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FLASH GENE
Symbol BACE1 contributors: mct/shn - updated : 29-06-2017
HGNC name beta-site APP-cleaving enzyme 1
HGNC id 933
Location 11q23.3      Physical location : 117.156.416 - 117.186.972
Synonym name
  • beta-secretase 1
  • beta-secretase 1 precursor variant 1
  • beta-site APP-cleaving enzyme 1
  • beta-site amyloid beta A4 precursor protein-cleaving enzyme
  • APP beta-secretase
  • memapsin 2
  • membrane-associated aspartic protease 2
  • aspartyl protease 2
  • transmembrane aspartic proteinase Asp2
  • Synonym symbol(s) KIAA1149, ASP2, BACE, HSPC104, FLJ90568
    EC.number 3.4.23.46
    DNA
    TYPE functioning gene
    STRUCTURE 30.57 kb     9 Exon(s)
    regulatory sequence Promoter
    Binding site   transcription factor   hormone   cAMP   HRE
    motif repetitive sequence   ALU   long interspersed repetitive elements
    text structure
  • promoter contains a functional Sp1 response element, and overexpression of the transcription factor Sp1 potentiates BACE gene expression and APP processing to generate Abeta
  • 91 bp fragment containing the Ap2 and stimulating protein (SP)1 binding sites constitutes the core promoter region playing an important role in regulating BACE activity in neurons
  • promoter region and 5' UTR contain multiple other transcription factor binding sites, such as activator protein (AP)1, cAMP response element binding protein (CREB), estrogen responsive element (ERE), glucocorticoid responsive element (GRE), "GC" box, nuclear factor (NF)-kappaB, signal transducer and activator of transcription (STAT)1, metal-regulatory elements, and possible Zeste binding sites
  • functional hypoxia-responsive element in the promoter
  • promoter activity is differentially regulated, and the 91-bp fragment represents a novel promoter region for cell type-specific regulation
  • MAPPING cloned Y linked N status provisional
    Map cen - D11S4142 - D11S1340 - BACE1 - D11S4092 - D11S4127 - qter
    RNA
    TRANSCRIPTS type messenger
    identificationnb exonstypebpproduct
    ProteinkDaAAspecific expressionYearPubmed
    9 splicing 5864 51 501 - 2009 19682432
  • isoform A
  • BACE501
  • 9 splicing 5789 58 476 . highly in pancreas (exocrine), brain, hippocampus . restricted to endoplasmic reticulum 2009 19682432
  • using a different splice site in the coding region compared to variant 1
  • lacking an internal segment
  • have a weaker or null beta-secretase activity
  • BACE476 generated from the cryptic acceptor site in exon 4
  • isoform B
  • BACE476
  • 9 splicing 5732 54 457 . highly in pancreas, brain . restricted to endoplasmic reticulum 2009 19682432
  • using a different splice site in the coding region compared to variant 1
  • lacking an internal segment and two N-glycosylation sites
  • have a weaker or null beta-secretase activity
  • isoform C
  • BACE457
  • 9 splicing 5657 43.4 432 highly in pancreas, brain 2009 19682432
  • isoform D
  • lacking two N-glycosylation sites
  • 8 splicing 5151 - 376 - 2009 19682432
    8 splicing 5226 - 401 - 2009 19682432
    EXPRESSION
    Type
       expressed in (based on citations)
    organ(s)
    SystemOrgan level 1Organ level 2Organ level 3Organ level 4LevelPubmedSpeciesStageRna symbol
    Digestivepancreas exocrine     Homo sapiens
    Endocrinepancreas     Homo sapiens
    Nervousbrainforebraincerebral cortex   Mus musculus
     brainlimbic systemhippocampus   Mus musculus
     brainhindbraincerebellum   Mus musculus
     brainhindbrainpons   Mus musculus
     brain   predominantly Homo sapiens
     spinal cord     Mus musculus
    tissue
    SystemTissueTissue level 1Tissue level 2LevelPubmedSpeciesStageRna symbol
    Epithelialsecretoryglandularendocrine  Homo sapiens
    Epithelialsecretoryglandularexocrine  Homo sapiens
    Nervouscentral  predominantly Homo sapiens
    cells
    SystemCellPubmedSpeciesStageRna symbol
    Nervousastrocyte Homo sapiens
    Nervousneuron Homo sapiens
    cell lineage
    cell lines
    fluid/secretion
    at STAGE
    PROTEIN
    PHYSICAL PROPERTIES
    STRUCTURE
    motifs/domains
  • a single transmembrane segment (TM1)
  • a cytoplasmic tail
  • an ectodomain cleaved and secreted from cells in a soluble form
  • a DISLL sequence in the cytosolic tail recognized by the GGA adaptor proteins
  • secondary structure
  • the single transmembrane domain of BACE1 alone determines the retention of BACE1 to the Golgi compartments
  • the transmembrane domain of BACE1 is required for the access of BACE1 enzymatic activity to the cellular APP substrate and hence for the optimal generation of the C-terminal fragment of APP (CTF99)
  • conjugated GlycoP , ubiquitinated
    mono polymer monomer
    isoforms Precursor preproprotein with a mature form of 51 kDa
    HOMOLOGY
    interspecies ortholog to Bace1, Mus musculus
    ortholog to Bace1, Rattus norvegicus
    ortholog to bace1, Danio rerio
    ortholog to BACE1, Pan troglodytes
    intraspecies homolog to BACE2
    Homologene
    FAMILY
  • peptidase A1 family
  • CATEGORY enzyme
    SUBCELLULAR LOCALIZATION     plasma membrane
        intracellular
    intracellular,cytoplasm,organelle,membrane
    intracellular,cytoplasm,organelle,Golgi
    intracellular,cytoplasm,organelle,endosome
    intracellular,cytoplasm,organelle,lysosome
    text
  • largely situated in the distal Golgi membrane with a minor presence in the endoplasmic reticulum, endosomes, and plasma membrane in human neuroblastoma SHEP cells and in mouse Neuro-2a cell lines
  • transGolgi network
  • intracellular trafficking of BACE1 between endosomes and the TGN appears to be tightly regulated and potentially influential on APP processing and the subsequent generation of Abeta
  • cycles between the trans-Golgi network (TGN), the plasma membrane, and endosomes by virtue of signals contained within its cytosolic C-terminal domain
  • basic FUNCTION
  • an N-glycosylated integral membrane protein that undergoes constitutive N-terminal processing in the Golgi apparatus
  • involved in the cleavage of full length amyloid precursor protein (APP) at the beta secretase site (not in pancreas)
  • is required for myelination and correct bundling of axons by Schwann cells, probably through processing of type III NRG1
  • membrane-bound aspartyl protease that specifically cleaves amyloid precursor protein (APP) at the beta-secretase site
  • a neuronal protein that modulates the processing of both APP and APLP2
  • BACE1-mediated cleavage of APP can facilitate learning, memory, and synaptic plasticity
  • is involved in the cleavage of membrane-bound PTGES2 which in turn enhance the generation of prostaglandin E2, resulting in increased amyloid beta production
  • role in generating the amyloid-beta peptides that are present in plaques of Alzheimer disease
  • potential vital role for BACE1 in axonal health
  • proteolytic activity of BACE1 is more important than that of ADAM10 in the control of myelination
  • neuronal beta-secretase that cleaves the amyloid-beta precursor protein, thus allowing the production of amyloid-beta
  • cleaves neuregulin 1 type III, a protein critical for myelination of peripheral axons by Schwann cells during development
  • aspartyl protease that catalyzes the proteolytic processing of APP and other plasma membrane protein precursors
  • main role of BACE1 is to cleave substrates in transit to the plasma membrane
  • BACE1 is responsible for CHL1 processing in the brain and synaptic membranes under physiological conditions
  • role in the control of coordinated movement through its regulation of muscle spindle physiology
  • BACE1 appears to function as a signaling protease that controls the balance of neurogenesis and astrogenesis via the JAG1-NOTCH pathway
  • BACE1 may likely play an important role in cell adhesion, neurite outgrowth and axon guidance by regulating CNTN2 surface levels
  • plays an essential role in sensory experience-dependent homeostatic synaptic plasticity in the neocortex
  • important functions to BACE1 in structural and functional synaptic plasticity in the mature brain, with implications for cognition
  • BACE1 in axons and Schwann cells is similarly important for remyelination of regenerated axons
  • CELLULAR PROCESS protein, degradation
    PHYSIOLOGICAL PROCESS
    PATHWAY
    metabolism
    signaling
    a component
    INTERACTION
    DNA
    RNA
    small molecule
    protein
  • nicastrin
  • phospholipid scramblase 1, PLSCR1
  • Presenilin-1, PS1
  • P-selectin glycoprotein ligand 1, PSGL-1
  • golgi-associated, gamma adaptin ear containing, ARF binding protein 1, GGA1
  • brain-specific type II membrane protein BRI3
  • lipoprotein receptor-related protein, LRP
  • in addition to its role in APP trafficking--LRP1 affects APP processing by competing for cleavage by BACE1
  • SCF(Fbx2) -E3 ligase
  • SORT1
  • NRG1
  • SREBF2, which can be modulated by the impairment of cerebral cholesterol homeostasis, has a direct role on BACE1 expression and may be involved in Alzheimer disease progression
  • is capable of cleaving APP in late compartments of the secretory pathway
  • L1CAM and CHL1 are physiological substrates for BACE1
  • APP-activated NFATC3 proteins were associated with astrocytic BACE1 gene expression via direct interaction with the BACE1 promoter region
  • APP-induced elevation of intracellular calcium levels potentiates BACE1 gene expression via calcineurin-related signaling in astrocytes
  • DNM1 likely affects amyloid generation through regulation of BACE1 subcellular localization and therefore its enzymatic activities
  • KCNE1 and KCNE2 cleavages are regulated by BACE1 and PSEN1/gamma-secretase activities under physiological conditions
  • RHEB interacts with BACE1 and degrades it through proteasomal and lysosomal pathways
  • BACE1-mediated CNTN2 cleavage tightly regulates the surface expression of CNTN2 in neuronal cells
  • RTN3 has previously been shown to interact with BACE1 and negatively regulate BACE1 activity
  • direct binding of NFATC4 to specific DNA sequences within BACE1 promoter region
  • novel role of CLEC4G in negatively regulating BACE1 function
  • link between TPPP and BACE1 in AD brains, suggesting that upregulated CDK5 activation by TPPP accelerates AD pathogenesis by enhancing BACE1 activity via phosphorylation
  • BACE1 modulates gating of KCNQ1 and cardiac delayed rectifier KCNQ1/KCNE1 (IKs)
  • USP8 plays a key role in the trafficking and degradation of BACE1 by deubiquitinating lysine 501
  • EGR1 promotes APP synthesis via transcriptional activation of BACE1, suggesting that EGR1 plays role in activation of BACE1 and acceleration of APP synthesis in Alzheimer disease brain
  • cell & other
    REGULATION
    inhibited by reticulon proteins
    RTN3
    Phosphorylated by casein kinase 1
    golgi-associated, gamma adaptin ear containing, ARF binding protein 1, GGA1
    TPPP/CDK5 complex at Thr252 and this phosphorylation increases BACE1 activity
    Other regulated at the transcriptional level and the transcription factor Sp1 plays an important role in regulation of BACE1 to process APP generating Abeta in Alzheimer disease
    RTN3 specifically blocks access of BACE1 to APP within neurons
    degradated by Ubiquitin carboxyl-terminal hydrolase L1, UCHL1
    induction of neuronal autophagy enhances BACE1 turnover, which is suppressed by lysosomal inhibition
    ASSOCIATED DISORDERS
    corresponding disease(s)
    Other morbid association(s)
    TypeGene ModificationChromosome rearrangementProtein expressionProtein Function
    constitutional       gain of function
    in late-onset Alzheimer's disease
    constitutional     --over  
    due to loss of specific miRNAsin sporadic Alzheimer disease
    constitutional       loss of function
    inhibition of BACE1 could potentially impair NRG1 signaling activity
    constitutional     --over  
    elevated vascular BACE1 may contribute to deficiency of OCLN in cerebral vessels, which ultimately has a critical role in pathogenesis of cerebral amyloid angiopathy (CAA) and its related hemorrhage
    constitutional     --over  
    early in mild cognitive impairment (MCI) and is possibly induced by TNF and BACE1 enzymatic activity may be important for conversion of MCI to Alzheimer
    Susceptibility to Alzheimer disease (AD)
    Variant & Polymorphism other exon 5 GG genotype associated to the APOE epsilon 4-allele increase the risk to develop Alzheimer disease
    Candidate gene 91-bp fragment represents a novel promoter region for cell type-specific regulation and might be a useful target to regulate BACE1 expression leading to Abeta production and to understand the neuropathogenesis of Alzheimer disease
    Marker
    Therapy target
    SystemTypeDisorderPubmed
    neurologyneurodegenerativealzheimer
    key target for Alzheimer drug development (hypoxia facilitates Alzheimer disease pathogenesis by up-regulating BACE1 gene expression, and increasing cerebral perfusion may benefit Alzheimer disease patients)
    neurologyneurodegenerativealzheimer
    therapeutic potential of inhibiting BACE1 in Alzheimer disease and Down syndrome
    neurologyacquired 
    BACE1 inhibition is a potential therapeutic approach to accelerate regeneration and recovery after peripheral nerve damage.
    neurologyneurodegenerativealzheimer
    unique modulatory effect of cellular S1P on BACE1 activity is a novel potential therapeutic target for Alzheimer's disease
    neurologyneurodegenerativealzheimer
    inhibition of NFAT-mediated BACE1 expression may be a valuable drug target for AD therapy
    neurologyneurodegenerativealzheimer
    therapies able to accelerate BACE1 degradation (e.g. by increasing BACE1 ubiquitination) may represent a potential treatment for Alzheimer disease
    ANIMAL & CELL MODELS
  • BACE knockout mice develop normally and showed no consistent phenotypic differences from their wild-type littermates, including overall normal tissue morphology and brain histochemistry, normal blood and urine chemistries, normal blood-cell composition, and no overt behavioral and neuromuscular effects
  • Brain and primary cortical cultures from BACE knockout mice showed no detectable beta-secretase activity, and primary cortical cultures from BACE knockout mice produced much less Abeta from APP
  • BACE1 null mice engineered to overexpress human APP (BACE1(-/-).Tg2576(+)) are rescued from Abeta-dependent hippocampal memory deficits
  • amyloid precursor protein processing was altered in the BACE knockouts with Abeta levels decreasing and the levels of APLP2 proteolytic products were decreased
  • Overexpression of BACE in cultured cells led to increased APLP2 processing
  • a significant number of BACE1 knockout mice died in the first weeks after birth but the surviving are smaller than their littermate controls and present a hyperactive behavior and a subtle alterations in the steady-state inactivation of voltage-gated sodium channels was observed
  • enhanced memory and synaptic plasticity of mice overproducing APP are abolished by the ablation of one or both copies of the BACE1 gene, leading to a significant decrease in AICD but not of any other APP cleavage products
  • Cdk5 level and p25:p35 ratio were elevated and correlated with BACE1 level in brains of AD patients and 5XFAD transgenic mice