BACE1_MOUSE
ID BACE1_MOUSE Reviewed; 501 AA.
AC P56818; Q544D0;
DT 30-MAY-2000, integrated into UniProtKB/Swiss-Prot.
DT 14-AUG-2001, sequence version 2.
DT 03-AUG-2022, entry version 191.
DE RecName: Full=Beta-secretase 1 {ECO:0000305};
DE EC=3.4.23.46 {ECO:0000269|PubMed:29325091};
DE AltName: Full=Aspartyl protease 2;
DE Short=ASP2;
DE Short=Asp 2;
DE AltName: Full=Beta-site amyloid precursor protein cleaving enzyme 1;
DE Short=Beta-site APP cleaving enzyme 1;
DE AltName: Full=Memapsin-2;
DE AltName: Full=Membrane-associated aspartic protease 2;
DE Flags: Precursor;
GN Name=Bace1 {ECO:0000312|MGI:MGI:1346542}; Synonyms=Bace;
OS Mus musculus (Mouse).
OC Eukaryota; Metazoa; Chordata; Craniata; Vertebrata; Euteleostomi; Mammalia;
OC Eutheria; Euarchontoglires; Glires; Rodentia; Myomorpha; Muroidea; Muridae;
OC Murinae; Mus; Mus.
OX NCBI_TaxID=10090;
RN [1]
RP NUCLEOTIDE SEQUENCE [MRNA].
RX PubMed=10531052; DOI=10.1126/science.286.5440.735;
RA Vassar R., Bennett B.D., Babu-Khan S., Kahn S., Mendiaz E.A., Denis P.,
RA Teplow D.B., Ross S., Amarante P., Loeloff R., Luo Y., Fisher S.,
RA Fuller J., Edenson S., Lile J., Jarosinski M.A., Biere A.L., Curran E.,
RA Burgess T., Louis J.-C., Collins F., Treanor J., Rogers G., Citron M.;
RT "Beta-secretase cleavage of Alzheimer's amyloid precursor protein by the
RT transmembrane aspartic protease BACE.";
RL Science 286:735-741(1999).
RN [2]
RP SEQUENCE REVISION TO 6 AND 81-87.
RA Bennett B.D., Vassar R., Citron M.;
RL Submitted (JAN-2000) to the EMBL/GenBank/DDBJ databases.
RN [3]
RP NUCLEOTIDE SEQUENCE [MRNA].
RX PubMed=10591213; DOI=10.1038/990107;
RA Yan R., Bienkowski M.J., Shuck M.E., Miao H., Tory M.C., Pauley A.M.,
RA Brashier J.R., Stratman N.C., Mathews W.R., Buhl A.E., Carter D.B.,
RA Tomasselli A.G., Parodi L.A., Heinrikson R.L., Gurney M.E.;
RT "Membrane-anchored aspartyl protease with Alzheimer's disease beta-
RT secretase activity.";
RL Nature 402:533-537(1999).
RN [4]
RP NUCLEOTIDE SEQUENCE [LARGE SCALE MRNA].
RC STRAIN=C57BL/6J; TISSUE=Aorta, Head, and Testis;
RX PubMed=16141072; DOI=10.1126/science.1112014;
RA Carninci P., Kasukawa T., Katayama S., Gough J., Frith M.C., Maeda N.,
RA Oyama R., Ravasi T., Lenhard B., Wells C., Kodzius R., Shimokawa K.,
RA Bajic V.B., Brenner S.E., Batalov S., Forrest A.R., Zavolan M., Davis M.J.,
RA Wilming L.G., Aidinis V., Allen J.E., Ambesi-Impiombato A., Apweiler R.,
RA Aturaliya R.N., Bailey T.L., Bansal M., Baxter L., Beisel K.W., Bersano T.,
RA Bono H., Chalk A.M., Chiu K.P., Choudhary V., Christoffels A.,
RA Clutterbuck D.R., Crowe M.L., Dalla E., Dalrymple B.P., de Bono B.,
RA Della Gatta G., di Bernardo D., Down T., Engstrom P., Fagiolini M.,
RA Faulkner G., Fletcher C.F., Fukushima T., Furuno M., Futaki S.,
RA Gariboldi M., Georgii-Hemming P., Gingeras T.R., Gojobori T., Green R.E.,
RA Gustincich S., Harbers M., Hayashi Y., Hensch T.K., Hirokawa N., Hill D.,
RA Huminiecki L., Iacono M., Ikeo K., Iwama A., Ishikawa T., Jakt M.,
RA Kanapin A., Katoh M., Kawasawa Y., Kelso J., Kitamura H., Kitano H.,
RA Kollias G., Krishnan S.P., Kruger A., Kummerfeld S.K., Kurochkin I.V.,
RA Lareau L.F., Lazarevic D., Lipovich L., Liu J., Liuni S., McWilliam S.,
RA Madan Babu M., Madera M., Marchionni L., Matsuda H., Matsuzawa S., Miki H.,
RA Mignone F., Miyake S., Morris K., Mottagui-Tabar S., Mulder N., Nakano N.,
RA Nakauchi H., Ng P., Nilsson R., Nishiguchi S., Nishikawa S., Nori F.,
RA Ohara O., Okazaki Y., Orlando V., Pang K.C., Pavan W.J., Pavesi G.,
RA Pesole G., Petrovsky N., Piazza S., Reed J., Reid J.F., Ring B.Z.,
RA Ringwald M., Rost B., Ruan Y., Salzberg S.L., Sandelin A., Schneider C.,
RA Schoenbach C., Sekiguchi K., Semple C.A., Seno S., Sessa L., Sheng Y.,
RA Shibata Y., Shimada H., Shimada K., Silva D., Sinclair B., Sperling S.,
RA Stupka E., Sugiura K., Sultana R., Takenaka Y., Taki K., Tammoja K.,
RA Tan S.L., Tang S., Taylor M.S., Tegner J., Teichmann S.A., Ueda H.R.,
RA van Nimwegen E., Verardo R., Wei C.L., Yagi K., Yamanishi H.,
RA Zabarovsky E., Zhu S., Zimmer A., Hide W., Bult C., Grimmond S.M.,
RA Teasdale R.D., Liu E.T., Brusic V., Quackenbush J., Wahlestedt C.,
RA Mattick J.S., Hume D.A., Kai C., Sasaki D., Tomaru Y., Fukuda S.,
RA Kanamori-Katayama M., Suzuki M., Aoki J., Arakawa T., Iida J., Imamura K.,
RA Itoh M., Kato T., Kawaji H., Kawagashira N., Kawashima T., Kojima M.,
RA Kondo S., Konno H., Nakano K., Ninomiya N., Nishio T., Okada M., Plessy C.,
RA Shibata K., Shiraki T., Suzuki S., Tagami M., Waki K., Watahiki A.,
RA Okamura-Oho Y., Suzuki H., Kawai J., Hayashizaki Y.;
RT "The transcriptional landscape of the mammalian genome.";
RL Science 309:1559-1563(2005).
RN [5]
RP NUCLEOTIDE SEQUENCE [LARGE SCALE MRNA].
RC STRAIN=C57BL/6J; TISSUE=Brain;
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 project:
RT the Mammalian Gene Collection (MGC).";
RL Genome Res. 14:2121-2127(2004).
RN [6]
RP PROTEIN SEQUENCE OF 301-307, AND IDENTIFICATION BY MASS SPECTROMETRY.
RC STRAIN=OF1; TISSUE=Hippocampus;
RA Lubec G., Sunyer B., Chen W.-Q.;
RL Submitted (JAN-2009) to UniProtKB.
RN [7]
RP DISRUPTION PHENOTYPE.
RX PubMed=15987683; DOI=10.1074/jbc.m505249200;
RA Dominguez D., Tournoy J., Hartmann D., Huth T., Cryns K., Deforce S.,
RA Serneels L., Camacho I.E., Marjaux E., Craessaerts K., Roebroek A.J.M.,
RA Schwake M., D'Hooge R., Bach P., Kalinke U., Moechars D., Alzheimer C.,
RA Reiss K., Saftig P., De Strooper B.;
RT "Phenotypic and biochemical analyses of BACE1- and BACE2-deficient mice.";
RL J. Biol. Chem. 280:30797-30806(2005).
RN [8]
RP INTERACTION WITH SORL1.
RX PubMed=16407538; DOI=10.1523/jneurosci.3882-05.2006;
RA Spoelgen R., von Arnim C.A., Thomas A.V., Peltan I.D., Koker M., Deng A.,
RA Irizarry M.C., Andersen O.M., Willnow T.E., Hyman B.T.;
RT "Interaction of the cytosolic domains of sorLA/LR11 with the amyloid
RT precursor protein (APP) and beta-secretase beta-site APP-cleaving enzyme.";
RL J. Neurosci. 26:418-428(2006).
RN [9]
RP PALMITOYLATION AT CYS-474; CYS-478; CYS-482 AND CYS-485, MUTAGENESIS OF
RP CYS-474; CYS-478; CYS-482 AND CYS-485, AND SUBCELLULAR LOCATION.
RX PubMed=19074428; DOI=10.1074/jbc.m808920200;
RA Vetrivel K.S., Meckler X., Chen Y., Nguyen P.D., Seidah N.G., Vassar R.,
RA Wong P.C., Fukata M., Kounnas M.Z., Thinakaran G.;
RT "Alzheimer disease Abeta production in the absence of S-palmitoylation-
RT dependent targeting of BACE1 to lipid rafts.";
RL J. Biol. Chem. 284:3793-3803(2009).
RN [10]
RP PHOSPHORYLATION [LARGE SCALE ANALYSIS] AT SER-498, AND IDENTIFICATION BY
RP MASS SPECTROMETRY [LARGE SCALE ANALYSIS].
RC TISSUE=Brain, and Heart;
RX PubMed=21183079; DOI=10.1016/j.cell.2010.12.001;
RA Huttlin E.L., Jedrychowski M.P., Elias J.E., Goswami T., Rad R.,
RA Beausoleil S.A., Villen J., Haas W., Sowa M.E., Gygi S.P.;
RT "A tissue-specific atlas of mouse protein phosphorylation and expression.";
RL Cell 143:1174-1189(2010).
RN [11]
RP SUBCELLULAR LOCATION.
RX PubMed=23931995; DOI=10.1016/j.neuron.2013.05.035;
RA Das U., Scott D.A., Ganguly A., Koo E.H., Tang Y., Roy S.;
RT "Activity-induced convergence of APP and BACE-1 in acidic microdomains via
RT an endocytosis-dependent pathway.";
RL Neuron 79:447-460(2013).
RN [12]
RP GLYCOSYLATION, SUBCELLULAR LOCATION, AND DISRUPTION PHENOTYPE.
RX PubMed=25592972; DOI=10.15252/emmm.201404438;
RA Kizuka Y., Kitazume S., Fujinawa R., Saito T., Iwata N., Saido T.C.,
RA Nakano M., Yamaguchi Y., Hashimoto Y., Staufenbiel M., Hatsuta H.,
RA Murayama S., Manya H., Endo T., Taniguchi N.;
RT "An aberrant sugar modification of BACE1 blocks its lysosomal targeting in
RT Alzheimer's disease.";
RL EMBO Mol. Med. 7:175-189(2015).
RN [13]
RP GLYCOSYLATION AT ASN-153; ASN-172; ASN-223 AND ASN-354, INDUCTION BY
RP OXIDATIVE STRESS, MUTAGENESIS OF ASN-153; ASN-172; ASN-223 AND ASN-354, AND
RP SUBCELLULAR LOCATION.
RX PubMed=26467158; DOI=10.1042/bj20150607;
RA Kizuka Y., Nakano M., Kitazume S., Saito T., Saido T.C., Taniguchi N.;
RT "Bisecting GlcNAc modification stabilizes BACE1 protein under oxidative
RT stress conditions.";
RL Biochem. J. 473:21-30(2016).
RN [14]
RP FUNCTION, CATALYTIC ACTIVITY, INTERACTION WITH ADAM10, SUBCELLULAR
RP LOCATION, TISSUE SPECIFICITY, AND MUTAGENESIS OF ASP-93.
RX PubMed=29325091; DOI=10.1093/jmcb/mjy001;
RA Wang X., Wang C., Pei G.;
RT "alpha-secretase ADAM10 physically interacts with beta-secretase BACE1 in
RT neurons and regulates CHL1 proteolysis.";
RL J. Mol. Cell Biol. 10:411-422(2018).
CC -!- FUNCTION: Responsible for the proteolytic processing of the amyloid
CC precursor protein (APP) (PubMed:29325091). Cleaves at the N-terminus of
CC the A-beta peptide sequence, between residues 671 and 672 of APP, leads
CC to the generation and extracellular release of beta-cleaved soluble
CC APP, and a corresponding cell-associated C-terminal fragment which is
CC later released by gamma-secretase (PubMed:29325091). Cleaves CHL1
CC (PubMed:29325091). {ECO:0000269|PubMed:29325091}.
CC -!- CATALYTIC ACTIVITY:
CC Reaction=Broad endopeptidase specificity. Cleaves Glu-Val-Asn-Leu-|-
CC Asp-Ala-Glu-Phe in the Swedish variant of Alzheimer's amyloid
CC precursor protein.; EC=3.4.23.46;
CC Evidence={ECO:0000269|PubMed:29325091};
CC -!- ACTIVITY REGULATION: Inhibited by RTN3 and RTN4.
CC {ECO:0000250|UniProtKB:P56817}.
CC -!- SUBUNIT: Monomer. Interacts (via DXXLL motif) with GGA1, GGA2 and GGA3
CC (via their VHS domain); the interaction highly increases when BACE1 is
CC phosphorylated at Ser-498. Interacts with RTN1; RTN2; RTN3 and RTN4;
CC the interaction leads to inhibition of amyloid precursor protein
CC processing (By similarity). Interacts with SNX6. Interacts with PCSK9.
CC Interacts with NAT8 and NAT8B. Interacts with BIN1 (By similarity).
CC Interacts (via extracellular domain) with ADAM10 (via extracellular
CC domain) (PubMed:29325091). Interacts with SORL1; this interaction may
CC affect binding with APP and hence reduce APP cleavage
CC (PubMed:16407538). {ECO:0000250|UniProtKB:P56817,
CC ECO:0000269|PubMed:16407538, ECO:0000269|PubMed:29325091}.
CC -!- SUBCELLULAR LOCATION: Cell membrane {ECO:0000250|UniProtKB:P56817};
CC Single-pass type I membrane protein {ECO:0000305}. Golgi apparatus,
CC trans-Golgi network {ECO:0000269|PubMed:19074428}. Endoplasmic
CC reticulum {ECO:0000250|UniProtKB:P56817}. Endosome
CC {ECO:0000269|PubMed:19074428}. Late endosome
CC {ECO:0000269|PubMed:25592972}. Early endosome
CC {ECO:0000269|PubMed:25592972}. Cell surface
CC {ECO:0000269|PubMed:26467158}. Cytoplasmic vesicle membrane
CC {ECO:0000250|UniProtKB:P56817}. Membrane raft
CC {ECO:0000269|PubMed:19074428}. Lysosome {ECO:0000269|PubMed:25592972}.
CC Recycling endosome {ECO:0000269|PubMed:23931995}. Cell projection, axon
CC {ECO:0000269|PubMed:29325091}. Cell projection, dendrite
CC {ECO:0000269|PubMed:29325091}. Note=Predominantly localized to the
CC later Golgi/trans-Golgi network (TGN) and minimally detectable in the
CC early Golgi compartments. A small portion is also found in the
CC endoplasmic reticulum, endosomes and on the cell surface (By
CC similarity). Colocalization with APP in early endosomes is due to
CC addition of bisecting N-acetylglucosamine wich blocks targeting to late
CC endosomes and lysosomes (PubMed:25592972). Retrogradly transported from
CC endosomal compartments to the trans-Golgi network in a
CC phosphorylation- and GGA1- dependent manner (By similarity).
CC {ECO:0000250|UniProtKB:P56817, ECO:0000269|PubMed:25592972}.
CC -!- TISSUE SPECIFICITY: Expressed in the brain, specifically in neurons and
CC astrocytes (at protein level). {ECO:0000269|PubMed:29325091}.
CC -!- INDUCTION: In brain oxidative stress induced by amyloid-beta deposition
CC during aging increases protein levels. {ECO:0000269|PubMed:26467158}.
CC -!- DOMAIN: DXXLL motif is required for a proper endocytosis and retrograde
CC transport to the trans-Golgi network, as well as for regulation of
CC lysosomal degradation. {ECO:0000250|UniProtKB:P56817}.
CC -!- DOMAIN: The transmembrane domain is necessary for its activity. It
CC determines its late Golgi localization and access to its substrate,
CC APP. {ECO:0000250|UniProtKB:P56817}.
CC -!- PTM: N-Glycosylated (By similarity). Addition of a bisecting N-
CC acetylglucosamine by MGAT3 blocks lysosomal targeting, further
CC degradation and is required for maintaining stability under stress
CC conditions (PubMed:25592972, PubMed:26467158). {ECO:0000250,
CC ECO:0000250|UniProtKB:P56817, ECO:0000269|PubMed:25592972,
CC ECO:0000269|PubMed:26467158}.
CC -!- PTM: Palmitoylation mediates lipid raft localization.
CC {ECO:0000269|PubMed:19074428}.
CC -!- PTM: Acetylated in the endoplasmic reticulum at Lys-126, Lys-275, Lys-
CC 279, Lys-285, Lys-299, Lys-300 and Lys-307. Acetylation by NAT8 and
CC NAT8B is transient and deacetylation probably occurs in the Golgi.
CC Acetylation regulates the maturation, the transport to the plasma
CC membrane, the stability and the expression of the protein.
CC {ECO:0000250|UniProtKB:P56817}.
CC -!- PTM: Ubiquitinated at Lys-501, ubiquitination leads to lysosomal
CC degradation. Monoubiquitinated and 'Lys-63'-linked polyubitinated.
CC Deubiquitnated by USP8; inhibits lysosomal degradation.
CC {ECO:0000250|UniProtKB:P56817}.
CC -!- PTM: Phosphorylation at Ser-498 is required for interaction with GGA1
CC and retrograded transport from endosomal compartments to the trans-
CC Golgi network. Non-phosphorylated BACE1 enters a direct recycling route
CC to the cell surface. {ECO:0000250|UniProtKB:P56817}.
CC -!- DISRUPTION PHENOTYPE: Mice show a higher mortality rate early in life.
CC {ECO:0000269|PubMed:15987683, ECO:0000269|PubMed:25592972}.
CC -!- SIMILARITY: Belongs to the peptidase A1 family. {ECO:0000305}.
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DR EMBL; AF190726; AAF04143.2; -; mRNA.
DR EMBL; AF200346; AAF17082.1; -; mRNA.
DR EMBL; AK014464; BAB29370.1; -; mRNA.
DR EMBL; AK033112; BAC28156.1; -; mRNA.
DR EMBL; AK041285; BAC30889.1; -; mRNA.
DR EMBL; BC048189; AAH48189.1; -; mRNA.
DR CCDS; CCDS23135.1; -.
DR RefSeq; NP_001139419.1; NM_001145947.2.
DR RefSeq; NP_035922.4; NM_011792.6.
DR AlphaFoldDB; P56818; -.
DR BMRB; P56818; -.
DR SMR; P56818; -.
DR BioGRID; 204741; 8.
DR IntAct; P56818; 2.
DR MINT; P56818; -.
DR STRING; 10090.ENSMUSP00000034591; -.
DR BindingDB; P56818; -.
DR ChEMBL; CHEMBL4593; -.
DR GuidetoPHARMACOLOGY; 2330; -.
DR MEROPS; A01.004; -.
DR GlyGen; P56818; 4 sites.
DR iPTMnet; P56818; -.
DR PhosphoSitePlus; P56818; -.
DR SwissPalm; P56818; -.
DR jPOST; P56818; -.
DR MaxQB; P56818; -.
DR PaxDb; P56818; -.
DR PeptideAtlas; P56818; -.
DR PRIDE; P56818; -.
DR ProteomicsDB; 273594; -.
DR ABCD; P56818; 1 sequenced antibody.
DR Antibodypedia; 4285; 912 antibodies from 46 providers.
DR DNASU; 23821; -.
DR Ensembl; ENSMUST00000034591; ENSMUSP00000034591; ENSMUSG00000032086.
DR GeneID; 23821; -.
DR KEGG; mmu:23821; -.
DR UCSC; uc009pgh.2; mouse.
DR CTD; 23621; -.
DR MGI; MGI:1346542; Bace1.
DR VEuPathDB; HostDB:ENSMUSG00000032086; -.
DR eggNOG; KOG1339; Eukaryota.
DR GeneTree; ENSGT00940000157786; -.
DR InParanoid; P56818; -.
DR OMA; ELEDCGY; -.
DR OrthoDB; 753343at2759; -.
DR PhylomeDB; P56818; -.
DR TreeFam; TF329595; -.
DR BRENDA; 3.4.23.46; 3474.
DR BioGRID-ORCS; 23821; 2 hits in 73 CRISPR screens.
DR ChiTaRS; Bace1; mouse.
DR PRO; PR:P56818; -.
DR Proteomes; UP000000589; Chromosome 9.
DR RNAct; P56818; protein.
DR Bgee; ENSMUSG00000032086; Expressed in external carotid artery and 242 other tissues.
DR ExpressionAtlas; P56818; baseline and differential.
DR Genevisible; P56818; MM.
DR GO; GO:0030424; C:axon; IDA:MGI.
DR GO; GO:0009986; C:cell surface; IDA:MGI.
DR GO; GO:0031410; C:cytoplasmic vesicle; IDA:MGI.
DR GO; GO:0030659; C:cytoplasmic vesicle membrane; IEA:UniProtKB-SubCell.
DR GO; GO:0030425; C:dendrite; ISO:MGI.
DR GO; GO:0005769; C:early endosome; IDA:MGI.
DR GO; GO:0005783; C:endoplasmic reticulum; IEA:UniProtKB-SubCell.
DR GO; GO:0005768; C:endosome; IDA:UniProtKB.
DR GO; GO:0005794; C:Golgi apparatus; ISS:UniProtKB.
DR GO; GO:0098686; C:hippocampal mossy fiber to CA3 synapse; IDA:SynGO.
DR GO; GO:0005887; C:integral component of plasma membrane; ISO:MGI.
DR GO; GO:0005770; C:late endosome; ISS:UniProtKB.
DR GO; GO:0005764; C:lysosome; ISS:UniProtKB.
DR GO; GO:0016020; C:membrane; IDA:MGI.
DR GO; GO:0045121; C:membrane raft; IEA:UniProtKB-SubCell.
DR GO; GO:0005771; C:multivesicular body; ISO:MGI.
DR GO; GO:0043025; C:neuronal cell body; ISO:MGI.
DR GO; GO:0005886; C:plasma membrane; IDA:UniProtKB.
DR GO; GO:0098793; C:presynapse; IDA:SynGO.
DR GO; GO:0055037; C:recycling endosome; IDA:UniProtKB.
DR GO; GO:0008021; C:synaptic vesicle; ISO:MGI.
DR GO; GO:0005802; C:trans-Golgi network; IDA:UniProtKB.
DR GO; GO:0001540; F:amyloid-beta binding; ISO:MGI.
DR GO; GO:0004190; F:aspartic-type endopeptidase activity; IDA:MGI.
DR GO; GO:0004175; F:endopeptidase activity; IDA:MGI.
DR GO; GO:0019899; F:enzyme binding; ISO:MGI.
DR GO; GO:0008233; F:peptidase activity; ISO:MGI.
DR GO; GO:0042987; P:amyloid precursor protein catabolic process; IGI:ARUK-UCL.
DR GO; GO:0034205; P:amyloid-beta formation; ISO:MGI.
DR GO; GO:0050435; P:amyloid-beta metabolic process; IDA:MGI.
DR GO; GO:1904646; P:cellular response to amyloid-beta; IEA:Ensembl.
DR GO; GO:0071280; P:cellular response to copper ion; IEA:Ensembl.
DR GO; GO:0071287; P:cellular response to manganese ion; IEA:Ensembl.
DR GO; GO:0050966; P:detection of mechanical stimulus involved in sensory perception of pain; ISO:MGI.
DR GO; GO:0006509; P:membrane protein ectodomain proteolysis; IMP:UniProtKB.
DR GO; GO:0007613; P:memory; TAS:ARUK-UCL.
DR GO; GO:0050804; P:modulation of chemical synaptic transmission; IGI:ARUK-UCL.
DR GO; GO:0043525; P:positive regulation of neuron apoptotic process; ISO:MGI.
DR GO; GO:0060134; P:prepulse inhibition; ISO:MGI.
DR GO; GO:0016485; P:protein processing; ISO:MGI.
DR GO; GO:0006508; P:proteolysis; IDA:MGI.
DR GO; GO:0048167; P:regulation of synaptic plasticity; TAS:ARUK-UCL.
DR GO; GO:2000300; P:regulation of synaptic vesicle exocytosis; IMP:SynGO.
DR GO; GO:0010288; P:response to lead ion; IEA:Ensembl.
DR GO; GO:0009314; P:response to radiation; IEA:Ensembl.
DR CDD; cd05473; beta_secretase_like; 1.
DR Gene3D; 2.40.70.10; -; 2.
DR InterPro; IPR001461; Aspartic_peptidase_A1.
DR InterPro; IPR001969; Aspartic_peptidase_AS.
DR InterPro; IPR009119; BACE.
DR InterPro; IPR009120; BACE1.
DR InterPro; IPR033874; Memapsin-like.
DR InterPro; IPR033121; PEPTIDASE_A1.
DR InterPro; IPR021109; Peptidase_aspartic_dom_sf.
DR PANTHER; PTHR47965; PTHR47965; 1.
DR PANTHER; PTHR47965:SF69; PTHR47965:SF69; 1.
DR Pfam; PF00026; Asp; 1.
DR PRINTS; PR01815; BACEFAMILY.
DR PRINTS; PR00792; PEPSIN.
DR SUPFAM; SSF50630; SSF50630; 1.
DR PROSITE; PS00141; ASP_PROTEASE; 1.
DR PROSITE; PS51767; PEPTIDASE_A1; 1.
PE 1: Evidence at protein level;
KW Acetylation; Aspartyl protease; Cell membrane; Cell projection;
KW Cytoplasmic vesicle; Direct protein sequencing; Disulfide bond;
KW Endoplasmic reticulum; Endosome; Glycoprotein; Golgi apparatus; Hydrolase;
KW Isopeptide bond; Lipoprotein; Lysosome; Membrane; Palmitate;
KW Phosphoprotein; Protease; Reference proteome; Signal; Transmembrane;
KW Transmembrane helix; Ubl conjugation; Zymogen.
FT SIGNAL 1..21
FT /evidence="ECO:0000255"
FT PROPEP 22..45
FT /evidence="ECO:0000255"
FT /id="PRO_0000025941"
FT CHAIN 46..501
FT /note="Beta-secretase 1"
FT /id="PRO_0000025942"
FT TOPO_DOM 22..457
FT /note="Extracellular"
FT /evidence="ECO:0000255"
FT TRANSMEM 458..478
FT /note="Helical"
FT /evidence="ECO:0000255"
FT TOPO_DOM 479..501
FT /note="Cytoplasmic"
FT /evidence="ECO:0000255"
FT DOMAIN 75..416
FT /note="Peptidase A1"
FT /evidence="ECO:0000255|PROSITE-ProRule:PRU01103"
FT REGION 39..58
FT /note="Disordered"
FT /evidence="ECO:0000256|SAM:MobiDB-lite"
FT REGION 479..501
FT /note="Interaction with RTN3"
FT /evidence="ECO:0000250"
FT MOTIF 496..500
FT /note="DXXLL"
FT /evidence="ECO:0000250|UniProtKB:P56817"
FT COMPBIAS 43..58
FT /note="Basic and acidic residues"
FT /evidence="ECO:0000256|SAM:MobiDB-lite"
FT ACT_SITE 93
FT /evidence="ECO:0000255|PROSITE-ProRule:PRU10094"
FT ACT_SITE 289
FT /evidence="ECO:0000255|PROSITE-ProRule:PRU10094"
FT MOD_RES 126
FT /note="N6-acetyllysine"
FT /evidence="ECO:0000250|UniProtKB:P56817"
FT MOD_RES 275
FT /note="N6-acetyllysine"
FT /evidence="ECO:0000250|UniProtKB:P56817"
FT MOD_RES 279
FT /note="N6-acetyllysine"
FT /evidence="ECO:0000250|UniProtKB:P56817"
FT MOD_RES 285
FT /note="N6-acetyllysine"
FT /evidence="ECO:0000250|UniProtKB:P56817"
FT MOD_RES 299
FT /note="N6-acetyllysine"
FT /evidence="ECO:0000250|UniProtKB:P56817"
FT MOD_RES 300
FT /note="N6-acetyllysine"
FT /evidence="ECO:0000250|UniProtKB:P56817"
FT MOD_RES 307
FT /note="N6-acetyllysine"
FT /evidence="ECO:0000250|UniProtKB:P56817"
FT MOD_RES 498
FT /note="Phosphoserine"
FT /evidence="ECO:0007744|PubMed:21183079"
FT LIPID 474
FT /note="S-palmitoyl cysteine"
FT /evidence="ECO:0000269|PubMed:19074428"
FT LIPID 478
FT /note="S-palmitoyl cysteine"
FT /evidence="ECO:0000269|PubMed:19074428"
FT LIPID 482
FT /note="S-palmitoyl cysteine"
FT /evidence="ECO:0000269|PubMed:19074428"
FT LIPID 485
FT /note="S-palmitoyl cysteine"
FT /evidence="ECO:0000269|PubMed:19074428"
FT CARBOHYD 153
FT /note="N-linked (GlcNAc...) asparagine"
FT /evidence="ECO:0000269|PubMed:26467158"
FT CARBOHYD 172
FT /note="N-linked (GlcNAc...) asparagine"
FT /evidence="ECO:0000269|PubMed:26467158"
FT CARBOHYD 223
FT /note="N-linked (GlcNAc...) asparagine"
FT /evidence="ECO:0000269|PubMed:26467158"
FT CARBOHYD 354
FT /note="N-linked (GlcNAc...) asparagine"
FT /evidence="ECO:0000269|PubMed:26467158"
FT DISULFID 216..420
FT /evidence="ECO:0000250"
FT DISULFID 278..443
FT /evidence="ECO:0000250"
FT DISULFID 330..380
FT /evidence="ECO:0000250"
FT CROSSLNK 501
FT /note="Glycyl lysine isopeptide (Lys-Gly) (interchain with
FT G-Cter in ubiquitin)"
FT /evidence="ECO:0000250|UniProtKB:P56817"
FT MUTAGEN 93
FT /note="D->A: Loss of catalytic activity."
FT /evidence="ECO:0000269|PubMed:29325091"
FT MUTAGEN 153
FT /note="N->S: Decreases bisecting N-acetylglucosamine
FT levels. Almost abolishes bisecting N-acetylglucosamine
FT levels but has no effect on surface expression; when
FT associated with S-223."
FT /evidence="ECO:0000269|PubMed:26467158"
FT MUTAGEN 172
FT /note="N->S: Slightly decreases bisecting N-
FT acetylglucosamine levels."
FT /evidence="ECO:0000269|PubMed:26467158"
FT MUTAGEN 223
FT /note="N->S: Decreases bisecting N-acetylglucosamine
FT levels. Almost abolishes bisecting N-acetylglucosamine
FT levels but has no effect on surface expression; when
FT associated with S-153."
FT /evidence="ECO:0000269|PubMed:26467158"
FT MUTAGEN 354
FT /note="N->S: Slightly decreases bisecting N-
FT acetylglucosamine levels."
FT /evidence="ECO:0000269|PubMed:26467158"
FT MUTAGEN 474
FT /note="C->A: Completely abolishes S-palmitoylation; when
FT associated with A-478; A-482 and A-485. Doesn't affect
FT trans-Golgi network and endosome localization; when
FT associated with A-478; A-482 and A-485. Reduces membrane
FT raft association; when associated with A-478; A-482 and A-
FT 485. Doesn't affect APP processing; when associated with A-
FT 478; A-482 and A-485."
FT /evidence="ECO:0000269|PubMed:19074428"
FT MUTAGEN 478
FT /note="C->A: Significantly reduces S-palmitoylation; when
FT associated with A-482 and A-485. Completely abolishes S-
FT palmitoylation; when associated with A-474; A-482 and A-
FT 485. Doesn't affect trans-Golgi network and endosome
FT localization; when associated with A-474; A-482 and A-485.
FT Reduces membrane raft association; when associated with A-
FT 474; A-482 and A-485. Doesn't affect APP processing; when
FT associated with A-474; A-482 and A-485."
FT /evidence="ECO:0000269|PubMed:19074428"
FT MUTAGEN 482
FT /note="C->A: Significantly reduces S-palmitoylation; when
FT associated with A-478 and A-485. Completely abolishes S-
FT palmitoylation; when associated with A-474; A-478 and A-
FT 485. Doesn't affect trans-Golgi network and endosome
FT localization; when associated with A-474; A-478 and A-485.
FT Reduces membrane raft association; when associated with A-
FT 474; A-478 and A-485. Doesn't affect APP processing; when
FT associated with A-474; A-478 and A-485."
FT /evidence="ECO:0000269|PubMed:19074428"
FT MUTAGEN 485
FT /note="C->A: Significantly reduces S-palmitoylation; when
FT associated with A-478 and A-482. Completely abolishes S-
FT palmitoylation; when associated with A-474; A-478 and A-
FT 482. Doesn't affect trans-Golgi network and endosome
FT localization; when associated with A-474; A-478 and A-482.
FT Reduces membrane raft association; when associated with A-
FT 474; A-478 and A-482. Doesn't affect APP processing; when
FT associated with A-474; A-478 and A-482."
FT /evidence="ECO:0000269|PubMed:19074428"
SQ SEQUENCE 501 AA; 55748 MW; C085A013145E474E CRC64;
MAPALHWLLL WVGSGMLPAQ GTHLGIRLPL RSGLAGPPLG LRLPRETDEE SEEPGRRGSF
VEMVDNLRGK SGQGYYVEMT VGSPPQTLNI LVDTGSSNFA VGAAPHPFLH RYYQRQLSST
YRDLRKGVYV PYTQGKWEGE LGTDLVSIPH GPNVTVRANI AAITESDKFF INGSNWEGIL
GLAYAEIARP DDSLEPFFDS LVKQTHIPNI FSLQLCGAGF PLNQTEALAS VGGSMIIGGI
DHSLYTGSLW YTPIRREWYY EVIIVRVEIN GQDLKMDCKE YNYDKSIVDS GTTNLRLPKK
VFEAAVKSIK AASSTEKFPD GFWLGEQLVC WQAGTTPWNI FPVISLYLMG EVTNQSFRIT
ILPQQYLRPV EDVATSQDDC YKFAVSQSST GTVMGAVIME GFYVVFDRAR KRIGFAVSAC
HVHDEFRTAA VEGPFVTADM EDCGYNIPQT DESTLMTIAY VMAAICALFM LPLCLMVCQW
RCLRCLRHQH DDFADDISLL K
