BACE1

This gene encodes a member of the peptidase A1 family of aspartic proteases. Alternative splicing results in multiple transcript variants, at least one of which encodes a preproprotein that is proteolytically processed to generate the mature protease. This transmembrane protease catalyzes the first step in the formation of amyloid beta peptide from amyloid precursor protein. Amyloid beta peptides are the main constituent of amyloid beta plaques, which accumulate in the brains of human Alzheimer's disease patients. [provided by RefSeq, Nov 2015]

Full Name

Beta-Secretase 1

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).

Biological Process

Amyloid-beta formation Source: ARUK-UCL
Amyloid-beta metabolic process Source: UniProtKB
Amyloid fibril formation Source: Reactome
Amyloid precursor protein catabolic process Source: ARUK-UCL
Cellular response to amyloid-beta Source: Ensembl
Cellular response to copper ion Source: Ensembl
Cellular response to manganese ion Source: Ensembl
Detection of mechanical stimulus involved in sensory perception of pain Source: Ensembl
Membrane protein ectodomain proteolysis Source: UniProtKB
Positive regulation of neuron apoptotic process Source: ARUK-UCL
Prepulse inhibition Source: Ensembl
Protein processing Source: ARUK-UCL
Proteolysis Source: UniProtKB
Regulation of synaptic vesicle exocytosis Source: Ensembl
Response to lead ion Source: Ensembl
Response to radiation Source: Ensembl

Cellular Location

Endoplasmic reticulum; Trans-Golgi network; Endosome; Late endosome; Early endosome; Recycling endosome; Cell membrane; Lysosome; Cell surface; Cytoplasmic vesicle membrane; Membrane raft; Axon; 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 (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).

Topology

Extracellular: 22-457 aa
Helical: 458-478 aa
Cytoplasmic: 479-501 aa

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).
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.
Palmitoylation mediates lipid raft localization.
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).
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.