BACE1_BOVIN
ID BACE1_BOVIN Reviewed; 501 AA.
AC Q2HJ40;
DT 11-JUL-2006, integrated into UniProtKB/Swiss-Prot.
DT 21-MAR-2006, sequence version 1.
DT 03-AUG-2022, entry version 118.
DE RecName: Full=Beta-secretase 1;
DE EC=3.4.23.46 {ECO:0000250|UniProtKB:P56817};
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;
OS Bos taurus (Bovine).
OC Eukaryota; Metazoa; Chordata; Craniata; Vertebrata; Euteleostomi; Mammalia;
OC Eutheria; Laurasiatheria; Artiodactyla; Ruminantia; Pecora; Bovidae;
OC Bovinae; Bos.
OX NCBI_TaxID=9913;
RN [1]
RP NUCLEOTIDE SEQUENCE [LARGE SCALE MRNA].
RC STRAIN=Hereford; TISSUE=Uterus;
RG NIH - Mammalian Gene Collection (MGC) project;
RL Submitted (FEB-2006) to the EMBL/GenBank/DDBJ databases.
CC -!- FUNCTION: Responsible for the proteolytic processing of the amyloid
CC precursor protein (APP). Cleaves at the N-terminus of the A-beta
CC peptide sequence, between residues 671 and 672 of APP, leads to the
CC generation and extracellular release of beta-cleaved soluble APP, and a
CC corresponding cell-associated C-terminal fragment which is later
CC released by gamma-secretase (By similarity). Cleaves CHL1 (By
CC similarity). {ECO:0000250|UniProtKB:P56817,
CC ECO:0000250|UniProtKB:P56818}.
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:0000250|UniProtKB:P56817};
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) (By similarity). Interacts with SORL1; this interaction may
CC affect binding with APP and hence reduce APP cleavage (By similarity).
CC {ECO:0000250|UniProtKB:P56817, ECO:0000250|UniProtKB:P56818}.
CC -!- SUBCELLULAR LOCATION: Cell membrane {ECO:0000250|UniProtKB:P56817};
CC Single-pass type I membrane protein {ECO:0000250|UniProtKB:P56817}.
CC Golgi apparatus, trans-Golgi network {ECO:0000250|UniProtKB:P56817}.
CC Endoplasmic reticulum {ECO:0000250|UniProtKB:P56817}. Endosome
CC {ECO:0000250|UniProtKB:P56817}. Cell surface
CC {ECO:0000250|UniProtKB:P56817}. Cytoplasmic vesicle membrane
CC {ECO:0000250|UniProtKB:P56817}; Single-pass type I membrane protein
CC {ECO:0000250|UniProtKB:P56817}. Membrane raft
CC {ECO:0000250|UniProtKB:P56818}. Lysosome
CC {ECO:0000250|UniProtKB:P56817}. Late endosome
CC {ECO:0000250|UniProtKB:P56817}. Early endosome
CC {ECO:0000250|UniProtKB:P56817}. Recycling endosome
CC {ECO:0000250|UniProtKB:P56817}. Cell projection, axon
CC {ECO:0000250|UniProtKB:P56818}. Cell projection, dendrite
CC {ECO:0000250|UniProtKB:P56818}. 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 (By similarity). 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:0000250|UniProtKB:P56818}.
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: Palmitoylation mediates lipid raft localization.
CC {ECO:0000250|UniProtKB:P56818}.
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 -!- 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 (By similarity). {ECO:0000250|UniProtKB:P56817,
CC ECO:0000250|UniProtKB:P56818}.
CC -!- SIMILARITY: Belongs to the peptidase A1 family. {ECO:0000305}.
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DR EMBL; BC113325; AAI13326.1; -; mRNA.
DR RefSeq; NP_001039996.1; NM_001046531.1.
DR AlphaFoldDB; Q2HJ40; -.
DR BMRB; Q2HJ40; -.
DR SMR; Q2HJ40; -.
DR STRING; 9913.ENSBTAP00000039837; -.
DR MEROPS; A01.004; -.
DR PaxDb; Q2HJ40; -.
DR PRIDE; Q2HJ40; -.
DR Ensembl; ENSBTAT00000040056; ENSBTAP00000039837; ENSBTAG00000019365.
DR GeneID; 614333; -.
DR KEGG; bta:614333; -.
DR CTD; 23621; -.
DR VEuPathDB; HostDB:ENSBTAG00000019365; -.
DR VGNC; VGNC:26400; BACE1.
DR eggNOG; KOG1339; Eukaryota.
DR GeneTree; ENSGT00940000157786; -.
DR HOGENOM; CLU_039009_0_0_1; -.
DR InParanoid; Q2HJ40; -.
DR OMA; ELEDCGY; -.
DR OrthoDB; 753343at2759; -.
DR TreeFam; TF329595; -.
DR Proteomes; UP000009136; Chromosome 15.
DR Bgee; ENSBTAG00000019365; Expressed in floor plate of diencephalon and 105 other tissues.
DR ExpressionAtlas; Q2HJ40; baseline and differential.
DR GO; GO:0030424; C:axon; IEA:UniProtKB-SubCell.
DR GO; GO:0009986; C:cell surface; ISS:UniProtKB.
DR GO; GO:0030659; C:cytoplasmic vesicle membrane; IEA:UniProtKB-SubCell.
DR GO; GO:0030425; C:dendrite; IEA:UniProtKB-SubCell.
DR GO; GO:0005769; C:early endosome; ISS:UniProtKB.
DR GO; GO:0005783; C:endoplasmic reticulum; IEA:UniProtKB-SubCell.
DR GO; GO:0005768; C:endosome; ISS:UniProtKB.
DR GO; GO:0005794; C:Golgi apparatus; ISS:UniProtKB.
DR GO; GO:0098686; C:hippocampal mossy fiber to CA3 synapse; IEA:Ensembl.
DR GO; GO:0005887; C:integral component of plasma membrane; IEA:Ensembl.
DR GO; GO:0005770; C:late endosome; ISS:UniProtKB.
DR GO; GO:0005764; C:lysosome; ISS:UniProtKB.
DR GO; GO:0045121; C:membrane raft; IEA:UniProtKB-SubCell.
DR GO; GO:0005771; C:multivesicular body; IEA:Ensembl.
DR GO; GO:0005886; C:plasma membrane; IBA:GO_Central.
DR GO; GO:0098793; C:presynapse; IEA:Ensembl.
DR GO; GO:0055037; C:recycling endosome; ISS:UniProtKB.
DR GO; GO:0005802; C:trans-Golgi network; ISS:UniProtKB.
DR GO; GO:0001540; F:amyloid-beta binding; IEA:Ensembl.
DR GO; GO:0004190; F:aspartic-type endopeptidase activity; ISS:UniProtKB.
DR GO; GO:0004175; F:endopeptidase activity; ISS:UniProtKB.
DR GO; GO:0019899; F:enzyme binding; IEA:Ensembl.
DR GO; GO:0034205; P:amyloid-beta formation; IEA:Ensembl.
DR GO; GO:0050435; P:amyloid-beta metabolic process; ISS:UniProtKB.
DR GO; GO:0006509; P:membrane protein ectodomain proteolysis; IBA:GO_Central.
DR GO; GO:0043525; P:positive regulation of neuron apoptotic process; IEA:Ensembl.
DR GO; GO:0016485; P:protein processing; IEA:Ensembl.
DR GO; GO:0006508; P:proteolysis; ISS:UniProtKB.
DR GO; GO:2000300; P:regulation of synaptic vesicle exocytosis; 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 2: Evidence at transcript level;
KW Acetylation; Aspartyl protease; Cell membrane; Cell projection;
KW Cytoplasmic vesicle; Disulfide bond; Endoplasmic reticulum; Endosome;
KW Glycoprotein; Golgi apparatus; Hydrolase; Isopeptide bond; Lipoprotein;
KW Lysosome; Membrane; Palmitate; Phosphoprotein; Protease;
KW Reference proteome; Signal; Transmembrane; Transmembrane helix;
KW Ubl conjugation; Zymogen.
FT SIGNAL 1..21
FT /evidence="ECO:0000255"
FT PROPEP 22..45
FT /evidence="ECO:0000250"
FT /id="PRO_0000245802"
FT CHAIN 46..501
FT /note="Beta-secretase 1"
FT /id="PRO_0000245803"
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:0000250|UniProtKB:P56818"
FT LIPID 474
FT /note="S-palmitoyl cysteine"
FT /evidence="ECO:0000250|UniProtKB:P56818"
FT LIPID 478
FT /note="S-palmitoyl cysteine"
FT /evidence="ECO:0000250|UniProtKB:P56818"
FT LIPID 482
FT /note="S-palmitoyl cysteine"
FT /evidence="ECO:0000250|UniProtKB:P56818"
FT LIPID 485
FT /note="S-palmitoyl cysteine"
FT /evidence="ECO:0000250|UniProtKB:P56818"
FT CARBOHYD 153
FT /note="N-linked (GlcNAc...) asparagine"
FT /evidence="ECO:0000255"
FT CARBOHYD 172
FT /note="N-linked (GlcNAc...) asparagine"
FT /evidence="ECO:0000255"
FT CARBOHYD 223
FT /note="N-linked (GlcNAc...) asparagine"
FT /evidence="ECO:0000255"
FT CARBOHYD 354
FT /note="N-linked (GlcNAc...) asparagine"
FT /evidence="ECO:0000255"
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"
SQ SEQUENCE 501 AA; 55725 MW; 8E5EA730FC91C295 CRC64;
MAQALPWLLL WMGSGVLPAH GSQPGIRLPL RSGLGGAPLG LRLPRETDEE SEEPGRRGSF
VEMVDNLRGK SGQGYYVEMT LGSPPQTLNI LVDTGSSNFA VGAAPHPFLH RYYQRQLSST
YRDLRKGVYV PYTQGKWEGE LGTDLVSIPH GPNVTVRANI AAITESDKFF INGSNWEGIL
GLAYAEIARP DDSLEPFFDS LVKQTHVPNL FSLQLCGAGF PLNQSEALAS VGGSMIIGGI
DHSLYMGSLW YTPIRREWYY EVIIVRVEIN GQDLKMDCKE YNYDKSIVDS GTTNLRLPKK
VFEAAVKSIK AASSTEKFPD GFWLGEQLVC WQAGTTPWNI FPVISLYLMG EVTNQSFRIT
ILPQQYLRPV EDVATSQDDC YKFAISQSST GTVMGAVIME GFYVVFDRAR KRIGFAVSAC
HVHDEFRTAA VEGPFVTPDM EDCGYNIPQT DESTLMTIAY VMAAICALFM LPLCLMVCQW
RCLRCLRHQH DDFADDISLL K
