Bace1
Domain
DXXLL motif is required for a proper endocytosis and retrograde transport to the trans-Golgi network, as well as for regulation of lysosomal degradation.
The transmembrane domain is necessary for its activity. It determines its late Golgi localization and access to its substrate, APP.
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).
Post-translational modifications
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).
Palmitoylation mediates lipid raft localization.
Acetylated in the endoplasmic reticulum at Lys-126, Lys-275, Lys-279, Lys-285, Lys-299, Lys-300 and Lys-307 (PubMed:20826464). 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.
Ubiquitinated at Lys-501, ubiquitination leads to lysosomal degradation. Monoubiquitinated and 'Lys-63'-linked polyubitinated. Deubiquitnated by USP8; inhibits lysosomal degradation.
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.
Sequence Similarities
Belongs to the peptidase A1 family.
Tissue Specificity
Expressed in the brain, specifically in neurons and astrocytes (at protein level).
Cellular localization
- Cell membrane
- Single-pass type I membrane protein
- Golgi apparatus
- trans-Golgi network
- Endoplasmic reticulum
- Endosome
- Late endosome
- Early endosome
- Cell surface
- Cytoplasmic vesicle membrane
- Membrane raft
- Lysosome
- Recycling endosome
- Cell projection
- Axon
- Cell projection
- Dendrite
- 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).
Alternative names
Bace, Bace1, Beta-secretase 1, Aspartyl protease 2, Beta-site amyloid precursor protein cleaving enzyme 1, Memapsin-2, Membrane-associated aspartic protease 2, ASP2, Asp 2, Beta-site APP cleaving enzyme 1