BACE1_CAVPO
ID BACE1_CAVPO Reviewed; 473 AA.
AC Q1KLR6;
DT 11-JUL-2006, integrated into UniProtKB/Swiss-Prot.
DT 30-MAY-2006, sequence version 1.
DT 03-AUG-2022, entry version 101.
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 Cavia porcellus (Guinea pig).
OC Eukaryota; Metazoa; Chordata; Craniata; Vertebrata; Euteleostomi; Mammalia;
OC Eutheria; Euarchontoglires; Glires; Rodentia; Hystricomorpha; Caviidae;
OC Cavia.
OX NCBI_TaxID=10141;
RN [1]
RP NUCLEOTIDE SEQUENCE [MRNA].
RA Christensen S.;
RT "Beta-site amyloid precursor protein cleaving enzyme 1 (BACE1) mRNA from
RT guinea pig.";
RL Submitted (APR-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-470. 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-123, Lys-247, Lys-
CC 251, Lys-257, Lys-271, Lys-272, and Lys-279. 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-473, 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-470 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; DQ471956; ABF13340.1; -; mRNA.
DR RefSeq; NP_001166390.1; NM_001172919.1.
DR AlphaFoldDB; Q1KLR6; -.
DR SMR; Q1KLR6; -.
DR STRING; 10141.ENSCPOP00000011476; -.
DR MEROPS; A01.004; -.
DR GeneID; 100135485; -.
DR KEGG; cpoc:100135485; -.
DR CTD; 23621; -.
DR eggNOG; KOG1339; Eukaryota.
DR HOGENOM; CLU_039009_0_0_1; -.
DR InParanoid; Q1KLR6; -.
DR OMA; ELEDCGY; -.
DR TreeFam; TF329595; -.
DR Proteomes; UP000005447; Unassembled WGS sequence.
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:0016021; C:integral component of membrane; IEA:UniProtKB-KW.
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:0005886; C:plasma membrane; IEA:UniProtKB-SubCell.
DR GO; GO:0055037; C:recycling endosome; ISS:UniProtKB.
DR GO; GO:0005802; C:trans-Golgi network; ISS:UniProtKB.
DR GO; GO:0004190; F:aspartic-type endopeptidase activity; ISS:UniProtKB.
DR GO; GO:0004175; F:endopeptidase activity; ISS:UniProtKB.
DR GO; GO:0050435; P:amyloid-beta metabolic process; ISS:UniProtKB.
DR GO; GO:0006508; P:proteolysis; ISS:UniProtKB.
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; 2.
DR PANTHER; PTHR47965:SF69; PTHR47965:SF69; 2.
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_0000245804"
FT CHAIN 46..473
FT /note="Beta-secretase 1"
FT /id="PRO_0000245805"
FT TOPO_DOM 22..429
FT /note="Extracellular"
FT /evidence="ECO:0000255"
FT TRANSMEM 430..450
FT /note="Helical"
FT /evidence="ECO:0000255"
FT TOPO_DOM 451..473
FT /note="Cytoplasmic"
FT /evidence="ECO:0000255"
FT DOMAIN 72..388
FT /note="Peptidase A1"
FT /evidence="ECO:0000255|PROSITE-ProRule:PRU01103"
FT REGION 451..473
FT /note="Interaction with RTN3"
FT /evidence="ECO:0000250"
FT MOTIF 468..472
FT /note="DXXLL"
FT /evidence="ECO:0000250|UniProtKB:P56817"
FT ACT_SITE 90
FT /evidence="ECO:0000255|PROSITE-ProRule:PRU10094"
FT ACT_SITE 261
FT /evidence="ECO:0000255|PROSITE-ProRule:PRU10094"
FT MOD_RES 123
FT /note="N6-acetyllysine"
FT /evidence="ECO:0000250|UniProtKB:P56817"
FT MOD_RES 247
FT /note="N6-acetyllysine"
FT /evidence="ECO:0000250|UniProtKB:P56817"
FT MOD_RES 251
FT /note="N6-acetyllysine"
FT /evidence="ECO:0000250|UniProtKB:P56817"
FT MOD_RES 257
FT /note="N6-acetyllysine"
FT /evidence="ECO:0000250|UniProtKB:P56817"
FT MOD_RES 271
FT /note="N6-acetyllysine"
FT /evidence="ECO:0000250|UniProtKB:P56817"
FT MOD_RES 272
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 470
FT /note="Phosphoserine"
FT /evidence="ECO:0000250|UniProtKB:P56818"
FT LIPID 446
FT /note="S-palmitoyl cysteine"
FT /evidence="ECO:0000250|UniProtKB:P56818"
FT LIPID 450
FT /note="S-palmitoyl cysteine"
FT /evidence="ECO:0000250|UniProtKB:P56818"
FT LIPID 454
FT /note="S-palmitoyl cysteine"
FT /evidence="ECO:0000250|UniProtKB:P56818"
FT LIPID 457
FT /note="S-palmitoyl cysteine"
FT /evidence="ECO:0000250|UniProtKB:P56818"
FT CARBOHYD 150
FT /note="N-linked (GlcNAc...) asparagine"
FT /evidence="ECO:0000255"
FT CARBOHYD 169
FT /note="N-linked (GlcNAc...) asparagine"
FT /evidence="ECO:0000255"
FT CARBOHYD 195
FT /note="N-linked (GlcNAc...) asparagine"
FT /evidence="ECO:0000255"
FT CARBOHYD 326
FT /note="N-linked (GlcNAc...) asparagine"
FT /evidence="ECO:0000255"
FT DISULFID 188..392
FT /evidence="ECO:0000250"
FT DISULFID 250..415
FT /evidence="ECO:0000250"
FT DISULFID 302..352
FT /evidence="ECO:0000250"
FT CROSSLNK 473
FT /note="Glycyl lysine isopeptide (Lys-Gly) (interchain with
FT G-Cter in ubiquitin)"
FT /evidence="ECO:0000250|UniProtKB:P56817"
SQ SEQUENCE 473 AA; 52576 MW; F9583693A13F86E9 CRC64;
MAPALPWLLL WVGSGVLPVH GTQDGIRLPL RSGLAGAPLG LRLPRETDEE PGRRGSFVEM
VDNLRGKSGQ GYYVEMTVGS PPQTLNILVD TGSSNFAVGA APHPFLHRYY QRQRSSTYRD
LRKGVYVPYT QGKWEGELGT DLVSIPHGPN VTVRANIAAI TESDKFFING SNWEGILGLA
YAEIARLCGA GFPLNQSEAV ASVGGSMIIG GIDHSLYTGN LWYTPIRREW YYEVIIVRVE
INGQDLKMDC KEYNYDKSIV DSGTTNLRLP KKVFEAAVKS IKAASSTEKF PDGFWLGEQL
VCWQAGTTPW NIFPVISLYL MGEVTNQSFR ITILPQQYLR PVEDVATSQD DCYKFAISQS
STGTVMGAVI MEGFYVVFDR ARKRIGFAVS ACHVHDEFRT ATVEGPFVTP DMEDCGYNIP
QTDESTLMTI AYVMAAICAL FMLPLCLMVC QWRCLRCLRH QHDDFADDIS LLK
