ID AGRIN_HUMAN Reviewed; 2068 AA. AC O00468; Q5SVA1; Q5SVA2; Q60FE1; Q7KYS8; Q8N4J5; Q96IC1; Q9BTD4; DT 25-OCT-2004, integrated into UniProtKB/Swiss-Prot. DT 12-SEP-2018, sequence version 6. DT 13-FEB-2019, entry version 182. 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; DE Flags: Precursor; GN Name=AGRN; Synonyms=AGRIN; OS Homo sapiens (Human). OC Eukaryota; Metazoa; Chordata; Craniata; Vertebrata; Euteleostomi; OC Mammalia; Eutheria; Euarchontoglires; Primates; Haplorrhini; OC Catarrhini; Hominidae; Homo. OX NCBI_TaxID=9606; RN [1] RP NUCLEOTIDE SEQUENCE [MRNA] (ISOFORM 6). RC TISSUE=Retinal pigment epithelium; RA Kato S.; RL Submitted (SEP-2004) to the EMBL/GenBank/DDBJ databases. RN [2] RP NUCLEOTIDE SEQUENCE [LARGE SCALE GENOMIC DNA]. RX PubMed=16710414; DOI=10.1038/nature04727; RA Gregory S.G., Barlow K.F., McLay K.E., Kaul R., Swarbreck D., RA Dunham A., Scott C.E., Howe K.L., Woodfine K., Spencer C.C.A., RA Jones M.C., Gillson C., Searle S., Zhou Y., Kokocinski F., RA McDonald L., Evans R., Phillips K., Atkinson A., Cooper R., Jones C., RA Hall R.E., Andrews T.D., Lloyd C., Ainscough R., Almeida J.P., RA Ambrose K.D., Anderson F., Andrew R.W., Ashwell R.I.S., Aubin K., RA Babbage A.K., Bagguley C.L., Bailey J., Beasley H., Bethel G., RA Bird C.P., Bray-Allen S., Brown J.Y., Brown A.J., Buckley D., RA Burton J., Bye J., Carder C., Chapman J.C., Clark S.Y., Clarke G., RA Clee C., Cobley V., Collier R.E., Corby N., Coville G.J., Davies J., RA Deadman R., Dunn M., Earthrowl M., Ellington A.G., Errington H., RA Frankish A., Frankland J., French L., Garner P., Garnett J., Gay L., RA Ghori M.R.J., Gibson R., Gilby L.M., Gillett W., Glithero R.J., RA Grafham D.V., Griffiths C., Griffiths-Jones S., Grocock R., RA Hammond S., Harrison E.S.I., Hart E., Haugen E., Heath P.D., RA Holmes S., Holt K., Howden P.J., Hunt A.R., Hunt S.E., Hunter G., RA Isherwood J., James R., Johnson C., Johnson D., Joy A., Kay M., RA Kershaw J.K., Kibukawa M., Kimberley A.M., King A., Knights A.J., RA Lad H., Laird G., Lawlor S., Leongamornlert D.A., Lloyd D.M., RA Loveland J., Lovell J., Lush M.J., Lyne R., Martin S., RA Mashreghi-Mohammadi M., Matthews L., Matthews N.S.W., McLaren S., RA Milne S., Mistry S., Moore M.J.F., Nickerson T., O'Dell C.N., RA Oliver K., Palmeiri A., Palmer S.A., Parker A., Patel D., Pearce A.V., RA Peck A.I., Pelan S., Phelps K., Phillimore B.J., Plumb R., Rajan J., RA Raymond C., Rouse G., Saenphimmachak C., Sehra H.K., Sheridan E., RA Shownkeen R., Sims S., Skuce C.D., Smith M., Steward C., RA Subramanian S., Sycamore N., Tracey A., Tromans A., Van Helmond Z., RA Wall M., Wallis J.M., White S., Whitehead S.L., Wilkinson J.E., RA Willey D.L., Williams H., Wilming L., Wray P.W., Wu Z., Coulson A., RA Vaudin M., Sulston J.E., Durbin R.M., Hubbard T., Wooster R., RA Dunham I., Carter N.P., McVean G., Ross M.T., Harrow J., Olson M.V., RA Beck S., Rogers J., Bentley D.R.; RT "The DNA sequence and biological annotation of human chromosome 1."; RL Nature 441:315-321(2006). RN [3] RP NUCLEOTIDE SEQUENCE [MRNA] OF 20-2068 (ISOFORM 6), AND TISSUE RP SPECIFICITY. RX PubMed=9652404; DOI=10.1046/j.1432-1327.1998.2540123.x; RA Groffen A.J.A., Buskens C.A.F., Van Kuppevelt T.H., Veerkamp J.H., RA Monnens L.A.H., Van den Heuvel L.P.W.J.; RT "Primary structure and high expression of human agrin in basement RT membranes of adult lung and kidney."; RL Eur. J. Biochem. 254:123-128(1998). RN [4] RP NUCLEOTIDE SEQUENCE [MRNA] OF 20-172 (ISOFORMS 1/3/4/5/6/7), AND RP INTERACTION WITH LAMININ. RX PubMed=9151673; DOI=10.1083/jcb.137.3.671; RA Denzer A.J., Brandenberger R., Gesemann M., Chiquet M., Ruegg M.A.; RT "Agrin binds to the nerve-muscle basal lamina via laminin."; RL J. Cell Biol. 137:671-683(1997). RN [5] RP NUCLEOTIDE SEQUENCE [LARGE SCALE MRNA] OF 1558-2068 (ISOFORM 6), AND RP NUCLEOTIDE SEQUENCE [LARGE SCALE MRNA] OF 1869-2068 (ISOFORM 3). RC TISSUE=Brain, Colon, and Kidney; RX PubMed=15489334; DOI=10.1101/gr.2596504; RG The MGC Project Team; RT "The status, quality, and expansion of the NIH full-length cDNA RT project: the Mammalian Gene Collection (MGC)."; RL Genome Res. 14:2121-2127(2004). RN [6] RP IDENTIFICATION OF TRANSMEMBRANE ISOFORM (ISOFORM 2). RX PubMed=11161480; DOI=10.1006/mcne.2000.0932; RA Neumann F.R., Bittcher G., Annies M., Schumacher B., Kroger S., RA 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 [7] RP IDENTIFICATION OF TRANSMEMBRANE ISOFORM (ISOFORM 2), ALTERNATIVE RP SPLICING, AND TISSUE SPECIFICITY. RX PubMed=16487930; DOI=10.1016/j.bbrc.2006.01.161; RA Kumar P., Ferns M.J., Meizel S.; RT "Identification of agrinSN isoform and muscle-specific receptor RT tyrosine kinase (MuSK) in sperm."; RL Biochem. Biophys. Res. Commun. 342:522-528(2006). RN [8] RP ERRATUM. RA Kumar P., Ferns M.J., Meizel S.; RL Biochem. Biophys. Res. Commun. 344:453-453(2006). RN [9] RP GLYCOSYLATION [LARGE SCALE ANALYSIS] AT ASN-135. RC TISSUE=Liver; RX PubMed=19159218; DOI=10.1021/pr8008012; RA Chen R., Jiang X., Sun D., Han G., Wang F., Ye M., Wang L., Zou H.; RT "Glycoproteomics analysis of human liver tissue by combination of RT multiple enzyme digestion and hydrazide chemistry."; RL J. Proteome Res. 8:651-661(2009). RN [10] RP IDENTIFICATION BY MASS SPECTROMETRY, TISSUE SPECIFICITY, AND RP SUBCELLULAR LOCATION. RX PubMed=20551380; DOI=10.1074/mcp.M110.001693; RA Didangelos A., Yin X., Mandal K., Baumert M., Jahangiri M., Mayr M.; RT "Proteomics characterization of extracellular space components in the RT human aorta."; RL Mol. Cell. Proteomics 9:2048-2062(2010). RN [11] RP INTERACTION WITH LRP4, AND FUNCTION. RX PubMed=21969364; DOI=10.1074/jbc.M111.279307; RA Zhang W., Coldefy A.S., Hubbard S.R., Burden S.J.; RT "Agrin binds to the N-terminal region of Lrp4 protein and stimulates RT association between Lrp4 and the first immunoglobulin-like domain in RT muscle-specific kinase (MuSK)."; RL J. Biol. Chem. 286:40624-40630(2011). RN [12] RP POTENTIAL USAGE AS A BIOMARKER FOR SARCOPENIA. RX PubMed=22683512; DOI=10.1016/j.exger.2012.05.021; RA Drey M., Sieber C.C., Bauer J.M., Uter W., Dahinden P., Fariello R.G., RA Vrijbloed J.W.; RT "C-terminal Agrin Fragment as a potential marker for sarcopenia caused RT by degeneration of the neuromuscular junction."; RL Exp. Gerontol. 48:76-80(2013). RN [13] RP INVOLVEMENT IN CMS8, VARIANT CMS8 ARG-1709, VARIANTS LEU-23; ASN-58; RP ILE-105; MET-267; SER-375; VAL-728; ARG-852; MET-984; PHE-1088; RP LYS-1118; ARG-1135; LEU-1240; ARG-1341; LEU-1451; THR-1514; HIS-1565; RP ILE-1666; GLN-1671; PRO-1698; HIS-1734; ASN-1789 AND VAL-2046, RP FUNCTION, AND CHARACTERIZATION OF VARIANT CMS8 ARG-1709. RX PubMed=19631309; DOI=10.1016/j.ajhg.2009.06.015; RA Huze C., Bauche S., Richard P., Chevessier F., Goillot E., Gaudon K., RA Ben Ammar A., Chaboud A., Grosjean I., Lecuyer H.A., Bernard V., RA Rouche A., Alexandri N., Kuntzer T., Fardeau M., Fournier E., RA Brancaccio A., Ruegg M.A., Koenig J., Eymard B., Schaeffer L., RA Hantai D.; RT "Identification of an agrin mutation that causes congenital myasthenia RT and affects synapse function."; RL Am. J. Hum. Genet. 85:155-167(2009). RN [14] RP ERRATUM. RA Huze C., Bauche S., Richard P., Chevessier F., Goillot E., Gaudon K., RA Ben Ammar A., Chaboud A., Grosjean I., Lecuyer H.A., Bernard V., RA Rouche A., Alexandri N., Kuntzer T., Fardeau M., Fournier E., RA Brancaccio A., Ruegg M.A., Koenig J., Eymard B., Schaeffer L., RA Hantai D.; RL Am. J. Hum. Genet. 85:536-536(2009). RN [15] RP VARIANT CMS8 PHE-1727, INTERACTION WITH DAG1, AND CHARACTERIZATION OF RP VARIANT CMS8 PHE-1727. RX PubMed=22205389; DOI=10.1007/s00439-011-1132-4; RA Maselli R.A., Fernandez J.M., Arredondo J., Navarro C., Ngo M., RA Beeson D., Cagney O., Williams D.C., Wollmann R.L., Yarov-Yarovoy V., RA Ferns M.J.; RT "LG2 agrin mutation causing severe congenital myasthenic syndrome RT mimics functional characteristics of non-neural (z-) agrin."; RL Hum. Genet. 131:1123-1135(2012). RN [16] RP VARIANT VAL-745, VARIANTS CMS8 SER-76; ILE-105 AND ARG-1875, AND RP CHARACTERIZATION OF VARIANTS CMS8 SER-76 AND ILE-105. RX PubMed=24951643; DOI=10.1093/brain/awu160; RA Nicole S., Chaouch A., Torbergsen T., Bauche S., de Bruyckere E., RA Fontenille M.J., Horn M.A., van Ghelue M., Loeseth S., Issop Y., RA Cox D., Mueller J.S., Evangelista T., Staalberg E., Ioos C., RA Barois A., Brochier G., Sternberg D., Fournier E., Hantai D., RA Abicht A., Dusl M., Laval S.H., Griffin H., Eymard B., Lochmueller H.; RT "Agrin mutations lead to a congenital myasthenic syndrome with distal RT muscle weakness and atrophy."; RL Brain 137:2429-2443(2014). CC -!- FUNCTION: Isoform 1: heparan sulfate basal lamina glycoprotein CC that plays a central role in the formation and the maintenance of CC the neuromuscular junction (NMJ) and directs key events in CC postsynaptic differentiation. Component of the AGRN-LRP4 receptor CC complex that induces the phosphorylation and activation of MUSK. CC The activation of MUSK in myotubes induces the formation of NMJ by CC regulating different processes including the transcription of CC specific genes and the clustering of AChR in the postsynaptic CC membrane. Calcium ions are required for maximal AChR clustering. CC AGRN function in neurons is highly regulated by alternative CC splicing, glycan binding and proteolytic processing. Modulates CC calcium ion homeostasis in neurons, specifically by inducing an CC increase in cytoplasmic calcium ions. Functions differentially in CC the central nervous system (CNS) by inhibiting the alpha(3)- CC subtype of Na+/K+-ATPase and evoking depolarization at CNS CC synapses. This secreted isoform forms a bridge, after release from CC motor neurons, to basal lamina through binding laminin via the NtA CC domain. CC -!- FUNCTION: Isoform 2: transmembrane form that is the predominate CC form in neurons of the brain, induces dendritic filopodia and CC synapse formation in mature hippocampal neurons in large part due CC to the attached glycosaminoglycan chains and the action of Rho- CC family GTPases. CC -!- FUNCTION: Isoform 1, isoform 4 and isoform 5: neuron-specific (z+) CC isoforms that contain C-terminal insertions of 8-19 AA are potent CC activators of AChR clustering. Isoform 5, agrin (z+8), containing CC the 8-AA insert, forms a receptor complex in myotubules containing CC the neuronal AGRN, the muscle-specific kinase MUSK and LRP4, a CC member of the LDL receptor family. The splicing factors, NOVA1 and CC NOVA2, regulate AGRN splicing and production of the 'z' isoforms. CC -!- FUNCTION: Isoform 3 and isoform 6: lack any 'z' insert, are CC muscle-specific and may be involved in endothelial cell CC differentiation. CC -!- FUNCTION: Agrin N-terminal 110 kDa subunit: is involved in CC regulation of neurite outgrowth probably due to the presence of CC the glycosaminoglcan (GAG) side chains of heparan and chondroitin CC sulfate attached to the Ser/Thr- and Gly/Ser-rich regions. Also CC involved in modulation of growth factor signaling (By similarity). CC {ECO:0000250, ECO:0000269|PubMed:19631309, CC ECO:0000269|PubMed:21969364}. CC -!- FUNCTION: Agrin C-terminal 22 kDa fragment: this released fragment CC is 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 (By similarity). Interacts (N-terminal subunit) CC with TGF-beta family members, BMP2 AND BMP4; the interactions CC inhibit the activity of these growth factors. Interacts with CC TGFB1; the interaction enhances the activity of TGFB1 (By CC similarity). Component of the AGRN-LRP4 complex that consists of a CC tetramer of two AGRN-LRP4 heterodimers. Interacts (via the laminin CC G-like 3 domain) directly with LRP4; the interaction is required CC for activation of MUSK and clustering of AChR and requires the CC 'z8' insert present in the z(+8) isoforms. Interacts with DAG1; CC the interaction is influenced by cell surface glycosaminoglycans CC and by alternative splicing of AGRN. {ECO:0000250, CC ECO:0000269|PubMed:21969364, ECO:0000269|PubMed:22205389, CC ECO:0000269|PubMed:9151673}. CC -!- INTERACTION: CC O15265:ATXN7; NbExp=2; IntAct=EBI-947482, EBI-708350; CC -!- SUBCELLULAR LOCATION: Isoform 1: Secreted, extracellular space, CC extracellular matrix {ECO:0000269|PubMed:20551380}. Note=Synaptic CC basal lamina at the neuromuscular junction. CC {ECO:0000250|UniProtKB:P31696}. CC -!- SUBCELLULAR LOCATION: Isoform 2: Cell junction, synapse CC {ECO:0000250|UniProtKB:A2ASQ1}. Cell membrane CC {ECO:0000250|UniProtKB:A2ASQ1}; Single-pass type II membrane CC protein {ECO:0000250|UniProtKB:A2ASQ1}. CC -!- ALTERNATIVE PRODUCTS: CC Event=Alternative splicing; Named isoforms=7; CC Comment=Many isoforms may exist depending on the occurrence and CC length of inserts at the x, y or z splice site. Four 'z' CC isoforms can be produced with inserts of 0, 8, 11 or 19 AA. CC Isoforms differ in their acetylcholine receptor clustering CC activity and tissue specificity.; CC Name=1; Synonyms=Secreted agrin, LN-agrin; CC IsoId=O00468-1; Sequence=Displayed; CC Name=2; Synonyms=Transmembrane agrin, TM-agrin; CC IsoId=O00468-2; Sequence=VSP_045753, VSP_045754; CC Note=Produced by usage of an alternative first exon.; CC Name=3; Synonyms=Agrin z(0); CC IsoId=O00468-3; Sequence=VSP_045756; CC Name=4; Synonyms=Agrin z(+11); CC IsoId=O00468-4; Sequence=VSP_045757; CC Name=5; Synonyms=Agrin z(+8); CC IsoId=O00468-5; Sequence=VSP_045758; CC Name=6; Synonyms=Agrin y(0)z(0); CC IsoId=O00468-6; Sequence=VSP_045755, VSP_045756; CC Name=7; Synonyms=y(0); CC IsoId=O00468-7; Sequence=VSP_045755; CC -!- TISSUE SPECIFICITY: Expressed in basement membranes of lung and CC kidney. Muscle- and neuron-specific isoforms are found. Isoforms CC (y+) with the 4 AA insert and (z+8) isoforms with the 8 AA insert CC are all neuron-specific. Isoforms (z+11) are found in both CC neuronal and non-neuronal tissues. {ECO:0000269|PubMed:16487930, CC ECO:0000269|PubMed:20551380, ECO:0000269|PubMed:9652404}. CC -!- DOMAIN: The NtA domain, absent in TM-agrin, is required for CC binding laminin and connecting to basal lamina. CC -!- DOMAIN: Both laminin G-like 2 (G2) and laminin G-like 3 (G3) CC domains are required for alpha-dystroglycan/DAG1 binding. G3 CC domain is required for C-terminal heparin, heparan sulfate and CC sialic acid binding (By similarity). {ECO:0000250}. 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 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 CC contains heparan sulfate (HS) chains and the second cluster CC (Ser/Thr-rich), contains chondroitin sulfate (CS) chains. Heparin CC and heparin sulfate binding in the G3 domain is independent of CC calcium ions. Binds heparin with a stoichiometry of 2:1. Binds CC sialic acid with a stoichiometry of 1:1 and binding requires CC calcium ions (By similarity). {ECO:0000250}. CC -!- PTM: At synaptic junctions, cleaved at two conserved sites, alpha CC and beta, by neurotrypsin. Cleavage at the alpha-site produces the CC agrin N-terminal 110-kDa subunit and the agrin C-terminal 110-kDa CC subunit. Further cleavage of agrin C-terminal 110-kDa subunit at CC the beta site produces the C-terminal fragments, agrin C-terminal CC 90 kDa fragment and agrin C-terminal 22 kDa fragment. Excessive CC cleavage at the beta-site releases large amounts of the agrin C- CC terminal 22 kDa fragment leading to destabilization at the CC neuromuscular junction (NMJ). CC -!- DISEASE: Myasthenic syndrome, congenital, 8 (CMS8) [MIM:615120]: A CC form of congenital myasthenic syndrome, a group of disorders CC characterized by failure of neuromuscular transmission, including CC pre-synaptic, synaptic, and post-synaptic disorders that are not CC of autoimmune origin. Clinical features are easy fatigability and CC muscle weakness. CMS8 is an autosomal recessive disease CC characterized by prominent defects of both the pre- and CC postsynaptic regions. Affected individuals have onset of muscle CC weakness in early childhood; the severity of the weakness and CC muscles affected is variable. {ECO:0000269|PubMed:19631309, CC ECO:0000269|PubMed:22205389, ECO:0000269|PubMed:24951643}. CC Note=The disease is caused by mutations affecting the gene CC represented in this entry. CC -!- MISCELLANEOUS: Cleaved C-terminal fragments may be used as a CC biomarker for sarcopenia, age-related progressive loss of skeletal CC muscle. {ECO:0000305|PubMed:22683512}. CC -!- CAUTION: The unknown residue 'x' in the transmembrane isoform is CC probably a proline residue by similarity to mouse and rat CC sequences. {ECO:0000305}. CC -!- WEB RESOURCE: Name=The Leiden Muscular Dystrophy pages, Agrin CC (AGRN); Note=Leiden Open Variation Database (LOVD); CC URL="http://www.lovd.nl/AGRN"; CC ----------------------------------------------------------------------- CC Copyrighted by the UniProt Consortium, see https://www.uniprot.org/terms CC Distributed under the Creative Commons Attribution (CC BY 4.0) License CC ----------------------------------------------------------------------- DR EMBL; AB191264; BAD52440.1; -; mRNA. DR EMBL; AL645608; -; NOT_ANNOTATED_CDS; Genomic_DNA. DR EMBL; AF016903; AAC39776.1; -; mRNA. DR EMBL; U84406; AAB52917.1; -; mRNA. DR EMBL; BC004220; AAH04220.2; -; mRNA. DR EMBL; BC007649; AAH07649.1; -; mRNA. DR EMBL; BC034009; AAH34009.1; -; mRNA. DR EMBL; BC063620; AAH63620.1; -; mRNA. DR CCDS; CCDS30551.1; -. [O00468-6] DR RefSeq; NP_001292204.1; NM_001305275.1. [O00468-1] DR RefSeq; NP_940978.2; NM_198576.3. [O00468-6] DR RefSeq; XP_005244806.1; XM_005244749.3. [O00468-3] DR UniGene; Hs.273330; -. DR UniGene; Hs.602356; -. DR ProteinModelPortal; O00468; -. DR SMR; O00468; -. DR BioGrid; 132000; 20. DR IntAct; O00468; 13. DR MINT; O00468; -. DR STRING; 9606.ENSP00000368678; -. DR CarbonylDB; O00468; -. DR GlyConnect; 998; -. DR iPTMnet; O00468; -. DR PhosphoSitePlus; O00468; -. DR BioMuta; AGRN; -. DR EPD; O00468; -. DR jPOST; O00468; -. DR PaxDb; O00468; -. DR PeptideAtlas; O00468; -. DR PRIDE; O00468; -. DR ProteomicsDB; 47914; -. DR Ensembl; ENST00000379370; ENSP00000368678; ENSG00000188157. [O00468-6] DR GeneID; 375790; -. DR KEGG; hsa:375790; -. DR UCSC; uc001ack.3; human. [O00468-1] DR CTD; 375790; -. DR DisGeNET; 375790; -. DR EuPathDB; HostDB:ENSG00000188157.13; -. DR GeneCards; AGRN; -. DR GeneReviews; AGRN; -. DR HGNC; HGNC:329; AGRN. DR HPA; HPA040090; -. DR MalaCards; AGRN; -. DR MIM; 103320; gene. DR MIM; 615120; phenotype. DR neXtProt; NX_O00468; -. DR OpenTargets; ENSG00000188157; -. DR Orphanet; 98913; Postsynaptic congenital myasthenic syndromes. DR Orphanet; 98914; Presynaptic congenital myasthenic syndromes. DR PharmGKB; PA24626; -. DR eggNOG; ENOG410ITSI; Eukaryota. DR eggNOG; ENOG410YKSA; LUCA. DR GeneTree; ENSGT00940000158337; -. DR HOGENOM; HOG000033860; -. DR HOVERGEN; HBG080471; -. DR InParanoid; O00468; -. DR KO; K06254; -. DR OMA; FQGVLIL; -. DR OrthoDB; 414294at2759; -. DR TreeFam; TF326548; -. DR Reactome; R-HSA-1971475; A tetrasaccharide linker sequence is required for GAG synthesis. DR Reactome; R-HSA-2022928; HS-GAG biosynthesis. DR Reactome; R-HSA-2024096; HS-GAG degradation. DR Reactome; R-HSA-216083; Integrin cell surface interactions. DR Reactome; R-HSA-3000171; Non-integrin membrane-ECM interactions. DR Reactome; R-HSA-3000178; ECM proteoglycans. DR Reactome; R-HSA-3560783; Defective B4GALT7 causes EDS, progeroid type. DR Reactome; R-HSA-3560801; Defective B3GAT3 causes JDSSDHD. DR Reactome; R-HSA-3656237; Defective EXT2 causes exostoses 2. DR Reactome; R-HSA-3656253; Defective EXT1 causes exostoses 1, TRPS2 and CHDS. DR Reactome; R-HSA-419037; NCAM1 interactions. DR Reactome; R-HSA-4420332; Defective B3GALT6 causes EDSP2 and SEMDJL1. DR Reactome; R-HSA-975634; Retinoid metabolism and transport. DR SignaLink; O00468; -. DR ChiTaRS; AGRN; human. DR GeneWiki; Agrin; -. DR GenomeRNAi; 375790; -. DR PRO; PR:O00468; -. DR Proteomes; UP000005640; Chromosome 1. DR Bgee; ENSG00000188157; Expressed in 221 organ(s), highest expression level in right uterine tube. DR ExpressionAtlas; O00468; baseline and differential. DR Genevisible; O00468; HS. DR GO; GO:0005604; C:basement membrane; IDA:UniProtKB. DR GO; GO:0030054; C:cell junction; IEA:UniProtKB-KW. DR GO; GO:0062023; C:collagen-containing extracellular matrix; IDA:UniProtKB. DR GO; GO:0005829; C:cytosol; IDA:HPA. DR GO; GO:0070062; C:extracellular exosome; HDA:UniProtKB. DR GO; GO:0005576; C:extracellular region; TAS:Reactome. DR GO; GO:0005796; C:Golgi lumen; TAS:Reactome. DR GO; GO:0016021; C:integral component of membrane; IEA:UniProtKB-KW. DR GO; GO:0043202; C:lysosomal lumen; TAS:Reactome. DR GO; GO:0005886; C:plasma membrane; IDA:HPA. DR GO; GO:0045202; C:synapse; ISS:UniProtKB. DR GO; GO:0005509; F:calcium ion binding; ISS:UniProtKB. DR GO; GO:0035374; F:chondroitin sulfate binding; ISS:UniProtKB. DR GO; GO:0002162; F:dystroglycan binding; ISS:UniProtKB. DR GO; GO:0005201; F:extracellular matrix structural constituent; HDA:BHF-UCL. DR GO; GO:0043395; F:heparan sulfate proteoglycan binding; ISS:UniProtKB. DR GO; GO:0043236; F:laminin binding; TAS:UniProtKB. DR GO; GO:0033691; F:sialic acid binding; ISS:UniProtKB. DR GO; GO:0005200; F:structural constituent of cytoskeleton; TAS:UniProtKB. DR GO; GO:0045162; P:clustering of voltage-gated sodium channels; TAS:UniProtKB. DR GO; GO:0030198; P:extracellular matrix organization; TAS:Reactome. DR GO; GO:0007213; P:G protein-coupled acetylcholine receptor signaling pathway; TAS:UniProtKB. DR GO; GO:0006024; P:glycosaminoglycan biosynthetic process; TAS:Reactome. DR GO; GO:0006027; P:glycosaminoglycan catabolic process; TAS:Reactome. DR GO; GO:0051491; P:positive regulation of filopodium assembly; ISS:UniProtKB. DR GO; GO:0043547; P:positive regulation of GTPase activity; ISS:UniProtKB. DR GO; GO:0045887; P:positive regulation of synaptic growth at neuromuscular junction; ISS:UniProtKB. DR GO; GO:0045944; P:positive regulation of transcription by RNA polymerase II; ISS:UniProtKB. DR GO; GO:0043113; P:receptor clustering; IDA:UniProtKB. DR GO; GO:0001523; P:retinoid metabolic process; TAS:Reactome. DR GO; GO:0007165; P:signal transduction; TAS:UniProtKB. DR GO; GO:0050808; P:synapse organization; TAS:UniProtKB. DR Gene3D; 3.30.70.960; -; 1. DR InterPro; IPR013320; ConA-like_dom_sf. DR InterPro; IPR001881; EGF-like_Ca-bd_dom. DR InterPro; IPR013032; EGF-like_CS. 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; IPR002049; Laminin_EGF. DR InterPro; IPR001791; Laminin_G. DR InterPro; IPR004850; NtA_dom. DR InterPro; IPR000082; SEA_dom. DR InterPro; IPR036364; SEA_dom_sf. DR InterPro; IPR008993; TIMP-like_OB-fold. DR Pfam; PF00008; EGF; 2. 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; PF03146; NtA; 1. DR Pfam; PF01390; SEA; 1. DR SMART; SM00181; EGF; 7. DR SMART; SM00179; EGF_CA; 3. DR SMART; SM00180; EGF_Lam; 2. DR SMART; SM00057; FIMAC; 4. 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; SSF50242; SSF50242; 1. 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; PS51121; NTA; 1. DR PROSITE; PS50024; SEA; 1. PE 1: Evidence at protein level; KW Alternative splicing; Calcium; Cell junction; Cell membrane; KW Complete proteome; Congenital myasthenic syndrome; KW Developmental protein; Differentiation; Disease mutation; KW Disulfide bond; EGF-like domain; Extracellular matrix; Glycoprotein; KW Heparan sulfate; Laminin EGF-like domain; Membrane; Phosphoprotein; KW Polymorphism; Proteoglycan; Reference proteome; Repeat; Secreted; KW Signal; Synapse; Transmembrane; Transmembrane helix. FT SIGNAL 1 29 {ECO:0000255}. FT CHAIN 30 2068 Agrin. FT /FTId=PRO_0000007471. FT CHAIN 30 1102 Agrin N-terminal 110 kDa subunit. FT {ECO:0000250}. FT /FTId=PRO_0000421613. FT CHAIN 1103 2068 Agrin C-terminal 110 kDa subunit. FT {ECO:0000250}. FT /FTId=PRO_0000421614. FT CHAIN 1103 1863 Agrin C-terminal 90 kDa fragment. FT {ECO:0000250}. FT /FTId=PRO_0000421615. FT CHAIN 1864 2068 Agrin C-terminal 22 kDa fragment. FT {ECO:0000250}. FT /FTId=PRO_0000421616. FT DOMAIN 30 157 NtA. {ECO:0000255|PROSITE- FT ProRule:PRU00443}. FT DOMAIN 191 244 Kazal-like 1. {ECO:0000255|PROSITE- FT ProRule:PRU00798}. FT DOMAIN 264 319 Kazal-like 2. {ECO:0000255|PROSITE- FT ProRule:PRU00798}. FT DOMAIN 337 391 Kazal-like 3. {ECO:0000255|PROSITE- FT ProRule:PRU00798}. FT DOMAIN 408 463 Kazal-like 4. {ECO:0000255|PROSITE- FT ProRule:PRU00798}. FT DOMAIN 484 536 Kazal-like 5. {ECO:0000255|PROSITE- FT ProRule:PRU00798}. FT DOMAIN 540 601 Kazal-like 6. {ECO:0000255|PROSITE- FT ProRule:PRU00798}. FT DOMAIN 607 666 Kazal-like 7. {ECO:0000255|PROSITE- FT ProRule:PRU00798}. FT DOMAIN 699 752 Kazal-like 8. {ECO:0000255|PROSITE- FT ProRule:PRU00798}. FT DOMAIN 793 846 Laminin EGF-like 1. {ECO:0000255|PROSITE- FT ProRule:PRU00460}. FT DOMAIN 847 893 Laminin EGF-like 2. {ECO:0000255|PROSITE- FT ProRule:PRU00460}. FT DOMAIN 917 971 Kazal-like 9. {ECO:0000255|PROSITE- FT ProRule:PRU00798}. FT DOMAIN 1130 1252 SEA. {ECO:0000255|PROSITE- FT ProRule:PRU00188}. FT DOMAIN 1329 1367 EGF-like 1. {ECO:0000255|PROSITE- FT ProRule:PRU00076}. FT DOMAIN 1372 1548 Laminin G-like 1. {ECO:0000255|PROSITE- FT ProRule:PRU00122}. FT DOMAIN 1549 1586 EGF-like 2. {ECO:0000255|PROSITE- FT ProRule:PRU00076}. FT DOMAIN 1588 1625 EGF-like 3. {ECO:0000255|PROSITE- FT ProRule:PRU00076}. FT DOMAIN 1635 1822 Laminin G-like 2. {ECO:0000255|PROSITE- FT ProRule:PRU00122}. FT DOMAIN 1818 1857 EGF-like 4. {ECO:0000255|PROSITE- FT ProRule:PRU00076}. FT DOMAIN 1868 2065 Laminin G-like 3. {ECO:0000255|PROSITE- FT ProRule:PRU00122}. FT CA_BIND 1941 2009 {ECO:0000250}. FT COMPBIAS 671 677 Gly/Ser-rich. FT COMPBIAS 974 1099 Ser/Thr-rich. FT COMPBIAS 1058 1097 Gly/Ser-rich. FT COMPBIAS 1254 1324 Ser/Thr-rich. FT SITE 1102 1103 Cleavage, alpha site; by neurotrypsin. FT {ECO:0000250}. FT SITE 1250 1250 Alternative splice site to produce 'x' FT isoforms. {ECO:0000250}. FT SITE 1751 1751 Alternative splice site to produce 'y' FT isoforms. {ECO:0000250}. FT SITE 1862 1862 Critical for cleavage by neurotrypsin. FT {ECO:0000250}. FT SITE 1863 1864 Cleavage, beta site; by neurotrypsin. FT {ECO:0000250}. FT SITE 1888 1888 Alternative splice site to produce 'z' FT isoforms. {ECO:0000250}. FT SITE 1892 1892 Highly important for the agrin receptor FT complex activity of the 'z(8)' insert. FT {ECO:0000250}. FT MOD_RES 674 674 Phosphoserine. FT {ECO:0000250|UniProtKB:A2ASQ1}. FT MOD_RES 676 676 Phosphoserine. FT {ECO:0000250|UniProtKB:A2ASQ1}. FT CARBOHYD 135 135 N-linked (GlcNAc...) asparagine. FT {ECO:0000269|PubMed:19159218}. FT CARBOHYD 250 250 N-linked (GlcNAc...) asparagine. FT {ECO:0000255}. FT CARBOHYD 777 777 N-linked (GlcNAc...) asparagine. FT {ECO:0000255}. FT CARBOHYD 932 932 N-linked (GlcNAc...) asparagine. FT {ECO:0000255}. FT CARBOHYD 1835 1835 O-linked (Fuc...) serine. FT {ECO:0000250|UniProtKB:P25304}. FT DISULFID 31 103 {ECO:0000250}. FT DISULFID 152 177 Or C-152 with C-183. FT DISULFID 197 228 {ECO:0000255|PROSITE-ProRule:PRU00798}. FT DISULFID 202 221 {ECO:0000255|PROSITE-ProRule:PRU00798}. FT DISULFID 210 242 {ECO:0000255|PROSITE-ProRule:PRU00798}. FT DISULFID 270 303 {ECO:0000255|PROSITE-ProRule:PRU00798}. FT DISULFID 276 296 {ECO:0000255|PROSITE-ProRule:PRU00798}. FT DISULFID 285 317 {ECO:0000255|PROSITE-ProRule:PRU00798}. FT DISULFID 349 368 {ECO:0000255|PROSITE-ProRule:PRU00798}. FT DISULFID 357 389 {ECO:0000255|PROSITE-ProRule:PRU00798}. FT DISULFID 414 447 {ECO:0000255|PROSITE-ProRule:PRU00798}. FT DISULFID 421 440 {ECO:0000255|PROSITE-ProRule:PRU00798}. FT DISULFID 429 461 {ECO:0000255|PROSITE-ProRule:PRU00798}. FT DISULFID 490 520 {ECO:0000255|PROSITE-ProRule:PRU00798}. FT DISULFID 494 513 {ECO:0000255|PROSITE-ProRule:PRU00798}. FT DISULFID 502 534 {ECO:0000255|PROSITE-ProRule:PRU00798}. FT DISULFID 546 585 {ECO:0000255|PROSITE-ProRule:PRU00798}. FT DISULFID 555 578 {ECO:0000255|PROSITE-ProRule:PRU00798}. FT DISULFID 567 599 {ECO:0000255|PROSITE-ProRule:PRU00798}. FT DISULFID 613 650 {ECO:0000255|PROSITE-ProRule:PRU00798}. FT DISULFID 623 643 {ECO:0000255|PROSITE-ProRule:PRU00798}. FT DISULFID 632 664 {ECO:0000255|PROSITE-ProRule:PRU00798}. FT DISULFID 705 736 {ECO:0000255|PROSITE-ProRule:PRU00798}. FT DISULFID 709 729 {ECO:0000255|PROSITE-ProRule:PRU00798}. FT DISULFID 718 750 {ECO:0000255|PROSITE-ProRule:PRU00798}. FT DISULFID 793 805 {ECO:0000250}. FT DISULFID 795 812 {ECO:0000250}. FT DISULFID 814 823 {ECO:0000250}. FT DISULFID 826 844 {ECO:0000250}. FT DISULFID 847 859 {ECO:0000250}. FT DISULFID 849 866 {ECO:0000250}. FT DISULFID 868 877 {ECO:0000250}. FT DISULFID 880 891 {ECO:0000250}. FT DISULFID 923 955 {ECO:0000255|PROSITE-ProRule:PRU00798}. FT DISULFID 928 948 {ECO:0000255|PROSITE-ProRule:PRU00798}. FT DISULFID 937 969 {ECO:0000255|PROSITE-ProRule:PRU00798}. FT DISULFID 1333 1344 {ECO:0000250}. FT DISULFID 1338 1355 {ECO:0000250}. FT DISULFID 1357 1366 {ECO:0000250}. FT DISULFID 1519 1548 {ECO:0000250}. FT DISULFID 1553 1564 {ECO:0000250}. FT DISULFID 1558 1574 {ECO:0000250}. FT DISULFID 1576 1585 {ECO:0000250}. FT DISULFID 1592 1603 {ECO:0000250}. FT DISULFID 1597 1613 {ECO:0000250}. FT DISULFID 1615 1624 {ECO:0000250}. FT DISULFID 1822 1836 {ECO:0000250}. FT DISULFID 1830 1845 {ECO:0000250}. FT DISULFID 1847 1856 {ECO:0000250}. FT DISULFID 2039 2065 {ECO:0000250}. FT VAR_SEQ 1 104 Missing (in isoform 2). {ECO:0000305}. FT /FTId=VSP_045753. FT VAR_SEQ 105 154 NQVSTGDTRIFFVNPAPPYLWPAHKNELMLNSSLMRITLRN FT LEEVEFCVE -> MPXLAVARDTRQPAGASLLVRGFMVPCN FT ACLILLATATLGFAVLLFLNNY (in isoform 2). FT {ECO:0000305}. FT /FTId=VSP_045754. FT VAR_SEQ 1752 1755 Missing (in isoform 6 and isoform 7). FT {ECO:0000305}. FT /FTId=VSP_045755. FT VAR_SEQ 1889 1907 Missing (in isoform 3 and isoform 6). FT {ECO:0000303|PubMed:9652404, FT ECO:0000303|Ref.1}. FT /FTId=VSP_045756. FT VAR_SEQ 1889 1896 Missing (in isoform 4). {ECO:0000305}. FT /FTId=VSP_045757. FT VAR_SEQ 1897 1907 Missing (in isoform 5). {ECO:0000305}. FT /FTId=VSP_045758. FT VARIANT 23 23 V -> L. {ECO:0000269|PubMed:19631309}. FT /FTId=VAR_068724. FT VARIANT 58 58 D -> N. {ECO:0000269|PubMed:19631309}. FT /FTId=VAR_068725. FT VARIANT 76 76 G -> S (in CMS8; results in decreased FT AChR clustering). FT {ECO:0000269|PubMed:24951643}. FT /FTId=VAR_071367. FT VARIANT 105 105 N -> I (in CMS8; results in decreased FT AChR clustering). FT {ECO:0000269|PubMed:19631309, FT ECO:0000269|PubMed:24951643}. FT /FTId=VAR_068726. FT VARIANT 267 267 T -> M. {ECO:0000269|PubMed:19631309}. FT /FTId=VAR_068727. FT VARIANT 375 375 A -> S (in dbSNP:rs138031468). FT {ECO:0000269|PubMed:19631309}. FT /FTId=VAR_068728. FT VARIANT 728 728 E -> V (in dbSNP:rs113288277). FT {ECO:0000269|PubMed:19631309}. FT /FTId=VAR_068729. FT VARIANT 745 745 A -> V. {ECO:0000269|PubMed:24951643}. FT /FTId=VAR_071368. FT VARIANT 852 852 Q -> R (in dbSNP:rs9697293). FT {ECO:0000269|PubMed:19631309}. FT /FTId=VAR_068730. FT VARIANT 984 984 V -> M. {ECO:0000269|PubMed:19631309}. FT /FTId=VAR_068731. FT VARIANT 1088 1088 L -> F (in dbSNP:rs150132566). FT {ECO:0000269|PubMed:19631309}. FT /FTId=VAR_068732. FT VARIANT 1118 1118 T -> K (in dbSNP:rs149159118). FT {ECO:0000269|PubMed:19631309}. FT /FTId=VAR_068733. FT VARIANT 1135 1135 Q -> R (in dbSNP:rs142416636). FT {ECO:0000269|PubMed:19631309}. FT /FTId=VAR_068734. FT VARIANT 1240 1240 P -> L (in dbSNP:rs142620337). FT {ECO:0000269|PubMed:19631309}. FT /FTId=VAR_068735. FT VARIANT 1341 1341 G -> R. {ECO:0000269|PubMed:19631309}. FT /FTId=VAR_068736. FT VARIANT 1451 1451 P -> L. {ECO:0000269|PubMed:19631309}. FT /FTId=VAR_068737. FT VARIANT 1514 1514 A -> T (in dbSNP:rs111818381). FT {ECO:0000269|PubMed:19631309}. FT /FTId=VAR_068738. FT VARIANT 1565 1565 Q -> H (in dbSNP:rs199876002). FT {ECO:0000269|PubMed:19631309}. FT /FTId=VAR_068739. FT VARIANT 1666 1666 V -> I (in dbSNP:rs17160775). FT {ECO:0000269|PubMed:19631309}. FT /FTId=VAR_048966. FT VARIANT 1671 1671 R -> Q. {ECO:0000269|PubMed:19631309}. FT /FTId=VAR_068740. FT VARIANT 1698 1698 R -> P. {ECO:0000269|PubMed:19631309}. FT /FTId=VAR_068741. FT VARIANT 1709 1709 G -> R (in CMS8; results in disruption of FT the neuromuscular junction architecture; FT does not affect phosphorylation of MUSK; FT does not affect AChR clustering). FT {ECO:0000269|PubMed:19631309}. FT /FTId=VAR_068742. FT VARIANT 1727 1727 V -> F (in CMS8; decreased AGRN-induced FT clustering of AChR by >100-fold and FT decreased phosphorylation of the MUSK FT receptor and AChR beta subunit by about FT 10-fold. Increased binding to alpha- FT dystroglycan). FT {ECO:0000269|PubMed:22205389}. FT /FTId=VAR_069066. FT VARIANT 1734 1734 R -> H (in dbSNP:rs145444272). FT {ECO:0000269|PubMed:19631309}. FT /FTId=VAR_068743. FT VARIANT 1789 1789 D -> N. {ECO:0000269|PubMed:19631309}. FT /FTId=VAR_068744. FT VARIANT 1875 1875 G -> R (in CMS8). FT {ECO:0000269|PubMed:24951643}. FT /FTId=VAR_071369. FT VARIANT 2046 2046 G -> V. {ECO:0000269|PubMed:19631309}. FT /FTId=VAR_068745. FT CONFLICT 343 343 L -> R (in Ref. 3; AAC39776). FT {ECO:0000305}. SQ SEQUENCE 2068 AA; 217320 MW; 8B3E3D0FF65517F0 CRC64; MAGRSHPGPL RPLLPLLVVA ACVLPGAGGT CPERALERRE EEANVVLTGT VEEILNVDPV QHTYSCKVRV WRYLKGKDLV ARESLLDGGN KVVISGFGDP LICDNQVSTG DTRIFFVNPA PPYLWPAHKN ELMLNSSLMR ITLRNLEEVE FCVEDKPGTH FTPVPPTPPD ACRGMLCGFG AVCEPNAEGP GRASCVCKKS PCPSVVAPVC GSDASTYSNE CELQRAQCSQ QRRIRLLSRG PCGSRDPCSN VTCSFGSTCA RSADGLTASC LCPATCRGAP EGTVCGSDGA DYPGECQLLR RACARQENVF KKFDGPCDPC QGALPDPSRS CRVNPRTRRP EMLLRPESCP ARQAPVCGDD GVTYENDCVM GRSGAARGLL LQKVRSGQCQ GRDQCPEPCR FNAVCLSRRG RPRCSCDRVT CDGAYRPVCA QDGRTYDSDC WRQQAECRQQ RAIPSKHQGP CDQAPSPCLG VQCAFGATCA VKNGQAACEC LQACSSLYDP VCGSDGVTYG SACELEATAC TLGREIQVAR KGPCDRCGQC RFGALCEAET GRCVCPSECV ALAQPVCGSD GHTYPSECML HVHACTHQIS LHVASAGPCE TCGDAVCAFG AVCSAGQCVC PRCEHPPPGP VCGSDGVTYG SACELREAAC LQQTQIEEAR AGPCEQAECG SGGSGSGEDG DCEQELCRQR GGIWDEDSED GPCVCDFSCQ SVPGSPVCGS DGVTYSTECE LKKARCESQR GLYVAAQGAC RGPTFAPLPP VAPLHCAQTP YGCCQDNITA ARGVGLAGCP SACQCNPHGS YGGTCDPATG QCSCRPGVGG LRCDRCEPGF WNFRGIVTDG RSGCTPCSCD PQGAVRDDCE QMTGLCSCKP GVAGPKCGQC PDGRALGPAG CEADASAPAT CAEMRCEFGA RCVEESGSAH CVCPMLTCPE ANATKVCGSD GVTYGNECQL KTIACRQGLQ ISIQSLGPCQ EAVAPSTHPT SASVTVTTPG LLLSQALPAP PGALPLAPSS TAHSQTTPPP SSRPRTTASV PRTTVWPVLT VPPTAPSPAP SLVASAFGES GSTDGSSDEE LSGDQEASGG GSGGLEPLEG SSVATPGPPV ERASCYNSAL GCCSDGKTPS LDAEGSNCPA TKVFQGVLEL EGVEGQELFY TPEMADPKSE LFGETARSIE STLDDLFRNS DVKKDFRSVR LRDLGPGKSV RAIVDVHFDP TTAFRAPDVA RALLRQIQVS RRRSLGVRRP LQEHVRFMDF DWFPAFITGA TSGAIAAGAT ARATTASRLP SSAVTPRAPH PSHTSQPVAK TTAAPTTRRP PTTAPSRVPG RRPPAPQQPP KPCDSQPCFH GGTCQDWALG GGFTCSCPAG RGGAVCEKVL GAPVPAFEGR SFLAFPTLRA YHTLRLALEF RALEPQGLLL YNGNARGKDF LALALLDGRV QLRFDTGSGP AVLTSAVPVE PGQWHRLELS RHWRRGTLSV DGETPVLGES PSGTDGLNLD TDLFVGGVPE DQAAVALERT FVGAGLRGCI RLLDVNNQRL ELGIGPGAAT RGSGVGECGD HPCLPNPCHG GAPCQNLEAG RFHCQCPPGR VGPTCADEKS PCQPNPCHGA APCRVLPEGG AQCECPLGRE GTFCQTASGQ DGSGPFLADF NGFSHLELRG LHTFARDLGE KMALEVVFLA RGPSGLLLYN GQKTDGKGDF VSLALRDRRL EFRYDLGKGA AVIRSREPVT LGAWTRVSLE RNGRKGALRV GDGPRVLGES PKSRKVPHTV LNLKEPLYVG GAPDFSKLAR AAAVSSGFDG AIQLVSLGGR QLLTPEHVLR QVDVTSFAGH PCTRASGHPC LNGASCVPRE AAYVCLCPGG FSGPHCEKGL VEKSAGDVDT LAFDGRTFVE YLNAVTESEL ANEIPVPETL DSGALHSEKA LQSNHFELSL RTEATQGLVL WSGKATERAD YVALAIVDGH LQLSYNLGSQ PVVLRSTVPV NTNRWLRVVA HREQREGSLQ VGNEAPVTGS SPLGATQLDT DGALWLGGLP ELPVGPALPK AYGTGFVGCL RDVVVGRHPL HLLEDAVTKP ELRPCPTP //