Affinage

BACE2

Beta-secretase 2 · UniProt Q9Y5Z0

Length
518 aa
Mass
56.2 kDa
Annotated
2026-06-09
100 papers in source corpus 31 papers cited in narrative 31 extracted findings
Cross-family judge vs UniProt: tie faithfulness: 7/7 claims corpus-supported (100%)

Mechanistic narrative

Synthesis pass · prose summary of the discoveries below

BACE2 is a membrane-anchored aspartyl protease of the A1 family that functions as a regulated ectodomain sheddase, processing a diverse set of transmembrane substrates across the secretory and endosomal pathways (PMID:16305800, PMID:10683441). It matures by autocatalytic removal of its prodomain (cleavage between Leu62 and Ala63) within the ER/early Golgi, a step abolished by mutation of the catalytic aspartate (D110N), after which mature enzyme traffics through ER, Golgi, TGN, endosomes, and the plasma membrane in a transmembrane-domain-dependent manner (PMID:11316808, PMID:11423558). Its crystal structure confirms the canonical aspartic-protease fold with an enlarged C-terminal domain and active-site pockets (S3, S2, S1', S2') distinct from BACE1, and the enzyme samples an ensemble of low-energy conformations (PMID:16305800, PMID:23695257). On APP, BACE2 acts principally as an anti-amyloidogenic protease, cleaving within the Aβ domain at the theta site (Phe19-Phe20) to raise sAPP/p3-like products and suppress Aβ, while retaining conditional beta-site activity that is normally restrained by the APP juxtamembrane helix and unmasked by clusterin binding during aging (PMID:12065613, PMID:16816112, PMID:30626751); it additionally degrades Aβ peptide directly with catalytic efficiency rivaling IDE (PMID:22986058). This protective function is gene-dose sensitive: BACE2 trisomy suppresses Alzheimer-like pathology in Down syndrome organoids, and loss-of-function variants drive Aβ-dependent neuronal death (PMID:32647257, PMID:35110536). Beyond the brain, BACE2 sheds Tmem27 to control pancreatic β-cell mass and glucose homeostasis, processes the melanosomal protein PMEL to enable functional amyloid fibril formation and pigmentation, cleaves the lymphangiogenic receptor VEGFR3 to limit its signaling, and acts on the insulin receptor, Kv2.1, IAPP, and glial substrates including SEZ6L/SEZ6L2 and VCAM-1 under inflammatory conditions (PMID:21907142, PMID:23754390, PMID:38888964, PMID:29804876, PMID:29703946, PMID:26840340, PMID:23430253, PMID:30456346). Genetic ablation in mice and zebrafish yields viable animals with pigmentation and melanophore phenotypes non-redundant with BACE1 (PMID:23754390, PMID:15987683, PMID:23406323).

Mechanistic history

Synthesis pass · year-by-year structured walk · 14 steps
  1. 2000 High

    Establishing that BACE2 is a membrane-anchored aspartic protease capable of cleaving APP defined the enzyme's basic biochemical identity and placed it alongside BACE1 as a candidate amyloidogenic protease.

    Evidence In vitro translation, cell transfection, glycosylation analysis, and cell-based cleavage/active-site mutagenesis assays on APP

    PMID:10683441 PMID:10931940

    Open questions at the time
    • Did not resolve whether net effect on Aβ is amyloidogenic or anti-amyloidogenic
    • Physiological substrates beyond APP unknown
  2. 2001 High

    Defining the autocatalytic prodomain cleavage site and showing BACE2 acts mainly within the Aβ domain rather than at the beta-site reframed its role as an alternative alpha/theta-secretase and clarified its maturation and trafficking.

    Evidence D110N active-site mutagenesis, fusion-protein and synthetic-peptide cleavage assays, cell fractionation, and subcellular localization with TM-domain chimeras

    PMID:11316808 PMID:11423558

    Open questions at the time
    • Compartment in which physiologically relevant cleavage occurs not fully resolved
    • Regulation of trafficking not defined
  3. 2002 High

    Direct radiosequencing pinned the APP cleavage to Phe19-Phe20 within the Aβ domain, biochemically proving BACE2 suppresses rather than generates Aβ.

    Evidence Radiosequencing of membrane-bound C-terminal cleavage products with compartment-specific cell-based processing

    PMID:12065613

    Open questions at the time
    • Whether this anti-amyloidogenic activity operates in vivo in human brain untested at this stage
  4. 2005 High

    Crystallization of mature BACE2 with a transition-state inhibitor provided the structural basis for active-site differences from BACE1, enabling rational inhibitor and selectivity considerations.

    Evidence X-ray crystallography at 3.1 Å of autocatalytically activated, refolded recombinant BACE2

    PMID:16305800

    Open questions at the time
    • No substrate-bound structure
    • Conformational dynamics not captured by single structure
  5. 2005 High

    Knockout mice and cell-type analysis showed BACE2 is dispensable for normal development but contributes to glial (not neuronal) Aβ generation, distinguishing it physiologically from BACE1.

    Evidence Single and double BACE1/BACE2 knockout mice with biochemical Aβ analysis in neurons and glia

    PMID:15987683

    Open questions at the time
    • Physiological substrate underlying any phenotype not identified here
    • Cell-type basis of glial-specific activity unexplained
  6. 2011 High

    Identification of Tmem27 as a BACE2 substrate established a non-neural physiological role controlling pancreatic β-cell mass and glucose homeostasis, opening BACE2 as a metabolic drug target.

    Evidence siRNA screen, genetic knockout mice, pharmacological inhibition with β-cell mass and glucose readouts; substrate structural requirements defined by mutagenesis and biochemistry

    PMID:21907142 PMID:22628310

    Open questions at the time
    • Mechanism linking Tmem27 shedding to proliferation incomplete
    • Translation of inhibitor metabolic effects to humans untested
  7. 2012 High

    Demonstration that BACE2 directly degrades Aβ peptide with IDE-like efficiency added a second anti-amyloidogenic mechanism beyond protective APP cleavage.

    Evidence Genome-scale cDNA screen, in vitro Aβ degradation with cleavage-site mapping and catalytic efficiency measurement, cell-based Aβ lowering

    PMID:22986058

    Open questions at the time
    • In vivo contribution of Aβ degradation versus APP cleavage not quantified
    • Cellular site of Aβ degradation unclear
  8. 2013 High

    Identification of PMEL processing and SEZ6L/SEZ6L2 shedding defined BACE2's physiological substrate repertoire in melanosomes and β-cells, explaining pigmentation phenotypes and tissue-specific, non-redundant function.

    Evidence Bace2 knockout mice, RNA silencing, pharmacologic inhibition, overexpression, and quantitative sheddome proteomics; additional crystal structures defining conformational ensemble

    PMID:23430253 PMID:23695257 PMID:23754390

    Open questions at the time
    • Full substrate spectrum across tissues not exhaustively mapped
    • Signaling consequences of SEZ6L family shedding unresolved
  9. 2013 High

    Non-redundant phenotypes in zebrafish and definition of BACE2 turnover via macroautophagy clarified its distinct biology and a route for regulating its abundance and activity.

    Evidence Zinc-finger-nuclease KO and double-KO zebrafish phenotyping; pharmacological lysosome/proteasome inhibition with half-life and APP-cleavage readouts

    PMID:23406323 PMID:23773066

    Open questions at the time
    • Signals targeting BACE2 to lysosomal degradation unknown
    • Relationship of zebrafish melanocyte phenotype to mammalian substrates partial
  10. 2016 High

    Pharmacological inhibition causing irreversible hair depigmentation linked on-target BACE2 PMEL processing to a defined safety/biomarker consequence of BACE inhibitors.

    Evidence Dual BACE1/2 inhibitor across wild-type and bace2 genotypes in vivo plus in vitro melanocyte validation; in vitro IAPP cleavage/fibrillation mapping

    PMID:26840340 PMID:26912421

    Open questions at the time
    • IAPP cleavage shown only in vitro, physiological relevance unestablished
    • Reversibility/mechanism of pigmentation loss incomplete
  11. 2018 Medium

    Discovery of insulin receptor, Kv2.1, and glial inflammatory substrates broadened BACE2's signaling reach into PI3K/mTOR control, neuronal excitability/apoptosis, and neuroinflammation.

    Evidence Zebrafish bace2 mutant with chemical suppressor epistasis; cell-based Kv2.1 cleavage mapping with electrophysiology and apoptosis assays; glial sheddome proteomics with TNF stimulation

    PMID:29703946 PMID:29804876 PMID:30456346

    Open questions at the time
    • Mammalian relevance of zebrafish insulin-receptor shedding untested
    • Physiological role of inflammation-induced VCAM-1 shedding undefined
  12. 2019 Medium

    Showing that the APP juxtamembrane helix restrains BACE2 beta-cleavage and that clusterin/aging unmask it provided a conditional switch converting BACE2 from protective to amyloidogenic.

    Evidence Cell-based APP cleavage assays with JH mutants, clusterin co-IP, and aged mouse brain biochemistry

    PMID:30626751

    Open questions at the time
    • Quantitative contribution of this switch to age-related amyloidogenesis unknown
    • Structural basis of clusterin-JH interaction not resolved
  13. 2020 High

    Gene-dose experiments in human trisomy 21 organoids established BACE2 as a dose-sensitive Alzheimer suppressor and revealed cross-inhibition of its protective activity by BACE1 inhibitors.

    Evidence CRISPR/Cas9 editing of trisomy 21 cerebral organoids, Aβ peptide profiling by mass spectrometry, DS CSF analysis, BACE1 inhibitor treatment; complementary LOF-variant organoid rescue by APP removal

    PMID:32647257 PMID:35110536

    Open questions at the time
    • Whether BACE2 enhancement is therapeutically tractable untested
    • In vivo human relevance beyond organoid/CSF data limited
  14. 2024 High

    Identifying VEGFR3 as a BACE2-specific shed substrate connected the enzyme to lymphangiogenic signaling and provided soluble VEGFR3 as a translational pharmacodynamic marker of BACE2 activity.

    Evidence Genetic and pharmacological BACE2 inactivation in human LECs, plasma sVEGFR3 measurement in mouse/NHP/human, zebrafish LEC migration, VEGFR3 signaling analysis

    PMID:38888964

    Open questions at the time
    • Physiological/pathological consequences of altered lymphangiogenesis upon chronic inhibition unclear
    • Tissue specificity of VEGFR3 shedding not mapped

Open questions

Synthesis pass · forward-looking unresolved questions
  • How BACE2 substrate selection and the protective-versus-amyloidogenic balance are coordinated across tissues, trafficking compartments, and disease states remains unresolved.
  • No unified model of how compartmental localization dictates which substrate is cleaved
  • Regulators that toggle theta- versus beta-site APP cleavage in vivo unknown
  • Therapeutic window separating protective Aβ effects from pigmentation/metabolic/lymphatic on-target liabilities undefined

Mechanism profile

Synthesis pass · controlled-vocabulary classification · explore literature graph →
Molecular activity
GO:0140096 catalytic activity, acting on a protein 6 GO:0016787 hydrolase activity 3
Localization
GO:0005886 plasma membrane 4 GO:0005794 Golgi apparatus 3 GO:0005783 endoplasmic reticulum 2 GO:0005768 endosome 1 GO:0031410 cytoplasmic vesicle 1
Pathway
R-HSA-392499 Metabolism of proteins 4 GO:0140096 catalytic activity, acting on a protein 2 R-HSA-1643685 Disease 2
Partners
APPINSRKCNB1PMELSEZ6LTMEM27VCAM1VEGFR3

Evidence

Reading pass · 31 per-paper findings extracted from the source corpus
Year Finding Method Journal Conf PMIDs
2000 BACE2 cleaves APP at the beta-secretase site (Asp1) and more efficiently at a site within the Aβ domain (near Phe19-Phe20); the Flemish missense mutation of APP markedly increases Aβ production by BACE2 but not BACE1; mutation of a conserved active-site Asp inhibits beta-site cleavage but not cleavage within Aβ by both enzymes. Cell-based cleavage assays, active-site mutagenesis, APP mutant analysis Proceedings of the National Academy of Sciences of the United States of America High 10931940
2000 BACE2 is a membrane-anchored aspartic protease with a predicted transmembrane region; in vitro translation and cell transfection showed it encodes a glycosylated protein that localizes mainly intracellularly but also to some extent at the plasma membrane. In vitro translation, cell transfection, glycosylation analysis FEBS letters Medium 10683441
2000 ASP1 (BACE2) expressed as an Fc fusion protein exhibits beta-secretase activity, cleaving both wild-type and Swedish-variant APP peptides at the beta-secretase site; overexpression of ASP1 in APP-expressing cells increases beta-secretase-derived soluble APP and the corresponding C-terminal fragment, but paradoxically decreases soluble Aβ secretion; ASP1 co-localizes with APP in Golgi/ER compartments. Cell-based overexpression, N-terminal sequencing of fusion protein, immunocytochemistry Molecular and cellular neurosciences Medium 11083922
2001 BACE2 prodomain processing is autocatalytic: cleavage occurs between Leu62 and Ala63; BACE2 cleaved a maltose-binding protein–prodomain fusion and a synthetic peptide at this site; mutation of the catalytic Asp (D110N) abolished processing; prodomain removal occurs intramolecularly within the ER/early Golgi, and mature BACE2 is expressed on the cell surface. Mutagenesis (D110N active-site mutant), fusion protein cleavage assay, synthetic peptide cleavage, cell fractionation/surface expression analysis The Journal of biological chemistry High 11316808
2001 In cells, BACE2 functions primarily as an alternative alpha-secretase, cleaving APP near the alpha-secretase site (mainly Phe19-Phe20 and Phe20-Ala21) with limited effect at the beta-site; purified BACE2 can be autoactivated in vitro; BACE2 localizes to ER, Golgi, TGN, endosomes, and plasma membrane, with localization dependent on its transmembrane domain; BACE2 chimeras that increase TGN localization do not alter APP processing patterns. Purified protein autoactivation, cell-based APP processing assay, subcellular localization by immunofluorescence, chimeric protein analysis The Journal of biological chemistry High 11423558
2002 BACE2 cleaves APP in cells between Phe19 and Phe20 within the Aβ domain (not at the beta-secretase site), resulting in increased APPsα and p3-like products and reduced Aβ production; this cleavage occurs in the Golgi and later secretory compartments; radiosequencing of the membrane-bound C-terminal cleavage product confirmed the exact cleavage site. Radiosequencing of C-terminal cleavage products, cell-based APP processing, compartment-specific analysis Journal of neurochemistry High 12065613
2003 Stably transfected HEK293 cells overexpressing BACE2 produce the C-terminal fragment C79 (corresponding to cleavage between Phe19-Phe20), less genuine Aβ1-40/42, and higher sAPPβ and N-terminal-truncated Aβ species; BACE2 activity is enhanced by the Swedish APP mutation and is maximal at pH 4.5. Stable cell transfection, characterization of APP-derived catabolites, fluorimetric assay at varying pH The Journal of biological chemistry Medium 12736275
2005 Crystal structure of mature BACE2 in complex with a hydroxyethylamine transition-state inhibitor determined at 3.1 Å; structure confirms BACE2 follows the general fold of A1 aspartic proteases but its C-terminal domain is larger than other family members; differences in S3, S2, S1' and S2' active-site substrate pockets compared to BACE1 were identified; mature BACE2 was produced by autocatalytic activation of pro-BACE2 refolded from E. coli inclusion bodies. X-ray crystallography, recombinant protein expression and refolding, autocatalytic activation Journal of molecular biology High 16305800
2006 BACE2 cleaves APP at a novel theta (θ) site downstream of the alpha-site, abolishing Aβ production; lentiviral overexpression of BACE2 markedly reduces Aβ production in primary neurons from Swedish-mutant APP transgenic mice; BACE1, not BACE2, is responsible for the major beta-secretase activity in Down syndrome. Lentiviral overexpression, primary neuronal culture, Aβ ELISA, APP cleavage site mapping FASEB journal Medium 16816112
2005 BACE2 overexpression significantly increases sAPP levels (non-amyloidogenic) in conditioned media and markedly reduces Aβ production; knockdown of BACE2 results in increased APP C83; BACE2 processes APP within the Aβ domain at a site downstream of the alpha-secretase cleavage site, not at the beta-site; BACE2 and BACE1 have distinct transcriptional regulation (TATA-less promoter, Sp1 can regulate both but promoters share little similarity). Overexpression/knockdown in cells, sAPP and Aβ quantification, promoter characterization, transcription factor analysis FASEB journal Medium 15857888
2011 Bace2 is the sheddase of the proproliferative plasma membrane protein Tmem27 in pancreatic β-cells; identified through siRNA screen; mice with functionally inactive Bace2 and insulin-resistant mice treated with a BACE2 inhibitor both display augmented β-cell mass and improved glucose homeostasis due to increased insulin levels. siRNA screen, genetic knockout mice, pharmacological inhibition, glucose homeostasis measurements, β-cell mass quantification Cell metabolism High 21907142
2012 Tmem27 dimerization (mediated by intracellular cysteine) prevents Bace2 cleavage; extracellular asparagine glycosylation is essential for Tmem27 trafficking to the plasma membrane and its processing by Bace2; the amount of Tmem27 at the plasma membrane is proportional to total cell levels upon glucose stimulation and Bace2 inhibition; the double phenylalanine motif in the Tmem27 cleavage site acts as an intramolecular Bace2 inhibitor. Tmem27 mutational analysis, co-immunoprecipitation, glycosylation mutants, pharmacological inhibition, cell surface biotinylation Biological chemistry High 22628310
2012 BACE2 is a potent Aβ-degrading protease in vitro, cleaving Aβ at three peptide bonds (Phe19-Phe20, Phe20-Ala21, and Leu34-Met35, with Leu34-Met35 being the initial and principal site); BACE2 catalytic efficiency exceeds all known Aβ-degrading proteases except IDE; BACE2 overexpression in cultured cells lowers net Aβ levels comparably to IDE and greater than neprilysin or ECE1. Genome-scale cDNA screen, in vitro Aβ degradation assay, catalytic efficiency measurement, cell-based Aβ lowering assay Molecular neurodegeneration High 22986058
2013 BACE2 processes PMEL (melanocyte protein) by cleaving its integral membrane form within the juxtamembrane domain, releasing the PMEL luminal domain into endosomal precursors for amyloid fibril formation and melanosome morphogenesis; Bace2-/- but not Bace1-/- mice display coat color defects; confirmed using RNA silencing, pharmacologic inhibition, and BACE2 overexpression in human melanocytic cell lines. Bace2 knockout mice, RNA silencing, pharmacological inhibition, BACE2 overexpression, biochemical and morphological analyses of melanocytes Proceedings of the National Academy of Sciences of the United States of America High 23754390
2013 Systematic proteomic analysis of BACE2 substrates in pancreatic β-cells identified SEZ6L and SEZ6L2 (seizure 6 protein family members) as specific BACE2 substrates; BACE2 regulates a distinct, β-cell-enriched set of ectodomain shedding targets, non-redundant with BACE1 substrates. Quantitative proteomics (loss- and gain-of-function in vitro and in vivo models), mass spectrometry-based sheddome/secretome analysis The Journal of biological chemistry High 23430253
2013 BACE2 degradation is mediated by the macroautophagy-lysosome pathway (half-life ~20 h); lysosomal inhibition increased BACE2 protein levels while proteasomal inhibition had no effect; lysosomal inhibition also increased BACE2 cleavage of APP. Pharmacological inhibition of lysosomes and proteasomes, protein half-life measurement, APP processing assay The European journal of neuroscience Medium 23773066
2016 Pharmacological inhibition of BACE2 (and BACE1) in mice inhibits PMEL17 proteolytic processing, leading to dose-dependent irreversible hair depigmentation; BACE2-mediated PMEL17 processing was confirmed in vitro in mouse and human melanocytes; bace2-/- mice show PMEL17 processing deficiency and hair depigmentation. Pharmacological inhibition (dual BACE1/2 inhibitor NB-360) in wild-type and bace2+/- and bace2-/- mice, in vitro melanocyte assays Scientific reports High 26912421
2016 BACE2 cleaves human IAPP (islet amyloid polypeptide) at two distinct sites in the mature IAPP sequence; BACE2-mediated proteolysis modulates human IAPP fibrillation and leads to IAPP protein degradation. In vitro BACE2 cleavage assay with IAPP substrate, fibrillation assay, proteolysis mapping PloS one Medium 26840340
2018 BACE2 is expressed in discrete subsets of neurons and glia in the adult mouse brain; four new BACE2 substrates in cultured glia were identified: VCAM-1, DNER, FGFR1, and plexin domain containing 2; TNF induced a drastic increase in BACE2-mediated shedding of VCAM-1 in CSF under proinflammatory conditions. Immunohistochemistry of mouse brain, proteomics of conditioned media from BACE2 KO vs WT glia, TNF stimulation, CSF analysis Life science alliance Medium 30456346
2018 BACE2 cleaves the potassium channel Kv2.1 at Thr376, Ala717, and Ser769, disrupting Kv2.1 clustering on the cell membrane, resulting in decreased delayed rectifier K+ current and a hyperpolarizing shift; cleaved Kv2.1 forms reduce the delayed rectifier surge and reduce neuronal apoptosis. Cell-based cleavage assays, electrophysiology, site-directed identification of cleavage sites, apoptosis assays in primary neurons Molecular psychiatry Medium 29703946
2018 In zebrafish, Bace2 cleaves the insulin receptor as a sheddase in melanophores; loss of bace2 (wanderlust mutant) causes hyperdendritic, hyperproliferative melanophores with aberrant localization due to hyperactive insulin/PI3K/mTOR signaling; inhibition of insulin/PI3Kγ/mTOR signaling rescues the wanderlust phenotype. Zebrafish bace2 mutant (wanderlust), chemical suppressor screen, insulin receptor cleavage assay, epistasis analysis with PI3K/mTOR inhibitors Developmental cell High 29804876
2019 BACE2 also processes APP at the beta-site; the juxtamembrane helix (JH) of APP normally inhibits BACE2 beta-secretase activity; JH-disrupting mutations and clusterin binding to JH trigger BACE2-mediated beta-cleavage of APP; both BACE2 and clusterin are elevated in aged mouse brains, enhancing beta-cleavage during aging. Cell-based APP cleavage assays with JH mutants, clusterin binding/co-IP, aged mouse brain biochemistry JCI insight Medium 30626751
2010 In pancreatic β-cells, BACE2 co-localizes with clathrin-coated vesicles at the plasma membrane; pharmacological inhibition or silencing of BACE2 increases BACE2 content in clathrin-coated vesicles, reduces insulin internalization rate, decreases insulin receptor β-subunit at the plasma membrane (increased in Golgi), and reduces insulin gene expression, indicating a role for BACE2 in insulin receptor trafficking. Immunofluorescence colocalization, pharmacological inhibition, siRNA silencing, insulin internalization assay, western blot of subcellular fractions American journal of physiology. Endocrinology and metabolism Medium 20943756
2020 BACE2 trisomy in Down syndrome is a gene dose-sensitive AD suppressor; CRISPR/Cas9 elimination of the third copy of BACE2 in trisomy 21 cerebral organoids triggered AD-like pathology (Aβ deposits, tau pathology, neuronal loss); T21 organoids secrete increased Aβ-preventing (Aβ1-19) and Aβ-degradation products (Aβ1-20, Aβ1-34); this protective mechanism is cross-inhibited by BACE1 inhibitors. CRISPR/Cas9 gene editing of trisomy 21 cerebral organoids, Aβ peptide profiling by mass spectrometry, CSF analysis in DS patients, BACE1 inhibitor treatment Molecular psychiatry High 32647257
2024 BACE2 is the protease responsible for shedding of the lymphangiogenic receptor VEGFR3 from lymphatic endothelial cells; BACE2 (not BACE1) inactivation inhibited VEGFR3 shedding from primary human lymphatic endothelial cells, reduced soluble VEGFR3 in blood of mice, non-human primates, and humans, and increased full-length VEGFR3 and VEGFR3 signaling; in zebrafish, BACE2 inactivation enhanced LEC migration; soluble VEGFR3 can serve as pharmacodynamic plasma marker for BACE2 activity. Genetic and pharmacological BACE2 inactivation in primary human LECs, mouse/NHP/human plasma sVEGFR3 measurement, zebrafish LEC migration assay, VEGFR3 signaling analysis The Journal of clinical investigation High 38888964
2013 Multiple high-resolution crystal structures of BACE2 in six different packing environments were obtained using surface mutagenesis and co-crystallization with Fab fragments, Fynomers, and Xaperones; these structures define an ensemble of low-energy conformations accessible to the enzyme. X-ray crystallography with multiple crystallization helpers (Fab, Fynomers, Xaperones, surface mutagenesis) Acta crystallographica. Section D, Biological crystallography High 23695257
2010 In rat astrocytes, beta-secretase activity and Aβ production are due to BACE2 (not BACE1), whose expression is blocked at the translational level in astrocytes; neuroinflammatory changes can both positively and negatively modulate BACE2-dependent beta-secretase activity in astrocytes. Primary astrocyte cultures, translational regulation analysis, Aβ production assay, proinflammatory stimulation The European journal of neuroscience Medium 21073551
2021 BACE2 overexpression in ocular melanoma cells inhibits tumor progression in vitro and in vivo; BACE2 regulates TMEM38B expression, and the BACE2/TMEM38B axis modulates calcium release from the endoplasmic reticulum; increased N6-methyladenosine (m6A) RNA methylation leads to upregulation of BACE2 mRNA in ocular melanoma. BACE2 knockdown/overexpression in cell lines and xenografts, TMEM38B expression analysis, calcium flux assay, m6A methylation analysis Molecular therapy Medium 33601055
2022 BACE2 loss-of-function mutation (BACE2G446R) in human pluripotent stem cell-derived brain organoids causes increased apoptosis and elevated Aβ oligomers resembling AD phenotypes; these phenotypes are rescued by APP removal; BACE2WT overexpression in organoids carrying APP Swedish/Indiana mutations attenuates Aβ accumulation and neuronal cell death. hPSC-derived brain organoids with BACE2 loss-of-function variant, CRISPR/APP knockout rescue, BACE2 overexpression in AD mutant organoids Cell death discovery Medium 35110536
2005 BACE2 knockout mice display an overall healthy phenotype; combined BACE1/BACE2 deficiency enhances BACE1-/- lethality; BACE2 contributes to Aβ generation in glia (which lack BACE1 activity), not in neurons. Genetic knockout mice (single and double KO), biochemical Aβ analysis in neurons and glia The Journal of biological chemistry High 15987683
2013 In zebrafish, loss of Bace2 results in a specific melanocyte migration and morphology phenotype not observed in Bace1-/- fish; double homozygous bace1-/-; bace2-/- fish do not enhance single mutant phenotypes, indicating non-redundant, distinct physiological functions for Bace1 and Bace2. Zinc finger nuclease-mediated gene editing to generate Bace1 and Bace2 KO zebrafish, phenotypic analysis of single and double mutants Journal of neurochemistry High 23406323

Source papers

Stage 0 corpus · 100 papers · ranked by NIH iCite citations
Year Title Journal Citations PMID
2000 BACE2, a beta -secretase homolog, cleaves at the beta site and within the amyloid-beta region of the amyloid-beta precursor protein. Proceedings of the National Academy of Sciences of the United States of America 340 10931940
2005 Phenotypic and biochemical analyses of BACE1- and BACE2-deficient mice. The Journal of biological chemistry 297 15987683
1995 The membrane protein CD9/DRAP 27 potentiates the juxtacrine growth factor activity of the membrane-anchored heparin-binding EGF-like growth factor. The Journal of cell biology 267 7876316
2000 Expression analysis of BACE2 in brain and peripheral tissues. The Journal of biological chemistry 252 10749877
2013 BACE2 processes PMEL to form the melanosome amyloid matrix in pigment cells. Proceedings of the National Academy of Sciences of the United States of America 154 23754390
2001 BACE2 functions as an alternative alpha-secretase in cells. The Journal of biological chemistry 149 11423558
2000 ASP1 (BACE2) cleaves the amyloid precursor protein at the beta-secretase site. Molecular and cellular neurosciences 147 11083922
2006 BACE2, as a novel APP theta-secretase, is not responsible for the pathogenesis of Alzheimer's disease in Down syndrome. FASEB journal : official publication of the Federation of American Societies for Experimental Biology 142 16816112
2011 Bace2 is a β cell-enriched protease that regulates pancreatic β cell function and mass. Cell metabolism 126 21907142
2005 Distinct transcriptional regulation and function of the human BACE2 and BACE1 genes. FASEB journal : official publication of the Federation of American Societies for Experimental Biology 118 15857888
2000 The gene encoding DRAP (BACE2), a glycosylated transmembrane protein of the aspartic protease family, maps to the down critical region. FEBS letters 117 10683441
2009 BACE1 and BACE2 enzymatic activities in Alzheimer's disease. Journal of neurochemistry 101 19968762
2020 Patient-specific Alzheimer-like pathology in trisomy 21 cerebral organoids reveals BACE2 as a gene dose-sensitive AD suppressor in human brain. Molecular psychiatry 97 32647257
2013 Amyloid-β protein (Aβ) Glu11 is the major β-secretase site of β-site amyloid-β precursor protein-cleaving enzyme 1(BACE1), and shifting the cleavage site to Aβ Asp1 contributes to Alzheimer pathogenesis. The European journal of neuroscience 93 23773065
2004 Cloning, yeast expression, isolation, and vaccine testing of recombinant Ancylostoma-secreted protein (ASP)-1 and ASP-2 from Ancylostoma ceylanicum. The Journal of infectious diseases 93 14976610
2002 A non-amyloidogenic function of BACE-2 in the secretory pathway. Journal of neurochemistry 93 12065613
2013 Systematic proteomic analysis identifies β-site amyloid precursor protein cleaving enzyme 2 and 1 (BACE2 and BACE1) substrates in pancreatic β-cells. The Journal of biological chemistry 81 23430253
2004 Insights from modeling the tertiary structure of human BACE2. Journal of proteome research 79 15473697
2019 BACE2, a conditional β-secretase, contributes to Alzheimer's disease pathogenesis. JCI insight 71 30626751
2000 A new aspartyl protease on 21q22.3, BACE2, is highly similar to Alzheimer's amyloid precursor protein beta-secretase. Cytogenetics and cell genetics 71 10965118
2019 Molecular Mechanism of Binding Selectivity of Inhibitors toward BACE1 and BACE2 Revealed by Multiple Short Molecular Dynamics Simulations and Free-Energy Predictions. ACS chemical neuroscience 66 31545898
2016 Pharmacological BACE1 and BACE2 inhibition induces hair depigmentation by inhibiting PMEL17 processing in mice. Scientific reports 60 26912421
2003 BACE1- and BACE2-expressing human cells: characterization of beta-amyloid precursor protein-derived catabolites, design of a novel fluorimetric assay, and identification of new in vitro inhibitors. The Journal of biological chemistry 60 12736275
2016 Bacillus thuringiensis Crystal Protein Cry6Aa Triggers Caenorhabditis elegans Necrosis Pathway Mediated by Aspartic Protease (ASP-1). PLoS pathogens 58 26795495
2013 Loss of Bace2 in zebrafish affects melanocyte migration and is distinct from Bace1 knock out phenotypes. Journal of neurochemistry 55 23406323
2007 The proteins BACE1 and BACE2 and beta-secretase activity in normal and Alzheimer's disease brain. Biochemical Society transactions 55 17511655
2018 BACE2 distribution in major brain cell types and identification of novel substrates. Life science alliance 54 30456346
2000 Aspartic proteases from the nematode Caenorhabditis elegans. Structural organization and developmental and cell-specific expression of asp-1. The Journal of biological chemistry 54 10854422
2012 Identification of BACE2 as an avid ß-amyloid-degrading protease. Molecular neurodegeneration 53 22986058
2011 BACE2 expression increases in human neurodegenerative disease. The American journal of pathology 53 22074738
1975 Synthesis and evaluation of (Des-Asp1)angiotensin I as a precursor for (Des-Asp1)angiotensin II ("Angiotensin III"). Journal of medicinal chemistry 51 172631
2018 Asp1 Bifunctional Activity Modulates Spindle Function via Controlling Cellular Inositol Pyrophosphate Levels in Schizosaccharomyces pombe. Molecular and cellular biology 48 29440310
2006 Altered beta-secretase enzyme kinetics and levels of both BACE1 and BACE2 in the Alzheimer's disease brain. FEBS letters 45 17113083
1999 Cloning of Aire, the mouse homologue of the autoimmune regulator (AIRE) gene responsible for autoimmune polyglandular syndrome type 1 (ASP1). Genomics 42 10049587
2005 Crystal structure of human BACE2 in complex with a hydroxyethylamine transition-state inhibitor. Journal of molecular biology 41 16305800
2001 Association studies using novel polymorphisms in BACE1 and BACE2. Neuroreport 41 11435901
2010 Asp1, a conserved 1/3 inositol polyphosphate kinase, regulates the dimorphic switch in Schizosaccharomyces pombe. Molecular and cellular biology 40 20624911
1976 Evidence that des-Asp1 angiotensin II mediates the renin-angiotensin response. Circulation research 40 178468
2003 BACE-2 is overexpressed in Down's syndrome. Experimental neurology 39 12895444
2001 Presence of BACE1 and BACE2 in muscle fibres of patients with sporadic inclusion-body myositis. Lancet (London, England) 39 11747923
1977 (Des-Asp1) angiotensin I: a study of its pressor and steroidogenic activities in conscious rats. Endocrinology 39 187407
2015 Asp1 from Schizosaccharomyces pombe binds a [2Fe-2S](2+) cluster which inhibits inositol pyrophosphate 1-phosphatase activity. Biochemistry 38 26422458
1977 [Des-Asp1] angiotensin II: mediator of the renin-angiotensin system? Federation proceedings 38 321257
2003 BACE1 and BACE2 in pathologic and normal human muscle. Experimental neurology 37 12618121
1976 The effects of des-Asp1-angiotensin II on blood pressure, plasma aldosterone concentration, and plasma renin activity in the rabbit. Circulation research 37 178463
2013 Polymorphisms in BACE2 may affect the age of onset Alzheimer's dementia in Down syndrome. Neurobiology of aging 35 24462566
2010 BACE2 plays a role in the insulin receptor trafficking in pancreatic ß-cells. American journal of physiology. Endocrinology and metabolism 35 20943756
1990 Intracerebroventricularly infused [D-Arg1]angiotensin III, is superior to [D-Asp1]angiotensin II, as a pressor agent in rats. Brain research 35 2357530
2001 Prodomain processing of Asp1 (BACE2) is autocatalytic. The Journal of biological chemistry 34 11316808
1994 Degradation of angiotensin I to [des-Asp1]angiotensin I by a novel aminopeptidase in the rat hypothalamus. Biochemical pharmacology 34 8093092
2009 Allosteric and binding properties of Asp1-Glu382 truncated recombinant human serum albumin--an optical and NMR spectroscopic investigation. The FEBS journal 33 19298387
1999 Identification and characterization of Schizosaccharomyces pombe asp1(+), a gene that interacts with mutations in the Arp2/3 complex and actin. Genetics 32 10388810
2016 Identification of Human Islet Amyloid Polypeptide as a BACE2 Substrate. PloS one 31 26840340
2003 Transfer and expression of an artificial storage protein (ASP1) gene in cassava (Manihot esculenta Crantz). Transgenic research 31 12739891
2021 m6A RNA hypermethylation-induced BACE2 boosts intracellular calcium release and accelerates tumorigenesis of ocular melanoma. Molecular therapy : the journal of the American Society of Gene Therapy 30 33601055
2019 Discovery of AM-6494: A Potent and Orally Efficacious β-Site Amyloid Precursor Protein Cleaving Enzyme 1 (BACE1) Inhibitor with in Vivo Selectivity over BACE2. Journal of medicinal chemistry 30 31589043
2019 Structure-Based Design of Selective β-Site Amyloid Precursor Protein Cleaving Enzyme 1 (BACE1) Inhibitors: Targeting the Flap to Gain Selectivity over BACE2. Journal of medicinal chemistry 29 31021626
2010 Induction of protection against divergent H5N1 influenza viruses using a recombinant fusion protein linking influenza M2e to Onchocerca volvulus activation associated protein-1 (ASP-1) adjuvant. Vaccine 29 20732469
2022 BACE2 variant identified from HSCR patient causes AD-like phenotypes in hPSC-derived brain organoids. Cell death discovery 28 35110536
2010 β-Secretase activity in rat astrocytes: translational block of BACE1 and modulation of BACE2 expression. The European journal of neuroscience 28 21073551
2005 Chromosome 21 BACE2 haplotype associates with Alzheimer's disease: a two-stage study. Journal of the neurological sciences 27 16023140
2021 Cell surface GRP78 regulates BACE2 via lysosome-dependent manner to maintain mesenchymal phenotype of glioma stem cells. Journal of experimental & clinical cancer research : CR 26 33413577
2006 Functional domains of the BACE1 and BACE2 promoters and mechanisms of transcriptional suppression of the BACE2 promoter in normal neuronal cells. Journal of molecular neuroscience : MN 25 16757811
2018 Cleavage of potassium channel Kv2.1 by BACE2 reduces neuronal apoptosis. Molecular psychiatry 24 29703946
2014 Binding interaction between a queen pheromone component HOB and pheromone binding protein ASP1 of Apis cerana. International journal of biological macromolecules 24 25195542
2013 Mapping the conformational space accessible to BACE2 using surface mutants and cocrystals with Fab fragments, Fynomers and Xaperones. Acta crystallographica. Section D, Biological crystallography 24 23695257
2008 Vaccine testing of a recombinant activation-associated secreted protein (ASP1) from Ostertagia ostertagi. Parasite immunology 24 18086018
1999 Behavioural and histological effects of atrazine on freshwater molluscs (Physa acuta Drap. and Ancylus fluviatilis Müll. Gastropoda). Journal of applied toxicology : JAT 24 10513681
1977 Stimulation of corticosteroid biosynthesis by angiotensin I [des-asp1]angiotensin I, angiotensin II and [des-asp1]-angiotensin II in bovine adrenal fasciculata cells. Endocrinology 24 196831
2013 Structure of Ostertagia ostertagi ASP-1: insights into disulfide-mediated cyclization and dimerization. Acta crystallographica. Section D, Biological crystallography 23 23519657
2001 Disulfide pairing and secondary structure of ASP1, an olfactory-binding protein from honeybee (Apis mellifera L). The journal of peptide research : official journal of the American Peptide Society 23 12005423
1980 Biological activity of des-Asp1-angiotensin I in man. The Journal of clinical endocrinology and metabolism 23 7350186
1976 Des-Asp1-angiotensin I: a metabolite of angiotensin I in the perfused feline adrenal. European journal of pharmacology 23 954820
2009 Characterization of a mouse model overexpressing beta-site APP-cleaving enzyme 2 reveals a new role for BACE2. Genes, brain, and behavior 22 19840121
2016 Reversible and Species-Specific Depigmentation Effects of AZD3293, a BACE Inhibitor for the Treatment of Alzheimer's Disease, Are Related to BACE2 Inhibition and Confined to Epidermis and Hair. The journal of prevention of Alzheimer's disease 21 29199322
2019 Transcriptional Corepressor ASP1 and CLV-Like Signaling Regulate Meristem Maintenance in Rice. Plant physiology 20 31079034
2019 Common BACE2 Polymorphisms are Associated with Altered Risk for Alzheimer's Disease and CSF Amyloid Biomarkers in APOE ε4 Non-Carriers. Scientific reports 19 31270419
2016 A comparative molecular dynamics study on BACE1 and BACE2 flap flexibility. Journal of receptor and signal transduction research 19 26804314
2014 Inhibition of BACE2 counteracts hIAPP-induced insulin secretory defects in pancreatic β-cells. FASEB journal : official publication of the Federation of American Societies for Experimental Biology 19 25342134
2013 BACE2 as a new diabetes target: a patent review (2010 - 2012). Expert opinion on therapeutic patents 19 23506624
2013 BACE2 degradation mediated by the macroautophagy-lysosome pathway. The European journal of neuroscience 19 23773066
2010 In vivo effects of APP are not exacerbated by BACE2 co-overexpression: behavioural characterization of a double transgenic mouse model. Amino acids 19 20596738
1994 The ASP1 gene of Saccharomyces cerevisiae, encoding the intracellular isozyme of L-asparaginase. Gene 19 8026756
2021 The PPIP5K Family Member Asp1 Controls Inorganic Polyphosphate Metabolism in S. pombe. Journal of fungi (Basel, Switzerland) 18 34436165
2019 Highly Selective and Potent Human β-Secretase 2 (BACE2) Inhibitors against Type 2 Diabetes: Design, Synthesis, X-ray Structure and Structure-Activity Relationship Studies. ChemMedChem 18 30637955
2018 Distant Insulin Signaling Regulates Vertebrate Pigmentation through the Sheddase Bace2. Developmental cell 18 29804876
2017 BACE2 suppression promotes β-cell survival and function in a model of type 2 diabetes induced by human islet amyloid polypeptide overexpression. Cellular and molecular life sciences : CMLS 18 28337562
1978 Formation of DES-ASP1-angiotensin II is not an obligatory step in the steroidogenic action of angiotensin II in the canine adrenal. Endocrinology 18 744059
2023 BACE2: A Promising Neuroprotective Candidate for Alzheimer's Disease. Journal of Alzheimer's disease : JAD 17 36463454
2019 Isolation and Characterization of Multidrug Resistance Aeromonas salmonicida subsp. salmonicida and Its Infecting Novel Phage ASP-1 from Goldfish (Carassius auratus). Indian journal of microbiology 16 31031430
1979 Formation of angiotensin III from [des-Asp1]angiotensin I in the mesentric vasculature. The American journal of physiology 16 464116
2013 A tale of two drug targets: the evolutionary history of BACE1 and BACE2. Frontiers in genetics 15 24381583
2012 Tmem27 dimerization, deglycosylation, plasma membrane depletion, and the extracellular Phe-Phe motif are negative regulators of cleavage by Bace2. Biological chemistry 15 22628310
1978 Correlation of the biological activity and solution conformation of [Asp1,Ile5]- and [Phe4,Tyr8]angiotensin II. Proceedings of the National Academy of Sciences of the United States of America 15 29291
2016 Inositol Pyrophosphate Kinase Asp1 Modulates Chromosome Segregation Fidelity and Spindle Function in Schizosaccharomyces pombe. Molecular and cellular biology 14 27697865
2014 Amino acid sequence and structural comparison of BACE1 and BACE2 using evolutionary trace method. TheScientificWorldJournal 14 25254246
2007 Saturation of the secretory pathway by overexpression of a hookworm (Necator americanus) Protein (Na-ASP1). Methods in molecular biology (Clifton, N.J.) 14 17951635
2006 Characterization of the human beta-secretase 2 (BACE2) 5'-flanking region: identification of a 268-bp region as the basal BACE2 promoter. Journal of molecular neuroscience : MN 14 16757812
2024 The Alzheimer's disease-linked protease BACE2 cleaves VEGFR3 and modulates its signaling. The Journal of clinical investigation 13 38888964
2023 Next Generation Therapeutic Strategy for Treatment and Prevention of Alzheimer's Disease and Aging-Associated Cognitive Decline: Transient, Once-in-a-Lifetime-Only Depletion of Intraneuronal Aβ (iAβ) by Its Targeted Degradation via Augmentation of Intra-iAβ-Cleaving Activities of BACE1 and/or BACE2. International journal of molecular sciences 13 38139415

Missed literature

Know a paper Affinage missed for BACE2? Flag it for the maintainers and the community.

No submissions yet.