like 3 domain) directly with LRP4; the interaction is required for
CC activation of MUSK and clustering of AChR and requires the 'z8' insert
CC present in the z(+8) isoforms. Interacts (N-terminal subunit) with TGF-
CC beta family members, BMP2 AND BMP4; the interactions inhibit the
CC activity of these growth factors. Interacts with TGFB1; the interaction
CC enhances the activity of TGFB1. Interacts with DAG1; the interaction is
CC influenced by cell surface glycosaminoglycans and by alternative
CC splicing of AGRN. {ECO:0000269|PubMed:20505824,
CC ECO:0000269|PubMed:22302937, ECO:0000269|PubMed:8653787,
CC ECO:0000269|PubMed:8693000}.
CC -!- INTERACTION:
CC P25304; Q8VI56: Lrp4; Xeno; NbExp=3; IntAct=EBI-2106099, EBI-2106160;
CC -!- SUBCELLULAR LOCATION: Synapse {ECO:0000269|PubMed:8653787}. Cell
CC membrane {ECO:0000269|PubMed:11161480}; Single-pass type II membrane
CC protein {ECO:0000269|PubMed:11161480}.
CC -!- ALTERNATIVE PRODUCTS:
CC Event=Alternative splicing; Named isoforms=6;
CC Comment=Many isoforms exist depending on the occurrence and length of
CC inserts at the x, y or z splice site. There are 4 'z' isoforms
CC produced with inserts of 0, 8, 11 or 19 AA. Isoforms differ in their
CC acetylcholine receptor clustering activity and tissue specificity. In
CC addition, a secreted isoform may be produced by alternative usage of
CC the first exon.;
CC Name=1; Synonyms=Transmembrane agrin, TM-agrin, Agrin z(+19);
CC IsoId=P25304-1; Sequence=Displayed;
CC Name=2; Synonyms=Agrin x(0);
CC IsoId=P25304-2; Sequence=VSP_001365;
CC Name=3; Synonyms=Agrin z(0);
CC IsoId=P25304-3; Sequence=VSP_001366;
CC Name=4; Synonyms=Agrin z(+11);
CC IsoId=P25304-4; Sequence=VSP_001367;
CC Name=5; Synonyms=Agrin z(+8);
CC IsoId=P25304-5; Sequence=VSP_001368;
CC Name=6; Synonyms=Agrin y(0);
CC IsoId=P25304-6; Sequence=VSP_045759;
CC -!- TISSUE SPECIFICITY: Embryonic nervous system and muscle.
CC {ECO:0000269|PubMed:1851019, ECO:0000269|PubMed:8398142}.
CC -!- DEVELOPMENTAL STAGE: More abundant early in development. At E13, highly
CC expressed in the developing nervous system. Isoform y(+4)z(0),
CC containing the 'y' insert but no 'z' insert, is the most prevelant at
CC this stage with pronounced expression in developing spinal and
CC sympathetic ganglia. Isoforms with no 'y' insert (y0) localized to
CC peripheral tissue. At E15, y(+4) isoform continues to be highly
CC expressed in neural tissue predominantly in the spinal column and
CC developing brain. The y(0) isoform is weakly expressed in capillaries
CC and meninges and the y(0)(z0) in non-neural tissues, predominantly in
CC epithelial cells lining the developing lung bronchioles and kidney
CC tubules. Isoforms Z(+8) and z(+19) are highly expressed in ventral
CC motor columns and facial nerve with weaker expression throughout spinal
CC cord tissue. At later stages of development, isoform y(4)z(0) is the
CC most prominent form in developing cortex, corpus striatum, hippocampus
CC and cerebellum. Isoform y(0)z(0) expression is still detected in brain
CC capillaries at stage P1. The z(+19) isoform is most highly expressed
CC from E15 to E18 and declines slightly to P1. Isoforms y(1)4z(0) and
CC y(+4)z(+8) are still expressed in adulthood, the former scattered
CC throughout the spinal cord gray matter and, the latter, in motor
CC neurons of the ventral spinal cord. {ECO:0000269|PubMed:1326608,
CC ECO:0000269|PubMed:7472435}.
CC -!- DOMAIN: Both laminin G-like 2 (G2) and laminin G-like 3 (G3) domains
CC are required for alpha-dystroglycan binding. G3 domain is required for
CC C-terminal heparin, heparan sulfate and sialic acid binding.
CC -!- PTM: Contains heparan and chondroitin sulfate chains and alpha-
CC dystroglycan as well as N-linked and O-linked oligosaccharides.
CC Glycosaminoglycans (GAGs), present in the agrin N-terminal 110 kDa
CC fragment, are required for induction of filopodia in hippocampal
CC neurons. The first cluster (Gly/Ser-rich) for GAG attachment contains
CC heparan sulfate (HS) chains and the second cluster (Ser/Thr-rich),
CC contains chondroitin sulfate (CS) chains. Heparin and heparin sulfate
CC binding in the G3 doamin is independent of calcium ions. Binds heparin
CC with a stoichiometry of 2:1. Binds sialic acid with a stoichiometry of
CC 1:1 and binding requires calcium ions. {ECO:0000269|PubMed:18775496,
CC ECO:0000269|PubMed:8398142}.
CC -!- PTM: At synaptic junctions, cleaved at two conserved sites, alpha and
CC beta, by neurotrypsin. Cleavage at the alpha-site produces the agrin N-
CC terminal 110-kDa subunit and the agrin C-terminal 110-kDa subunit.
CC Further cleavage of agrin C-terminal 110-kDa subunit at the beta site
CC produces the C-terminal fragments, agrin C-terminal 90 kDa fragment and
CC agrin C-terminal 22 kDa fragment. Excessive cleavage at the beta-site
CC releases large amounts of the agrin C-terminal 22 kDa fragment leading
CC to destabilization at the neuromuscular junction (NMJ).
CC {ECO:0000269|PubMed:17586728, ECO:0000269|PubMed:20980386}.
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DR EMBL; M64780; AAA40702.1; -; mRNA.
DR EMBL; M64780; AAA40703.1; -; mRNA.
DR EMBL; S44194; AAB23326.1; -; mRNA.
DR PIR; JH0399; AGRT.
DR RefSeq; NP_786930.1; NM_175754.1. [P25304-3]
DR PDB; 3V64; X-ray; 2.85 A; A/B=1759-1959.
DR PDB; 3V65; X-ray; 3.30 A; A/C=1759-1959.
DR PDBsum; 3V64; -.
DR PDBsum; 3V65; -.
DR AlphaFoldDB; P25304; -.
DR SMR; P25304; -.
DR IntAct; P25304; 4.
DR STRING; 10116.ENSRNOP00000050623; -.
DR CarbonylDB; P25304; -.
DR GlyGen; P25304; 5 sites.
DR iPTMnet; P25304; -.
DR PhosphoSitePlus; P25304; -.
DR SwissPalm; P25304; -.
DR PaxDb; P25304; -.
DR PRIDE; P25304; -.
DR GeneID; 25592; -.
DR KEGG; rno:25592; -.
DR CTD; 375790; -.
DR RGD; 2067; Agrn.
DR eggNOG; KOG3509; Eukaryota.
DR InParanoid; P25304; -.
DR OrthoDB; 414294at2759; -.
DR PhylomeDB; P25304; -.
DR Reactome; R-RNO-1971475; A tetrasaccharide linker sequence is required for GAG synthesis.
DR Reactome; R-RNO-2022928; HS-GAG biosynthesis.
DR Reactome; R-RNO-2024096; HS-GAG degradation.
DR Reactome; R-RNO-3000178; ECM proteoglycans.
DR Reactome; R-RNO-975634; Retinoid metabolism and transport.
DR PRO; PR:P25304; -.
DR Proteomes; UP000002494; Unplaced.
DR GO; GO:0070161; C:anchoring junction; IEA:UniProtKB-KW.
DR GO; GO:0044295; C:axonal growth cone; IDA:RGD.
DR GO; GO:0005604; C:basement membrane; IDA:RGD.
DR GO; GO:0009986; C:cell surface; ISO:RGD.
DR GO; GO:0062023; C:collagen-containing extracellular matrix; ISO:RGD.
DR GO; GO:0031012; C:extracellular matrix; TAS:RGD.
DR GO; GO:0005576; C:extracellular region; TAS:Reactome.
DR GO; GO:0005615; C:extracellular space; ISO:RGD.
DR GO; GO:0098978; C:glutamatergic synapse; IDA:SynGO.
DR GO; GO:0016021; C:integral component of membrane; IEA:UniProtKB-KW.
DR GO; GO:0042383; C:sarcolemma; ISO:RGD.
DR GO; GO:0045202; C:synapse; IDA:UniProtKB.
DR GO; GO:0043083; C:synaptic cleft; ISO:RGD.
DR GO; GO:0030548; F:acetylcholine receptor regulator activity; ISO:RGD.
DR GO; GO:0042030; F:ATPase inhibitor activity; ISO:RGD.
DR GO; GO:0036122; F:BMP binding; IPI:RGD.
DR GO; GO:0005509; F:calcium ion binding; IDA:UniProtKB.
DR GO; GO:0035374; F:chondroitin sulfate binding; ISS:UniProtKB.
DR GO; GO:0002162; F:dystroglycan binding; IDA:UniProtKB.
DR GO; GO:0043395; F:heparan sulfate proteoglycan binding; ISS:UniProtKB.
DR GO; GO:0033691; F:sialic acid binding; ISS:UniProtKB.
DR GO; GO:0050431; F:transforming growth factor beta binding; IPI:RGD.
DR GO; GO:0044325; F:transmembrane transporter binding; ISO:RGD.
DR GO; GO:0009887; P:animal organ morphogenesis; IBA:GO_Central.
DR GO; GO:0030154; P:cell differentiation; IEA:UniProtKB-KW.
DR GO; GO:0007268; P:chemical synaptic transmission; IMP:RGD.
DR GO; GO:1903407; P:negative regulation of P-type sodium:potassium-exchanging transporter activity; ISO:RGD.
DR GO; GO:1903277; P:negative regulation of sodium ion export across plasma membrane; ISO:RGD.
DR GO; GO:0007528; P:neuromuscular junction development; ISO:RGD.
DR GO; GO:0045213; P:neurotransmitter receptor metabolic process; ISO:RGD.
DR GO; GO:0007009; P:plasma membrane organization; ISO:RGD.
DR GO; GO:0051491; P:positive regulation of filopodium assembly; IDA:UniProtKB.
DR GO; GO:0043547; P:positive regulation of GTPase activity; IDA:UniProtKB.
DR GO; GO:0043525; P:positive regulation of neuron apoptotic process; ISO:RGD.
DR GO; GO:0050731; P:positive regulation of peptidyl-tyrosine phosphorylation; IDA:UniProtKB.
DR GO; GO:0032092; P:positive regulation of protein binding; ISO:RGD.
DR GO; GO:2000541; P:positive regulation of protein geranylgeranylation; ISO:RGD.
DR GO; GO:0001934; P:positive regulation of protein phosphorylation; IMP:UniProtKB.
DR GO; GO:0061098; P:positive regulation of protein tyrosine kinase activity; ISO:RGD.
DR GO; GO:0045887; P:positive regulation of synaptic assembly at neuromuscular junction; ISS:UniProtKB.
DR GO; GO:0045944; P:positive regulation of transcription by RNA polymerase II; IDA:UniProtKB.
DR GO; GO:0043113; P:receptor clustering; IDA:MGI.
DR GO; GO:1902667; P:regulation of axon guidance; IDA:RGD.
DR GO; GO:0086036; P:regulation of cardiac muscle cell membrane potential; ISO:RGD.
DR GO; GO:0055117; P:regulation of cardiac muscle contraction; ISO:RGD.
DR GO; GO:0043087; P:regulation of GTPase activity; ISO:RGD.
DR GO; GO:0070507; P:regulation of microtubule cytoskeleton organization; IDA:RGD.
DR GO; GO:0001932; P:regulation of protein phosphorylation; IDA:UniProtKB.
DR GO; GO:0050807; P:regulation of synapse organization; IDA:SynGO.
DR GO; GO:0071340; P:skeletal muscle acetylcholine-gated channel clustering; IDA:UniProtKB.
DR GO; GO:0007416; P:synapse assembly; IMP:RGD.
DR GO; GO:0009888; P:tissue development; IBA:GO_Central.
DR CDD; cd00055; EGF_Lam; 2.
DR CDD; cd00110; LamG; 3.
DR Gene3D; 3.30.70.960; -; 1.
DR InterPro; IPR013320; ConA-like_dom_sf.
DR InterPro; IPR001881; EGF-like_Ca-bd_dom.
DR InterPro; IPR000742; EGF-like_dom.
DR InterPro; IPR003884; FacI_MAC.
DR InterPro; IPR003645; Fol_N.
DR InterPro; IPR002350; Kazal_dom.
DR InterPro; IPR036058; Kazal_dom_sf.
DR InterPro; IPR001791; Laminin_G.
DR InterPro; IPR002049; LE_dom.
DR InterPro; IPR000082; SEA_dom.
DR InterPro; IPR036364; SEA_dom_sf.
DR Pfam; PF00008; EGF; 3.
DR Pfam; PF00050; Kazal_1; 1.
DR Pfam; PF07648; Kazal_2; 8.
DR Pfam; PF00053; Laminin_EGF; 2.
DR Pfam; PF00054; Laminin_G_1; 3.
DR Pfam; PF01390; SEA; 1.
DR SMART; SM00181; EGF; 6.
DR SMART; SM00179; EGF_CA; 3.
DR SMART; SM00180; EGF_Lam; 2.
DR SMART; SM00057; FIMAC; 3.
DR SMART; SM00274; FOLN; 5.
DR SMART; SM00280; KAZAL; 9.
DR SMART; SM00282; LamG; 3.
DR SMART; SM00200; SEA; 1.
DR SUPFAM; SSF100895; SSF100895; 9.
DR SUPFAM; SSF49899; SSF49899; 3.
DR SUPFAM; SSF82671; SSF82671; 1.
DR PROSITE; PS00022; EGF_1; 6.
DR PROSITE; PS01186; EGF_2; 1.
DR PROSITE; PS50026; EGF_3; 4.
DR PROSITE; PS01248; EGF_LAM_1; 1.
DR PROSITE; PS50027; EGF_LAM_2; 2.
DR PROSITE; PS51465; KAZAL_2; 9.
DR PROSITE; PS50025; LAM_G_DOMAIN; 3.
DR PROSITE; PS50024; SEA; 1.
PE 1: Evidence at protein level;
KW 3D-structure; Alternative splicing; Calcium; Cell membrane;
KW Developmental protein; Differentiation; Disulfide bond; EGF-like domain;
KW Glycoprotein; Heparan sulfate; Laminin EGF-like domain; Membrane;
KW Metal-binding; Phosphoprotein; Proteoglycan; Reference proteome; Repeat;
KW Signal-anchor; Synapse; Transmembrane; Transmembrane helix.
FT CHAIN 1..1959
FT /note="Agrin"
FT /id="PRO_0000007472"
FT CHAIN 27..995
FT /note="Agrin N-terminal 110 kDa subunit"
FT /id="PRO_0000421621"
FT CHAIN 996..1959
FT /note="Agrin C-terminal 110 kDa subunit"
FT /id="PRO_0000421622"
FT CHAIN 996..1754
FT /note="Agrin C-terminal 90 kDa fragment"
FT /id="PRO_0000421623"
FT CHAIN 1755..1959
FT /note="Agrin C-terminal 22 kDa fragment"
FT /id="PRO_0000421624"
FT TOPO_DOM 1..26
FT /note="Cytoplasmic"
FT /evidence="ECO:0000255"
FT TRANSMEM 27..47
FT /note="Helical; Signal-anchor for type II membrane protein"
FT /evidence="ECO:0000255"
FT TOPO_DOM 48..1959
FT /note="Extracellular"
FT /evidence="ECO:0000255"
FT DOMAIN 86..139
FT /note="Kazal-like 1"
FT /evidence="ECO:0000255|PROSITE-ProRule:PRU00798"
FT DOMAIN 159..214
FT /note="Kazal-like 2"
FT /evidence="ECO:0000255|PROSITE-ProRule:PRU00798"
FT DOMAIN 232..286
FT /note="Kazal-like 3"
FT /evidence="ECO:0000255|PROSITE-ProRule:PRU00798"
FT DOMAIN 303..358
FT /note="Kazal-like 4"
FT /evidence="ECO:0000255|PROSITE-ProRule:PRU00798"
FT DOMAIN 379..431
FT /note="Kazal-like 5"
FT /evidence="ECO:0000255|PROSITE-ProRule:PRU00798"
FT DOMAIN 442..496
FT /note="Kazal-like 6"
FT /evidence="ECO:0000255|PROSITE-ProRule:PRU00798"
FT DOMAIN 502..561
FT /note="Kazal-like 7"
FT /evidence="ECO:0000255|PROSITE-ProRule:PRU00798"
FT DOMAIN 594..647
FT /note="Kazal-like 8"
FT /evidence="ECO:0000255|PROSITE-ProRule:PRU00798"
FT DOMAIN 688..741
FT /note="Laminin EGF-like 1"
FT /evidence="ECO:0000255|PROSITE-ProRule:PRU00460"
FT DOMAIN 742..788
FT /note="Laminin EGF-like 2"
FT /evidence="ECO:0000255|PROSITE-ProRule:PRU00460"
FT DOMAIN 810..866
FT /note="Kazal-like 9"
FT /evidence="ECO:0000255|PROSITE-ProRule:PRU00798"
FT DOMAIN 1023..1145
FT /note="SEA"
FT /evidence="ECO:0000255|PROSITE-ProRule:PRU00188"
FT DOMAIN 1220..1258
FT /note="EGF-like 1"
FT /evidence="ECO:0000255|PROSITE-ProRule:PRU00076"
FT DOMAIN 1263..1439
FT /note="Laminin G-like 1"
FT /evidence="ECO:0000255|PROSITE-ProRule:PRU00122"
FT DOMAIN 1440..1477
FT /note="EGF-like 2"
FT /evidence="ECO:0000255|PROSITE-ProRule:PRU00076"
FT DOMAIN 1479..1516
FT /note="EGF-like 3"
FT /evidence="ECO:0000255|PROSITE-ProRule:PRU00076"
FT DOMAIN 1526..1708
FT /note="Laminin G-like 2"
FT /evidence="ECO:0000255|PROSITE-ProRule:PRU00122"
FT DOMAIN 1709..1748
FT /note="EGF-like 4"
FT /evidence="ECO:0000255|PROSITE-ProRule:PRU00076"
FT DOMAIN 1784..1956
FT /note="Laminin G-like 3"
FT /evidence="ECO:0000255|PROSITE-ProRule:PRU00122"
FT REGION 951..980
FT /note="Disordered"
FT /evidence="ECO:0000256|SAM:MobiDB-lite"
FT REGION 1173..1228
FT /note="Disordered"
FT /evidence="ECO:0000256|SAM:MobiDB-lite"
FT BINDING 1831
FT /ligand="Ca(2+)"
FT /ligand_id="ChEBI:CHEBI:29108"
FT /evidence="ECO:0007744|PDB:3V64, ECO:0007744|PDB:3V65"
FT BINDING 1848
FT /ligand="Ca(2+)"
FT /ligand_id="ChEBI:CHEBI:29108"
FT /evidence="ECO:0007744|PDB:3V64, ECO:0007744|PDB:3V65"
FT BINDING 1898
FT /ligand="Ca(2+)"
FT /ligand_id="ChEBI:CHEBI:29108"
FT /evidence="ECO:0007744|PDB:3V64, ECO:0007744|PDB:3V65"
FT BINDING 1900
FT /ligand="Ca(2+)"
FT /ligand_id="ChEBI:CHEBI:29108"
FT /evidence="ECO:0007744|PDB:3V64"
FT SITE 995..996
FT /note="Cleavage, alpha site; by neurotrypsin"
FT SITE 1143
FT /note="Alternative splice site to produce 'x' isoforms"
FT SITE 1642
FT /note="Alternative splice site to produce 'y' isoforms"
FT SITE 1753
FT /note="Critical for cleavage by neurotrypsin"
FT SITE 1754..1755
FT /note="Cleavage, beta site; by neurotrypsin"
FT SITE 1779
FT /note="Alternative splice site to produce 'z' isoforms"
FT SITE 1783
FT /note="Highly important for the agrin receptor complex
FT activity of the 'z(8)' insert"
FT MOD_RES 569
FT /note="Phosphoserine"
FT /evidence="ECO:0000250|UniProtKB:A2ASQ1"
FT MOD_RES 571
FT /note="Phosphoserine"
FT /evidence="ECO:0000250|UniProtKB:A2ASQ1"
FT CARBOHYD 145
FT /note="N-linked (GlcNAc...) asparagine"
FT /evidence="ECO:0000255"
FT CARBOHYD 672
FT /note="N-linked (GlcNAc...) asparagine"
FT /evidence="ECO:0000255"
FT CARBOHYD 827
FT /note="N-linked (GlcNAc...) asparagine"
FT /evidence="ECO:0000255"
FT CARBOHYD 957
FT /note="N-linked (GlcNAc...) asparagine"
FT /evidence="ECO:0000255"
FT CARBOHYD 1726
FT /note="O-linked (Fuc...) serine"
FT /evidence="ECO:0000269|PubMed:18775496"
FT DISULFID 92..123
FT /evidence="ECO:0000255|PROSITE-ProRule:PRU00798"
FT DISULFID 97..116
FT /evidence="ECO:0000255|PROSITE-ProRule:PRU00798"
FT DISULFID 105..137
FT /evidence="ECO:0000255|PROSITE-ProRule:PRU00798"
FT DISULFID 165..198
FT /evidence="ECO:0000255|PROSITE-ProRule:PRU00798"
FT DISULFID 171..191
FT /evidence="ECO:0000255|PROSITE-ProRule:PRU00798"
FT DISULFID 180..212
FT /evidence="ECO:0000255|PROSITE-ProRule:PRU00798"
FT DISULFID 244..263
FT /evidence="ECO:0000255|PROSITE-ProRule:PRU00798"
FT DISULFID 252..284
FT /evidence="ECO:0000255|PROSITE-ProRule:PRU00798"
FT DISULFID 309..342
FT /evidence="ECO:0000255|PROSITE-ProRule:PRU00798"
FT DISULFID 316..335
FT /evidence="ECO:0000255|PROSITE-ProRule:PRU00798"
FT DISULFID 324..356
FT /evidence="ECO:0000255|PROSITE-ProRule:PRU00798"
FT DISULFID 385..415
FT /evidence="ECO:0000255|PROSITE-ProRule:PRU00798"
FT DISULFID 389..408
FT /evidence="ECO:0000255|PROSITE-ProRule:PRU00798"
FT DISULFID 397..429
FT /evidence="ECO:0000255|PROSITE-ProRule:PRU00798"
FT DISULFID 448..480
FT /evidence="ECO:0000255|PROSITE-ProRule:PRU00798"
FT DISULFID 454..473
FT /evidence="ECO:0000255|PROSITE-ProRule:PRU00798"
FT DISULFID 462..494
FT /evidence="ECO:0000255|PROSITE-ProRule:PRU00798"
FT DISULFID 508..545
FT /evidence="ECO:0000255|PROSITE-ProRule:PRU00798"
FT DISULFID 518..538
FT /evidence="ECO:0000255|PROSITE-ProRule:PRU00798"
FT DISULFID 527..559
FT /evidence="ECO:0000255|PROSITE-ProRule:PRU00798"
FT DISULFID 600..631
FT /evidence="ECO:0000255|PROSITE-ProRule:PRU00798"
FT DISULFID 604..624
FT /evidence="ECO:0000255|PROSITE-ProRule:PRU00798"
FT DISULFID 613..645
FT /evidence="ECO:0000255|PROSITE-ProRule:PRU00798"
FT DISULFID 688..700
FT /evidence="ECO:0000250"
FT DISULFID 690..707
FT /evidence="ECO:0000250"
FT DISULFID 709..718
FT /evidence="ECO:0000250"
FT DISULFID 721..739
FT /evidence="ECO:0000250"
FT DISULFID 742..754
FT /evidence="ECO:0000250"
FT DISULFID 744..761
FT /evidence="ECO:0000250"
FT DISULFID 763..772
FT /evidence="ECO:0000250"
FT DISULFID 775..786
FT /evidence="ECO:0000250"
FT DISULFID 816..850
FT /evidence="ECO:0000255|PROSITE-ProRule:PRU00798"
FT DISULFID 823..843
FT /evidence="ECO:0000255|PROSITE-ProRule:PRU00798"
FT DISULFID 832..864
FT /evidence="ECO:0000255|PROSITE-ProRule:PRU00798"
FT DISULFID 1224..1235
FT /evidence="ECO:0000250"
FT DISULFID 1229..1246
FT /evidence="ECO:0000250"
FT DISULFID 1248..1257
FT /evidence="ECO:0000250"
FT DISULFID 1410..1439
FT /evidence="ECO:0000250"
FT DISULFID 1483..1494
FT /evidence="ECO:0000250"
FT DISULFID 1488..1504
FT /evidence="ECO:0000250"
FT DISULFID 1506..1515
FT /evidence="ECO:0000250"
FT DISULFID 1713..1727
FT /evidence="ECO:0000250"
FT DISULFID 1721..1736
FT /evidence="ECO:0000250"
FT DISULFID 1738..1747
FT /evidence="ECO:0000250"
FT DISULFID 1930..1956
FT /evidence="ECO:0000250"
FT VAR_SEQ 1144..1152
FT /note="Missing (in isoform 2)"
FT /evidence="ECO:0000303|PubMed:1326608"
FT /id="VSP_001365"
FT VAR_SEQ 1643..1646
FT /note="Missing (in isoform 6)"
FT /evidence="ECO:0000305"
FT /id="VSP_045759"
FT VAR_SEQ 1780..1798
FT /note="Missing (in isoform 3)"
FT /evidence="ECO:0000303|PubMed:1326608,
FT ECO:0000303|PubMed:1851019"
FT /id="VSP_001366"
FT VAR_SEQ 1780..1787
FT /note="Missing (in isoform 5)"
FT /evidence="ECO:0000303|PubMed:1326608"
FT /id="VSP_001368"
FT VAR_SEQ 1788..1798
FT /note="Missing (in isoform 4)"
FT /evidence="ECO:0000303|PubMed:1326608"
FT /id="VSP_001367"
FT MUTAGEN 566..571
FT /note="SGGSGS->AGGAGA: Abolishes heparan sulfate (HS)
FT binding, greatly reduced branched retraction fiber (BRF)
FT formation, filopodia formation reduced by about 50% and
FT lowered RAC1 and CDK1 activation. No chondroitin sulfate
FT (CS) nor heparan sulfate attachment, almost no branched
FT retraction fiber (BRF) formation, filopodia formation
FT reduced by about 60% and lowered RAC1 and CDK1 activation;
FT when associated with 953-AGA-955."
FT MUTAGEN 953..955
FT /note="SGS->AGA: Abolishes chondroitin sulfate (CS)
FT binding, greatly reduced branched retraction fiber (BRF)
FT formation, filopodia formation reduced by about 50% and
FT lowered RAC1 and CDK1 activation. No chondroitin sulfate
FT (CS) nor heparan sulfate (HS) binding almost no retraction
FT fiber (BRF) formation, filopodia formation reduced by about
FT 60% lowered RAC1 and CDK1 activation; when associated with
FT 566-AGGAGA-571."
FT MUTAGEN 991
FT /note="P->A: About 13% reduction in cleavage by
FT neurotrypsin."
FT /evidence="ECO:0000269|PubMed:17586728"
FT MUTAGEN 992
FT /note="P->A: About 64% reduction in cleavage by
FT neurotrypsin."
FT /evidence="ECO:0000269|PubMed:17586728"
FT MUTAGEN 993
FT /note="I->A: About 60% reduction in cleavage by
FT neurotrypsin."
FT /evidence="ECO:0000269|PubMed:17586728"
FT MUTAGEN 994
FT /note="E->A: Almost completely abolishes cleavage by
FT neurotrypsin."
FT /evidence="ECO:0000269|PubMed:17586728"
FT MUTAGEN 995
FT /note="R->A: Completely abolishes cleavage by
FT neurotrypsin."
FT /evidence="ECO:0000269|PubMed:17586728"
FT MUTAGEN 995
FT /note="R->K: About 30% reduction in cleavage by
FT neurotrypsin."
FT /evidence="ECO:0000269|PubMed:17586728"
FT MUTAGEN 1726
FT /note="S->A: Abolishes fucosylation of muscle agrin.
FT Stimulates MUSK phosphorylation and increases AChR
FT clustering."
FT /evidence="ECO:0000269|PubMed:18775496"
FT MUTAGEN 1751
FT /note="L->A: About 23% reduction in cleavage by
FT neurotrypsin. Reduces cleavage by neurotrypsin by about
FT 90%; when associated with A-1752. Completely abolishes
FT cleavage by neurotrypsin; when associated with A-1753."
FT /evidence="ECO:0000269|PubMed:17586728"
FT MUTAGEN 1752
FT /note="V->A: About 41% reduction in cleavage by
FT neurotrypsin. Reduces cleavage by neurotrypsin by about
FT 90%; when associated with A-1751. Completely abolishes
FT cleavage by neurotrypsin; when associated with A-1753."
FT /evidence="ECO:0000269|PubMed:17586728"
FT MUTAGEN 1753
FT /note="E->A,K: Almost completely abolishes cleavage by
FT neurotrypsin. Completely abolishes cleavage by
FT neurotrypsin; when associated with A-1751 or A-1752."
FT /evidence="ECO:0000269|PubMed:17586728"
FT MUTAGEN 1753
FT /note="E->D,L,Q: About 20% reduction in cleavage by
FT neurotrypsin."
FT /evidence="ECO:0000269|PubMed:17586728"
FT MUTAGEN 1754
FT /note="K->A: Completely abolishes cleavage by
FT neurotrypsin."
FT /evidence="ECO:0000269|PubMed:17586728"
FT MUTAGEN 1754
FT /note="K->R: About 55% reduction in cleavage by
FT neurotrypsin."
FT /evidence="ECO:0000269|PubMed:17586728"
FT MUTAGEN 1755
FT /note="S->A: About 62% reduction in cleavage by
FT neurotrypsin."
FT /evidence="ECO:0000269|PubMed:17586728"
FT MUTAGEN 1756
FT /note="V->A: Slight reduction in cleavage by neurotrypsin."
FT /evidence="ECO:0000269|PubMed:17586728"
FT MUTAGEN 1757
FT /note="G->A: Slight reduction in cleavage by neurotrypsin."
FT /evidence="ECO:0000269|PubMed:17586728"
FT MUTAGEN 1780
FT /note="E->A: Slight reduction in AChR clustering ability."
FT /evidence="ECO:0000269|PubMed:20566625"
FT MUTAGEN 1781
FT /note="L->A: Slight reduction in AChR clustering ability.
FT Slight reduction in AChR clustering ability."
FT /evidence="ECO:0000269|PubMed:20566625"
FT MUTAGEN 1782
FT /note="T->A: Slight reduction in AChR clustering ability."
FT /evidence="ECO:0000269|PubMed:20566625"
FT MUTAGEN 1783
FT /note="N->A: Abolishes formation of AGRN-LRP4 complex and
FT MUSK activation. No AChR clustering activity."
FT /evidence="ECO:0000269|PubMed:20566625,
FT ECO:0000269|PubMed:22302937"
FT MUTAGEN 1784
FT /note="E->A: Significant reduction in AChR clustering
FT ability."
FT /evidence="ECO:0000269|PubMed:20566625"
FT MUTAGEN 1785
FT /note="I->A: Significant reduction in AChR clustering
FT ability."
FT /evidence="ECO:0000269|PubMed:20566625,
FT ECO:0000269|PubMed:22302937"
FT MUTAGEN 1785
FT /note="I->S: Abolishes formation of AGRN-LRP4 complex and
FT MUSK activation."
FT /evidence="ECO:0000269|PubMed:20566625,
FT ECO:0000269|PubMed:22302937"
FT MUTAGEN 1786
FT /note="P->A: Significant reduction in AChR clustering
FT ability."
FT /evidence="ECO:0000269|PubMed:20566625"
FT MUTAGEN 1806
FT /note="H->L: No effect on formation of AGRN-LRP4 complex
FT nor on MUSK activation."
FT /evidence="ECO:0000269|PubMed:22302937"
FT MUTAGEN 1831
FT /note="D->A: Abolishes calcium binding, lowering of binding
FT to myotubes and some loss of AChR clustering activity; when
FT associated with A-1900."
FT /evidence="ECO:0000269|PubMed:20566625"
FT MUTAGEN 1876
FT /note="R->E: No effect formation of AGRN-LRP4 complex nor
FT on MUSK activation."
FT /evidence="ECO:0000269|PubMed:22302937"
FT MUTAGEN 1900
FT /note="D->A: Abolishes calcium binding, lowering of binding
FT to myotubes and some loss of AChR clustering activity; when
FT associated with A-1831."
FT /evidence="ECO:0000269|PubMed:20566625"
FT MUTAGEN 1938
FT /note="H->L: No effect formation of AGRN-LRP4 complex nor
FT on MUSK activation."
FT /evidence="ECO:0000269|PubMed:22302937"
FT CONFLICT 315..317
FT /note="Missing (in Ref. 1; AAA40702)"
FT /evidence="ECO:0000305"
FT STRAND 1761..1767
FT /evidence="ECO:0007829|PDB:3V64"
FT STRAND 1770..1773
FT /evidence="ECO:0007829|PDB:3V64"
FT HELIX 1779..1782
FT /evidence="ECO:0007829|PDB:3V64"
FT STRAND 1800..1812
FT /evidence="ECO:0007829|PDB:3V64"
FT STRAND 1816..1824
FT /evidence="ECO:0007829|PDB:3V64"
FT STRAND 1826..1829
FT /evidence="ECO:0007829|PDB:3V65"
FT STRAND 1832..1838
FT /evidence="ECO:0007829|PDB:3V64"
FT STRAND 1841..1850
FT /evidence="ECO:0007829|PDB:3V64"
FT STRAND 1853..1860
FT /evidence="ECO:0007829|PDB:3V64"
FT STRAND 1863..1865
FT /evidence="ECO:0007829|PDB:3V65"
FT STRAND 1867..1874
FT /evidence="ECO:0007829|PDB:3V64"
FT STRAND 1877..1882
FT /evidence="ECO:0007829|PDB:3V64"
FT STRAND 1888..1891
FT /evidence="ECO:0007829|PDB:3V64"
FT STRAND 1899..1901
FT /evidence="ECO:0007829|PDB:3V64"
FT STRAND 1903..1908
FT /evidence="ECO:0007829|PDB:3V64"
FT HELIX 1921..1923
FT /evidence="ECO:0007829|PDB:3V64"
FT STRAND 1928..1936
FT /evidence="ECO:0007829|PDB:3V64"
FT TURN 1943..1946
FT /evidence="ECO:0007829|PDB:3V64"
SQ SEQUENCE 1959 AA; 208646 MW; 7FEFDFDAFF89CC31 CRC64;
MPPLPLEHRP RQEPGASMLV RYFMIPCNIC LILLATSTLG FAVLLFLSNY KPGIHFTPAP
PTPPDVCRGM LCGFGAVCEP SVEDPGRASC VCKKNACPAT VAPVCGSDAS TYSNECELQR
AQCNQQRRIR LLRQGPCGSR DPCANVTCSF GSTCVPSADG QTASCLCPTT CFGAPDGTVC
GSDGVDYPSE CQLLSHACAS QEHIFKKFNG PCDPCQGSMS DLNHICRVNP RTRHPEMLLR
PENCPAQHTP ICGDDGVTYE NDCVMSRIGA TRGLLLQKVR SGQCQTRDQC PETCQFNSVC
LSRRGRPHCS CDRVTCDGSY RPVCAQDGHT YNNDCWRQQA ECRQQRAIPP KHQGPCDQTP
SPCHGVQCAF GAVCTVKNGK AECECQRVCS GIYDPVCGSD GVTYGSVCEL ESMACTLGRE
IQVARRGPCD PCGQCRFGSL CEVETGRCVC PSECVESAQP VCGSDGHTYA SECELHVHAC
THQISLYVAS AGHCQTCGEK VCTFGAVCSA GQCVCPRCEH PPPGPVCGSD GVTYLSACEL
REAACQQQVQ IEEAHAGPCE PAECGSGGSG SGEDDECEQE LCRQRGGIWD EDSEDGPCVC
DFSCQSVPRS PVCGSDGVTY GTECDLKKAR CESQQELYVA AQGACRGPTL APLLPVAFPH
CAQTPYGCCQ DNFTAAQGVG LAGCPSTCHC NPHGSYSGTC DPATGQCSCR PGVGGLRCDR
CEPGFWNFRG IVTDGHSGCT PCSCDPRGAV RDDCEQMTGL CSCRPGVAGP KCGQCPDGQV
LGHLGCEADP MTPVTCVEIH CEFGASCVEK AGFAQCICPT LTCPEANSTK VCGSDGVTYG
NECQLKAIAC RQRLDISTQS LGPCQESVTP GASPTSASMT TPRHILSKTL PFPHNSLPLS
PGSTTHDWPT PLPISPHTTV SIPRSTAWPV LTVPPTAAAS DVTSLATSIF SESGSANGSG
DEELSGDEEA SGGGSGGLEP PVGSIVVTHG PPIERASCYN SPLGCCSDGK TPSLDSEGSN
CPATKAFQGV LELEGVEGQE LFYTPEMADP KSELFGETAR SIESTLDDLF RNSDVKKDFW
SVRLRELGPG KLVRAIVDVH FDPTTAFQAS DVGQALLRQI QVSRPWALAV RRPLQEHVRF
LDFDWFPTFF TGAATGTTAA MATARATTVS RLPASSVTPR VYPSHTSRPV GRTTAPPTTR
RPPTTATNMD RPRTPGHQQP SKSCDSQPCL HGGTCQDQDS GKGFTCSCTA GRGGSVCEKV
QPPSMPAFKG HSFLAFPTLR AYHTLRLALE FRALETEGLL LYNGNARGKD FLALALLDGR
VQFRFDTGSG PAVLTSLVPV EPGRWHRLEL SRHWRQGTLS VDGETPVVGE SPSGTDGLNL
DTNLYVGGIP EEQVAMVLDR TSVGVGLKGC IRMLDINNQQ LELSDWQRAA VQSSGVGECG
DHPCLPNPCH GGALCQALEA GMFLCQCPPG RFGPTCADEK SPCQPNPCHG AAPCRVLSSG
GAKCECPLGR SGTFCQTVLE TAGSRPFLAD FNGFSYLELK GLHTFERDLG EKMALEMVFL
ARGPSGLLLY NGQKTDGKGD FVSLALHNRH LEFCYDLGKG AAVIRSKEPI ALGTWVRVFL
ERNGRKGALQ VGDGPRVLGE SPKSRKVPHT MLNLKEPLYI GGAPDFSKLA RGAAVSSGFS
GVIQLVSLRG HQLLTQEHVL RAVDVSPFAD HPCTQALGNP CLNGGSCVPR EATYECLCPG
GFSGLHCEKG LVEKSVGDLE TLAFDGRTYI EYLNAVIESE LTNEIPAPET LDSRALFSEK
ALQSNHFELS LRTEATQGLV LWIGKAAERA DYMALAIVDG HLQLSYDLGS QPVVLRSTVK
VNTNRWLRIR AHREHREGSL QVGNEAPVTG SSPLGATQLD TDGALWLGGL QKLPVGQALP
KAYGTGFVGC LRDVVVGHRQ LHLLEDAVTK PELRPCPTP
