| IED ID | IndEnz0002018744 |
| Enzyme Type ID | protease018744 |
| Protein Name |
Agrin Cleaved into: Agrin N-terminal 110 kDa subunit; Agrin C-terminal 110 kDa subunit; Agrin C-terminal 90 kDa fragment C90 ; Agrin C-terminal 22 kDa fragment C22 |
| Gene Name | Agrn Agrin |
| Organism | Rattus norvegicus (Rat) |
| Taxonomic Lineage | cellular organisms Eukaryota Opisthokonta Metazoa Eumetazoa Bilateria Deuterostomia Chordata Craniata Vertebrata Gnathostomata (jawed vertebrates) Teleostomi Euteleostomi Sarcopterygii Dipnotetrapodomorpha Tetrapoda Amniota Mammalia Theria Eutheria Boreoeutheria Euarchontoglires Glires (Rodents and rabbits) Rodentia Myomorpha (mice and others) Muroidea Muridae Murinae Rattus Rattus norvegicus (Rat) |
| Enzyme Sequence | MPPLPLEHRPRQEPGASMLVRYFMIPCNICLILLATSTLGFAVLLFLSNYKPGIHFTPAPPTPPDVCRGMLCGFGAVCEPSVEDPGRASCVCKKNACPATVAPVCGSDASTYSNECELQRAQCNQQRRIRLLRQGPCGSRDPCANVTCSFGSTCVPSADGQTASCLCPTTCFGAPDGTVCGSDGVDYPSECQLLSHACASQEHIFKKFNGPCDPCQGSMSDLNHICRVNPRTRHPEMLLRPENCPAQHTPICGDDGVTYENDCVMSRIGATRGLLLQKVRSGQCQTRDQCPETCQFNSVCLSRRGRPHCSCDRVTCDGSYRPVCAQDGHTYNNDCWRQQAECRQQRAIPPKHQGPCDQTPSPCHGVQCAFGAVCTVKNGKAECECQRVCSGIYDPVCGSDGVTYGSVCELESMACTLGREIQVARRGPCDPCGQCRFGSLCEVETGRCVCPSECVESAQPVCGSDGHTYASECELHVHACTHQISLYVASAGHCQTCGEKVCTFGAVCSAGQCVCPRCEHPPPGPVCGSDGVTYLSACELREAACQQQVQIEEAHAGPCEPAECGSGGSGSGEDDECEQELCRQRGGIWDEDSEDGPCVCDFSCQSVPRSPVCGSDGVTYGTECDLKKARCESQQELYVAAQGACRGPTLAPLLPVAFPHCAQTPYGCCQDNFTAAQGVGLAGCPSTCHCNPHGSYSGTCDPATGQCSCRPGVGGLRCDRCEPGFWNFRGIVTDGHSGCTPCSCDPRGAVRDDCEQMTGLCSCRPGVAGPKCGQCPDGQVLGHLGCEADPMTPVTCVEIHCEFGASCVEKAGFAQCICPTLTCPEANSTKVCGSDGVTYGNECQLKAIACRQRLDISTQSLGPCQESVTPGASPTSASMTTPRHILSKTLPFPHNSLPLSPGSTTHDWPTPLPISPHTTVSIPRSTAWPVLTVPPTAAASDVTSLATSIFSESGSANGSGDEELSGDEEASGGGSGGLEPPVGSIVVTHGPPIERASCYNSPLGCCSDGKTPSLDSEGSNCPATKAFQGVLELEGVEGQELFYTPEMADPKSELFGETARSIESTLDDLFRNSDVKKDFWSVRLRELGPGKLVRAIVDVHFDPTTAFQASDVGQALLRQIQVSRPWALAVRRPLQEHVRFLDFDWFPTFFTGAATGTTAAMATARATTVSRLPASSVTPRVYPSHTSRPVGRTTAPPTTRRPPTTATNMDRPRTPGHQQPSKSCDSQPCLHGGTCQDQDSGKGFTCSCTAGRGGSVCEKVQPPSMPAFKGHSFLAFPTLRAYHTLRLALEFRALETEGLLLYNGNARGKDFLALALLDGRVQFRFDTGSGPAVLTSLVPVEPGRWHRLELSRHWRQGTLSVDGETPVVGESPSGTDGLNLDTNLYVGGIPEEQVAMVLDRTSVGVGLKGCIRMLDINNQQLELSDWQRAAVQSSGVGECGDHPCLPNPCHGGALCQALEAGMFLCQCPPGRFGPTCADEKSPCQPNPCHGAAPCRVLSSGGAKCECPLGRSGTFCQTVLETAGSRPFLADFNGFSYLELKGLHTFERDLGEKMALEMVFLARGPSGLLLYNGQKTDGKGDFVSLALHNRHLEFCYDLGKGAAVIRSKEPIALGTWVRVFLERNGRKGALQVGDGPRVLGESPKSRKVPHTMLNLKEPLYIGGAPDFSKLARGAAVSSGFSGVIQLVSLRGHQLLTQEHVLRAVDVSPFADHPCTQALGNPCLNGGSCVPREATYECLCPGGFSGLHCEKGLVEKSVGDLETLAFDGRTYIEYLNAVIESELTNEIPAPETLDSRALFSEKALQSNHFELSLRTEATQGLVLWIGKAAERADYMALAIVDGHLQLSYDLGSQPVVLRSTVKVNTNRWLRIRAHREHREGSLQVGNEAPVTGSSPLGATQLDTDGALWLGGLQKLPVGQALPKAYGTGFVGCLRDVVVGHRQLHLLEDAVTKPELRPCPTP |
| Enzyme Length | 1959 |
| Uniprot Accession Number | P25304 |
| Absorption | |
| Active Site | |
| Activity Regulation | |
| Binding Site | |
| Calcium Binding | CA_BIND 1831..1900 |
| catalytic Activity | |
| DNA Binding | |
| EC Number | |
| Enzyme Function | FUNCTION: [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.; FUNCTION: 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.; FUNCTION: [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). {ECO:0000250, ECO:0000269|PubMed:18775496, ECO:0000269|PubMed:19524020, ECO:0000269|PubMed:20471381, ECO:0000269|PubMed:20505824, ECO:0000269|PubMed:20566625, ECO:0000269|PubMed:8398142, ECO:0000269|PubMed:8653787, ECO:0000269|PubMed:8693000}.; FUNCTION: [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. |
| Temperature Dependency | |
| PH Dependency | |
| Pathway | |
| nucleotide Binding | |
| Features | Alternative sequence (5); Beta strand (15); Calcium binding (1); Chain (5); Disulfide bond (45); Domain (19); Glycosylation (5); Helix (2); Modified residue (2); Mutagenesis (31); Region (2); Sequence conflict (1); Site (7); Topological domain (2); Transmembrane (1); Turn (1) |
| Keywords | 3D-structure;Alternative splicing;Calcium;Cell junction;Cell membrane;Developmental protein;Differentiation;Disulfide bond;EGF-like domain;Glycoprotein;Heparan sulfate;Laminin EGF-like domain;Membrane;Phosphoprotein;Proteoglycan;Reference proteome;Repeat;Signal-anchor;Synapse;Transmembrane;Transmembrane helix |
| Interact With | Q8VI56 |
| Induction | |
| Subcellular Location | SUBCELLULAR LOCATION: Cell junction, synapse {ECO:0000269|PubMed:8653787}. Cell membrane {ECO:0000269|PubMed:11161480}; Single-pass type II membrane protein {ECO:0000269|PubMed:11161480}. |
| Modified Residue | MOD_RES 569; /note=Phosphoserine; /evidence=ECO:0000250|UniProtKB:A2ASQ1; MOD_RES 571; /note=Phosphoserine; /evidence=ECO:0000250|UniProtKB:A2ASQ1 |
| Post Translational Modification | PTM: 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. {ECO:0000269|PubMed:18775496, ECO:0000269|PubMed:8398142}.; PTM: 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). {ECO:0000269|PubMed:17586728, ECO:0000269|PubMed:20980386}. |
| Signal Peptide | |
| Structure 3D | X-ray crystallography (2) |
| Cross Reference PDB | 3V64; 3V65; |
| Mapped Pubmed ID | 12486121; 12796478; 14697677; 15155732; 15711988; 15883200; 16630822; 17870250; 18848351; 18957220; 25151458; 8205617; |
| Motif | |
| Gene Encoded By | |
| Mass | 208,646 |
| Kinetics | |
| Metal Binding | |
| Rhea ID | |
| Cross Reference Brenda |