Detail Information for IndEnz0002013976
IED ID IndEnz0002013976
Enzyme Type ID protease013976
Protein Name Beta-secretase 1
EC 3.4.23.46
Aspartyl protease 2
ASP2
Asp 2
Beta-site amyloid precursor protein cleaving enzyme 1
Beta-site APP cleaving enzyme 1
Memapsin-2
Membrane-associated aspartic protease 2
Gene Name Bace1 Bace
Organism Mus musculus (Mouse)
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 Mus Mus Mus musculus (Mouse)
Enzyme Sequence MAPALHWLLLWVGSGMLPAQGTHLGIRLPLRSGLAGPPLGLRLPRETDEESEEPGRRGSFVEMVDNLRGKSGQGYYVEMTVGSPPQTLNILVDTGSSNFAVGAAPHPFLHRYYQRQLSSTYRDLRKGVYVPYTQGKWEGELGTDLVSIPHGPNVTVRANIAAITESDKFFINGSNWEGILGLAYAEIARPDDSLEPFFDSLVKQTHIPNIFSLQLCGAGFPLNQTEALASVGGSMIIGGIDHSLYTGSLWYTPIRREWYYEVIIVRVEINGQDLKMDCKEYNYDKSIVDSGTTNLRLPKKVFEAAVKSIKAASSTEKFPDGFWLGEQLVCWQAGTTPWNIFPVISLYLMGEVTNQSFRITILPQQYLRPVEDVATSQDDCYKFAVSQSSTGTVMGAVIMEGFYVVFDRARKRIGFAVSACHVHDEFRTAAVEGPFVTADMEDCGYNIPQTDESTLMTIAYVMAAICALFMLPLCLMVCQWRCLRCLRHQHDDFADDISLLK
Enzyme Length 501
Uniprot Accession Number P56818
Absorption
Active Site ACT_SITE 93; /evidence=ECO:0000255|PROSITE-ProRule:PRU10094; ACT_SITE 289; /evidence=ECO:0000255|PROSITE-ProRule:PRU10094
Activity Regulation ACTIVITY REGULATION: Inhibited by RTN3 and RTN4. {ECO:0000250|UniProtKB:P56817}.
Binding Site
Calcium Binding
catalytic Activity CATALYTIC ACTIVITY: Reaction=Broad endopeptidase specificity. Cleaves Glu-Val-Asn-Leu-|-Asp-Ala-Glu-Phe in the Swedish variant of Alzheimer's amyloid precursor protein.; EC=3.4.23.46; Evidence={ECO:0000269|PubMed:29325091};
DNA Binding
EC Number 3.4.23.46
Enzyme Function FUNCTION: Responsible for the proteolytic processing of the amyloid precursor protein (APP) (PubMed:29325091). Cleaves at the N-terminus of the A-beta peptide sequence, between residues 671 and 672 of APP, leads to the generation and extracellular release of beta-cleaved soluble APP, and a corresponding cell-associated C-terminal fragment which is later released by gamma-secretase (PubMed:29325091). Cleaves CHL1 (PubMed:29325091). {ECO:0000269|PubMed:29325091}.
Temperature Dependency
PH Dependency
Pathway
nucleotide Binding
Features Active site (2); Chain (1); Compositional bias (1); Cross-link (1); Disulfide bond (3); Domain (1); Glycosylation (4); Lipidation (4); Modified residue (8); Motif (1); Mutagenesis (9); Propeptide (1); Region (2); Signal peptide (1); Topological domain (2); Transmembrane (1)
Keywords Acetylation;Aspartyl protease;Cell membrane;Cell projection;Cytoplasmic vesicle;Direct protein sequencing;Disulfide bond;Endoplasmic reticulum;Endosome;Glycoprotein;Golgi apparatus;Hydrolase;Isopeptide bond;Lipoprotein;Lysosome;Membrane;Palmitate;Phosphoprotein;Protease;Reference proteome;Signal;Transmembrane;Transmembrane helix;Ubl conjugation;Zymogen
Interact With
Induction INDUCTION: In brain oxidative stress induced by amyloid-beta deposition during aging increases protein levels. {ECO:0000269|PubMed:26467158}.
Subcellular Location SUBCELLULAR LOCATION: Cell membrane {ECO:0000250|UniProtKB:P56817}; Single-pass type I membrane protein {ECO:0000305}. Golgi apparatus, trans-Golgi network {ECO:0000269|PubMed:19074428}. Endoplasmic reticulum {ECO:0000250|UniProtKB:P56817}. Endosome {ECO:0000269|PubMed:19074428}. Late endosome {ECO:0000269|PubMed:25592972}. Early endosome {ECO:0000269|PubMed:25592972}. Cell surface {ECO:0000269|PubMed:26467158}. Cytoplasmic vesicle membrane {ECO:0000250|UniProtKB:P56817}. Membrane raft {ECO:0000269|PubMed:19074428}. Lysosome {ECO:0000269|PubMed:25592972}. Recycling endosome {ECO:0000269|PubMed:23931995}. Cell projection, axon {ECO:0000269|PubMed:29325091}. Cell projection, dendrite {ECO:0000269|PubMed:29325091}. Note=Predominantly localized to the later Golgi/trans-Golgi network (TGN) and minimally detectable in the early Golgi compartments. A small portion is also found in the endoplasmic reticulum, endosomes and on the cell surface (By similarity). Colocalization with APP in early endosomes is due to addition of bisecting N-acetylglucosamine wich blocks targeting to late endosomes and lysosomes (PubMed:25592972). Retrogradly transported from endosomal compartments to the trans-Golgi network in a phosphorylation- and GGA1- dependent manner (By similarity). {ECO:0000250|UniProtKB:P56817, ECO:0000269|PubMed:25592972}.
Modified Residue MOD_RES 126; /note=N6-acetyllysine; /evidence=ECO:0000250|UniProtKB:P56817; MOD_RES 275; /note=N6-acetyllysine; /evidence=ECO:0000250|UniProtKB:P56817; MOD_RES 279; /note=N6-acetyllysine; /evidence=ECO:0000250|UniProtKB:P56817; MOD_RES 285; /note=N6-acetyllysine; /evidence=ECO:0000250|UniProtKB:P56817; MOD_RES 299; /note=N6-acetyllysine; /evidence=ECO:0000250|UniProtKB:P56817; MOD_RES 300; /note=N6-acetyllysine; /evidence=ECO:0000250|UniProtKB:P56817; MOD_RES 307; /note=N6-acetyllysine; /evidence=ECO:0000250|UniProtKB:P56817; MOD_RES 498; /note=Phosphoserine; /evidence=ECO:0007744|PubMed:21183079
Post Translational Modification PTM: N-Glycosylated (By similarity). Addition of a bisecting N-acetylglucosamine by MGAT3 blocks lysosomal targeting, further degradation and is required for maintaining stability under stress conditions (PubMed:25592972, PubMed:26467158). {ECO:0000250, ECO:0000250|UniProtKB:P56817, ECO:0000269|PubMed:25592972, ECO:0000269|PubMed:26467158}.; PTM: Palmitoylation mediates lipid raft localization. {ECO:0000269|PubMed:19074428}.; PTM: Acetylated in the endoplasmic reticulum at Lys-126, Lys-275, Lys-279, Lys-285, Lys-299, Lys-300 and Lys-307. Acetylation by NAT8 and NAT8B is transient and deacetylation probably occurs in the Golgi. Acetylation regulates the maturation, the transport to the plasma membrane, the stability and the expression of the protein. {ECO:0000250|UniProtKB:P56817}.; PTM: Ubiquitinated at Lys-501, ubiquitination leads to lysosomal degradation. Monoubiquitinated and 'Lys-63'-linked polyubitinated. Deubiquitnated by USP8; inhibits lysosomal degradation. {ECO:0000250|UniProtKB:P56817}.; PTM: Phosphorylation at Ser-498 is required for interaction with GGA1 and retrograded transport from endosomal compartments to the trans-Golgi network. Non-phosphorylated BACE1 enters a direct recycling route to the cell surface. {ECO:0000250|UniProtKB:P56817}.
Signal Peptide SIGNAL 1..21; /evidence=ECO:0000255
Structure 3D
Cross Reference PDB -
Mapped Pubmed ID 10725249; 11032903; 11217851; 11224535; 11224536; 11406613; 11740561; 12466851; 12509807; 12904583; 13678669; 14664815; 14715132; 14717705; 15080893; 15123597; 15364953; 15466887; 15485862; 15509532; 15522224; 15583033; 15584902; 15606899; 15745965; 15824102; 15886206; 15917100; 15951428; 16027115; 16267225; 16354928; 16420434; 16990514; 17091494; 17099708; 17157415; 17258906; 17303576; 17307738; 17409228; 17470798; 17494994; 17573534; 17576410; 17616527; 17644063; 17897958; 17920016; 17980964; 18081741; 18263584; 18341989; 18385378; 18413858; 18434550; 18587408; 18650431; 18660751; 18680556; 18753368; 18845544; 18945886; 18986979; 19118188; 19196715; 19214738; 19251705; 19287391; 19332646; 19357271; 19683527; 19737556; 19907078; 19920078; 19935654; 20092558; 20092570; 20097169; 20163459; 20212127; 20453200; 20484053; 20505099; 20592204; 20595388; 20704561; 20724034; 20731874; 20833873; 20886088; 20943921; 21146496; 21190943; 21209097; 21246381; 21423189; 21490216; 21542009; 21630010; 21642424; 21695060; 21795680; 21812781; 21825135; 21880018; 21907142; 21933711; 22008266; 22042227; 22049418; 22052506; 22166205; 22170863; 22204380; 22205609; 22223639; 22249458; 22267734; 22355745; 22490838; 22692213; 22721728; 22728099; 22728825; 22836275; 22843498; 22895721; 22903875; 22912719; 22988240; 23048024; 23202730; 23274884; 23335052; 23430253; 23504710; 23507144; 23541064; 23596049; 23613819; 23663737; 23713656; 23750206; 23754390; 23792428; 23820808; 23825420; 23831026; 23951005; 24005676; 24368770; 24373286; 24386896; 24405708; 24630972; 24637500; 24797530; 24806669; 24827165; 24889041; 24907271; 24963413; 25051175; 25156639; 25384422; 25457554; 25481013; 25567526; 25599931; 25663301; 25716831; 25740511; 25884928; 25912880; 25955795; 25957769; 25961820; 26062786; 26091071; 26240147; 26283960; 26296617; 26299962; 26314636; 26322584; 26404616; 26414661; 26454161; 26497029; 26563932; 26642089; 26663083; 26710318; 26755586; 26833257; 26900752; 26923405; 26987953; 26993139; 27080468; 27084579; 27179792; 27294139; 27372924; 27404286; 27517085; 27565738; 27576688; 27687728; 27707970; 27716410; 27791018; 27853315; 28004339; 28028177; 28159908; 28191691; 28281673; 28502705; 28626014; 28669600; 28696204; 28739891; 28855330; 28869759; 29311632; 29315574; 29444819; 29507146; 29610518; 29632166; 29702127; 29716987; 29979789; 30079376; 30120949; 30232227; 30315100; 30456346; 30626721; 30647119; 30701309; 30756113; 30776900; 30784815; 30837353; 31014193; 31110178; 31164420; 31209103; 31303501; 31442405; 31513457; 31527119; 31741224; 31743528; 31882662; 31992816; 32290105; 32407295; 32408680; 32444547; 32668504; 32913125; 32921309; 33052800; 33074142; 33208500; 33311478; 33548223; 34302009; 34500034; 34956559;
Motif MOTIF 496..500; /note=DXXLL; /evidence=ECO:0000250|UniProtKB:P56817
Gene Encoded By
Mass 55,748
Kinetics
Metal Binding
Rhea ID
Cross Reference Brenda 3.4.23.46;