| IED ID | IndEnz0002014494 |
| Enzyme Type ID | protease014494 |
| 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 KIAA1149 |
| Organism | Homo sapiens (Human) |
| 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 Primates Haplorrhini Simiiformes Catarrhini Hominoidea (apes) Hominidae (great apes) Homininae Homo Homo sapiens (Human) |
| Enzyme Sequence | MAQALPWLLLWMGAGVLPAHGTQHGIRLPLRSGLGGAPLGLRLPRETDEEPEEPGRRGSFVEMVDNLRGKSGQGYYVEMTVGSPPQTLNILVDTGSSNFAVGAAPHPFLHRYYQRQLSSTYRDLRKGVYVPYTQGKWEGELGTDLVSIPHGPNVTVRANIAAITESDKFFINGSNWEGILGLAYAEIARPDDSLEPFFDSLVKQTHVPNLFSLQLCGAGFPLNQSEVLASVGGSMIIGGIDHSLYTGSLWYTPIRREWYYEVIIVRVEINGQDLKMDCKEYNYDKSIVDSGTTNLRLPKKVFEAAVKSIKAASSTEKFPDGFWLGEQLVCWQAGTTPWNIFPVISLYLMGEVTNQSFRITILPQQYLRPVEDVATSQDDCYKFAISQSSTGTVMGAVIMEGFYVVFDRARKRIGFAVSACHVHDEFRTAAVEGPFVTLDMEDCGYNIPQTDESTLMTIAYVMAAICALFMLPLCLMVCQWRCLRCLRQQHDDFADDISLLK |
| Enzyme Length | 501 |
| Uniprot Accession Number | P56817 |
| 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:0000269|PubMed:15286784, ECO:0000269|PubMed:16965550}. |
| 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:10677483}; |
| DNA Binding | |
| EC Number | 3.4.23.46 |
| Enzyme Function | FUNCTION: Responsible for the proteolytic processing of the amyloid precursor protein (APP). 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:10656250, PubMed:10677483, PubMed:20354142). Cleaves CHL1 (By similarity). {ECO:0000250|UniProtKB:P56818, ECO:0000269|PubMed:10656250, ECO:0000269|PubMed:10677483, ECO:0000269|PubMed:20354142}. |
| Temperature Dependency | |
| PH Dependency | |
| Pathway | |
| nucleotide Binding | |
| Features | Active site (2); Alternative sequence (4); Beta strand (26); Chain (1); Compositional bias (1); Cross-link (1); Disulfide bond (3); Domain (1); Frameshift (1); Glycosylation (4); Helix (13); Lipidation (4); Modified residue (8); Motif (1); Mutagenesis (6); Natural variant (2); Propeptide (1); Region (2); Signal peptide (1); Topological domain (2); Transmembrane (1); Turn (9) |
| Keywords | 3D-structure;Acetylation;Alternative splicing;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 | O14672; P05067; Q9UJY5; Q9UJY4; Q9NZ52; P10997; Q9Y287; Q03721; P49768; Q9UNH7; Q8BNX1; O95197-3; Q9NQC3-2; Q9NQC3-3 |
| Induction | INDUCTION: Up-regulated by the Ca(2+)-regulated transcription factor NFATC4. {ECO:0000269|PubMed:25663301}. |
| Subcellular Location | SUBCELLULAR LOCATION: Cell membrane {ECO:0000269|PubMed:11466313}; Single-pass type I membrane protein {ECO:0000305|PubMed:11466313}. Golgi apparatus, trans-Golgi network {ECO:0000269|PubMed:11466313, ECO:0000269|PubMed:15615712, ECO:0000269|PubMed:15886016, ECO:0000269|PubMed:17425515, ECO:0000269|PubMed:20354142, ECO:0000269|PubMed:23109336}. Endoplasmic reticulum {ECO:0000269|PubMed:11466313, ECO:0000269|PubMed:17425515}. Endosome {ECO:0000269|PubMed:11466313, ECO:0000269|PubMed:15886016}. Cell surface {ECO:0000269|PubMed:11466313, ECO:0000269|PubMed:15886016, ECO:0000269|PubMed:17425515, ECO:0000269|PubMed:23109336}. Cytoplasmic vesicle membrane {ECO:0000269|PubMed:11466313, ECO:0000269|PubMed:15886016}; Single-pass type I membrane protein {ECO:0000305|PubMed:11466313}. Membrane raft {ECO:0000250|UniProtKB:P56818}. Lysosome {ECO:0000269|PubMed:16033761, ECO:0000269|PubMed:23109336, ECO:0000269|PubMed:27084579, ECO:0000269|PubMed:27302062}. Late endosome {ECO:0000269|PubMed:16033761, ECO:0000269|PubMed:23109336, ECO:0000269|PubMed:27084579, ECO:0000269|PubMed:27302062}. Early endosome {ECO:0000269|PubMed:15615712, ECO:0000269|PubMed:15886016, ECO:0000269|PubMed:23109336, ECO:0000269|PubMed:27084579, ECO:0000269|PubMed:27302062}. Recycling endosome {ECO:0000269|PubMed:15886016, ECO:0000269|PubMed:27084579, ECO:0000269|PubMed:27302062}. Cell projection, axon {ECO:0000250|UniProtKB:P56818}. Cell projection, dendrite {ECO:0000250|UniProtKB:P56818}. 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 (PubMed:17425515, PubMed:11466313). Colocalization with APP in early endosomes is due to addition of bisecting N-acetylglucosamine wich blocks targeting to late endosomes and lysosomes (By similarity). Retrogradly transported from endosomal compartments to the trans-Golgi network in a phosphorylation- and GGA1- dependent manner (PubMed:15886016). {ECO:0000250|UniProtKB:P56818, ECO:0000269|PubMed:11466313, ECO:0000269|PubMed:15886016, ECO:0000269|PubMed:17425515}. |
| Modified Residue | MOD_RES 126; /note="N6-acetyllysine"; /evidence="ECO:0000269|PubMed:17425515, ECO:0000269|PubMed:19011241"; MOD_RES 275; /note="N6-acetyllysine"; /evidence="ECO:0000269|PubMed:17425515, ECO:0000269|PubMed:19011241"; MOD_RES 279; /note="N6-acetyllysine"; /evidence="ECO:0000269|PubMed:17425515, ECO:0000269|PubMed:19011241"; MOD_RES 285; /note="N6-acetyllysine"; /evidence="ECO:0000269|PubMed:17425515, ECO:0000269|PubMed:19011241"; MOD_RES 299; /note="N6-acetyllysine"; /evidence="ECO:0000269|PubMed:17425515, ECO:0000269|PubMed:19011241"; MOD_RES 300; /note="N6-acetyllysine"; /evidence="ECO:0000269|PubMed:17425515, ECO:0000269|PubMed:19011241"; MOD_RES 307; /note="N6-acetyllysine"; /evidence="ECO:0000269|PubMed:17425515, ECO:0000269|PubMed:19011241"; MOD_RES 498; /note="Phosphoserine"; /evidence="ECO:0000269|PubMed:15886016" |
| Post Translational Modification | PTM: N-Glycosylated (PubMed:11083922, PubMed:17425515). Addition of a bisecting N-acetylglucosamine by MGAT3 blocks lysosomal targeting, further degradation and is required for maintaining stability under stress conditions (By similarity). {ECO:0000250|UniProtKB:P56818, ECO:0000269|PubMed:11083922, ECO:0000269|PubMed:17425515}.; 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:0000269|PubMed:17425515, ECO:0000269|PubMed:19011241}.; PTM: Palmitoylation mediates lipid raft localization. {ECO:0000250|UniProtKB:P56818}.; PTM: Ubiquitinated at Lys-501, ubiquitination leads to lysosomal degradation (PubMed:27302062, PubMed:16033761, PubMed:20484053, PubMed:23109336). Monoubiquitinated and 'Lys-63'-linked polyubitinated (PubMed:20484053). Deubiquitnated by USP8; inhibits lysosomal degradation (PubMed:27302062). {ECO:0000269|PubMed:16033761, ECO:0000269|PubMed:20484053, ECO:0000269|PubMed:23109336, ECO:0000269|PubMed:27302062}.; 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:0000269|PubMed:15886016}. |
| Signal Peptide | SIGNAL 1..21; /evidence=ECO:0000255 |
| Structure 3D | X-ray crystallography (430) |
| Cross Reference PDB | 1FKN; 1M4H; 1PY1; 1SGZ; 1TQF; 1UJJ; 1UJK; 1W50; 1W51; 1XN2; 1XN3; 1XS7; 1YM2; 1YM4; 2B8L; 2B8V; 2F3E; 2F3F; 2FDP; 2G94; 2HIZ; 2HM1; 2IQG; 2IRZ; 2IS0; 2NTR; 2OAH; 2OF0; 2OHK; 2OHL; 2OHM; 2OHN; 2OHP; 2OHQ; 2OHR; 2OHS; 2OHT; 2OHU; 2P4J; 2P83; 2P8H; 2PH6; 2PH8; 2Q11; 2Q15; 2QK5; 2QMD; 2QMF; 2QMG; 2QP8; 2QU2; 2QU3; 2QZK; 2QZL; 2VA5; 2VA6; 2VA7; 2VIE; 2VIJ; 2VIY; 2VIZ; 2VJ6; 2VJ7; 2VJ9; 2VKM; 2VNM; 2VNN; 2WEZ; 2WF0; 2WF1; 2WF2; 2WF3; 2WF4; 2WJO; 2XFI; 2XFJ; 2XFK; 2ZDZ; 2ZE1; 2ZHR; 2ZHS; 2ZHT; 2ZHU; 2ZHV; 2ZJH; 2ZJI; 2ZJJ; 2ZJK; 2ZJL; 2ZJM; 2ZJN; 3BRA; 3BUF; 3BUG; 3BUH; 3CIB; 3CIC; 3CID; 3CKP; 3CKR; 3DM6; 3DUY; 3DV1; 3DV5; 3EXO; 3FKT; 3H0B; 3HVG; 3HW1; 3I25; 3IGB; 3IN3; 3IN4; 3IND; 3INE; 3INF; 3INH; 3IVH; 3IVI; 3IXJ; 3IXK; 3K5C; 3K5D; 3K5F; 3K5G; 3KMX; 3KMY; 3KN0; 3KYR; 3L38; 3L3A; 3L58; 3L59; 3L5B; 3L5C; 3L5D; 3L5E; 3L5F; 3LHG; 3LNK; 3LPI; 3LPJ; 3LPK; 3MSJ; 3MSK; 3MSL; 3N4L; 3NSH; 3OHF; 3OHH; 3OOZ; 3PI5; 3QBH; 3QI1; 3R1G; 3R2F; 3RSV; 3RSX; 3RTH; 3RTM; 3RTN; 3RU1; 3RVI; 3S2O; 3S7L; 3S7M; 3SKF; 3SKG; 3TPJ; 3TPL; 3TPP; 3TPR; 3U6A; 3UDH; 3UDJ; 3UDK; 3UDM; 3UDN; 3UDP; 3UDQ; 3UDR; 3UDY; 3UFL; 3UQP; 3UQR; 3UQU; 3UQW; 3UQX; 3VEU; 3VF3; 3VG1; 3VV6; 3VV7; 3VV8; 3WB4; 3WB5; 3ZMG; 3ZOV; 4ACU; 4ACX; 4AZY; 4B00; 4B05; 4B0Q; 4B1C; 4B1D; 4B1E; 4B70; 4B72; 4B77; 4B78; 4BEK; 4BFD; 4D83; 4D85; 4D88; 4D89; 4D8C; 4DH6; 4DI2; 4DJU; 4DJV; 4DJW; 4DJX; 4DJY; 4DPF; 4DPI; 4DUS; 4DV9; 4DVF; 4EWO; 4EXG; 4FCO; 4FGX; 4FM7; 4FM8; 4FRI; 4FRJ; 4FRK; 4FRS; 4FS4; 4FSE; 4FSL; 4GID; 4GMI; 4H1E; 4H3F; 4H3G; 4H3I; 4H3J; 4HA5; 4HZT; 4I0D; 4I0E; 4I0F; 4I0G; 4I0H; 4I0I; 4I0J; 4I0Z; 4I10; 4I11; 4I12; 4I1C; 4IVS; 4IVT; 4J0P; 4J0T; 4J0V; 4J0Y; 4J0Z; 4J17; 4J1C; 4J1E; 4J1F; 4J1H; 4J1I; 4J1K; 4JOO; 4JP9; 4JPC; 4JPE; 4K8S; 4K9H; 4KE0; 4KE1; 4L7G; 4L7H; 4L7J; 4LC7; 4LXA; 4LXK; 4LXM; 4N00; 4PZW; 4PZX; 4R5N; 4R8Y; 4R91; 4R92; 4R93; 4R95; 4RCD; 4RCE; 4RCF; 4RRN; 4RRO; 4RRS; 4TRW; 4TRY; 4TRZ; 4WTU; 4WY1; 4WY6; 4X2L; 4X7I; 4XKX; 4XXS; 4YBI; 4ZPE; 4ZPF; 4ZPG; 4ZSM; 4ZSP; 4ZSQ; 4ZSR; 5CLM; 5DQC; 5ENK; 5ENM; 5EZX; 5EZZ; 5F00; 5F01; 5HD0; 5HDU; 5HDV; 5HDX; 5HDZ; 5HE4; 5HE5; 5HE7; 5HTZ; 5HU0; 5HU1; 5I3V; 5I3W; 5I3X; 5I3Y; 5IE1; 5KQF; 5KR8; 5MBW; 5MCO; 5MCQ; 5MXD; 5QCO; 5QCP; 5QCQ; 5QCR; 5QCS; 5QCT; 5QCU; 5QCV; 5QCW; 5QCX; 5QCY; 5QCZ; 5QD0; 5QD1; 5QD2; 5QD3; 5QD4; 5QD5; 5QD6; 5QD7; 5QD8; 5QD9; 5QDA; 5QDB; 5QDC; 5QDD; 5T1U; 5T1W; 5TOL; 5UYU; 5V0N; 5YGX; 5YGY; 6BFD; 6BFE; 6BFW; 6BFX; 6C2I; 6DHC; 6DMI; 6E3Z; 6EJ2; 6EJ3; 6EQM; 6FGY; 6JSE; 6JSF; 6JSG; 6JSN; 6JT3; 6JT4; 6NV7; 6NV9; 6NW3; 6OD6; 6PZ4; 6UVP; 6UVV; 6UVY; 6UWP; 6UWV; 6WNY; 7B1E; 7B1P; 7B1Q; 7D2V; 7D2X; 7D36; 7D5A; 7DCZ; 7MYI; 7MYR; 7MYU; 7N66; |
| Mapped Pubmed ID | 10956649; 11234778; 11278841; 11684351; 11714100; 11741910; 11744168; 11847218; 11860271; 11922623; 12054507; 12054559; 12093293; 12112088; 12135764; 12223024; 12270690; 12438920; 12445809; 12471021; 12514700; 12535780; 12586838; 12618121; 12649271; 12665519; 12801932; 12824768; 12857759; 12928915; 14507929; 14681914; 14699153; 14701757; 14748006; 14748707; 14978286; 14991462; 15034149; 15059975; 15059977; 15117318; 15197182; 15211591; 15213451; 15234966; 15247262; 15452128; 15466887; 15566281; 15582402; 15584902; 15592644; 15671026; 15784960; 15824102; 15857888; 15880353; 15931081; 16027115; 16078837; 16181410; 16243299; 16246054; 16249081; 16263281; 16279945; 16342950; 16354928; 16449801; 16451048; 16605258; 16611980; 16620080; 16690314; 16716081; 16757811; 16769154; 16816111; 16854060; 16897184; 16908986; 17046251; 17049233; 17112725; 17113083; 17149856; 17174011; 17257835; 17293612; 17300163; 17307738; 17315856; 17315857; 17331621; 17409228; 17432843; 17434734; 17458843; 17482814; 17511654; 17576410; 17596706; 17601350; 17685503; 17699523; 17761418; 17827011; 17854420; 17897958; 17961921; 17980584; 17985862; 18023580; 18039469; 18162398; 18163181; 18166458; 18171614; 18171615; 18180160; 18182389; 18182766; 18226904; 18255190; 18263584; 18289105; 18307033; 18374657; 18378702; 18393796; 18434152; 18434550; 18457381; 18468890; 18581272; 18587408; 18632981; 18650447; 18695061; 18790604; 18798280; 18805488; 18811140; 18842420; 18977241; 19036583; 19056495; 19057901; 19074428; 19106624; 19153172; 19195886; 19195887; 19196715; 19302194; 19344981; 19372755; 19405102; 19406640; 19409780; 19428244; 19429494; 19462468; 19477642; 19508864; 19682432; 19757823; 19799414; 19811916; 19815556; 19827607; 19889475; 19963375; 19968289; 19968762; 20036448; 20041192; 20043696; 20043700; 20045648; 20066010; 20080541; 20089133; 20122837; 20127045; 20128595; 20158188; 20164582; 20172717; 20202842; 20212127; 20223661; 20236612; 20347593; 20455082; 20579874; 20607864; 20634069; 20656487; 20685197; 20726888; 20806954; 20822903; 20849576; 20853423; 20880704; 20930275; 20930286; 20946940; 21078556; 21209097; 21245145; 21321391; 21329555; 21354237; 21388807; 21440067; 21500352; 21565331; 21576249; 21585286; 21613622; 21642424; 21707077; 21712774; 21726644; 21779381; 21782431; 21795680; 21825135; 21835615; 21942621; 21974952; 22045484; 22052506; 22071305; 22090477; 22122287; 22122349; 22130130; 22150401; 22178568; 22194329; 22223639; 22267734; 22275252; 22299711; 22303960; 22306812; 22325942; 22351782; 22380629; 22390835; 22450048; 22468639; 22468684; 22468999; 22553349; 22621900; 22698785; 22709416; 22721728; 22726800; 22728099; 22775589; 22796214; 22801501; 22846573; 22879628; 22924815; 22928914; 22940630; 22952813; 22954357; 22975420; 22984865; 22988240; 22989333; 22998419; 23010268; 23017051; 23021373; 23023105; 23024787; 23030502; 23036023; 23036978; 23048024; 23126626; 23127467; 23142975; 23180460; 23181502; 23202730; 23312803; 23344193; 23412139; 23443094; 23465612; 23504710; 23537249; 23566348; 23570791; 23577068; 23590342; 23596049; 23676825; 23681056; 23695257; 23701002; 23713656; 23735744; 23750206; 23769639; 23820808; 23856050; 23970038; 23981898; 24051074; 24081378; 24305806; 24332014; 24352696; 24361992; 24368770; 24397738; 24405708; 24556009; 24612608; 24613671; 24646365; 24739782; 24780121; 24806670; 24827165; 24893886; 24900403; 24907271; 24970022; 25025689; 25100603; 25147112; 25171714; 25241761; 25247712; 25254246; 25315299; 25319692; 25363711; 25389560; 25411915; 25455483; 25523424; 25553677; 25567526; 25592972; 25609634; 25613679; 25695670; 25699151; 25716831; 25773675; 25779965; 25781223; 25863267; 25934480; 25955795; 25957769; 25965961; 25973041; 26001341; 26062786; 26195137; 26228060; 26264846; 26317805; 26378740; 26401691; 26402014; 26473367; 26563932; 26639974; 26642089; 26663083; 26804314; 26828303; 26833257; 26846559; 26878596; 26937601; 26978477; 26985314; 27253079; 27275774; 27321278; 27347366; 27559936; 27687728; 27784219; 27816517; 27853315; 27858713; 27933948; 27997172; 28091531; 28109317; 28296235; 28384043; 28427814; 28637867; 28687442; 28869548; 28923680; 28946017; 29027981; 29088532; 29142073; 29266373; 29315574; 29316899; 29348391; 29356939; 29391167; 29426770; 29538306; 29581300; 29595667; 29610518; 29617572; 29632166; 29733614; 29764741; 29775538; 29860633; 29961672; 29970308; 29981845; 30108829; 30224383; 30264484; 30273642; 30457858; 30496823; 30571961; 30626721; 30805871; 30959172; 31021626; 31110178; 31290061; 31413800; 31549827; 31549838; 31589043; 31595422; 31601077; 31657130; 31703329; 31745860; 31760580; 31786008; 31876684; 31936569; 31974851; 32019490; 32223911; 32408680; 32430144; 32442083; 32459964; 32527542; 32668504; 32690068; 32804135; 32867761; 32917964; 33010267; 33090569; 33160139; 33197504; 33393683; 33548223; 33588527; 33719429; 33722254; 33765486; 33844524; 34002480; 34081466; 34203347; 34375641; 34534363; 34553934; |
| Motif | MOTIF 496..500; /note=DXXLL; /evidence=ECO:0000269|PubMed:15886016 |
| Gene Encoded By | |
| Mass | 55,764 |
| Kinetics | BIOPHYSICOCHEMICAL PROPERTIES: Kinetic parameters: KM=15.2 mM for APP cleaved by PSEN1 (at pH4) {ECO:0000269|PubMed:10677483}; KM=1 mM for APP Swedish variant (at pH4) {ECO:0000269|PubMed:10677483}; Note=kcat is 0.67 sec(-1) and 2.45 sec(-1) for APP cleaved by PSEN1 and APP Swedish variant, respectively (PubMed:10677483). {ECO:0000269|PubMed:10677483}; |
| Metal Binding | |
| Rhea ID | |
| Cross Reference Brenda | 3.4.23.46; |