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.
| GO Term | Evidence | Action | Reason |
|---|---|---|---|
| GO:0005886 plasma membrane | IBA GO_REF:0000033 | ACCEPT | 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. Reason: Core: well-supported site of active gamma-secretase (IDA/TAS/IBA). |
| GO:0016485 protein processing | IBA GO_REF:0000033 | ACCEPT | Summary: Nicastrin contributes to the proteolytic processing of gamma-secretase substrates (Notch, APP, and other type I membrane proteins) via regulated intramembrane proteolysis. Reason: Core processing role of the complex (IDA/IMP/IGI/IBA). |
| GO:0007220 Notch receptor processing | IBA GO_REF:0000033 | ACCEPT | Summary: Nicastrin-containing gamma-secretase performs the regulated intramembrane (S3) cleavage of Notch receptors that releases NICD; nicastrin recognizes the Notch NEXT substrate. Reason: Core biological process of the complex; nicastrin is essential (IDA/IMP; structure with Notch1). |
| GO:0012505 endomembrane system | IEA GO_REF:0000117 | ACCEPT | Summary: Nicastrin distributes across the endomembrane system (ER, Golgi, endosomes) reflecting biogenesis, maturation and the multiple sites where gamma-secretase acts. Reason: Accurate parent-level localization of the complex (IEA). |
| GO:0016020 membrane | IEA GO_REF:0000120 | ACCEPT | Summary: Nicastrin is a single-pass type I transmembrane glycoprotein; its membrane integration is required for assembly into the membrane-embedded gamma-secretase complex. Reason: Core localization: confirmed type I membrane protein (IDA/EXP, structures). |
| GO:0016485 protein processing | IEA GO_REF:0000120 | ACCEPT | Summary: Nicastrin contributes to the proteolytic processing of gamma-secretase substrates (Notch, APP, and other type I membrane proteins) via regulated intramembrane proteolysis. Reason: Core processing role of the complex (IDA/IMP/IGI/IBA). |
| GO:0030659 cytoplasmic vesicle membrane | IEA GO_REF:0000044 | ACCEPT | Summary: UniProt annotates nicastrin as a cytoplasmic vesicle membrane protein, consistent with trafficking of the gamma-secretase complex through the endomembrane/vesicular system. Reason: Supported by experimental subcellular location (EXP/IEA). |
| GO:0042470 melanosome | IEA GO_REF:0000044 | KEEP AS NON CORE | Summary: Nicastrin was identified by mass spectrometry in melanosome fractions; this reflects shared endomembrane trafficking rather than a melanosome-specific role. Reason: Proteomic large-scale localization, non-core (IEA/SubCell). |
| GO:0099503 secretory vesicle | IEA GO_REF:0000117 | ACCEPT | Summary: Nicastrin associates with secretory vesicle membranes during transport of mature gamma-secretase toward the cell surface. Reason: Consistent with vesicular trafficking of the complex (IEA). |
| GO:0005515 protein binding | IPI PMID:12297508 Mammalian APH-1 interacts with presenilin and nicastrin and ... | MARK AS OVER ANNOTATED | Summary: Generic protein binding is uninformative; nicastrin's meaningful interactions (substrate CTFs, complex subunits) are better captured by adaptor/complex-membership terms. Reason: Uninformative generic binding; superseded by specific MF/CC terms (IPI). |
| GO:0005515 protein binding | IPI PMID:15322109 Both the sequence and length of the C terminus of PEN-2 are ... | MARK AS OVER ANNOTATED | Summary: Generic protein binding is uninformative; nicastrin's meaningful interactions (substrate CTFs, complex subunits) are better captured by adaptor/complex-membership terms. Reason: Uninformative generic binding; superseded by specific MF/CC terms (IPI). |
| GO:0005515 protein binding | IPI PMID:15890777 CD147 is a regulatory subunit of the gamma-secretase complex... | MARK AS OVER ANNOTATED | Summary: Generic protein binding is uninformative; nicastrin's meaningful interactions (substrate CTFs, complex subunits) are better captured by adaptor/complex-membership terms. Reason: Uninformative generic binding; superseded by specific MF/CC terms (IPI). |
| GO:0005515 protein binding | IPI PMID:16641999 TMP21 is a presenilin complex component that modulates gamma... | MARK AS OVER ANNOTATED | Summary: Generic protein binding is uninformative; nicastrin's meaningful interactions (substrate CTFs, complex subunits) are better captured by adaptor/complex-membership terms. Reason: Uninformative generic binding; superseded by specific MF/CC terms (IPI). |
| GO:0005515 protein binding | IPI PMID:18201567 Cellular localization of Nicastrin affects amyloid beta spec... | MARK AS OVER ANNOTATED | Summary: Generic protein binding is uninformative; nicastrin's meaningful interactions (substrate CTFs, complex subunits) are better captured by adaptor/complex-membership terms. Reason: Uninformative generic binding; superseded by specific MF/CC terms (IPI). |
| GO:0005515 protein binding | IPI PMID:19376115 An alternative spliced mouse presenilin-2 mRNA encodes a nov... | MARK AS OVER ANNOTATED | Summary: Generic protein binding is uninformative; nicastrin's meaningful interactions (substrate CTFs, complex subunits) are better captured by adaptor/complex-membership terms. Reason: Uninformative generic binding; superseded by specific MF/CC terms (IPI). |
| GO:0005515 protein binding | IPI PMID:26280335 An atomic structure of human Ξ³-secretase. | MARK AS OVER ANNOTATED | Summary: Generic protein binding is uninformative; nicastrin's meaningful interactions (substrate CTFs, complex subunits) are better captured by adaptor/complex-membership terms. Reason: Uninformative generic binding; superseded by specific MF/CC terms (IPI). |
| GO:0005515 protein binding | IPI PMID:29611543 Intracellular trafficking of TREM2 is regulated by presenili... | MARK AS OVER ANNOTATED | Summary: Generic protein binding is uninformative; nicastrin's meaningful interactions (substrate CTFs, complex subunits) are better captured by adaptor/complex-membership terms. Reason: Uninformative generic binding; superseded by specific MF/CC terms (IPI). |
| GO:0005515 protein binding | IPI PMID:30559186 Bax inhibitor 1 is a Ξ³-secretase-independent presenilin-bind... | MARK AS OVER ANNOTATED | Summary: Generic protein binding is uninformative; nicastrin's meaningful interactions (substrate CTFs, complex subunits) are better captured by adaptor/complex-membership terms. Reason: Uninformative generic binding; superseded by specific MF/CC terms (IPI). |
| GO:0004175 endopeptidase activity | IEA GO_REF:0000107 | MARK AS OVER ANNOTATED | Summary: Generic endopeptidase activity is incorrectly attributed to nicastrin, which lacks catalytic residues; proteolysis is performed by the presenilin subunit of gamma-secretase. Reason: Non-catalytic subunit; activity is presenilin's (IEA). |
| GO:0005764 lysosome | IEA GO_REF:0000120 | ACCEPT | Summary: Nicastrin is detected in the lysosomal compartment consistent with trafficking of gamma-secretase through the late endolysosomal pathway. Reason: Consistent with endolysosomal pool of the complex (IEA). |
| GO:0005765 lysosomal membrane | IEA GO_REF:0000107 | ACCEPT | Summary: Mature gamma-secretase, including nicastrin, reaches lysosomal/late-endosomal membranes, a documented compartment for substrate processing and turnover. Reason: Supported lysosomal membrane localization (HDA/IEA). |
| GO:0005769 early endosome | IEA GO_REF:0000107 | ACCEPT | Summary: Active gamma-secretase, including nicastrin, localizes to early endosomes, an important site of APP processing and amyloid-beta generation. Reason: Endosomal pool is a recognized site of complex activity (IEA). |
| GO:0005783 endoplasmic reticulum | IEA GO_REF:0000107 | ACCEPT | Summary: Nicastrin is synthesized and initially N-glycosylated in the ER, where immature gamma-secretase subassembly begins before trafficking and maturation. Reason: Core: ER is the biogenesis/assembly compartment (IDA). |
| GO:0005794 Golgi apparatus | IEA GO_REF:0000107 | ACCEPT | Summary: Nicastrin transits the Golgi where it undergoes complex N-glycan maturation, a hallmark of the catalytically competent mature gamma-secretase. Reason: Maturation compartment for nicastrin glycosylation (IDA). |
| GO:0005886 plasma membrane | IEA GO_REF:0000120 | ACCEPT | 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. Reason: Core: well-supported site of active gamma-secretase (IDA/TAS/IBA). |
| GO:0008021 synaptic vesicle | IEA GO_REF:0000120 | KEEP AS NON CORE | Summary: Synaptic vesicle localization is an electronic, neuron-specific annotation reflecting vesicular trafficking, not a defining gamma-secretase location. Reason: Specialized neuronal localization, non-core (IEA). |
| GO:0008233 peptidase activity | IEA GO_REF:0000107 | MARK AS OVER ANNOTATED | Summary: Nicastrin has no peptidase activity despite a degenerate M28 aminopeptidase-like fold; the catalytic site is degenerate and proteolysis resides in presenilin. Reason: Pseudo-protease fold; no catalytic activity in NCSTN (IEA). |
| GO:0021549 cerebellum development | IEA GO_REF:0000107 | KEEP AS NON CORE | Summary: Gamma-secretase/Notch signaling influences cerebellar development; this is a downstream developmental consequence rather than nicastrin's direct molecular role. Reason: Downstream developmental process via Notch, non-core (IEA). |
| GO:0032991 protein-containing complex | IEA GO_REF:0000120 | ACCEPT | Summary: Nicastrin functions only as part of a hetero-oligomeric assembly; this generic complex term is subsumed by the specific gamma-secretase complex annotation. Reason: True but generic; the specific gamma-secretase complex term is preferred (IEA). |
| GO:0042383 sarcolemma | IEA GO_REF:0000107 | KEEP AS NON CORE | Summary: Sarcolemma (muscle plasma membrane) localization is an electronic tissue-specific annotation, a specialization of the general plasma-membrane pool. Reason: Tissue-specific plasma-membrane subtype, non-core (IEA). |
| GO:0042500 aspartic endopeptidase activity, intramembrane cleaving | IEA GO_REF:0000107 | MARK AS OVER ANNOTATED | 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. Reason: NCSTN is non-catalytic; this MF belongs to presenilin (IEA, electronic). |
| GO:0042734 presynaptic membrane | IEA GO_REF:0000107 | KEEP AS NON CORE | Summary: Electronic annotation places nicastrin at the presynaptic membrane, consistent with neuronal gamma-secretase activity but a specialized, non-core localization. Reason: Tissue-specialized localization, non-core (IEA). |
| GO:0070765 gamma-secretase complex | IEA GO_REF:0000107 | ACCEPT | 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. Reason: Core: NCSTN is a constitutive component of this complex (IDA/IPI, multiple cryo-EM structures). |
| GO:0097060 synaptic membrane | IEA GO_REF:0000107 | KEEP AS NON CORE | Summary: Synaptic-membrane localization reflects neuronal gamma-secretase processing of synaptic substrates; a specialized site rather than the core annotation. Reason: Neuronal specialized localization, non-core (IEA). |
| GO:0005789 endoplasmic reticulum membrane | NAS PMID:15274632 Purification and characterization of the human gamma-secreta... | ACCEPT | Summary: As a membrane protein, nicastrin resides in the ER membrane during early biogenesis and partial complex assembly prior to Golgi maturation. Reason: Core-consistent ER membrane localization (NAS, ComplexPortal). |
| GO:0005886 plasma membrane | IDA PMID:15274632 Purification and characterization of the human gamma-secreta... | ACCEPT | 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. Reason: Core: well-supported site of active gamma-secretase (IDA/TAS/IBA). |
| GO:0007220 Notch receptor processing | NAS PMID:10206645 A presenilin-1-dependent gamma-secretase-like protease media... | ACCEPT | Summary: Nicastrin-containing gamma-secretase performs the regulated intramembrane (S3) cleavage of Notch receptors that releases NICD; nicastrin recognizes the Notch NEXT substrate. Reason: Core biological process of the complex; nicastrin is essential (IDA/IMP; structure with Notch1). |
| GO:0031293 membrane protein intracellular domain proteolysis | IDA PMID:15274632 Purification and characterization of the human gamma-secreta... | ACCEPT | Summary: Gamma-secretase, via nicastrin substrate recognition, releases intracellular domains (e.g., NICD, AICD) by intramembrane cleavage of type I membrane substrates. Reason: Core: ICD-releasing regulated intramembrane proteolysis (IDA, ComplexPortal). |
| GO:0042987 amyloid precursor protein catabolic process | IDA PMID:15274632 Purification and characterization of the human gamma-secreta... | ACCEPT | Summary: Nicastrin engages APP C-terminal fragments (C83/C99) for gamma-secretase cleavage, driving the catabolic intramembrane processing of APP. Reason: Core: complex-mediated APP catabolism, nicastrin binds the CTFs (IDA/IGI/TAS). |
| GO:0070765 gamma-secretase complex | IPI PMID:26280335 An atomic structure of human Ξ³-secretase. | ACCEPT | 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. Reason: Core: NCSTN is a constitutive component of this complex (IDA/IPI, multiple cryo-EM structures). |
| GO:0000139 Golgi membrane | NAS PMID:15274632 Purification and characterization of the human gamma-secreta... | ACCEPT | Summary: Membrane-embedded nicastrin localizes to the Golgi membrane during glycan maturation and trafficking of the assembling complex. Reason: Consistent with Golgi maturation of the complex (NAS, ComplexPortal). |
| GO:0061133 endopeptidase activator activity | IMP PMID:12297508 Mammalian APH-1 interacts with presenilin and nicastrin and ... | ACCEPT | Summary: By recruiting and presenting substrate CTFs and stabilizing the mature complex, nicastrin is required for and potentiates presenilin endopeptidase activity within gamma-secretase. Reason: Core: nicastrin enables/activates complex protease activity (IMP/IGI). |
| GO:0061133 endopeptidase activator activity | IGI PMID:12763021 APH1, PEN2, and Nicastrin increase Abeta levels and gamma-se... | ACCEPT | Summary: By recruiting and presenting substrate CTFs and stabilizing the mature complex, nicastrin is required for and potentiates presenilin endopeptidase activity within gamma-secretase. Reason: Core: nicastrin enables/activates complex protease activity (IMP/IGI). |
| GO:0016020 membrane | EXP PMID:25918421 Structural basis of human Ξ³-secretase assembly. | ACCEPT | Summary: Nicastrin is a single-pass type I transmembrane glycoprotein; its membrane integration is required for assembly into the membrane-embedded gamma-secretase complex. Reason: Core localization: confirmed type I membrane protein (IDA/EXP, structures). |
| GO:0016020 membrane | EXP PMID:26623517 Sampling the conformational space of the catalytic subunit o... | ACCEPT | Summary: Nicastrin is a single-pass type I transmembrane glycoprotein; its membrane integration is required for assembly into the membrane-embedded gamma-secretase complex. Reason: Core localization: confirmed type I membrane protein (IDA/EXP, structures). |
| GO:0016020 membrane | EXP PMID:26776682 Structure of the transmembrane domain of human nicastrin-a c... | ACCEPT | Summary: Nicastrin is a single-pass type I transmembrane glycoprotein; its membrane integration is required for assembly into the membrane-embedded gamma-secretase complex. Reason: Core localization: confirmed type I membrane protein (IDA/EXP, structures). |
| GO:0030659 cytoplasmic vesicle membrane | EXP PMID:10993067 Nicastrin modulates presenilin-mediated notch/glp-1 signal t... | ACCEPT | Summary: UniProt annotates nicastrin as a cytoplasmic vesicle membrane protein, consistent with trafficking of the gamma-secretase complex through the endomembrane/vesicular system. Reason: Supported by experimental subcellular location (EXP/IEA). |
| GO:0030674 protein-macromolecule adaptor activity | IMP PMID:12297508 Mammalian APH-1 interacts with presenilin and nicastrin and ... | ACCEPT | 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. Reason: Core MF: nicastrin is the substrate-recognition/adaptor subunit (IMP/IGI; cryo-EM). |
| GO:0030674 protein-macromolecule adaptor activity | IGI PMID:12763021 APH1, PEN2, and Nicastrin increase Abeta levels and gamma-se... | ACCEPT | 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. Reason: Core MF: nicastrin is the substrate-recognition/adaptor subunit (IMP/IGI; cryo-EM). |
| GO:0007220 Notch receptor processing | IMP PMID:12297508 Mammalian APH-1 interacts with presenilin and nicastrin and ... | ACCEPT | Summary: Nicastrin-containing gamma-secretase performs the regulated intramembrane (S3) cleavage of Notch receptors that releases NICD; nicastrin recognizes the Notch NEXT substrate. Reason: Core biological process of the complex; nicastrin is essential (IDA/IMP; structure with Notch1). |
| GO:0007220 Notch receptor processing | IDA PMID:27608597 Specific combinations of presenilins and Aph1s affect the su... | ACCEPT | Summary: Nicastrin-containing gamma-secretase performs the regulated intramembrane (S3) cleavage of Notch receptors that releases NICD; nicastrin recognizes the Notch NEXT substrate. Reason: Core biological process of the complex; nicastrin is essential (IDA/IMP; structure with Notch1). |
| GO:0016485 protein processing | IMP PMID:12297508 Mammalian APH-1 interacts with presenilin and nicastrin and ... | ACCEPT | Summary: Nicastrin contributes to the proteolytic processing of gamma-secretase substrates (Notch, APP, and other type I membrane proteins) via regulated intramembrane proteolysis. Reason: Core processing role of the complex (IDA/IMP/IGI/IBA). |
| GO:0016485 protein processing | IGI PMID:12763021 APH1, PEN2, and Nicastrin increase Abeta levels and gamma-se... | ACCEPT | Summary: Nicastrin contributes to the proteolytic processing of gamma-secretase substrates (Notch, APP, and other type I membrane proteins) via regulated intramembrane proteolysis. Reason: Core processing role of the complex (IDA/IMP/IGI/IBA). |
| GO:0016485 protein processing | IDA PMID:27608597 Specific combinations of presenilins and Aph1s affect the su... | ACCEPT | Summary: Nicastrin contributes to the proteolytic processing of gamma-secretase substrates (Notch, APP, and other type I membrane proteins) via regulated intramembrane proteolysis. Reason: Core processing role of the complex (IDA/IMP/IGI/IBA). |
| GO:0034205 amyloid-beta formation | IMP PMID:12297508 Mammalian APH-1 interacts with presenilin and nicastrin and ... | ACCEPT | Summary: Gamma-secretase cleavage of APP C99, dependent on nicastrin-mediated substrate recognition, generates amyloid-beta peptides; a central, well-defined activity. Reason: Core APP-processing output of the complex (IDA/IMP/IGI). |
| GO:0034205 amyloid-beta formation | IGI PMID:12763021 APH1, PEN2, and Nicastrin increase Abeta levels and gamma-se... | ACCEPT | Summary: Gamma-secretase cleavage of APP C99, dependent on nicastrin-mediated substrate recognition, generates amyloid-beta peptides; a central, well-defined activity. Reason: Core APP-processing output of the complex (IDA/IMP/IGI). |
| GO:0034205 amyloid-beta formation | IDA PMID:27608597 Specific combinations of presenilins and Aph1s affect the su... | ACCEPT | Summary: Gamma-secretase cleavage of APP C99, dependent on nicastrin-mediated substrate recognition, generates amyloid-beta peptides; a central, well-defined activity. Reason: Core APP-processing output of the complex (IDA/IMP/IGI). |
| GO:0042987 amyloid precursor protein catabolic process | IGI PMID:12763021 APH1, PEN2, and Nicastrin increase Abeta levels and gamma-se... | ACCEPT | Summary: Nicastrin engages APP C-terminal fragments (C83/C99) for gamma-secretase cleavage, driving the catabolic intramembrane processing of APP. Reason: Core: complex-mediated APP catabolism, nicastrin binds the CTFs (IDA/IGI/TAS). |
| GO:0042987 amyloid precursor protein catabolic process | IDA PMID:27608597 Specific combinations of presenilins and Aph1s affect the su... | ACCEPT | Summary: Nicastrin engages APP C-terminal fragments (C83/C99) for gamma-secretase cleavage, driving the catabolic intramembrane processing of APP. Reason: Core: complex-mediated APP catabolism, nicastrin binds the CTFs (IDA/IGI/TAS). |
| GO:0070765 gamma-secretase complex | IDA PMID:12297508 Mammalian APH-1 interacts with presenilin and nicastrin and ... | ACCEPT | 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. Reason: Core: NCSTN is a constitutive component of this complex (IDA/IPI, multiple cryo-EM structures). |
| GO:0070765 gamma-secretase complex | IGI PMID:12763021 APH1, PEN2, and Nicastrin increase Abeta levels and gamma-se... | ACCEPT | 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. Reason: Core: NCSTN is a constitutive component of this complex (IDA/IPI, multiple cryo-EM structures). |
| GO:0005515 protein binding | IPI PMID:26094765 Proton myo-inositol cotransporter is a novel Ξ³-secretase ass... | MARK AS OVER ANNOTATED | Summary: Generic protein binding is uninformative; nicastrin's meaningful interactions (substrate CTFs, complex subunits) are better captured by adaptor/complex-membership terms. Reason: Uninformative generic binding; superseded by specific MF/CC terms (IPI). |
| GO:0051117 ATPase binding | IPI PMID:26094765 Proton myo-inositol cotransporter is a novel Ξ³-secretase ass... | KEEP AS NON CORE | 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. Reason: Specific partner binding, peripheral to core function (IPI). |
| GO:0070851 growth factor receptor binding | IPI PMID:26094765 Proton myo-inositol cotransporter is a novel Ξ³-secretase ass... | KEEP AS NON CORE | Summary: Nicastrin binds a growth factor receptor in a specific assay; consistent with gamma-secretase engaging receptor substrates but not its defining molecular function. Reason: Specific partner binding, non-core (IPI). |
| GO:0070765 gamma-secretase complex | NAS PMID:22086926 Down-regulation of the ATP-binding cassette transporter 2 (A... | ACCEPT | 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. Reason: Core: NCSTN is a constitutive component of this complex (IDA/IPI, multiple cryo-EM structures). |
| GO:0010008 endosome membrane | TAS Reactome:R-HSA-9010096 | ACCEPT | Summary: Nicastrin is present in endosomal membranes where the gamma-secretase complex cleaves internalized substrates such as APP-CTFs. Reason: Endosomal membrane is an active site of the complex (TAS, Reactome). |
| GO:0016020 membrane | IDA PMID:25043039 Three-dimensional structure of human Ξ³-secretase. | ACCEPT | Summary: Nicastrin is a single-pass type I transmembrane glycoprotein; its membrane integration is required for assembly into the membrane-embedded gamma-secretase complex. Reason: Core localization: confirmed type I membrane protein (IDA/EXP, structures). |
| GO:0016020 membrane | IDA PMID:26280335 An atomic structure of human Ξ³-secretase. | ACCEPT | Summary: Nicastrin is a single-pass type I transmembrane glycoprotein; its membrane integration is required for assembly into the membrane-embedded gamma-secretase complex. Reason: Core localization: confirmed type I membrane protein (IDA/EXP, structures). |
| GO:0034205 amyloid-beta formation | IMP PMID:25043039 Three-dimensional structure of human Ξ³-secretase. | ACCEPT | Summary: Gamma-secretase cleavage of APP C99, dependent on nicastrin-mediated substrate recognition, generates amyloid-beta peptides; a central, well-defined activity. Reason: Core APP-processing output of the complex (IDA/IMP/IGI). |
| GO:0034205 amyloid-beta formation | IMP PMID:26280335 An atomic structure of human Ξ³-secretase. | ACCEPT | Summary: Gamma-secretase cleavage of APP C99, dependent on nicastrin-mediated substrate recognition, generates amyloid-beta peptides; a central, well-defined activity. Reason: Core APP-processing output of the complex (IDA/IMP/IGI). |
| GO:0042982 amyloid precursor protein metabolic process | IDA PMID:25043039 Three-dimensional structure of human Ξ³-secretase. | ACCEPT | Summary: Nicastrin participates in APP metabolism as the substrate-recognition subunit presenting APP-CTFs to the gamma-secretase catalytic core. Reason: Core APP-processing role (IDA). |
| GO:0042982 amyloid precursor protein metabolic process | IDA PMID:26280335 An atomic structure of human Ξ³-secretase. | ACCEPT | Summary: Nicastrin participates in APP metabolism as the substrate-recognition subunit presenting APP-CTFs to the gamma-secretase catalytic core. Reason: Core APP-processing role (IDA). |
| GO:0070765 gamma-secretase complex | IDA PMID:25043039 Three-dimensional structure of human Ξ³-secretase. | ACCEPT | 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. Reason: Core: NCSTN is a constitutive component of this complex (IDA/IPI, multiple cryo-EM structures). |
| GO:0070765 gamma-secretase complex | IDA PMID:26280335 An atomic structure of human Ξ³-secretase. | ACCEPT | 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. Reason: Core: NCSTN is a constitutive component of this complex (IDA/IPI, multiple cryo-EM structures). |
| GO:0035577 azurophil granule membrane | TAS Reactome:R-HSA-6798739 | KEEP AS NON CORE | Summary: Nicastrin is annotated to the azurophil (neutrophil) granule membrane via neutrophil-degranulation pathways; a tissue-specific localization, not the core complex function. Reason: Pathway/tissue-specific secondary localization (TAS, Reactome). |
| GO:0005925 focal adhesion | HDA PMID:21423176 Analysis of the myosin-II-responsive focal adhesion proteome... | KEEP AS NON CORE | Summary: Nicastrin appears in focal adhesion proteomic fractions; this is a co-fractionation/contextual finding, not an established gamma-secretase function site. Reason: Secondary proteomics localization, non-core (HDA). |
| GO:0016020 membrane | HDA PMID:19946888 Defining the membrane proteome of NK cells. | ACCEPT | Summary: Nicastrin is a single-pass type I transmembrane glycoprotein; its membrane integration is required for assembly into the membrane-embedded gamma-secretase complex. Reason: Core localization: confirmed type I membrane protein (IDA/EXP, structures). |
| GO:0070062 extracellular exosome | HDA PMID:19056867 Large-scale proteomics and phosphoproteomics of urinary exos... | KEEP AS NON CORE | Summary: Nicastrin is recovered in exosome proteomes, likely reflecting membrane trafficking and secretion rather than a dedicated exosomal function of gamma-secretase. Reason: Proteomics-derived secondary localization, not core (HDA). |
| GO:0005765 lysosomal membrane | HDA PMID:17897319 Integral and associated lysosomal membrane proteins. | ACCEPT | Summary: Mature gamma-secretase, including nicastrin, reaches lysosomal/late-endosomal membranes, a documented compartment for substrate processing and turnover. Reason: Supported lysosomal membrane localization (HDA/IEA). |
| GO:0070062 extracellular exosome | HDA PMID:20458337 MHC class II-associated proteins in B-cell exosomes and pote... | KEEP AS NON CORE | Summary: Nicastrin is recovered in exosome proteomes, likely reflecting membrane trafficking and secretion rather than a dedicated exosomal function of gamma-secretase. Reason: Proteomics-derived secondary localization, not core (HDA). |
| GO:0005886 plasma membrane | TAS Reactome:R-HSA-1251997 | ACCEPT | 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. Reason: Core: well-supported site of active gamma-secretase (IDA/TAS/IBA). |
| GO:0005886 plasma membrane | TAS Reactome:R-HSA-193682 | ACCEPT | 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. Reason: Core: well-supported site of active gamma-secretase (IDA/TAS/IBA). |
| GO:0005886 plasma membrane | TAS Reactome:R-HSA-205112 | ACCEPT | 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. Reason: Core: well-supported site of active gamma-secretase (IDA/TAS/IBA). |
| GO:0005886 plasma membrane | TAS Reactome:R-HSA-2220988 | ACCEPT | 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. Reason: Core: well-supported site of active gamma-secretase (IDA/TAS/IBA). |
| GO:0005886 plasma membrane | TAS Reactome:R-HSA-3928656 | ACCEPT | 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. Reason: Core: well-supported site of active gamma-secretase (IDA/TAS/IBA). |
| GO:0005886 plasma membrane | TAS Reactome:R-HSA-6798739 | ACCEPT | 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. Reason: Core: well-supported site of active gamma-secretase (IDA/TAS/IBA). |
| GO:0005886 plasma membrane | TAS Reactome:R-HSA-9013361 | ACCEPT | 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. Reason: Core: well-supported site of active gamma-secretase (IDA/TAS/IBA). |
| GO:0005886 plasma membrane | TAS Reactome:R-HSA-9017817 | ACCEPT | 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. Reason: Core: well-supported site of active gamma-secretase (IDA/TAS/IBA). |
| GO:0005886 plasma membrane | TAS Reactome:R-HSA-9839376 | ACCEPT | 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. Reason: Core: well-supported site of active gamma-secretase (IDA/TAS/IBA). |
| GO:0005886 plasma membrane | TAS Reactome:R-NUL-2197556 | ACCEPT | 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. Reason: Core: well-supported site of active gamma-secretase (IDA/TAS/IBA). |
| GO:0005886 plasma membrane | TAS Reactome:R-NUL-9604300 | ACCEPT | 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. Reason: Core: well-supported site of active gamma-secretase (IDA/TAS/IBA). |
| GO:0005783 endoplasmic reticulum | IDA PMID:15274632 Purification and characterization of the human gamma-secreta... | ACCEPT | Summary: Nicastrin is synthesized and initially N-glycosylated in the ER, where immature gamma-secretase subassembly begins before trafficking and maturation. Reason: Core: ER is the biogenesis/assembly compartment (IDA). |
| GO:0005794 Golgi apparatus | IDA PMID:15274632 Purification and characterization of the human gamma-secreta... | ACCEPT | Summary: Nicastrin transits the Golgi where it undergoes complex N-glycan maturation, a hallmark of the catalytically competent mature gamma-secretase. Reason: Maturation compartment for nicastrin glycosylation (IDA). |
| GO:0006509 membrane protein ectodomain proteolysis | IDA PMID:15274632 Purification and characterization of the human gamma-secreta... | MODIFY | 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. Reason: Mislabeled granularity: NCSTN/gamma-secretase does intramembrane, not ectodomain, proteolysis (IDA). Proposed replacements: membrane protein intracellular domain proteolysis |
| GO:0007220 Notch receptor processing | TAS PMID:15274632 Purification and characterization of the human gamma-secreta... | ACCEPT | Summary: Nicastrin-containing gamma-secretase performs the regulated intramembrane (S3) cleavage of Notch receptors that releases NICD; nicastrin recognizes the Notch NEXT substrate. Reason: Core biological process of the complex; nicastrin is essential (IDA/IMP; structure with Notch1). |
| GO:0016485 protein processing | IDA PMID:15274632 Purification and characterization of the human gamma-secreta... | ACCEPT | Summary: Nicastrin contributes to the proteolytic processing of gamma-secretase substrates (Notch, APP, and other type I membrane proteins) via regulated intramembrane proteolysis. Reason: Core processing role of the complex (IDA/IMP/IGI/IBA). |
| GO:0042987 amyloid precursor protein catabolic process | TAS PMID:15274632 Purification and characterization of the human gamma-secreta... | ACCEPT | Summary: Nicastrin engages APP C-terminal fragments (C83/C99) for gamma-secretase cleavage, driving the catabolic intramembrane processing of APP. Reason: Core: complex-mediated APP catabolism, nicastrin binds the CTFs (IDA/IGI/TAS). |
| GO:0006508 proteolysis | NAS PMID:10993067 Nicastrin modulates presenilin-mediated notch/glp-1 signal t... | MODIFY | Summary: Generic proteolysis under-specifies the role; gamma-secretase performs regulated intramembrane (within-membrane) proteolysis of its substrates. Reason: Too general; a specific intramembrane proteolysis child applies (NAS). Proposed replacements: membrane protein proteolysis |
| GO:0016020 membrane | NAS PMID:10993067 Nicastrin modulates presenilin-mediated notch/glp-1 signal t... | ACCEPT | Summary: Nicastrin is a single-pass type I transmembrane glycoprotein; its membrane integration is required for assembly into the membrane-embedded gamma-secretase complex. Reason: Core localization: confirmed type I membrane protein (IDA/EXP, structures). |
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Download this section (compressed HTML)Q: How should GO distinguish NCSTN substrate-recognition/adaptor activity from the catalytic presenilin intramembrane aspartyl protease activity within gamma-secretase?
Suggested experts: gamma-secretase structural biology experts, GO molecular-function curators
Q: Which NCSTN-dependent gamma-secretase locations are physiologically active for APP versus Notch processing in vivo?
Suggested experts: APP trafficking experts, Notch signaling experts
Experiment: 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.
Type: endogenous gamma-secretase substrate recruitment assay
Experiment: 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.
Type: compartment-resolved gamma-secretase activity assay
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