id: Q92542
gene_symbol: NCSTN
product_type: PROTEIN
status: COMPLETE
taxon:
  id: NCBITaxon:9606
  label: Homo sapiens
description: >-
  NCSTN encodes nicastrin, a single-pass type I membrane glycoprotein and essential
  non-catalytic subunit of the gamma-secretase complex. Together with a presenilin
  catalytic subunit, APH1A or APH1B, and PSENEN/PEN-2, nicastrin forms a membrane-embedded
  intramembrane protease complex that processes substrates including APP and Notch
  receptors. Nicastrin contributes to complex assembly, maturation, substrate recruitment
  or presentation, and endoprotease activity rather than acting as the catalytic aspartyl
  protease itself. It functions in ER/Golgi/endomembrane, endosomal, and plasma-membrane
  compartments where gamma-secretase substrates are processed.
alternative_products:
- name: '1'
  id: Q92542-1
- name: '2'
  id: Q92542-2
  sequence_note: VSP_008385, VSP_008386
existing_annotations:
- term:
    id: GO:0005886
    label: plasma membrane
  evidence_type: IBA
  original_reference_id: GO_REF:0000033
  qualifier: is_active_in
  review:
    summary: A pool of mature gamma-secretase, including nicastrin, resides at the plasma membrane where it cleaves cell-surface substrate C-terminal fragments such as Notch NEXT.
    action: ACCEPT
    reason: 'Core: well-supported site of active gamma-secretase (IDA/TAS/IBA).'
- term:
    id: GO:0016485
    label: protein processing
  evidence_type: IBA
  original_reference_id: GO_REF:0000033
  qualifier: involved_in
  review:
    summary: Nicastrin contributes to the proteolytic processing of gamma-secretase substrates (Notch, APP, and other type I membrane proteins) via regulated intramembrane proteolysis.
    action: ACCEPT
    reason: Core processing role of the complex (IDA/IMP/IGI/IBA).
- term:
    id: GO:0007220
    label: Notch receptor processing
  evidence_type: IBA
  original_reference_id: GO_REF:0000033
  qualifier: involved_in
  review:
    summary: Nicastrin-containing gamma-secretase performs the regulated intramembrane (S3) cleavage of Notch receptors that releases NICD; nicastrin recognizes the Notch NEXT substrate.
    action: ACCEPT
    reason: Core biological process of the complex; nicastrin is essential (IDA/IMP; structure with Notch1).
- term:
    id: GO:0012505
    label: endomembrane system
  evidence_type: IEA
  original_reference_id: GO_REF:0000117
  qualifier: located_in
  review:
    summary: Nicastrin distributes across the endomembrane system (ER, Golgi, endosomes) reflecting biogenesis, maturation and the multiple sites where gamma-secretase acts.
    action: ACCEPT
    reason: Accurate parent-level localization of the complex (IEA).
- term:
    id: GO:0016020
    label: membrane
  evidence_type: IEA
  original_reference_id: GO_REF:0000120
  qualifier: located_in
  review:
    summary: Nicastrin is a single-pass type I transmembrane glycoprotein; its membrane integration is required for assembly into the membrane-embedded gamma-secretase complex.
    action: ACCEPT
    reason: 'Core localization: confirmed type I membrane protein (IDA/EXP, structures).'
- term:
    id: GO:0016485
    label: protein processing
  evidence_type: IEA
  original_reference_id: GO_REF:0000120
  qualifier: involved_in
  review:
    summary: Nicastrin contributes to the proteolytic processing of gamma-secretase substrates (Notch, APP, and other type I membrane proteins) via regulated intramembrane proteolysis.
    action: ACCEPT
    reason: Core processing role of the complex (IDA/IMP/IGI/IBA).
- term:
    id: GO:0030659
    label: cytoplasmic vesicle membrane
  evidence_type: IEA
  original_reference_id: GO_REF:0000044
  qualifier: located_in
  review:
    summary: UniProt annotates nicastrin as a cytoplasmic vesicle membrane protein, consistent with trafficking of the gamma-secretase complex through the endomembrane/vesicular system.
    action: ACCEPT
    reason: Supported by experimental subcellular location (EXP/IEA).
- term:
    id: GO:0042470
    label: melanosome
  evidence_type: IEA
  original_reference_id: GO_REF:0000044
  qualifier: located_in
  review:
    summary: Nicastrin was identified by mass spectrometry in melanosome fractions; this reflects shared endomembrane trafficking rather than a melanosome-specific role.
    action: KEEP_AS_NON_CORE
    reason: Proteomic large-scale localization, non-core (IEA/SubCell).
- term:
    id: GO:0099503
    label: secretory vesicle
  evidence_type: IEA
  original_reference_id: GO_REF:0000117
  qualifier: located_in
  review:
    summary: Nicastrin associates with secretory vesicle membranes during transport of mature gamma-secretase toward the cell surface.
    action: ACCEPT
    reason: Consistent with vesicular trafficking of the complex (IEA).
- term:
    id: GO:0005515
    label: protein binding
  evidence_type: IPI
  original_reference_id: PMID:12297508
  qualifier: enables
  review:
    summary: Generic protein binding is uninformative; nicastrin's meaningful interactions (substrate CTFs, complex subunits) are better captured by adaptor/complex-membership terms.
    action: MARK_AS_OVER_ANNOTATED
    reason: Uninformative generic binding; superseded by specific MF/CC terms (IPI).
- term:
    id: GO:0005515
    label: protein binding
  evidence_type: IPI
  original_reference_id: PMID:15322109
  qualifier: enables
  review:
    summary: Generic protein binding is uninformative; nicastrin's meaningful interactions (substrate CTFs, complex subunits) are better captured by adaptor/complex-membership terms.
    action: MARK_AS_OVER_ANNOTATED
    reason: Uninformative generic binding; superseded by specific MF/CC terms (IPI).
- term:
    id: GO:0005515
    label: protein binding
  evidence_type: IPI
  original_reference_id: PMID:15890777
  qualifier: enables
  review:
    summary: Generic protein binding is uninformative; nicastrin's meaningful interactions (substrate CTFs, complex subunits) are better captured by adaptor/complex-membership terms.
    action: MARK_AS_OVER_ANNOTATED
    reason: Uninformative generic binding; superseded by specific MF/CC terms (IPI).
- term:
    id: GO:0005515
    label: protein binding
  evidence_type: IPI
  original_reference_id: PMID:16641999
  qualifier: enables
  review:
    summary: Generic protein binding is uninformative; nicastrin's meaningful interactions (substrate CTFs, complex subunits) are better captured by adaptor/complex-membership terms.
    action: MARK_AS_OVER_ANNOTATED
    reason: Uninformative generic binding; superseded by specific MF/CC terms (IPI).
- term:
    id: GO:0005515
    label: protein binding
  evidence_type: IPI
  original_reference_id: PMID:18201567
  qualifier: enables
  review:
    summary: Generic protein binding is uninformative; nicastrin's meaningful interactions (substrate CTFs, complex subunits) are better captured by adaptor/complex-membership terms.
    action: MARK_AS_OVER_ANNOTATED
    reason: Uninformative generic binding; superseded by specific MF/CC terms (IPI).
- term:
    id: GO:0005515
    label: protein binding
  evidence_type: IPI
  original_reference_id: PMID:19376115
  qualifier: enables
  review:
    summary: Generic protein binding is uninformative; nicastrin's meaningful interactions (substrate CTFs, complex subunits) are better captured by adaptor/complex-membership terms.
    action: MARK_AS_OVER_ANNOTATED
    reason: Uninformative generic binding; superseded by specific MF/CC terms (IPI).
- term:
    id: GO:0005515
    label: protein binding
  evidence_type: IPI
  original_reference_id: PMID:26280335
  qualifier: enables
  review:
    summary: Generic protein binding is uninformative; nicastrin's meaningful interactions (substrate CTFs, complex subunits) are better captured by adaptor/complex-membership terms.
    action: MARK_AS_OVER_ANNOTATED
    reason: Uninformative generic binding; superseded by specific MF/CC terms (IPI).
- term:
    id: GO:0005515
    label: protein binding
  evidence_type: IPI
  original_reference_id: PMID:29611543
  qualifier: enables
  review:
    summary: Generic protein binding is uninformative; nicastrin's meaningful interactions (substrate CTFs, complex subunits) are better captured by adaptor/complex-membership terms.
    action: MARK_AS_OVER_ANNOTATED
    reason: Uninformative generic binding; superseded by specific MF/CC terms (IPI).
- term:
    id: GO:0005515
    label: protein binding
  evidence_type: IPI
  original_reference_id: PMID:30559186
  qualifier: enables
  review:
    summary: Generic protein binding is uninformative; nicastrin's meaningful interactions (substrate CTFs, complex subunits) are better captured by adaptor/complex-membership terms.
    action: MARK_AS_OVER_ANNOTATED
    reason: Uninformative generic binding; superseded by specific MF/CC terms (IPI).
- term:
    id: GO:0004175
    label: endopeptidase activity
  evidence_type: IEA
  original_reference_id: GO_REF:0000107
  qualifier: contributes_to
  review:
    summary: Generic endopeptidase activity is incorrectly attributed to nicastrin, which lacks catalytic residues; proteolysis is performed by the presenilin subunit of gamma-secretase.
    action: MARK_AS_OVER_ANNOTATED
    reason: Non-catalytic subunit; activity is presenilin's (IEA).
- term:
    id: GO:0005764
    label: lysosome
  evidence_type: IEA
  original_reference_id: GO_REF:0000120
  qualifier: located_in
  review:
    summary: Nicastrin is detected in the lysosomal compartment consistent with trafficking of gamma-secretase through the late endolysosomal pathway.
    action: ACCEPT
    reason: Consistent with endolysosomal pool of the complex (IEA).
- term:
    id: GO:0005765
    label: lysosomal membrane
  evidence_type: IEA
  original_reference_id: GO_REF:0000107
  qualifier: located_in
  review:
    summary: Mature gamma-secretase, including nicastrin, reaches lysosomal/late-endosomal membranes, a documented compartment for substrate processing and turnover.
    action: ACCEPT
    reason: Supported lysosomal membrane localization (HDA/IEA).
- term:
    id: GO:0005769
    label: early endosome
  evidence_type: IEA
  original_reference_id: GO_REF:0000107
  qualifier: located_in
  review:
    summary: Active gamma-secretase, including nicastrin, localizes to early endosomes, an important site of APP processing and amyloid-beta generation.
    action: ACCEPT
    reason: Endosomal pool is a recognized site of complex activity (IEA).
- term:
    id: GO:0005783
    label: endoplasmic reticulum
  evidence_type: IEA
  original_reference_id: GO_REF:0000107
  qualifier: located_in
  review:
    summary: Nicastrin is synthesized and initially N-glycosylated in the ER, where immature gamma-secretase subassembly begins before trafficking and maturation.
    action: ACCEPT
    reason: 'Core: ER is the biogenesis/assembly compartment (IDA).'
- term:
    id: GO:0005794
    label: Golgi apparatus
  evidence_type: IEA
  original_reference_id: GO_REF:0000107
  qualifier: located_in
  review:
    summary: Nicastrin transits the Golgi where it undergoes complex N-glycan maturation, a hallmark of the catalytically competent mature gamma-secretase.
    action: ACCEPT
    reason: Maturation compartment for nicastrin glycosylation (IDA).
- term:
    id: GO:0005886
    label: plasma membrane
  evidence_type: IEA
  original_reference_id: GO_REF:0000120
  qualifier: located_in
  review:
    summary: A pool of mature gamma-secretase, including nicastrin, resides at the plasma membrane where it cleaves cell-surface substrate C-terminal fragments such as Notch NEXT.
    action: ACCEPT
    reason: 'Core: well-supported site of active gamma-secretase (IDA/TAS/IBA).'
- term:
    id: GO:0008021
    label: synaptic vesicle
  evidence_type: IEA
  original_reference_id: GO_REF:0000120
  qualifier: located_in
  review:
    summary: Synaptic vesicle localization is an electronic, neuron-specific annotation reflecting vesicular trafficking, not a defining gamma-secretase location.
    action: KEEP_AS_NON_CORE
    reason: Specialized neuronal localization, non-core (IEA).
- term:
    id: GO:0008233
    label: peptidase activity
  evidence_type: IEA
  original_reference_id: GO_REF:0000107
  qualifier: enables
  review:
    summary: Nicastrin has no peptidase activity despite a degenerate M28 aminopeptidase-like fold; the catalytic site is degenerate and proteolysis resides in presenilin.
    action: MARK_AS_OVER_ANNOTATED
    reason: Pseudo-protease fold; no catalytic activity in NCSTN (IEA).
- term:
    id: GO:0021549
    label: cerebellum development
  evidence_type: IEA
  original_reference_id: GO_REF:0000107
  qualifier: involved_in
  review:
    summary: Gamma-secretase/Notch signaling influences cerebellar development; this is a downstream developmental consequence rather than nicastrin's direct molecular role.
    action: KEEP_AS_NON_CORE
    reason: Downstream developmental process via Notch, non-core (IEA).
- term:
    id: GO:0032991
    label: protein-containing complex
  evidence_type: IEA
  original_reference_id: GO_REF:0000120
  qualifier: part_of
  review:
    summary: Nicastrin functions only as part of a hetero-oligomeric assembly; this generic complex term is subsumed by the specific gamma-secretase complex annotation.
    action: ACCEPT
    reason: True but generic; the specific gamma-secretase complex term is preferred (IEA).
- term:
    id: GO:0042383
    label: sarcolemma
  evidence_type: IEA
  original_reference_id: GO_REF:0000107
  qualifier: located_in
  review:
    summary: Sarcolemma (muscle plasma membrane) localization is an electronic tissue-specific annotation, a specialization of the general plasma-membrane pool.
    action: KEEP_AS_NON_CORE
    reason: Tissue-specific plasma-membrane subtype, non-core (IEA).
- term:
    id: GO:0042500
    label: aspartic endopeptidase activity, intramembrane cleaving
  evidence_type: IEA
  original_reference_id: GO_REF:0000107
  qualifier: contributes_to
  review:
    summary: Intramembrane aspartyl-protease activity is the function of presenilin, not nicastrin; nicastrin is catalytically inactive and only recognizes substrate. The activity belongs to the complex/PSEN.
    action: MARK_AS_OVER_ANNOTATED
    reason: NCSTN is non-catalytic; this MF belongs to presenilin (IEA, electronic).
- term:
    id: GO:0042734
    label: presynaptic membrane
  evidence_type: IEA
  original_reference_id: GO_REF:0000107
  qualifier: is_active_in
  review:
    summary: Electronic annotation places nicastrin at the presynaptic membrane, consistent with neuronal gamma-secretase activity but a specialized, non-core localization.
    action: KEEP_AS_NON_CORE
    reason: Tissue-specialized localization, non-core (IEA).
- term:
    id: GO:0070765
    label: gamma-secretase complex
  evidence_type: IEA
  original_reference_id: GO_REF:0000107
  qualifier: part_of
  review:
    summary: Nicastrin is an obligate, structurally-defined subunit of the gamma-secretase complex (PSEN1/2, NCSTN, APH1A/B, PSENEN), confirmed by cryo-EM; this is its defining cellular localization.
    action: ACCEPT
    reason: 'Core: NCSTN is a constitutive component of this complex (IDA/IPI, multiple cryo-EM structures).'
- term:
    id: GO:0097060
    label: synaptic membrane
  evidence_type: IEA
  original_reference_id: GO_REF:0000107
  qualifier: located_in
  review:
    summary: Synaptic-membrane localization reflects neuronal gamma-secretase processing of synaptic substrates; a specialized site rather than the core annotation.
    action: KEEP_AS_NON_CORE
    reason: Neuronal specialized localization, non-core (IEA).
- term:
    id: GO:0005789
    label: endoplasmic reticulum membrane
  evidence_type: NAS
  original_reference_id: PMID:15274632
  qualifier: located_in
  review:
    summary: As a membrane protein, nicastrin resides in the ER membrane during early biogenesis and partial complex assembly prior to Golgi maturation.
    action: ACCEPT
    reason: Core-consistent ER membrane localization (NAS, ComplexPortal).
- term:
    id: GO:0005886
    label: plasma membrane
  evidence_type: IDA
  original_reference_id: PMID:15274632
  qualifier: located_in
  review:
    summary: A pool of mature gamma-secretase, including nicastrin, resides at the plasma membrane where it cleaves cell-surface substrate C-terminal fragments such as Notch NEXT.
    action: ACCEPT
    reason: 'Core: well-supported site of active gamma-secretase (IDA/TAS/IBA).'
- term:
    id: GO:0007220
    label: Notch receptor processing
  evidence_type: NAS
  original_reference_id: PMID:10206645
  qualifier: involved_in
  review:
    summary: Nicastrin-containing gamma-secretase performs the regulated intramembrane (S3) cleavage of Notch receptors that releases NICD; nicastrin recognizes the Notch NEXT substrate.
    action: ACCEPT
    reason: Core biological process of the complex; nicastrin is essential (IDA/IMP; structure with Notch1).
- term:
    id: GO:0031293
    label: membrane protein intracellular domain proteolysis
  evidence_type: IDA
  original_reference_id: PMID:15274632
  qualifier: involved_in
  review:
    summary: Gamma-secretase, via nicastrin substrate recognition, releases intracellular domains (e.g., NICD, AICD) by intramembrane cleavage of type I membrane substrates.
    action: ACCEPT
    reason: 'Core: ICD-releasing regulated intramembrane proteolysis (IDA, ComplexPortal).'
- term:
    id: GO:0042987
    label: amyloid precursor protein catabolic process
  evidence_type: IDA
  original_reference_id: PMID:15274632
  qualifier: involved_in
  review:
    summary: Nicastrin engages APP C-terminal fragments (C83/C99) for gamma-secretase cleavage, driving the catabolic intramembrane processing of APP.
    action: ACCEPT
    reason: 'Core: complex-mediated APP catabolism, nicastrin binds the CTFs (IDA/IGI/TAS).'
- term:
    id: GO:0070765
    label: gamma-secretase complex
  evidence_type: IPI
  original_reference_id: PMID:26280335
  qualifier: part_of
  review:
    summary: Nicastrin is an obligate, structurally-defined subunit of the gamma-secretase complex (PSEN1/2, NCSTN, APH1A/B, PSENEN), confirmed by cryo-EM; this is its defining cellular localization.
    action: ACCEPT
    reason: 'Core: NCSTN is a constitutive component of this complex (IDA/IPI, multiple cryo-EM structures).'
- term:
    id: GO:0000139
    label: Golgi membrane
  evidence_type: NAS
  original_reference_id: PMID:15274632
  qualifier: located_in
  review:
    summary: Membrane-embedded nicastrin localizes to the Golgi membrane during glycan maturation and trafficking of the assembling complex.
    action: ACCEPT
    reason: Consistent with Golgi maturation of the complex (NAS, ComplexPortal).
- term:
    id: GO:0061133
    label: endopeptidase activator activity
  evidence_type: IMP
  original_reference_id: PMID:12297508
  qualifier: enables
  review:
    summary: By recruiting and presenting substrate CTFs and stabilizing the mature complex, nicastrin is required for and potentiates presenilin endopeptidase activity within gamma-secretase.
    action: ACCEPT
    reason: 'Core: nicastrin enables/activates complex protease activity (IMP/IGI).'
- term:
    id: GO:0061133
    label: endopeptidase activator activity
  evidence_type: IGI
  original_reference_id: PMID:12763021
  qualifier: enables
  review:
    summary: By recruiting and presenting substrate CTFs and stabilizing the mature complex, nicastrin is required for and potentiates presenilin endopeptidase activity within gamma-secretase.
    action: ACCEPT
    reason: 'Core: nicastrin enables/activates complex protease activity (IMP/IGI).'
- term:
    id: GO:0016020
    label: membrane
  evidence_type: EXP
  original_reference_id: PMID:25918421
  qualifier: located_in
  review:
    summary: Nicastrin is a single-pass type I transmembrane glycoprotein; its membrane integration is required for assembly into the membrane-embedded gamma-secretase complex.
    action: ACCEPT
    reason: 'Core localization: confirmed type I membrane protein (IDA/EXP, structures).'
- term:
    id: GO:0016020
    label: membrane
  evidence_type: EXP
  original_reference_id: PMID:26623517
  qualifier: located_in
  review:
    summary: Nicastrin is a single-pass type I transmembrane glycoprotein; its membrane integration is required for assembly into the membrane-embedded gamma-secretase complex.
    action: ACCEPT
    reason: 'Core localization: confirmed type I membrane protein (IDA/EXP, structures).'
- term:
    id: GO:0016020
    label: membrane
  evidence_type: EXP
  original_reference_id: PMID:26776682
  qualifier: located_in
  review:
    summary: Nicastrin is a single-pass type I transmembrane glycoprotein; its membrane integration is required for assembly into the membrane-embedded gamma-secretase complex.
    action: ACCEPT
    reason: 'Core localization: confirmed type I membrane protein (IDA/EXP, structures).'
- term:
    id: GO:0030659
    label: cytoplasmic vesicle membrane
  evidence_type: EXP
  original_reference_id: PMID:10993067
  qualifier: located_in
  review:
    summary: UniProt annotates nicastrin as a cytoplasmic vesicle membrane protein, consistent with trafficking of the gamma-secretase complex through the endomembrane/vesicular system.
    action: ACCEPT
    reason: Supported by experimental subcellular location (EXP/IEA).
- term:
    id: GO:0030674
    label: protein-macromolecule adaptor activity
  evidence_type: IMP
  original_reference_id: PMID:12297508
  qualifier: enables
  review:
    summary: Nicastrin's large ectodomain acts as the substrate-recognition module of gamma-secretase, engaging the N-terminal stub of substrate CTFs and bridging them to the presenilin catalytic core.
    action: ACCEPT
    reason: 'Core MF: nicastrin is the substrate-recognition/adaptor subunit (IMP/IGI; cryo-EM).'
- term:
    id: GO:0030674
    label: protein-macromolecule adaptor activity
  evidence_type: IGI
  original_reference_id: PMID:12763021
  qualifier: enables
  review:
    summary: Nicastrin's large ectodomain acts as the substrate-recognition module of gamma-secretase, engaging the N-terminal stub of substrate CTFs and bridging them to the presenilin catalytic core.
    action: ACCEPT
    reason: 'Core MF: nicastrin is the substrate-recognition/adaptor subunit (IMP/IGI; cryo-EM).'
- term:
    id: GO:0007220
    label: Notch receptor processing
  evidence_type: IMP
  original_reference_id: PMID:12297508
  qualifier: involved_in
  review:
    summary: Nicastrin-containing gamma-secretase performs the regulated intramembrane (S3) cleavage of Notch receptors that releases NICD; nicastrin recognizes the Notch NEXT substrate.
    action: ACCEPT
    reason: Core biological process of the complex; nicastrin is essential (IDA/IMP; structure with Notch1).
- term:
    id: GO:0007220
    label: Notch receptor processing
  evidence_type: IDA
  original_reference_id: PMID:27608597
  qualifier: involved_in
  review:
    summary: Nicastrin-containing gamma-secretase performs the regulated intramembrane (S3) cleavage of Notch receptors that releases NICD; nicastrin recognizes the Notch NEXT substrate.
    action: ACCEPT
    reason: Core biological process of the complex; nicastrin is essential (IDA/IMP; structure with Notch1).
- term:
    id: GO:0016485
    label: protein processing
  evidence_type: IMP
  original_reference_id: PMID:12297508
  qualifier: involved_in
  review:
    summary: Nicastrin contributes to the proteolytic processing of gamma-secretase substrates (Notch, APP, and other type I membrane proteins) via regulated intramembrane proteolysis.
    action: ACCEPT
    reason: Core processing role of the complex (IDA/IMP/IGI/IBA).
- term:
    id: GO:0016485
    label: protein processing
  evidence_type: IGI
  original_reference_id: PMID:12763021
  qualifier: involved_in
  review:
    summary: Nicastrin contributes to the proteolytic processing of gamma-secretase substrates (Notch, APP, and other type I membrane proteins) via regulated intramembrane proteolysis.
    action: ACCEPT
    reason: Core processing role of the complex (IDA/IMP/IGI/IBA).
- term:
    id: GO:0016485
    label: protein processing
  evidence_type: IDA
  original_reference_id: PMID:27608597
  qualifier: involved_in
  review:
    summary: Nicastrin contributes to the proteolytic processing of gamma-secretase substrates (Notch, APP, and other type I membrane proteins) via regulated intramembrane proteolysis.
    action: ACCEPT
    reason: Core processing role of the complex (IDA/IMP/IGI/IBA).
- term:
    id: GO:0034205
    label: amyloid-beta formation
  evidence_type: IMP
  original_reference_id: PMID:12297508
  qualifier: involved_in
  review:
    summary: Gamma-secretase cleavage of APP C99, dependent on nicastrin-mediated substrate recognition, generates amyloid-beta peptides; a central, well-defined activity.
    action: ACCEPT
    reason: Core APP-processing output of the complex (IDA/IMP/IGI).
- term:
    id: GO:0034205
    label: amyloid-beta formation
  evidence_type: IGI
  original_reference_id: PMID:12763021
  qualifier: involved_in
  review:
    summary: Gamma-secretase cleavage of APP C99, dependent on nicastrin-mediated substrate recognition, generates amyloid-beta peptides; a central, well-defined activity.
    action: ACCEPT
    reason: Core APP-processing output of the complex (IDA/IMP/IGI).
- term:
    id: GO:0034205
    label: amyloid-beta formation
  evidence_type: IDA
  original_reference_id: PMID:27608597
  qualifier: involved_in
  review:
    summary: Gamma-secretase cleavage of APP C99, dependent on nicastrin-mediated substrate recognition, generates amyloid-beta peptides; a central, well-defined activity.
    action: ACCEPT
    reason: Core APP-processing output of the complex (IDA/IMP/IGI).
- term:
    id: GO:0042987
    label: amyloid precursor protein catabolic process
  evidence_type: IGI
  original_reference_id: PMID:12763021
  qualifier: involved_in
  review:
    summary: Nicastrin engages APP C-terminal fragments (C83/C99) for gamma-secretase cleavage, driving the catabolic intramembrane processing of APP.
    action: ACCEPT
    reason: 'Core: complex-mediated APP catabolism, nicastrin binds the CTFs (IDA/IGI/TAS).'
- term:
    id: GO:0042987
    label: amyloid precursor protein catabolic process
  evidence_type: IDA
  original_reference_id: PMID:27608597
  qualifier: involved_in
  review:
    summary: Nicastrin engages APP C-terminal fragments (C83/C99) for gamma-secretase cleavage, driving the catabolic intramembrane processing of APP.
    action: ACCEPT
    reason: 'Core: complex-mediated APP catabolism, nicastrin binds the CTFs (IDA/IGI/TAS).'
- term:
    id: GO:0070765
    label: gamma-secretase complex
  evidence_type: IDA
  original_reference_id: PMID:12297508
  qualifier: part_of
  review:
    summary: Nicastrin is an obligate, structurally-defined subunit of the gamma-secretase complex (PSEN1/2, NCSTN, APH1A/B, PSENEN), confirmed by cryo-EM; this is its defining cellular localization.
    action: ACCEPT
    reason: 'Core: NCSTN is a constitutive component of this complex (IDA/IPI, multiple cryo-EM structures).'
- term:
    id: GO:0070765
    label: gamma-secretase complex
  evidence_type: IGI
  original_reference_id: PMID:12763021
  qualifier: part_of
  review:
    summary: Nicastrin is an obligate, structurally-defined subunit of the gamma-secretase complex (PSEN1/2, NCSTN, APH1A/B, PSENEN), confirmed by cryo-EM; this is its defining cellular localization.
    action: ACCEPT
    reason: 'Core: NCSTN is a constitutive component of this complex (IDA/IPI, multiple cryo-EM structures).'
- term:
    id: GO:0005515
    label: protein binding
  evidence_type: IPI
  original_reference_id: PMID:26094765
  qualifier: enables
  review:
    summary: Generic protein binding is uninformative; nicastrin's meaningful interactions (substrate CTFs, complex subunits) are better captured by adaptor/complex-membership terms.
    action: MARK_AS_OVER_ANNOTATED
    reason: Uninformative generic binding; superseded by specific MF/CC terms (IPI).
- term:
    id: GO:0051117
    label: ATPase binding
  evidence_type: IPI
  original_reference_id: PMID:26094765
  qualifier: enables
  review:
    summary: A specific physical interaction of nicastrin with an ATPase; a documented partner binding but peripheral to its core substrate-recognition role in gamma-secretase.
    action: KEEP_AS_NON_CORE
    reason: Specific partner binding, peripheral to core function (IPI).
- term:
    id: GO:0070851
    label: growth factor receptor binding
  evidence_type: IPI
  original_reference_id: PMID:26094765
  qualifier: enables
  review:
    summary: Nicastrin binds a growth factor receptor in a specific assay; consistent with gamma-secretase engaging receptor substrates but not its defining molecular function.
    action: KEEP_AS_NON_CORE
    reason: Specific partner binding, non-core (IPI).
- term:
    id: GO:0070765
    label: gamma-secretase complex
  evidence_type: NAS
  original_reference_id: PMID:22086926
  qualifier: part_of
  review:
    summary: Nicastrin is an obligate, structurally-defined subunit of the gamma-secretase complex (PSEN1/2, NCSTN, APH1A/B, PSENEN), confirmed by cryo-EM; this is its defining cellular localization.
    action: ACCEPT
    reason: 'Core: NCSTN is a constitutive component of this complex (IDA/IPI, multiple cryo-EM structures).'
- term:
    id: GO:0010008
    label: endosome membrane
  evidence_type: TAS
  original_reference_id: Reactome:R-HSA-9010096
  qualifier: located_in
  review:
    summary: Nicastrin is present in endosomal membranes where the gamma-secretase complex cleaves internalized substrates such as APP-CTFs.
    action: ACCEPT
    reason: Endosomal membrane is an active site of the complex (TAS, Reactome).
- term:
    id: GO:0016020
    label: membrane
  evidence_type: IDA
  original_reference_id: PMID:25043039
  qualifier: located_in
  review:
    summary: Nicastrin is a single-pass type I transmembrane glycoprotein; its membrane integration is required for assembly into the membrane-embedded gamma-secretase complex.
    action: ACCEPT
    reason: 'Core localization: confirmed type I membrane protein (IDA/EXP, structures).'
- term:
    id: GO:0016020
    label: membrane
  evidence_type: IDA
  original_reference_id: PMID:26280335
  qualifier: located_in
  review:
    summary: Nicastrin is a single-pass type I transmembrane glycoprotein; its membrane integration is required for assembly into the membrane-embedded gamma-secretase complex.
    action: ACCEPT
    reason: 'Core localization: confirmed type I membrane protein (IDA/EXP, structures).'
- term:
    id: GO:0034205
    label: amyloid-beta formation
  evidence_type: IMP
  original_reference_id: PMID:25043039
  qualifier: involved_in
  review:
    summary: Gamma-secretase cleavage of APP C99, dependent on nicastrin-mediated substrate recognition, generates amyloid-beta peptides; a central, well-defined activity.
    action: ACCEPT
    reason: Core APP-processing output of the complex (IDA/IMP/IGI).
- term:
    id: GO:0034205
    label: amyloid-beta formation
  evidence_type: IMP
  original_reference_id: PMID:26280335
  qualifier: involved_in
  review:
    summary: Gamma-secretase cleavage of APP C99, dependent on nicastrin-mediated substrate recognition, generates amyloid-beta peptides; a central, well-defined activity.
    action: ACCEPT
    reason: Core APP-processing output of the complex (IDA/IMP/IGI).
- term:
    id: GO:0042982
    label: amyloid precursor protein metabolic process
  evidence_type: IDA
  original_reference_id: PMID:25043039
  qualifier: involved_in
  review:
    summary: Nicastrin participates in APP metabolism as the substrate-recognition subunit presenting APP-CTFs to the gamma-secretase catalytic core.
    action: ACCEPT
    reason: Core APP-processing role (IDA).
- term:
    id: GO:0042982
    label: amyloid precursor protein metabolic process
  evidence_type: IDA
  original_reference_id: PMID:26280335
  qualifier: involved_in
  review:
    summary: Nicastrin participates in APP metabolism as the substrate-recognition subunit presenting APP-CTFs to the gamma-secretase catalytic core.
    action: ACCEPT
    reason: Core APP-processing role (IDA).
- term:
    id: GO:0070765
    label: gamma-secretase complex
  evidence_type: IDA
  original_reference_id: PMID:25043039
  qualifier: part_of
  review:
    summary: Nicastrin is an obligate, structurally-defined subunit of the gamma-secretase complex (PSEN1/2, NCSTN, APH1A/B, PSENEN), confirmed by cryo-EM; this is its defining cellular localization.
    action: ACCEPT
    reason: 'Core: NCSTN is a constitutive component of this complex (IDA/IPI, multiple cryo-EM structures).'
- term:
    id: GO:0070765
    label: gamma-secretase complex
  evidence_type: IDA
  original_reference_id: PMID:26280335
  qualifier: part_of
  review:
    summary: Nicastrin is an obligate, structurally-defined subunit of the gamma-secretase complex (PSEN1/2, NCSTN, APH1A/B, PSENEN), confirmed by cryo-EM; this is its defining cellular localization.
    action: ACCEPT
    reason: 'Core: NCSTN is a constitutive component of this complex (IDA/IPI, multiple cryo-EM structures).'
- term:
    id: GO:0035577
    label: azurophil granule membrane
  evidence_type: TAS
  original_reference_id: Reactome:R-HSA-6798739
  qualifier: located_in
  review:
    summary: Nicastrin is annotated to the azurophil (neutrophil) granule membrane via neutrophil-degranulation pathways; a tissue-specific localization, not the core complex function.
    action: KEEP_AS_NON_CORE
    reason: Pathway/tissue-specific secondary localization (TAS, Reactome).
- term:
    id: GO:0005925
    label: focal adhesion
  evidence_type: HDA
  original_reference_id: PMID:21423176
  qualifier: located_in
  review:
    summary: Nicastrin appears in focal adhesion proteomic fractions; this is a co-fractionation/contextual finding, not an established gamma-secretase function site.
    action: KEEP_AS_NON_CORE
    reason: Secondary proteomics localization, non-core (HDA).
- term:
    id: GO:0016020
    label: membrane
  evidence_type: HDA
  original_reference_id: PMID:19946888
  qualifier: located_in
  review:
    summary: Nicastrin is a single-pass type I transmembrane glycoprotein; its membrane integration is required for assembly into the membrane-embedded gamma-secretase complex.
    action: ACCEPT
    reason: 'Core localization: confirmed type I membrane protein (IDA/EXP, structures).'
- term:
    id: GO:0070062
    label: extracellular exosome
  evidence_type: HDA
  original_reference_id: PMID:19056867
  qualifier: located_in
  review:
    summary: Nicastrin is recovered in exosome proteomes, likely reflecting membrane trafficking and secretion rather than a dedicated exosomal function of gamma-secretase.
    action: KEEP_AS_NON_CORE
    reason: Proteomics-derived secondary localization, not core (HDA).
- term:
    id: GO:0005765
    label: lysosomal membrane
  evidence_type: HDA
  original_reference_id: PMID:17897319
  qualifier: located_in
  review:
    summary: Mature gamma-secretase, including nicastrin, reaches lysosomal/late-endosomal membranes, a documented compartment for substrate processing and turnover.
    action: ACCEPT
    reason: Supported lysosomal membrane localization (HDA/IEA).
- term:
    id: GO:0070062
    label: extracellular exosome
  evidence_type: HDA
  original_reference_id: PMID:20458337
  qualifier: located_in
  review:
    summary: Nicastrin is recovered in exosome proteomes, likely reflecting membrane trafficking and secretion rather than a dedicated exosomal function of gamma-secretase.
    action: KEEP_AS_NON_CORE
    reason: Proteomics-derived secondary localization, not core (HDA).
- term:
    id: GO:0005886
    label: plasma membrane
  evidence_type: TAS
  original_reference_id: Reactome:R-HSA-1251997
  qualifier: located_in
  review:
    summary: A pool of mature gamma-secretase, including nicastrin, resides at the plasma membrane where it cleaves cell-surface substrate C-terminal fragments such as Notch NEXT.
    action: ACCEPT
    reason: 'Core: well-supported site of active gamma-secretase (IDA/TAS/IBA).'
- term:
    id: GO:0005886
    label: plasma membrane
  evidence_type: TAS
  original_reference_id: Reactome:R-HSA-193682
  qualifier: located_in
  review:
    summary: A pool of mature gamma-secretase, including nicastrin, resides at the plasma membrane where it cleaves cell-surface substrate C-terminal fragments such as Notch NEXT.
    action: ACCEPT
    reason: 'Core: well-supported site of active gamma-secretase (IDA/TAS/IBA).'
- term:
    id: GO:0005886
    label: plasma membrane
  evidence_type: TAS
  original_reference_id: Reactome:R-HSA-205112
  qualifier: located_in
  review:
    summary: A pool of mature gamma-secretase, including nicastrin, resides at the plasma membrane where it cleaves cell-surface substrate C-terminal fragments such as Notch NEXT.
    action: ACCEPT
    reason: 'Core: well-supported site of active gamma-secretase (IDA/TAS/IBA).'
- term:
    id: GO:0005886
    label: plasma membrane
  evidence_type: TAS
  original_reference_id: Reactome:R-HSA-2220988
  qualifier: located_in
  review:
    summary: A pool of mature gamma-secretase, including nicastrin, resides at the plasma membrane where it cleaves cell-surface substrate C-terminal fragments such as Notch NEXT.
    action: ACCEPT
    reason: 'Core: well-supported site of active gamma-secretase (IDA/TAS/IBA).'
- term:
    id: GO:0005886
    label: plasma membrane
  evidence_type: TAS
  original_reference_id: Reactome:R-HSA-3928656
  qualifier: located_in
  review:
    summary: A pool of mature gamma-secretase, including nicastrin, resides at the plasma membrane where it cleaves cell-surface substrate C-terminal fragments such as Notch NEXT.
    action: ACCEPT
    reason: 'Core: well-supported site of active gamma-secretase (IDA/TAS/IBA).'
- term:
    id: GO:0005886
    label: plasma membrane
  evidence_type: TAS
  original_reference_id: Reactome:R-HSA-6798739
  qualifier: located_in
  review:
    summary: A pool of mature gamma-secretase, including nicastrin, resides at the plasma membrane where it cleaves cell-surface substrate C-terminal fragments such as Notch NEXT.
    action: ACCEPT
    reason: 'Core: well-supported site of active gamma-secretase (IDA/TAS/IBA).'
- term:
    id: GO:0005886
    label: plasma membrane
  evidence_type: TAS
  original_reference_id: Reactome:R-HSA-9013361
  qualifier: located_in
  review:
    summary: A pool of mature gamma-secretase, including nicastrin, resides at the plasma membrane where it cleaves cell-surface substrate C-terminal fragments such as Notch NEXT.
    action: ACCEPT
    reason: 'Core: well-supported site of active gamma-secretase (IDA/TAS/IBA).'
- term:
    id: GO:0005886
    label: plasma membrane
  evidence_type: TAS
  original_reference_id: Reactome:R-HSA-9017817
  qualifier: located_in
  review:
    summary: A pool of mature gamma-secretase, including nicastrin, resides at the plasma membrane where it cleaves cell-surface substrate C-terminal fragments such as Notch NEXT.
    action: ACCEPT
    reason: 'Core: well-supported site of active gamma-secretase (IDA/TAS/IBA).'
- term:
    id: GO:0005886
    label: plasma membrane
  evidence_type: TAS
  original_reference_id: Reactome:R-HSA-9839376
  qualifier: located_in
  review:
    summary: A pool of mature gamma-secretase, including nicastrin, resides at the plasma membrane where it cleaves cell-surface substrate C-terminal fragments such as Notch NEXT.
    action: ACCEPT
    reason: 'Core: well-supported site of active gamma-secretase (IDA/TAS/IBA).'
- term:
    id: GO:0005886
    label: plasma membrane
  evidence_type: TAS
  original_reference_id: Reactome:R-NUL-2197556
  qualifier: located_in
  review:
    summary: A pool of mature gamma-secretase, including nicastrin, resides at the plasma membrane where it cleaves cell-surface substrate C-terminal fragments such as Notch NEXT.
    action: ACCEPT
    reason: 'Core: well-supported site of active gamma-secretase (IDA/TAS/IBA).'
- term:
    id: GO:0005886
    label: plasma membrane
  evidence_type: TAS
  original_reference_id: Reactome:R-NUL-9604300
  qualifier: located_in
  review:
    summary: A pool of mature gamma-secretase, including nicastrin, resides at the plasma membrane where it cleaves cell-surface substrate C-terminal fragments such as Notch NEXT.
    action: ACCEPT
    reason: 'Core: well-supported site of active gamma-secretase (IDA/TAS/IBA).'
- term:
    id: GO:0005783
    label: endoplasmic reticulum
  evidence_type: IDA
  original_reference_id: PMID:15274632
  qualifier: located_in
  review:
    summary: Nicastrin is synthesized and initially N-glycosylated in the ER, where immature gamma-secretase subassembly begins before trafficking and maturation.
    action: ACCEPT
    reason: 'Core: ER is the biogenesis/assembly compartment (IDA).'
- term:
    id: GO:0005794
    label: Golgi apparatus
  evidence_type: IDA
  original_reference_id: PMID:15274632
  qualifier: located_in
  review:
    summary: Nicastrin transits the Golgi where it undergoes complex N-glycan maturation, a hallmark of the catalytically competent mature gamma-secretase.
    action: ACCEPT
    reason: Maturation compartment for nicastrin glycosylation (IDA).
- term:
    id: GO:0006509
    label: membrane protein ectodomain proteolysis
  evidence_type: IDA
  original_reference_id: PMID:15274632
  qualifier: involved_in
  review:
    summary: Gamma-secretase performs intramembrane/intracellular-domain cleavage, not ectodomain shedding (the latter is done by alpha/beta-secretases); the intramembrane proteolysis term is more accurate.
    action: MODIFY
    reason: 'Mislabeled granularity: NCSTN/gamma-secretase does intramembrane, not ectodomain, proteolysis (IDA).'
    proposed_replacement_terms:
    - id: GO:0031293
      label: membrane protein intracellular domain proteolysis
- term:
    id: GO:0007220
    label: Notch receptor processing
  evidence_type: TAS
  original_reference_id: PMID:15274632
  qualifier: involved_in
  review:
    summary: Nicastrin-containing gamma-secretase performs the regulated intramembrane (S3) cleavage of Notch receptors that releases NICD; nicastrin recognizes the Notch NEXT substrate.
    action: ACCEPT
    reason: Core biological process of the complex; nicastrin is essential (IDA/IMP; structure with Notch1).
- term:
    id: GO:0016485
    label: protein processing
  evidence_type: IDA
  original_reference_id: PMID:15274632
  qualifier: involved_in
  review:
    summary: Nicastrin contributes to the proteolytic processing of gamma-secretase substrates (Notch, APP, and other type I membrane proteins) via regulated intramembrane proteolysis.
    action: ACCEPT
    reason: Core processing role of the complex (IDA/IMP/IGI/IBA).
- term:
    id: GO:0042987
    label: amyloid precursor protein catabolic process
  evidence_type: TAS
  original_reference_id: PMID:15274632
  qualifier: involved_in
  review:
    summary: Nicastrin engages APP C-terminal fragments (C83/C99) for gamma-secretase cleavage, driving the catabolic intramembrane processing of APP.
    action: ACCEPT
    reason: 'Core: complex-mediated APP catabolism, nicastrin binds the CTFs (IDA/IGI/TAS).'
- term:
    id: GO:0006508
    label: proteolysis
  evidence_type: NAS
  original_reference_id: PMID:10993067
  qualifier: involved_in
  review:
    summary: Generic proteolysis under-specifies the role; gamma-secretase performs regulated intramembrane (within-membrane) proteolysis of its substrates.
    action: MODIFY
    reason: Too general; a specific intramembrane proteolysis child applies (NAS).
    proposed_replacement_terms:
    - id: GO:0033619
      label: membrane protein proteolysis
- term:
    id: GO:0016020
    label: membrane
  evidence_type: NAS
  original_reference_id: PMID:10993067
  qualifier: located_in
  review:
    summary: Nicastrin is a single-pass type I transmembrane glycoprotein; its membrane integration is required for assembly into the membrane-embedded gamma-secretase complex.
    action: ACCEPT
    reason: 'Core localization: confirmed type I membrane protein (IDA/EXP, structures).'
references:
- id: GO_REF:0000033
  title: Annotation inferences using phylogenetic trees
  findings: []
- id: GO_REF:0000044
  title: Gene Ontology annotation based on UniProtKB/Swiss-Prot Subcellular Location vocabulary mapping, accompanied by conservative changes to GO terms applied by UniProt
  findings: []
- id: GO_REF:0000107
  title: Automatic transfer of experimentally verified manual GO annotation data to orthologs using Ensembl Compara
  findings: []
- id: GO_REF:0000117
  title: Electronic Gene Ontology annotations created by ARBA machine learning models
  findings: []
- id: GO_REF:0000120
  title: Combined Automated Annotation using Multiple IEA Methods
  findings: []
- id: PMID:10206645
  title: A presenilin-1-dependent gamma-secretase-like protease mediates release of Notch intracellular domain.
  findings: []
- id: PMID:10993067
  title: Nicastrin modulates presenilin-mediated notch/glp-1 signal transduction and betaAPP processing.
  findings: []
  reference_review:
    relevance: HIGH
    correctness: VERIFIED
    review_notes: Cached abstract directly supports nicastrin as a presenilin-associated component needed for Notch/GLP-1 and betaAPP intramembrane proteolysis.
- id: PMID:12297508
  title: Mammalian APH-1 interacts with presenilin and nicastrin and is required for intramembrane proteolysis of amyloid-beta precursor protein and Notch.
  findings: []
  reference_review:
    relevance: HIGH
    correctness: VERIFIED
    review_notes: Cached abstract supports nicastrin participation with APH-1 and presenilin in gamma-secretase-dependent APP and Notch proteolysis.
- id: PMID:12763021
  title: APH1, PEN2, and Nicastrin increase Abeta levels and gamma-secretase activity.
  findings: []
  reference_review:
    relevance: HIGH
    correctness: VERIFIED
    review_notes: Cached abstract identifies nicastrin with APH1/PEN2 as gamma-secretase complex components that are limiting for Abeta production and gamma-secretase activity.
- id: PMID:15274632
  title: Purification and characterization of the human gamma-secretase complex.
  findings: []
  reference_review:
    relevance: HIGH
    correctness: VERIFIED
    review_notes: Cached abstract reports purification of active human gamma-secretase and identifies mature nicastrin with presenilin, APH-1, and Pen-2 as core components.
- id: PMID:15322109
  title: Both the sequence and length of the C terminus of PEN-2 are critical for intermolecular interactions and function of presenilin complexes.
  findings: []
- id: PMID:15890777
  title: CD147 is a regulatory subunit of the gamma-secretase complex in Alzheimer's disease amyloid beta-peptide production.
  findings: []
- id: PMID:16641999
  title: TMP21 is a presenilin complex component that modulates gamma-secretase but not epsilon-secretase activity.
  findings: []
- id: PMID:17897319
  title: Integral and associated lysosomal membrane proteins.
  findings: []
- id: PMID:18201567
  title: Cellular localization of Nicastrin affects amyloid beta species production.
  findings: []
- id: PMID:19056867
  title: Large-scale proteomics and phosphoproteomics of urinary exosomes.
  findings: []
- id: PMID:19376115
  title: An alternative spliced mouse presenilin-2 mRNA encodes a novel gamma-secretase inhibitor.
  findings: []
- id: PMID:19946888
  title: Defining the membrane proteome of NK cells.
  findings: []
- id: PMID:20458337
  title: MHC class II-associated proteins in B-cell exosomes and potential functional implications for exosome biogenesis.
  findings: []
- id: PMID:21423176
  title: Analysis of the myosin-II-responsive focal adhesion proteome reveals a role for β-Pix in negative regulation of focal adhesion maturation.
  findings: []
- id: PMID:22086926
  title: Down-regulation of the ATP-binding cassette transporter 2 (Abca2) reduces amyloid-β production by altering Nicastrin maturation and intracellular localization.
  findings: []
- id: PMID:25043039
  title: Three-dimensional structure of human γ-secretase.
  findings: []
  reference_review:
    relevance: HIGH
    correctness: VERIFIED
    review_notes: Cached full-text record supports the four-subunit human gamma-secretase structure and the nicastrin extracellular-domain substrate-recruitment framing.
- id: PMID:25918421
  title: Structural basis of human γ-secretase assembly.
  findings: []
- id: PMID:26094765
  title: Proton myo-inositol cotransporter is a novel γ-secretase associated protein that regulates Aβ production without affecting Notch cleavage.
  findings: []
- id: PMID:26280335
  title: An atomic structure of human γ-secretase.
  findings: []
  reference_review:
    relevance: HIGH
    correctness: VERIFIED
    review_notes: Cached full-text record supports the atomic human gamma-secretase structure, including nicastrin positioning and its relationship to the presenilin active site.
- id: PMID:26623517
  title: Sampling the conformational space of the catalytic subunit of human γ-secretase.
  findings: []
- id: PMID:26776682
  title: Structure of the transmembrane domain of human nicastrin-a component of γ-secretase.
  findings: []
- id: PMID:27608597
  title: Specific combinations of presenilins and Aph1s affect the substrate specificity and activity of γ-secretase.
  findings: []
- id: PMID:29611543
  title: Intracellular trafficking of TREM2 is regulated by presenilin 1.
  findings: []
- id: PMID:30559186
  title: Bax inhibitor 1 is a γ-secretase-independent presenilin-binding protein.
  findings: []
- id: Reactome:R-HSA-1251997
  title: Cleavage of ERBB4m80 by gamma-scretase complex
  findings: []
- id: Reactome:R-HSA-193682
  title: gamma-secretase cleaves the p75NTR transmembrane domain
  findings: []
- id: Reactome:R-HSA-205112
  title: gamma-secretase cleaves p75NTR, releasing NRIF and TRAF6
  findings: []
- id: Reactome:R-HSA-2220988
  title: NEXT1 PEST domain mutants are cleaved to produce NICD1 PEST domain mutants
  findings: []
- id: Reactome:R-HSA-3928656
  title: gamma-secretase cleaves EPHB2
  findings: []
- id: Reactome:R-HSA-6798739
  title: Exocytosis of azurophil granule membrane proteins
  findings: []
- id: Reactome:R-HSA-9010096
  title: Gamma-secretase cleaves APP(672-770) to APP(672-711) and APP(672-713)
  findings: []
- id: Reactome:R-HSA-9013361
  title: NEXT3 is cleaved to produce NICD3
  findings: []
- id: Reactome:R-HSA-9017817
  title: Gamma-secretase cleaves YBX1:NOTCH3
  findings: []
- id: Reactome:R-HSA-9839376
  title: TGFBR3(784-851) degradation
  findings: []
- id: Reactome:R-NUL-2197556
  title: Gamma-secretase complex cleaves mNEXT2
  findings: []
- id: Reactome:R-NUL-9604300
  title: Gamma-secretase cleaves Notch4
  findings: []
core_functions:
- molecular_function:
    id: GO:0030674
    label: protein-macromolecule adaptor activity
  contributes_to_molecular_function:
    id: GO:0042500
    label: aspartic endopeptidase activity, intramembrane cleaving
  description: >-
    NCSTN is an essential non-catalytic gamma-secretase subunit that helps assemble
    and position the substrate-recognition extracellular domain of the complex, enabling
    presenilin-dependent intramembrane cleavage of APP, Notch receptors, and related
    substrates.
  directly_involved_in:
  - id: GO:0031293
    label: membrane protein intracellular domain proteolysis
  - id: GO:0007220
    label: Notch receptor processing
  - id: GO:0042987
    label: amyloid precursor protein catabolic process
  - id: GO:0034205
    label: amyloid-beta formation
  - id: GO:0016485
    label: protein processing
  locations:
  - id: GO:0005789
    label: endoplasmic reticulum membrane
  - id: GO:0000139
    label: Golgi membrane
  - id: GO:0010008
    label: endosome membrane
  - id: GO:0005886
    label: plasma membrane
  - id: GO:0016020
    label: membrane
  in_complex:
    id: GO:0070765
    label: gamma-secretase complex
  supported_by:
  - reference_id: PMID:10993067
    supporting_text: >-
      Nicastrin, a transmembrane glycoprotein, forms high molecular weight complexes
      with presenilin 1 and presenilin 2
  - reference_id: PMID:10993067
    supporting_text: >-
      functional components of a multimeric complex necessary for the intramembranous
      proteolysis of proteins such as Notch/GLP-1 and betaAPP
  - reference_id: PMID:25043039
    supporting_text: >-
      The γ-secretase complex consists of four components: presenilin, Pen-2, Aph-1,
      and Nicastrin
  - reference_id: PMID:25043039
    supporting_text: >-
      Nicastrin contains a large extracellular domain that is thought to be responsible
      for substrate recruitment
  - reference_id: PMID:12297508
    supporting_text: >-
      mAPH-1 is probably a functional component of the gamma-secretase complex required
      for the intramembrane proteolysis of APP and Notch
proposed_new_terms: []
suggested_questions:
- question: >-
    How should GO distinguish NCSTN substrate-recognition/adaptor activity from the
    catalytic presenilin intramembrane aspartyl protease activity within gamma-secretase?
  experts:
  - gamma-secretase structural biology experts
  - GO molecular-function curators
- question: >-
    Which NCSTN-dependent gamma-secretase locations are physiologically active for
    APP versus Notch processing in vivo?
  experts:
  - APP trafficking experts
  - Notch signaling experts
suggested_experiments:
- description: >-
    Use endogenous NCSTN variants or extracellular-domain mutants in human neurons
    and Notch reporter cells to separately measure complex assembly, substrate recruitment,
    APP cleavage, and Notch S3 cleavage.
  hypothesis: >-
    NCSTN primarily determines substrate presentation and complex maturation rather
    than catalytic chemistry.
  experiment_type: endogenous gamma-secretase substrate recruitment assay
- description: >-
    Map active gamma-secretase complexes containing tagged NCSTN across ER, Golgi,
    endosome, lysosome, and plasma membrane compartments with APP- and Notch-specific
    reporters.
  hypothesis: >-
    APP and Notch processing rely on overlapping but non-identical NCSTN-containing
    gamma-secretase pools.
  experiment_type: compartment-resolved gamma-secretase activity assay