PSEN2

UniProt ID: P49810
Organism: Homo sapiens
Review Status: COMPLETE
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Gene Description

Presenilin-2 is a multi-pass membrane aspartyl protease subunit of gamma-secretase complexes. After endoproteolytic maturation, PSEN2 N- and C-terminal fragments assemble with nicastrin, APH1, and PEN2 to cleave type I membrane-protein substrates, including APP-derived C-terminal fragments and Notch receptor substrates. PSEN2-containing complexes are distinguished from PSEN1 complexes by stronger late endosome/lysosome enrichment mediated by an AP-1-dependent N-terminal sorting motif, which shapes substrate access and intracellular amyloid-beta generation. Additional evidence links PSEN2 to endoplasmic-reticulum/mitochondrial calcium coupling and membrane-contact site biology, but these activities are secondary to its gamma-secretase catalytic role.

Existing Annotations Review

GO Term Evidence Action Reason
GO:0007219 Notch signaling pathway
IBA
GO_REF:0000033 		ACCEPT
Summary: PSEN2-containing gamma-secretase can mediate Notch receptor cleavage/signaling, although substrate preference varies by presenilin and APH1 isoform composition.
Reason: Experimental PSEN2 catalytic-site mutation impairs Notch signaling, and gamma-secretase biology includes Notch receptor substrate cleavage. Subunit-composition differences should be noted but do not negate the annotation.
Supporting Evidence:
PMID:15274632
This enzyme cleaves many type I membrane proteins, including the amyloid beta-protein (Abeta) precursor (APP) and the Notch receptor.
PMID:10497236
the PS2 D366A mutation not only blocks gamma-secretase activity but also inactivates PS2 activity in Notch signaling by inhibiting the proteolytic release of the cytoplasmic Notch1 domain.
PMID:27608597
PS2/Aph1b had a clear substrate specificity: APP-Gal4, but not Notch-Gal4, was cleaved.
GO:0042500 aspartic endopeptidase activity, intramembrane cleaving
IBA
GO_REF:0000033 		ACCEPT
Summary: PSEN2 provides the catalytic presenilin aspartyl protease activity within PSEN2-containing gamma-secretase complexes.
Reason: Mutational, biochemical, and structural evidence supports PSEN2 as a catalytic intramembrane-cleaving aspartyl protease subunit of gamma-secretase.
Supporting Evidence:
PMID:10652302
Here, we show that the two TM aspartates in PS2 are also critical for gamma-secretase activity, providing further evidence that PS2 is functionally homologous to PS1.
PMID:10497236
Cells expressing the PS2 D366A mutation exhibit significant deficits in proteolytic processing of beta-amyloid precursor protein indicating a defect in gamma-secretase activity.
PMID:27293189
The catalytic activity of the complex is provided by the PSEN1 or PSEN2 subunit isoforms, while three additional subunits, APH1A or B/C, nicastrin (NCT), and PEN-2 are needed to build a functional enzyme
GO:0055074 calcium ion homeostasis
IBA
GO_REF:0000033 		KEEP AS NON CORE
Summary: PSEN2 has evidence for roles in cellular calcium handling, especially ER-mitochondria calcium coupling, but this is secondary to the gamma-secretase catalytic role.
Reason: The annotation is biologically plausible and supported, but calcium ion homeostasis should be retained as non-core until normal in-vivo physiology is separated from mutant, overexpression, and disease-context phenotypes.
Supporting Evidence:
PMID:21285369
we show that overexpression or down-regulation of PS2, but not of presenilin 1 (PS1), modulates the Ca(2+) shuttling between ER and mitochondria
GO:0016485 protein processing
IBA
GO_REF:0000033 		KEEP AS NON CORE
Summary: PSEN2 participates in protein processing through gamma-secretase substrate cleavage, but this term is broad relative to the more informative intramembrane proteolysis annotations.
Reason: Retain as a true broad process context, while treating specific membrane-protein ectodomain proteolysis, APP processing, and Notch receptor processing as the informative core annotations.
Supporting Evidence:
PMID:15274632
This enzyme cleaves many type I membrane proteins, including the amyloid beta-protein (Abeta) precursor (APP) and the Notch receptor.
PMID:27608597
The γ-secretase complex comprises presenilin (PS), nicastrin (NCT), anterior pharynx-defective 1 (Aph1), and presenilin enhancer 2 (Pen2).
GO:0006509 membrane protein ectodomain proteolysis
IBA
GO_REF:0000033 		ACCEPT
Summary: PSEN2/gamma-secretase cleaves membrane-protein substrates after ectodomain shedding, including APP and Notch receptor fragments.
Reason: This process annotation reflects the general regulated intramembrane proteolysis activity of PSEN2-containing gamma-secretase complexes.
Supporting Evidence:
PMID:15274632
This enzyme cleaves many type I membrane proteins, including the amyloid beta-protein (Abeta) precursor (APP) and the Notch receptor.
PMID:27293189
The catalytic activity of the complex is provided by the PSEN1 or PSEN2 subunit isoforms, while three additional subunits, APH1A or B/C, nicastrin (NCT), and PEN-2 are needed to build a functional enzyme
PMID:27293189
sub-compartmentalization of the different γ-secretases and their substrates provides specificity as well as spatial and temporal control of their proteolytic activities.
GO:0034205 amyloid-beta formation
IBA
GO_REF:0000033 		ACCEPT
Summary: PSEN2-containing gamma-secretase cleaves APP-derived substrates and contributes to amyloid-beta formation, especially an intracellular late endosomal/lysosomal pool.
Reason: APP/Aβ production is a core substrate-processing output of PSEN2 gamma-secretase activity, with PSEN2 localization shaping the intracellular Aβ pool.
Supporting Evidence:
PMID:15274632
This enzyme cleaves many type I membrane proteins, including the amyloid beta-protein (Abeta) precursor (APP) and the Notch receptor.
PMID:10497236
Cells expressing the PS2 D366A mutation exhibit significant deficits in proteolytic processing of beta-amyloid precursor protein indicating a defect in gamma-secretase activity.
PMID:27293189
PSEN2 selectively cleaves late endosomal/lysosomal localized substrates and generates the prominent pool of intracellular Aβ that contains longer Aβ
GO:0070765 gamma-secretase complex
IBA
GO_REF:0000033 		ACCEPT
Summary: PSEN2 is a presenilin subunit of mature gamma-secretase complexes with nicastrin, APH1, and PEN2.
Reason: The complex annotation is central to PSEN2 biology because presenilin-containing gamma-secretase complexes perform the substrate-cleavage reactions attributed to PSEN2.
Supporting Evidence:
PMID:15274632
Extensive mass spectrometry of the purified proteins strongly suggests that PS-NTF/CTF, mNCT, Aph-1, and Pen-2 are the components of active gamma-secretase.
PMID:12297508
Presenilin and nicastrin are essential components of the gamma-secretase complex that is required for the intramembrane proteolysis of an increasing number of membrane proteins including the amyloid-beta precursor protein (APP) and Notch.
PMID:36272978
A γ-secretase complex comprises APH-1, Pen-2, nicastrin and the catalytic subunit presenilin
GO:0000139 Golgi membrane
IEA
GO_REF:0000044 		ACCEPT
Summary: PSEN2 is a multi-pass membrane protein detected in secretory-pathway compartments, including ER and Golgi, while mature PSEN2 complexes are especially enriched later in the endolysosomal route.
Reason: ER/Golgi localization is supported by presenilin localization studies and is compatible with gamma-secretase maturation and trafficking before PSEN2 enrichment in late endosome/lysosome compartments.
Supporting Evidence:
PMID:8574969
Immunochemical analyses indicate that PS1 and PS2 are similar in size and localized to similar intracellular compartments (endoplasmic reticulum and Golgi complex).
PMID:27293189
identified a unique motif in PSEN2 that directs this γ-secretase to late endosomes/lysosomes via a phosphorylation-dependent interaction with the AP-1 adaptor complex.
GO:0000776 kinetochore
IEA
GO_REF:0000117 		KEEP AS NON CORE
Summary: Older experimental literature reported presenilin localization to nuclear membrane, interphase kinetochore, and centrosome structures, but these locations are not central to current PSEN2 gamma-secretase biology.
Reason: Do not remove curator-supported or electronically propagated location annotations from incomplete evidence, but treat them as non-core because the evidence does not establish a primary PSEN2 function at these structures.
Supporting Evidence:
PMID:9298903
We have localized the presenilins to the nuclear membrane, its associated interphase kinetochores, and the centrosomes-all subcellular structures involved in cell cycle regulation and mitosis.
GO:0005765 lysosomal membrane
IEA
GO_REF:0000044 		ACCEPT
Summary: PSEN2-containing gamma-secretase is strongly enriched in late endosomal and lysosomal compartments.
Reason: Multiple experiments support PSEN2 late endosome/lysosome enrichment, and this localization helps explain PSEN2 substrate specificity and intracellular Aβ production.
Supporting Evidence:
PMID:27293189
identified a unique motif in PSEN2 that directs this γ-secretase to late endosomes/lysosomes via a phosphorylation-dependent interaction with the AP-1 adaptor complex.
PMID:27293189
This more restricted localization of PSEN2 is conserved in a wide range of cell lines, in primary neurons, and in brain.
PMID:27293189
PSEN2 selectively cleaves late endosomal/lysosomal localized substrates and generates the prominent pool of intracellular Aβ that contains longer Aβ
GO:0005789 endoplasmic reticulum membrane
IEA
GO_REF:0000044 		ACCEPT
Summary: PSEN2 is a multi-pass membrane protein detected in secretory-pathway compartments, including ER and Golgi, while mature PSEN2 complexes are especially enriched later in the endolysosomal route.
Reason: ER/Golgi localization is supported by presenilin localization studies and is compatible with gamma-secretase maturation and trafficking before PSEN2 enrichment in late endosome/lysosome compartments.
Supporting Evidence:
PMID:8574969
Immunochemical analyses indicate that PS1 and PS2 are similar in size and localized to similar intracellular compartments (endoplasmic reticulum and Golgi complex).
PMID:27293189
identified a unique motif in PSEN2 that directs this γ-secretase to late endosomes/lysosomes via a phosphorylation-dependent interaction with the AP-1 adaptor complex.
GO:0006509 membrane protein ectodomain proteolysis
IEA
GO_REF:0000117 		ACCEPT
Summary: PSEN2/gamma-secretase cleaves membrane-protein substrates after ectodomain shedding, including APP and Notch receptor fragments.
Reason: This process annotation reflects the general regulated intramembrane proteolysis activity of PSEN2-containing gamma-secretase complexes.
Supporting Evidence:
PMID:15274632
This enzyme cleaves many type I membrane proteins, including the amyloid beta-protein (Abeta) precursor (APP) and the Notch receptor.
PMID:27293189
The catalytic activity of the complex is provided by the PSEN1 or PSEN2 subunit isoforms, while three additional subunits, APH1A or B/C, nicastrin (NCT), and PEN-2 are needed to build a functional enzyme
PMID:27293189
sub-compartmentalization of the different γ-secretases and their substrates provides specificity as well as spatial and temporal control of their proteolytic activities.
GO:0007220 Notch receptor processing
IEA
GO_REF:0000117 		ACCEPT
Summary: PSEN2-containing gamma-secretase can mediate Notch receptor cleavage/signaling, although substrate preference varies by presenilin and APH1 isoform composition.
Reason: Experimental PSEN2 catalytic-site mutation impairs Notch signaling, and gamma-secretase biology includes Notch receptor substrate cleavage. Subunit-composition differences should be noted but do not negate the annotation.
Supporting Evidence:
PMID:15274632
This enzyme cleaves many type I membrane proteins, including the amyloid beta-protein (Abeta) precursor (APP) and the Notch receptor.
PMID:10497236
the PS2 D366A mutation not only blocks gamma-secretase activity but also inactivates PS2 activity in Notch signaling by inhibiting the proteolytic release of the cytoplasmic Notch1 domain.
PMID:27608597
PS2/Aph1b had a clear substrate specificity: APP-Gal4, but not Notch-Gal4, was cleaved.
GO:0016020 membrane
IEA
GO_REF:0000002 		MARK AS OVER ANNOTATED
Summary: PSEN2 is a multi-pass membrane protein, but the generic membrane term is too broad for curation value.
Reason: More specific ER, Golgi, late endosome/lysosome membrane, and gamma-secretase complex annotations capture the relevant localization and function.
Supporting Evidence:
PMID:8574969
Immunochemical analyses indicate that PS1 and PS2 are similar in size and localized to similar intracellular compartments (endoplasmic reticulum and Golgi complex).
PMID:27293189
identified a unique motif in PSEN2 that directs this γ-secretase to late endosomes/lysosomes via a phosphorylation-dependent interaction with the AP-1 adaptor complex.
GO:0016485 protein processing
IEA
GO_REF:0000120 		KEEP AS NON CORE
Summary: PSEN2 participates in protein processing through gamma-secretase substrate cleavage, but this term is broad relative to the more informative intramembrane proteolysis annotations.
Reason: Retain as a true broad process context, while treating specific membrane-protein ectodomain proteolysis, APP processing, and Notch receptor processing as the informative core annotations.
Supporting Evidence:
PMID:15274632
This enzyme cleaves many type I membrane proteins, including the amyloid beta-protein (Abeta) precursor (APP) and the Notch receptor.
PMID:27608597
The γ-secretase complex comprises presenilin (PS), nicastrin (NCT), anterior pharynx-defective 1 (Aph1), and presenilin enhancer 2 (Pen2).
GO:0031902 late endosome membrane
IEA
GO_REF:0000044 		ACCEPT
Summary: PSEN2-containing gamma-secretase is strongly enriched in late endosomal and lysosomal compartments.
Reason: Multiple experiments support PSEN2 late endosome/lysosome enrichment, and this localization helps explain PSEN2 substrate specificity and intracellular Aβ production.
Supporting Evidence:
PMID:27293189
identified a unique motif in PSEN2 that directs this γ-secretase to late endosomes/lysosomes via a phosphorylation-dependent interaction with the AP-1 adaptor complex.
PMID:27293189
This more restricted localization of PSEN2 is conserved in a wide range of cell lines, in primary neurons, and in brain.
PMID:27293189
PSEN2 selectively cleaves late endosomal/lysosomal localized substrates and generates the prominent pool of intracellular Aβ that contains longer Aβ
GO:0031965 nuclear membrane
IEA
GO_REF:0000117 		KEEP AS NON CORE
Summary: Older experimental literature reported presenilin localization to nuclear membrane, interphase kinetochore, and centrosome structures, but these locations are not central to current PSEN2 gamma-secretase biology.
Reason: Do not remove curator-supported or electronically propagated location annotations from incomplete evidence, but treat them as non-core because the evidence does not establish a primary PSEN2 function at these structures.
Supporting Evidence:
PMID:9298903
We have localized the presenilins to the nuclear membrane, its associated interphase kinetochores, and the centrosomes-all subcellular structures involved in cell cycle regulation and mitosis.
GO:0035556 intracellular signal transduction
IEA
GO_REF:0000002 		MARK AS OVER ANNOTATED
Summary: Intracellular signal transduction is too broad to describe PSEN2 function precisely.
Reason: PSEN2 affects signaling through specific gamma-secretase-mediated substrate processing and calcium-related phenotypes; the generic signaling term obscures those mechanisms.
GO:0042500 aspartic endopeptidase activity, intramembrane cleaving
IEA
GO_REF:0000002 		ACCEPT
Summary: PSEN2 provides the catalytic presenilin aspartyl protease activity within PSEN2-containing gamma-secretase complexes.
Reason: Mutational, biochemical, and structural evidence supports PSEN2 as a catalytic intramembrane-cleaving aspartyl protease subunit of gamma-secretase.
Supporting Evidence:
PMID:10652302
Here, we show that the two TM aspartates in PS2 are also critical for gamma-secretase activity, providing further evidence that PS2 is functionally homologous to PS1.
PMID:10497236
Cells expressing the PS2 D366A mutation exhibit significant deficits in proteolytic processing of beta-amyloid precursor protein indicating a defect in gamma-secretase activity.
PMID:27293189
The catalytic activity of the complex is provided by the PSEN1 or PSEN2 subunit isoforms, while three additional subunits, APH1A or B/C, nicastrin (NCT), and PEN-2 are needed to build a functional enzyme
GO:0042987 amyloid precursor protein catabolic process
IEA
GO_REF:0000002 		ACCEPT
Summary: PSEN2 participates in APP catabolism as the catalytic presenilin isoform in gamma-secretase complexes that process APP C-terminal fragments.
Reason: The annotation captures a specific and well-supported substrate class of PSEN2/gamma-secretase, rather than a generic disease association.
Supporting Evidence:
PMID:15274632
This enzyme cleaves many type I membrane proteins, including the amyloid beta-protein (Abeta) precursor (APP) and the Notch receptor.
PMID:10497236
Cells expressing the PS2 D366A mutation exhibit significant deficits in proteolytic processing of beta-amyloid precursor protein indicating a defect in gamma-secretase activity.
PMID:27293189
PSEN2 selectively cleaves late endosomal/lysosomal localized substrates and generates the prominent pool of intracellular Aβ that contains longer Aβ
GO:0005515 protein binding
IPI
PMID:21163940
Interactome mapping suggests new mechanistic details underly... 		MARK AS OVER ANNOTATED
Summary: Generic protein binding annotation for PSEN2. The reported interactions may be real, but GO:0005515 is not informative about PSEN2 molecular function.
Reason: Mark as over-annotated because specific curatable biology is gamma-secretase complex membership, substrate cleavage, AP-1-dependent trafficking, or calcium-coupled interactions rather than generic protein binding.
GO:0005515 protein binding
IPI
PMID:32814053
Interactome Mapping Provides a Network of Neurodegenerative ... 		MARK AS OVER ANNOTATED
Summary: Generic protein binding annotation for PSEN2. The reported interactions may be real, but GO:0005515 is not informative about PSEN2 molecular function.
Reason: Mark as over-annotated because specific curatable biology is gamma-secretase complex membership, substrate cleavage, AP-1-dependent trafficking, or calcium-coupled interactions rather than generic protein binding.
GO:0005515 protein binding
IPI
PMID:9223340
Interaction between amyloid precursor protein and presenilin... 		MARK AS OVER ANNOTATED
Summary: Generic protein binding annotation for PSEN2. The reported interactions may be real, but GO:0005515 is not informative about PSEN2 molecular function.
Reason: Mark as over-annotated because specific curatable biology is gamma-secretase complex membership, substrate cleavage, AP-1-dependent trafficking, or calcium-coupled interactions rather than generic protein binding.
Supporting Evidence:
PMID:9223340
wt and mutant PS1 and PS2 proteins form complexes with APP in living cells
GO:0001666 response to hypoxia
IEA
GO_REF:0000107 		UNDECIDED
Summary: Response-to-hypoxia is electronically inferred and not supported by the PSEN2 literature reviewed here.
Reason: No cached publication evidence was found that establishes hypoxia response as a PSEN2 function; retain as undecided rather than removing an electronic transfer without a full provenance review.
GO:0005769 early endosome
IEA
GO_REF:0000107 		KEEP AS NON CORE
Summary: Early endosome localization is consistent with AP-1-dependent PSEN2 routing toward late endosome/lysosome compartments, but it is not the best-supported mature steady-state compartment.
Reason: Retain as trafficking context rather than core localization because the strongest evidence emphasizes late endosome/lysosome enrichment.
Supporting Evidence:
PMID:27293189
identified a unique motif in PSEN2 that directs this γ-secretase to late endosomes/lysosomes via a phosphorylation-dependent interaction with the AP-1 adaptor complex.
GO:0008021 synaptic vesicle
IEA
GO_REF:0000107 		UNDECIDED
Summary: Synaptic-compartment annotations are plausible in neuronal contexts but are only electronically inferred here and not directly established by the cached PSEN2 evidence.
Reason: The local evidence supports neuronal somatodendritic endolysosomal PSEN2, but not this specific synaptic vesicle/presynaptic/synaptic membrane localization. Leave undecided pending stronger direct evidence.
Supporting Evidence:
PMID:27293189
This more restricted localization of PSEN2 is conserved in a wide range of cell lines, in primary neurons, and in brain.
GO:0042734 presynaptic membrane
IEA
GO_REF:0000107 		UNDECIDED
Summary: Synaptic-compartment annotations are plausible in neuronal contexts but are only electronically inferred here and not directly established by the cached PSEN2 evidence.
Reason: The local evidence supports neuronal somatodendritic endolysosomal PSEN2, but not this specific synaptic vesicle/presynaptic/synaptic membrane localization. Leave undecided pending stronger direct evidence.
Supporting Evidence:
PMID:27293189
This more restricted localization of PSEN2 is conserved in a wide range of cell lines, in primary neurons, and in brain.
GO:0097060 synaptic membrane
IEA
GO_REF:0000107 		UNDECIDED
Summary: Synaptic-compartment annotations are plausible in neuronal contexts but are only electronically inferred here and not directly established by the cached PSEN2 evidence.
Reason: The local evidence supports neuronal somatodendritic endolysosomal PSEN2, but not this specific synaptic vesicle/presynaptic/synaptic membrane localization. Leave undecided pending stronger direct evidence.
Supporting Evidence:
PMID:27293189
This more restricted localization of PSEN2 is conserved in a wide range of cell lines, in primary neurons, and in brain.
GO:0000139 Golgi membrane
EXP
PMID:8574969
Alzheimer-associated presenilins 1 and 2: neuronal expressio... 		ACCEPT
Summary: PSEN2 is a multi-pass membrane protein detected in secretory-pathway compartments, including ER and Golgi, while mature PSEN2 complexes are especially enriched later in the endolysosomal route.
Reason: ER/Golgi localization is supported by presenilin localization studies and is compatible with gamma-secretase maturation and trafficking before PSEN2 enrichment in late endosome/lysosome compartments.
Supporting Evidence:
PMID:8574969
Immunochemical analyses indicate that PS1 and PS2 are similar in size and localized to similar intracellular compartments (endoplasmic reticulum and Golgi complex).
PMID:27293189
identified a unique motif in PSEN2 that directs this γ-secretase to late endosomes/lysosomes via a phosphorylation-dependent interaction with the AP-1 adaptor complex.
GO:0005765 lysosomal membrane
EXP
PMID:27293189
Restricted Location of PSEN2/γ-Secretase Determines Substrat... 		ACCEPT
Summary: PSEN2-containing gamma-secretase is strongly enriched in late endosomal and lysosomal compartments.
Reason: Multiple experiments support PSEN2 late endosome/lysosome enrichment, and this localization helps explain PSEN2 substrate specificity and intracellular Aβ production.
Supporting Evidence:
PMID:27293189
identified a unique motif in PSEN2 that directs this γ-secretase to late endosomes/lysosomes via a phosphorylation-dependent interaction with the AP-1 adaptor complex.
PMID:27293189
This more restricted localization of PSEN2 is conserved in a wide range of cell lines, in primary neurons, and in brain.
PMID:27293189
PSEN2 selectively cleaves late endosomal/lysosomal localized substrates and generates the prominent pool of intracellular Aβ that contains longer Aβ
GO:0005789 endoplasmic reticulum membrane
EXP
PMID:8574969
Alzheimer-associated presenilins 1 and 2: neuronal expressio... 		ACCEPT
Summary: PSEN2 is a multi-pass membrane protein detected in secretory-pathway compartments, including ER and Golgi, while mature PSEN2 complexes are especially enriched later in the endolysosomal route.
Reason: ER/Golgi localization is supported by presenilin localization studies and is compatible with gamma-secretase maturation and trafficking before PSEN2 enrichment in late endosome/lysosome compartments.
Supporting Evidence:
PMID:8574969
Immunochemical analyses indicate that PS1 and PS2 are similar in size and localized to similar intracellular compartments (endoplasmic reticulum and Golgi complex).
PMID:27293189
identified a unique motif in PSEN2 that directs this γ-secretase to late endosomes/lysosomes via a phosphorylation-dependent interaction with the AP-1 adaptor complex.
GO:0031902 late endosome membrane
EXP
PMID:27293189
Restricted Location of PSEN2/γ-Secretase Determines Substrat... 		ACCEPT
Summary: PSEN2-containing gamma-secretase is strongly enriched in late endosomal and lysosomal compartments.
Reason: Multiple experiments support PSEN2 late endosome/lysosome enrichment, and this localization helps explain PSEN2 substrate specificity and intracellular Aβ production.
Supporting Evidence:
PMID:27293189
identified a unique motif in PSEN2 that directs this γ-secretase to late endosomes/lysosomes via a phosphorylation-dependent interaction with the AP-1 adaptor complex.
PMID:27293189
This more restricted localization of PSEN2 is conserved in a wide range of cell lines, in primary neurons, and in brain.
PMID:27293189
PSEN2 selectively cleaves late endosomal/lysosomal localized substrates and generates the prominent pool of intracellular Aβ that contains longer Aβ
GO:0044233 mitochondria-associated endoplasmic reticulum membrane contact site
ISS
GO_REF:0000024 		KEEP AS NON CORE
Summary: PSEN2 has evidence connecting it to ER-mitochondria membrane-contact biology and calcium cross-talk.
Reason: The location/interaction context is relevant to PSEN2 calcium biology, but it should remain non-core relative to gamma-secretase complex localization and protease activity.
Supporting Evidence:
PMID:21285369
This effect is not caused by a direct PS2 action on mitochondrial Ca(2+)-uptake machinery but rather by an increased physical interaction between ER and mitochondria
GO:0005515 protein binding
IPI
PMID:27293189
Restricted Location of PSEN2/γ-Secretase Determines Substrat... 		MARK AS OVER ANNOTATED
Summary: Generic protein binding annotation for PSEN2. The reported interactions may be real, but GO:0005515 is not informative about PSEN2 molecular function.
Reason: Mark as over-annotated because specific curatable biology is gamma-secretase complex membership, substrate cleavage, AP-1-dependent trafficking, or calcium-coupled interactions rather than generic protein binding.
Supporting Evidence:
PMID:27293189
identified a unique motif in PSEN2 that directs this γ-secretase to late endosomes/lysosomes via a phosphorylation-dependent interaction with the AP-1 adaptor complex.
GO:0005764 lysosome
IDA
PMID:27293189
Restricted Location of PSEN2/γ-Secretase Determines Substrat... 		ACCEPT
Summary: PSEN2-containing gamma-secretase is strongly enriched in late endosomal and lysosomal compartments.
Reason: Multiple experiments support PSEN2 late endosome/lysosome enrichment, and this localization helps explain PSEN2 substrate specificity and intracellular Aβ production.
Supporting Evidence:
PMID:27293189
identified a unique motif in PSEN2 that directs this γ-secretase to late endosomes/lysosomes via a phosphorylation-dependent interaction with the AP-1 adaptor complex.
PMID:27293189
This more restricted localization of PSEN2 is conserved in a wide range of cell lines, in primary neurons, and in brain.
PMID:27293189
PSEN2 selectively cleaves late endosomal/lysosomal localized substrates and generates the prominent pool of intracellular Aβ that contains longer Aβ
GO:0005770 late endosome
IDA
PMID:27293189
Restricted Location of PSEN2/γ-Secretase Determines Substrat... 		ACCEPT
Summary: PSEN2-containing gamma-secretase is strongly enriched in late endosomal and lysosomal compartments.
Reason: Multiple experiments support PSEN2 late endosome/lysosome enrichment, and this localization helps explain PSEN2 substrate specificity and intracellular Aβ production.
Supporting Evidence:
PMID:27293189
identified a unique motif in PSEN2 that directs this γ-secretase to late endosomes/lysosomes via a phosphorylation-dependent interaction with the AP-1 adaptor complex.
PMID:27293189
This more restricted localization of PSEN2 is conserved in a wide range of cell lines, in primary neurons, and in brain.
PMID:27293189
PSEN2 selectively cleaves late endosomal/lysosomal localized substrates and generates the prominent pool of intracellular Aβ that contains longer Aβ
GO:0034205 amyloid-beta formation
IDA
PMID:27293189
Restricted Location of PSEN2/γ-Secretase Determines Substrat... 		ACCEPT
Summary: PSEN2-containing gamma-secretase cleaves APP-derived substrates and contributes to amyloid-beta formation, especially an intracellular late endosomal/lysosomal pool.
Reason: APP/Aβ production is a core substrate-processing output of PSEN2 gamma-secretase activity, with PSEN2 localization shaping the intracellular Aβ pool.
Supporting Evidence:
PMID:15274632
This enzyme cleaves many type I membrane proteins, including the amyloid beta-protein (Abeta) precursor (APP) and the Notch receptor.
PMID:10497236
Cells expressing the PS2 D366A mutation exhibit significant deficits in proteolytic processing of beta-amyloid precursor protein indicating a defect in gamma-secretase activity.
PMID:27293189
PSEN2 selectively cleaves late endosomal/lysosomal localized substrates and generates the prominent pool of intracellular Aβ that contains longer Aβ
GO:0034205 amyloid-beta formation
IDA
PMID:36272978
Molecular basis for isoform-selective inhibition of presenil... 		ACCEPT
Summary: PSEN2-containing gamma-secretase cleaves APP-derived substrates and contributes to amyloid-beta formation, especially an intracellular late endosomal/lysosomal pool.
Reason: APP/Aβ production is a core substrate-processing output of PSEN2 gamma-secretase activity, with PSEN2 localization shaping the intracellular Aβ pool.
Supporting Evidence:
PMID:15274632
This enzyme cleaves many type I membrane proteins, including the amyloid beta-protein (Abeta) precursor (APP) and the Notch receptor.
PMID:10497236
Cells expressing the PS2 D366A mutation exhibit significant deficits in proteolytic processing of beta-amyloid precursor protein indicating a defect in gamma-secretase activity.
PMID:27293189
PSEN2 selectively cleaves late endosomal/lysosomal localized substrates and generates the prominent pool of intracellular Aβ that contains longer Aβ
GO:0035333 Notch receptor processing, ligand-dependent
IDA
PMID:27293189
Restricted Location of PSEN2/γ-Secretase Determines Substrat... 		ACCEPT
Summary: PSEN2-containing gamma-secretase can mediate Notch receptor cleavage/signaling, although substrate preference varies by presenilin and APH1 isoform composition.
Reason: Experimental PSEN2 catalytic-site mutation impairs Notch signaling, and gamma-secretase biology includes Notch receptor substrate cleavage. Subunit-composition differences should be noted but do not negate the annotation.
Supporting Evidence:
PMID:15274632
This enzyme cleaves many type I membrane proteins, including the amyloid beta-protein (Abeta) precursor (APP) and the Notch receptor.
PMID:10497236
the PS2 D366A mutation not only blocks gamma-secretase activity but also inactivates PS2 activity in Notch signaling by inhibiting the proteolytic release of the cytoplasmic Notch1 domain.
PMID:27608597
PS2/Aph1b had a clear substrate specificity: APP-Gal4, but not Notch-Gal4, was cleaved.
GO:0042500 aspartic endopeptidase activity, intramembrane cleaving
IDA
PMID:27293189
Restricted Location of PSEN2/γ-Secretase Determines Substrat... 		ACCEPT
Summary: PSEN2 provides the catalytic presenilin aspartyl protease activity within PSEN2-containing gamma-secretase complexes.
Reason: Mutational, biochemical, and structural evidence supports PSEN2 as a catalytic intramembrane-cleaving aspartyl protease subunit of gamma-secretase.
Supporting Evidence:
PMID:10652302
Here, we show that the two TM aspartates in PS2 are also critical for gamma-secretase activity, providing further evidence that PS2 is functionally homologous to PS1.
PMID:10497236
Cells expressing the PS2 D366A mutation exhibit significant deficits in proteolytic processing of beta-amyloid precursor protein indicating a defect in gamma-secretase activity.
PMID:27293189
The catalytic activity of the complex is provided by the PSEN1 or PSEN2 subunit isoforms, while three additional subunits, APH1A or B/C, nicastrin (NCT), and PEN-2 are needed to build a functional enzyme
GO:0042500 aspartic endopeptidase activity, intramembrane cleaving
IDA
PMID:36272978
Molecular basis for isoform-selective inhibition of presenil... 		ACCEPT
Summary: PSEN2 provides the catalytic presenilin aspartyl protease activity within PSEN2-containing gamma-secretase complexes.
Reason: Mutational, biochemical, and structural evidence supports PSEN2 as a catalytic intramembrane-cleaving aspartyl protease subunit of gamma-secretase.
Supporting Evidence:
PMID:10652302
Here, we show that the two TM aspartates in PS2 are also critical for gamma-secretase activity, providing further evidence that PS2 is functionally homologous to PS1.
PMID:10497236
Cells expressing the PS2 D366A mutation exhibit significant deficits in proteolytic processing of beta-amyloid precursor protein indicating a defect in gamma-secretase activity.
PMID:27293189
The catalytic activity of the complex is provided by the PSEN1 or PSEN2 subunit isoforms, while three additional subunits, APH1A or B/C, nicastrin (NCT), and PEN-2 are needed to build a functional enzyme
GO:0070765 gamma-secretase complex
IDA
PMID:36272978
Molecular basis for isoform-selective inhibition of presenil... 		ACCEPT
Summary: PSEN2 is a presenilin subunit of mature gamma-secretase complexes with nicastrin, APH1, and PEN2.
Reason: The complex annotation is central to PSEN2 biology because presenilin-containing gamma-secretase complexes perform the substrate-cleavage reactions attributed to PSEN2.
Supporting Evidence:
PMID:15274632
Extensive mass spectrometry of the purified proteins strongly suggests that PS-NTF/CTF, mNCT, Aph-1, and Pen-2 are the components of active gamma-secretase.
PMID:12297508
Presenilin and nicastrin are essential components of the gamma-secretase complex that is required for the intramembrane proteolysis of an increasing number of membrane proteins including the amyloid-beta precursor protein (APP) and Notch.
PMID:36272978
A γ-secretase complex comprises APH-1, Pen-2, nicastrin and the catalytic subunit presenilin
GO:0034205 amyloid-beta formation
IDA
PMID:10497236
A loss of function mutation of presenilin-2 interferes with ... 		ACCEPT
Summary: PSEN2-containing gamma-secretase cleaves APP-derived substrates and contributes to amyloid-beta formation, especially an intracellular late endosomal/lysosomal pool.
Reason: APP/Aβ production is a core substrate-processing output of PSEN2 gamma-secretase activity, with PSEN2 localization shaping the intracellular Aβ pool.
Supporting Evidence:
PMID:15274632
This enzyme cleaves many type I membrane proteins, including the amyloid beta-protein (Abeta) precursor (APP) and the Notch receptor.
PMID:10497236
Cells expressing the PS2 D366A mutation exhibit significant deficits in proteolytic processing of beta-amyloid precursor protein indicating a defect in gamma-secretase activity.
PMID:27293189
PSEN2 selectively cleaves late endosomal/lysosomal localized substrates and generates the prominent pool of intracellular Aβ that contains longer Aβ
GO:0034205 amyloid-beta formation
IDA
PMID:10652302
The transmembrane aspartates in presenilin 1 and 2 are oblig... 		ACCEPT
Summary: PSEN2-containing gamma-secretase cleaves APP-derived substrates and contributes to amyloid-beta formation, especially an intracellular late endosomal/lysosomal pool.
Reason: APP/Aβ production is a core substrate-processing output of PSEN2 gamma-secretase activity, with PSEN2 localization shaping the intracellular Aβ pool.
Supporting Evidence:
PMID:15274632
This enzyme cleaves many type I membrane proteins, including the amyloid beta-protein (Abeta) precursor (APP) and the Notch receptor.
PMID:10497236
Cells expressing the PS2 D366A mutation exhibit significant deficits in proteolytic processing of beta-amyloid precursor protein indicating a defect in gamma-secretase activity.
PMID:27293189
PSEN2 selectively cleaves late endosomal/lysosomal localized substrates and generates the prominent pool of intracellular Aβ that contains longer Aβ
GO:0034205 amyloid-beta formation
IDA
PMID:16752394
Mean age-of-onset of familial alzheimer disease caused by pr... 		ACCEPT
Summary: PSEN2-containing gamma-secretase cleaves APP-derived substrates and contributes to amyloid-beta formation, especially an intracellular late endosomal/lysosomal pool.
Reason: APP/Aβ production is a core substrate-processing output of PSEN2 gamma-secretase activity, with PSEN2 localization shaping the intracellular Aβ pool.
Supporting Evidence:
PMID:15274632
This enzyme cleaves many type I membrane proteins, including the amyloid beta-protein (Abeta) precursor (APP) and the Notch receptor.
PMID:10497236
Cells expressing the PS2 D366A mutation exhibit significant deficits in proteolytic processing of beta-amyloid precursor protein indicating a defect in gamma-secretase activity.
PMID:27293189
PSEN2 selectively cleaves late endosomal/lysosomal localized substrates and generates the prominent pool of intracellular Aβ that contains longer Aβ
GO:0035333 Notch receptor processing, ligand-dependent
IDA
PMID:10497236
A loss of function mutation of presenilin-2 interferes with ... 		ACCEPT
Summary: PSEN2-containing gamma-secretase can mediate Notch receptor cleavage/signaling, although substrate preference varies by presenilin and APH1 isoform composition.
Reason: Experimental PSEN2 catalytic-site mutation impairs Notch signaling, and gamma-secretase biology includes Notch receptor substrate cleavage. Subunit-composition differences should be noted but do not negate the annotation.
Supporting Evidence:
PMID:15274632
This enzyme cleaves many type I membrane proteins, including the amyloid beta-protein (Abeta) precursor (APP) and the Notch receptor.
PMID:10497236
the PS2 D366A mutation not only blocks gamma-secretase activity but also inactivates PS2 activity in Notch signaling by inhibiting the proteolytic release of the cytoplasmic Notch1 domain.
PMID:27608597
PS2/Aph1b had a clear substrate specificity: APP-Gal4, but not Notch-Gal4, was cleaved.
GO:0042500 aspartic endopeptidase activity, intramembrane cleaving
IDA
PMID:10497236
A loss of function mutation of presenilin-2 interferes with ... 		ACCEPT
Summary: PSEN2 provides the catalytic presenilin aspartyl protease activity within PSEN2-containing gamma-secretase complexes.
Reason: Mutational, biochemical, and structural evidence supports PSEN2 as a catalytic intramembrane-cleaving aspartyl protease subunit of gamma-secretase.
Supporting Evidence:
PMID:10652302
Here, we show that the two TM aspartates in PS2 are also critical for gamma-secretase activity, providing further evidence that PS2 is functionally homologous to PS1.
PMID:10497236
Cells expressing the PS2 D366A mutation exhibit significant deficits in proteolytic processing of beta-amyloid precursor protein indicating a defect in gamma-secretase activity.
PMID:27293189
The catalytic activity of the complex is provided by the PSEN1 or PSEN2 subunit isoforms, while three additional subunits, APH1A or B/C, nicastrin (NCT), and PEN-2 are needed to build a functional enzyme
GO:0042500 aspartic endopeptidase activity, intramembrane cleaving
IDA
PMID:10652302
The transmembrane aspartates in presenilin 1 and 2 are oblig... 		ACCEPT
Summary: PSEN2 provides the catalytic presenilin aspartyl protease activity within PSEN2-containing gamma-secretase complexes.
Reason: Mutational, biochemical, and structural evidence supports PSEN2 as a catalytic intramembrane-cleaving aspartyl protease subunit of gamma-secretase.
Supporting Evidence:
PMID:10652302
Here, we show that the two TM aspartates in PS2 are also critical for gamma-secretase activity, providing further evidence that PS2 is functionally homologous to PS1.
PMID:10497236
Cells expressing the PS2 D366A mutation exhibit significant deficits in proteolytic processing of beta-amyloid precursor protein indicating a defect in gamma-secretase activity.
PMID:27293189
The catalytic activity of the complex is provided by the PSEN1 or PSEN2 subunit isoforms, while three additional subunits, APH1A or B/C, nicastrin (NCT), and PEN-2 are needed to build a functional enzyme
GO:0042500 aspartic endopeptidase activity, intramembrane cleaving
IDA
PMID:16752394
Mean age-of-onset of familial alzheimer disease caused by pr... 		ACCEPT
Summary: PSEN2 provides the catalytic presenilin aspartyl protease activity within PSEN2-containing gamma-secretase complexes.
Reason: Mutational, biochemical, and structural evidence supports PSEN2 as a catalytic intramembrane-cleaving aspartyl protease subunit of gamma-secretase.
Supporting Evidence:
PMID:10652302
Here, we show that the two TM aspartates in PS2 are also critical for gamma-secretase activity, providing further evidence that PS2 is functionally homologous to PS1.
PMID:10497236
Cells expressing the PS2 D366A mutation exhibit significant deficits in proteolytic processing of beta-amyloid precursor protein indicating a defect in gamma-secretase activity.
PMID:27293189
The catalytic activity of the complex is provided by the PSEN1 or PSEN2 subunit isoforms, while three additional subunits, APH1A or B/C, nicastrin (NCT), and PEN-2 are needed to build a functional enzyme
GO:0016485 protein processing
IDA
PMID:27608597
Specific combinations of presenilins and Aph1s affect the su... 		KEEP AS NON CORE
Summary: PSEN2 participates in protein processing through gamma-secretase substrate cleavage, but this term is broad relative to the more informative intramembrane proteolysis annotations.
Reason: Retain as a true broad process context, while treating specific membrane-protein ectodomain proteolysis, APP processing, and Notch receptor processing as the informative core annotations.
Supporting Evidence:
PMID:15274632
This enzyme cleaves many type I membrane proteins, including the amyloid beta-protein (Abeta) precursor (APP) and the Notch receptor.
PMID:27608597
The γ-secretase complex comprises presenilin (PS), nicastrin (NCT), anterior pharynx-defective 1 (Aph1), and presenilin enhancer 2 (Pen2).
GO:0034205 amyloid-beta formation
IDA
PMID:27608597
Specific combinations of presenilins and Aph1s affect the su... 		ACCEPT
Summary: PSEN2-containing gamma-secretase cleaves APP-derived substrates and contributes to amyloid-beta formation, especially an intracellular late endosomal/lysosomal pool.
Reason: APP/Aβ production is a core substrate-processing output of PSEN2 gamma-secretase activity, with PSEN2 localization shaping the intracellular Aβ pool.
Supporting Evidence:
PMID:15274632
This enzyme cleaves many type I membrane proteins, including the amyloid beta-protein (Abeta) precursor (APP) and the Notch receptor.
PMID:10497236
Cells expressing the PS2 D366A mutation exhibit significant deficits in proteolytic processing of beta-amyloid precursor protein indicating a defect in gamma-secretase activity.
PMID:27293189
PSEN2 selectively cleaves late endosomal/lysosomal localized substrates and generates the prominent pool of intracellular Aβ that contains longer Aβ
GO:0042987 amyloid precursor protein catabolic process
IDA
PMID:27608597
Specific combinations of presenilins and Aph1s affect the su... 		ACCEPT
Summary: PSEN2 participates in APP catabolism as the catalytic presenilin isoform in gamma-secretase complexes that process APP C-terminal fragments.
Reason: The annotation captures a specific and well-supported substrate class of PSEN2/gamma-secretase, rather than a generic disease association.
Supporting Evidence:
PMID:15274632
This enzyme cleaves many type I membrane proteins, including the amyloid beta-protein (Abeta) precursor (APP) and the Notch receptor.
PMID:10497236
Cells expressing the PS2 D366A mutation exhibit significant deficits in proteolytic processing of beta-amyloid precursor protein indicating a defect in gamma-secretase activity.
PMID:27293189
PSEN2 selectively cleaves late endosomal/lysosomal localized substrates and generates the prominent pool of intracellular Aβ that contains longer Aβ
GO:0070765 gamma-secretase complex
IDA
PMID:12297508
Mammalian APH-1 interacts with presenilin and nicastrin and ... 		ACCEPT
Summary: PSEN2 is a presenilin subunit of mature gamma-secretase complexes with nicastrin, APH1, and PEN2.
Reason: The complex annotation is central to PSEN2 biology because presenilin-containing gamma-secretase complexes perform the substrate-cleavage reactions attributed to PSEN2.
Supporting Evidence:
PMID:15274632
Extensive mass spectrometry of the purified proteins strongly suggests that PS-NTF/CTF, mNCT, Aph-1, and Pen-2 are the components of active gamma-secretase.
PMID:12297508
Presenilin and nicastrin are essential components of the gamma-secretase complex that is required for the intramembrane proteolysis of an increasing number of membrane proteins including the amyloid-beta precursor protein (APP) and Notch.
PMID:36272978
A γ-secretase complex comprises APH-1, Pen-2, nicastrin and the catalytic subunit presenilin
GO:0110097 regulation of calcium import into the mitochondrion
IMP
PMID:21285369
Presenilin 2 modulates endoplasmic reticulum (ER)-mitochondr... 		KEEP AS NON CORE
Summary: PSEN2 modulates ER-mitochondria calcium transfer in cellular and neuronal culture systems.
Reason: This is a supported PSEN2-associated phenotype, but it is best curated as non-core relative to gamma-secretase activity until its normal in-vivo physiological scope is clearer.
Supporting Evidence:
PMID:21285369
we show that overexpression or down-regulation of PS2, but not of presenilin 1 (PS1), modulates the Ca(2+) shuttling between ER and mitochondria
PMID:21285369
This effect is not caused by a direct PS2 action on mitochondrial Ca(2+)-uptake machinery but rather by an increased physical interaction between ER and mitochondria
GO:0005886 plasma membrane
TAS
Reactome:R-HSA-1251997 		KEEP AS NON CORE
Summary: Plasma membrane localization is a plausible gamma-secretase context, but PSEN2 is much less abundant at the cell surface than PSEN1 in later comparative studies.
Reason: Retain the location as non-core context while treating late endosome/lysosome enrichment as the characteristic PSEN2 localization supported by the strongest PSEN2-specific evidence.
Supporting Evidence:
PMID:27293189
identified a unique motif in PSEN2 that directs this γ-secretase to late endosomes/lysosomes via a phosphorylation-dependent interaction with the AP-1 adaptor complex.
GO:0005886 plasma membrane
TAS
Reactome:R-HSA-193682 		KEEP AS NON CORE
Summary: Plasma membrane localization is a plausible gamma-secretase context, but PSEN2 is much less abundant at the cell surface than PSEN1 in later comparative studies.
Reason: Retain the location as non-core context while treating late endosome/lysosome enrichment as the characteristic PSEN2 localization supported by the strongest PSEN2-specific evidence.
Supporting Evidence:
PMID:27293189
identified a unique motif in PSEN2 that directs this γ-secretase to late endosomes/lysosomes via a phosphorylation-dependent interaction with the AP-1 adaptor complex.
GO:0005886 plasma membrane
TAS
Reactome:R-HSA-205112 		KEEP AS NON CORE
Summary: Plasma membrane localization is a plausible gamma-secretase context, but PSEN2 is much less abundant at the cell surface than PSEN1 in later comparative studies.
Reason: Retain the location as non-core context while treating late endosome/lysosome enrichment as the characteristic PSEN2 localization supported by the strongest PSEN2-specific evidence.
Supporting Evidence:
PMID:27293189
identified a unique motif in PSEN2 that directs this γ-secretase to late endosomes/lysosomes via a phosphorylation-dependent interaction with the AP-1 adaptor complex.
GO:0005886 plasma membrane
TAS
Reactome:R-HSA-2220988 		KEEP AS NON CORE
Summary: Plasma membrane localization is a plausible gamma-secretase context, but PSEN2 is much less abundant at the cell surface than PSEN1 in later comparative studies.
Reason: Retain the location as non-core context while treating late endosome/lysosome enrichment as the characteristic PSEN2 localization supported by the strongest PSEN2-specific evidence.
Supporting Evidence:
PMID:27293189
identified a unique motif in PSEN2 that directs this γ-secretase to late endosomes/lysosomes via a phosphorylation-dependent interaction with the AP-1 adaptor complex.
GO:0005886 plasma membrane
TAS
Reactome:R-HSA-3928656 		KEEP AS NON CORE
Summary: Plasma membrane localization is a plausible gamma-secretase context, but PSEN2 is much less abundant at the cell surface than PSEN1 in later comparative studies.
Reason: Retain the location as non-core context while treating late endosome/lysosome enrichment as the characteristic PSEN2 localization supported by the strongest PSEN2-specific evidence.
Supporting Evidence:
PMID:27293189
identified a unique motif in PSEN2 that directs this γ-secretase to late endosomes/lysosomes via a phosphorylation-dependent interaction with the AP-1 adaptor complex.
GO:0005886 plasma membrane
TAS
Reactome:R-HSA-9013361 		KEEP AS NON CORE
Summary: Plasma membrane localization is a plausible gamma-secretase context, but PSEN2 is much less abundant at the cell surface than PSEN1 in later comparative studies.
Reason: Retain the location as non-core context while treating late endosome/lysosome enrichment as the characteristic PSEN2 localization supported by the strongest PSEN2-specific evidence.
Supporting Evidence:
PMID:27293189
identified a unique motif in PSEN2 that directs this γ-secretase to late endosomes/lysosomes via a phosphorylation-dependent interaction with the AP-1 adaptor complex.
GO:0005886 plasma membrane
TAS
Reactome:R-HSA-9017817 		KEEP AS NON CORE
Summary: Plasma membrane localization is a plausible gamma-secretase context, but PSEN2 is much less abundant at the cell surface than PSEN1 in later comparative studies.
Reason: Retain the location as non-core context while treating late endosome/lysosome enrichment as the characteristic PSEN2 localization supported by the strongest PSEN2-specific evidence.
Supporting Evidence:
PMID:27293189
identified a unique motif in PSEN2 that directs this γ-secretase to late endosomes/lysosomes via a phosphorylation-dependent interaction with the AP-1 adaptor complex.
GO:0005886 plasma membrane
TAS
Reactome:R-HSA-9839376 		KEEP AS NON CORE
Summary: Plasma membrane localization is a plausible gamma-secretase context, but PSEN2 is much less abundant at the cell surface than PSEN1 in later comparative studies.
Reason: Retain the location as non-core context while treating late endosome/lysosome enrichment as the characteristic PSEN2 localization supported by the strongest PSEN2-specific evidence.
Supporting Evidence:
PMID:27293189
identified a unique motif in PSEN2 that directs this γ-secretase to late endosomes/lysosomes via a phosphorylation-dependent interaction with the AP-1 adaptor complex.
GO:0005886 plasma membrane
TAS
Reactome:R-NUL-2197556 		KEEP AS NON CORE
Summary: Plasma membrane localization is a plausible gamma-secretase context, but PSEN2 is much less abundant at the cell surface than PSEN1 in later comparative studies.
Reason: Retain the location as non-core context while treating late endosome/lysosome enrichment as the characteristic PSEN2 localization supported by the strongest PSEN2-specific evidence.
Supporting Evidence:
PMID:27293189
identified a unique motif in PSEN2 that directs this γ-secretase to late endosomes/lysosomes via a phosphorylation-dependent interaction with the AP-1 adaptor complex.
GO:0005886 plasma membrane
TAS
Reactome:R-NUL-9604300 		KEEP AS NON CORE
Summary: Plasma membrane localization is a plausible gamma-secretase context, but PSEN2 is much less abundant at the cell surface than PSEN1 in later comparative studies.
Reason: Retain the location as non-core context while treating late endosome/lysosome enrichment as the characteristic PSEN2 localization supported by the strongest PSEN2-specific evidence.
Supporting Evidence:
PMID:27293189
identified a unique motif in PSEN2 that directs this γ-secretase to late endosomes/lysosomes via a phosphorylation-dependent interaction with the AP-1 adaptor complex.
GO:0016020 membrane
HDA
PMID:19946888
Defining the membrane proteome of NK cells. 		MARK AS OVER ANNOTATED
Summary: PSEN2 is a multi-pass membrane protein, but the generic membrane term is too broad for curation value.
Reason: More specific ER, Golgi, late endosome/lysosome membrane, and gamma-secretase complex annotations capture the relevant localization and function.
Supporting Evidence:
PMID:8574969
Immunochemical analyses indicate that PS1 and PS2 are similar in size and localized to similar intracellular compartments (endoplasmic reticulum and Golgi complex).
PMID:27293189
identified a unique motif in PSEN2 that directs this γ-secretase to late endosomes/lysosomes via a phosphorylation-dependent interaction with the AP-1 adaptor complex.
GO:0005515 protein binding
IPI
PMID:10748169
Presenilin 2 interacts with sorcin, a modulator of the ryano... 		MARK AS OVER ANNOTATED
Summary: Generic protein binding annotation for PSEN2. The reported interactions may be real, but GO:0005515 is not informative about PSEN2 molecular function.
Reason: Mark as over-annotated because specific curatable biology is gamma-secretase complex membership, substrate cleavage, AP-1-dependent trafficking, or calcium-coupled interactions rather than generic protein binding.
Supporting Evidence:
PMID:10748169
the large hydrophilic loop region of presenilin 2 (PS2) with sorcin, a penta-EF-hand Ca(2+)-binding protein
GO:0000776 kinetochore
IDA
PMID:9298903
Alzheimer presenilins in the nuclear membrane, interphase ki... 		KEEP AS NON CORE
Summary: Older experimental literature reported presenilin localization to nuclear membrane, interphase kinetochore, and centrosome structures, but these locations are not central to current PSEN2 gamma-secretase biology.
Reason: Do not remove curator-supported or electronically propagated location annotations from incomplete evidence, but treat them as non-core because the evidence does not establish a primary PSEN2 function at these structures.
Supporting Evidence:
PMID:9298903
We have localized the presenilins to the nuclear membrane, its associated interphase kinetochores, and the centrosomes-all subcellular structures involved in cell cycle regulation and mitosis.
GO:0005637 nuclear inner membrane
IDA
PMID:9298903
Alzheimer presenilins in the nuclear membrane, interphase ki... 		KEEP AS NON CORE
Summary: Older experimental literature reported presenilin localization to nuclear membrane, interphase kinetochore, and centrosome structures, but these locations are not central to current PSEN2 gamma-secretase biology.
Reason: Do not remove curator-supported or electronically propagated location annotations from incomplete evidence, but treat them as non-core because the evidence does not establish a primary PSEN2 function at these structures.
Supporting Evidence:
PMID:9298903
We have localized the presenilins to the nuclear membrane, its associated interphase kinetochores, and the centrosomes-all subcellular structures involved in cell cycle regulation and mitosis.
GO:0005813 centrosome
IDA
PMID:9298903
Alzheimer presenilins in the nuclear membrane, interphase ki... 		KEEP AS NON CORE
Summary: Older experimental literature reported presenilin localization to nuclear membrane, interphase kinetochore, and centrosome structures, but these locations are not central to current PSEN2 gamma-secretase biology.
Reason: Do not remove curator-supported or electronically propagated location annotations from incomplete evidence, but treat them as non-core because the evidence does not establish a primary PSEN2 function at these structures.
Supporting Evidence:
PMID:9298903
We have localized the presenilins to the nuclear membrane, its associated interphase kinetochores, and the centrosomes-all subcellular structures involved in cell cycle regulation and mitosis.
GO:0032991 protein-containing complex
IDA
PMID:9632714
The presenilin 1 protein is a component of a high molecular ... 		MARK AS OVER ANNOTATED
Summary: PSEN2 forms higher-order membrane protein complexes, but GO:0032991 is much less informative than gamma-secretase complex membership.
Reason: Retain the idea that PSEN2 is complex-associated, but this broad cellular-component term should not substitute for the specific gamma-secretase complex annotation.
Supporting Evidence:
PMID:9632714
PS2 forms similar but independent complexes.
GO:0005515 protein binding
IPI
PMID:10366599
A myristoylated calcium-binding protein that preferentially ... 		MARK AS OVER ANNOTATED
Summary: Generic protein binding annotation for PSEN2. The reported interactions may be real, but GO:0005515 is not informative about PSEN2 molecular function.
Reason: Mark as over-annotated because specific curatable biology is gamma-secretase complex membership, substrate cleavage, AP-1-dependent trafficking, or calcium-coupled interactions rather than generic protein binding.
Supporting Evidence:
PMID:10366599
human PS2 protein interacts with a recently discovered calcium-binding protein which we refer to as calmyrin
GO:0005515 protein binding
IPI
PMID:12297508
Mammalian APH-1 interacts with presenilin and nicastrin and ... 		MARK AS OVER ANNOTATED
Summary: Generic protein binding annotation for PSEN2. The reported interactions may be real, but GO:0005515 is not informative about PSEN2 molecular function.
Reason: Mark as over-annotated because specific curatable biology is gamma-secretase complex membership, substrate cleavage, AP-1-dependent trafficking, or calcium-coupled interactions rather than generic protein binding.
Supporting Evidence:
PMID:12297508
Presenilin and nicastrin are essential components of the gamma-secretase complex that is required for the intramembrane proteolysis of an increasing number of membrane proteins including the amyloid-beta precursor protein (APP) and Notch.
GO:0005783 endoplasmic reticulum
IDA
PMID:15274632
Purification and characterization of the human gamma-secreta... 		ACCEPT
Summary: PSEN2 is a multi-pass membrane protein detected in secretory-pathway compartments, including ER and Golgi, while mature PSEN2 complexes are especially enriched later in the endolysosomal route.
Reason: ER/Golgi localization is supported by presenilin localization studies and is compatible with gamma-secretase maturation and trafficking before PSEN2 enrichment in late endosome/lysosome compartments.
Supporting Evidence:
PMID:8574969
Immunochemical analyses indicate that PS1 and PS2 are similar in size and localized to similar intracellular compartments (endoplasmic reticulum and Golgi complex).
PMID:27293189
identified a unique motif in PSEN2 that directs this γ-secretase to late endosomes/lysosomes via a phosphorylation-dependent interaction with the AP-1 adaptor complex.
GO:0005794 Golgi apparatus
IDA
PMID:15274632
Purification and characterization of the human gamma-secreta... 		ACCEPT
Summary: PSEN2 is a multi-pass membrane protein detected in secretory-pathway compartments, including ER and Golgi, while mature PSEN2 complexes are especially enriched later in the endolysosomal route.
Reason: ER/Golgi localization is supported by presenilin localization studies and is compatible with gamma-secretase maturation and trafficking before PSEN2 enrichment in late endosome/lysosome compartments.
Supporting Evidence:
PMID:8574969
Immunochemical analyses indicate that PS1 and PS2 are similar in size and localized to similar intracellular compartments (endoplasmic reticulum and Golgi complex).
PMID:27293189
identified a unique motif in PSEN2 that directs this γ-secretase to late endosomes/lysosomes via a phosphorylation-dependent interaction with the AP-1 adaptor complex.
GO:0005886 plasma membrane
IDA
PMID:15274632
Purification and characterization of the human gamma-secreta... 		KEEP AS NON CORE
Summary: Plasma membrane localization is a plausible gamma-secretase context, but PSEN2 is much less abundant at the cell surface than PSEN1 in later comparative studies.
Reason: Retain the location as non-core context while treating late endosome/lysosome enrichment as the characteristic PSEN2 localization supported by the strongest PSEN2-specific evidence.
Supporting Evidence:
PMID:27293189
identified a unique motif in PSEN2 that directs this γ-secretase to late endosomes/lysosomes via a phosphorylation-dependent interaction with the AP-1 adaptor complex.
GO:0006509 membrane protein ectodomain proteolysis
IDA
PMID:15274632
Purification and characterization of the human gamma-secreta... 		ACCEPT
Summary: PSEN2/gamma-secretase cleaves membrane-protein substrates after ectodomain shedding, including APP and Notch receptor fragments.
Reason: This process annotation reflects the general regulated intramembrane proteolysis activity of PSEN2-containing gamma-secretase complexes.
Supporting Evidence:
PMID:15274632
This enzyme cleaves many type I membrane proteins, including the amyloid beta-protein (Abeta) precursor (APP) and the Notch receptor.
PMID:27293189
The catalytic activity of the complex is provided by the PSEN1 or PSEN2 subunit isoforms, while three additional subunits, APH1A or B/C, nicastrin (NCT), and PEN-2 are needed to build a functional enzyme
PMID:27293189
sub-compartmentalization of the different γ-secretases and their substrates provides specificity as well as spatial and temporal control of their proteolytic activities.
GO:0007220 Notch receptor processing
TAS
PMID:15274632
Purification and characterization of the human gamma-secreta... 		ACCEPT
Summary: PSEN2-containing gamma-secretase can mediate Notch receptor cleavage/signaling, although substrate preference varies by presenilin and APH1 isoform composition.
Reason: Experimental PSEN2 catalytic-site mutation impairs Notch signaling, and gamma-secretase biology includes Notch receptor substrate cleavage. Subunit-composition differences should be noted but do not negate the annotation.
Supporting Evidence:
PMID:15274632
This enzyme cleaves many type I membrane proteins, including the amyloid beta-protein (Abeta) precursor (APP) and the Notch receptor.
PMID:10497236
the PS2 D366A mutation not only blocks gamma-secretase activity but also inactivates PS2 activity in Notch signaling by inhibiting the proteolytic release of the cytoplasmic Notch1 domain.
PMID:27608597
PS2/Aph1b had a clear substrate specificity: APP-Gal4, but not Notch-Gal4, was cleaved.
GO:0016485 protein processing
IDA
PMID:15274632
Purification and characterization of the human gamma-secreta... 		KEEP AS NON CORE
Summary: PSEN2 participates in protein processing through gamma-secretase substrate cleavage, but this term is broad relative to the more informative intramembrane proteolysis annotations.
Reason: Retain as a true broad process context, while treating specific membrane-protein ectodomain proteolysis, APP processing, and Notch receptor processing as the informative core annotations.
Supporting Evidence:
PMID:15274632
This enzyme cleaves many type I membrane proteins, including the amyloid beta-protein (Abeta) precursor (APP) and the Notch receptor.
PMID:27608597
The γ-secretase complex comprises presenilin (PS), nicastrin (NCT), anterior pharynx-defective 1 (Aph1), and presenilin enhancer 2 (Pen2).
GO:0042987 amyloid precursor protein catabolic process
TAS
PMID:15274632
Purification and characterization of the human gamma-secreta... 		ACCEPT
Summary: PSEN2 participates in APP catabolism as the catalytic presenilin isoform in gamma-secretase complexes that process APP C-terminal fragments.
Reason: The annotation captures a specific and well-supported substrate class of PSEN2/gamma-secretase, rather than a generic disease association.
Supporting Evidence:
PMID:15274632
This enzyme cleaves many type I membrane proteins, including the amyloid beta-protein (Abeta) precursor (APP) and the Notch receptor.
PMID:10497236
Cells expressing the PS2 D366A mutation exhibit significant deficits in proteolytic processing of beta-amyloid precursor protein indicating a defect in gamma-secretase activity.
PMID:27293189
PSEN2 selectively cleaves late endosomal/lysosomal localized substrates and generates the prominent pool of intracellular Aβ that contains longer Aβ

Core Functions

PSEN2 is a catalytic presenilin isoform in mature gamma-secretase complexes. It cleaves membrane-protein substrates including APP-derived C-terminal fragments and Notch receptor substrates, with PSEN2 complexes showing prominent late endosome/lysosome enrichment that shapes substrate specificity and intracellular amyloid-beta generation.

Molecular Function:
aspartic endopeptidase activity, intramembrane cleaving
Directly Involved In:
membrane protein ectodomain proteolysis amyloid precursor protein catabolic process amyloid-beta formation Notch receptor processing Notch signaling pathway
Cellular Locations:
endoplasmic reticulum membrane Golgi membrane late endosome membrane lysosomal membrane
In Complex:
gamma-secretase complex
Supporting Evidence:
  • PMID:15274632
    This enzyme cleaves many type I membrane proteins, including the amyloid beta-protein (Abeta) precursor (APP) and the Notch receptor.
  • PMID:15274632
    Extensive mass spectrometry of the purified proteins strongly suggests that PS-NTF/CTF, mNCT, Aph-1, and Pen-2 are the components of active gamma-secretase.
  • PMID:10652302
    Here, we show that the two TM aspartates in PS2 are also critical for gamma-secretase activity, providing further evidence that PS2 is functionally homologous to PS1.
  • PMID:27293189
    PSEN2 selectively cleaves late endosomal/lysosomal localized substrates and generates the prominent pool of intracellular Aβ that contains longer Aβ

References

GO_REF:0000002
Gene Ontology annotation through association of InterPro records with GO terms
GO_REF:0000024
Manual transfer of experimentally-verified manual GO annotation data to orthologs by curator judgment of sequence similarity
GO_REF:0000033
Annotation inferences using phylogenetic trees
GO_REF:0000044
Gene Ontology annotation based on UniProtKB/Swiss-Prot Subcellular Location vocabulary mapping, accompanied by conservative changes to GO terms applied by UniProt
GO_REF:0000107
Automatic transfer of experimentally verified manual GO annotation data to orthologs using Ensembl Compara
GO_REF:0000117
Electronic Gene Ontology annotations created by ARBA machine learning models
GO_REF:0000120
Combined Automated Annotation using Multiple IEA Methods
PMID:10366599
A myristoylated calcium-binding protein that preferentially interacts with the Alzheimer's disease presenilin 2 protein.
PMID:10497236
A loss of function mutation of presenilin-2 interferes with amyloid beta-peptide production and notch signaling.
PMID:10652302
The transmembrane aspartates in presenilin 1 and 2 are obligatory for gamma-secretase activity and amyloid beta-protein generation.
PMID:10748169
Presenilin 2 interacts with sorcin, a modulator of the ryanodine receptor.
PMID:12297508
Mammalian APH-1 interacts with presenilin and nicastrin and is required for intramembrane proteolysis of amyloid-beta precursor protein and Notch.
PMID:15274632
Purification and characterization of the human gamma-secretase complex.
PMID:16752394
Mean age-of-onset of familial alzheimer disease caused by presenilin mutations correlates with both increased Abeta42 and decreased Abeta40.
PMID:19946888
Defining the membrane proteome of NK cells.
PMID:21163940
Interactome mapping suggests new mechanistic details underlying Alzheimer's disease.
PMID:21285369
Presenilin 2 modulates endoplasmic reticulum (ER)-mitochondria interactions and Ca2+ cross-talk.
PMID:27293189
Restricted Location of PSEN2/γ-Secretase Determines Substrate Specificity and Generates an Intracellular Aβ Pool.
PMID:27608597
Specific combinations of presenilins and Aph1s affect the substrate specificity and activity of γ-secretase.
PMID:32814053
Interactome Mapping Provides a Network of Neurodegenerative Disease Proteins and Uncovers Widespread Protein Aggregation in Affected Brains.
PMID:36272978
Molecular basis for isoform-selective inhibition of presenilin-1 by MRK-560.
PMID:8574969
Alzheimer-associated presenilins 1 and 2: neuronal expression in brain and localization to intracellular membranes in mammalian cells.
PMID:9223340
Interaction between amyloid precursor protein and presenilins in mammalian cells: implications for the pathogenesis of Alzheimer disease.
PMID:9298903
Alzheimer presenilins in the nuclear membrane, interphase kinetochores, and centrosomes suggest a role in chromosome segregation.
PMID:9632714
The presenilin 1 protein is a component of a high molecular weight intracellular complex that contains beta-catenin.
Reactome:R-HSA-1251997
Cleavage of ERBB4m80 by gamma-scretase complex
Reactome:R-HSA-193682
gamma-secretase cleaves the p75NTR transmembrane domain
Reactome:R-HSA-205112
gamma-secretase cleaves p75NTR, releasing NRIF and TRAF6
Reactome:R-HSA-2220988
NEXT1 PEST domain mutants are cleaved to produce NICD1 PEST domain mutants
Reactome:R-HSA-3928656
gamma-secretase cleaves EPHB2
Reactome:R-HSA-9013361
NEXT3 is cleaved to produce NICD3
Reactome:R-HSA-9017817
Gamma-secretase cleaves YBX1:NOTCH3
Reactome:R-HSA-9839376
TGFBR3(784-851) degradation
Reactome:R-NUL-2197556
Gamma-secretase complex cleaves mNEXT2
Reactome:R-NUL-9604300
Gamma-secretase cleaves Notch4

Suggested Questions for Experts

Q: Which endogenous PSEN2-containing gamma-secretase complexes and APH1 isoform combinations define normal in-vivo PSEN2 substrate specificity across neuronal and non-neuronal tissues?

Suggested experts: gamma-secretase biology experts, GO membrane proteolysis curators

Q: Which PSEN2 late endosome/lysosome and ER/Golgi annotations correspond to mature active gamma-secretase complexes versus holoprotein trafficking or overexpression contexts?

Suggested experts: cell biology curators, endolysosomal trafficking experts

Q: Should PSEN2 ER-mitochondria calcium-coupling phenotypes be curated as conserved normal PSEN2 biology, or retained as context-dependent non-core phenotypes pending stronger in-vivo evidence?

Suggested experts: calcium signaling experts, neurobiology curators

Suggested Experiments

Experiment: Use endogenous tagging of PSEN2, APH1 isoforms, and active-substrate reporters in physiologic human neuronal and glial models to map active PSEN2 gamma-secretase by compartment.

Hypothesis: Only a subset of PSEN2-positive ER/Golgi/endolysosomal compartments contain mature complexes responsible for APP and Notch substrate cleavage.

Type: endogenous tagging/substrate reporter imaging

Experiment: Compare wild-type PSEN2, catalytically inactive PSEN2, and AP-1-sorting-motif PSEN2 mutants in knock-in cells or animal models under baseline non-disease conditions.

Hypothesis: AP-1-dependent late endosome/lysosome localization is a normal determinant of PSEN2 substrate specificity, not only a disease-model artifact.

Type: knock-in cell biology and substrate proteomics

Experiment: Measure ER-mitochondria contact dynamics and calcium transfer in endogenous PSEN2 knock-in models while separating catalytic-site, holoprotein, and sorting-motif effects.

Hypothesis: PSEN2 calcium-coupling phenotypes are mechanistically separable from gamma-secretase catalytic activity and may depend on PSEN2 localization or maturation state.

Type: calcium imaging and organelle-contact analysis

📚 Additional Documentation

Notes

(PSEN2-notes.md)

PSEN2 Notes

2026-06-19

Manual notes created because provider deep research was unavailable in this run.
timeout 180 just deep-research-falcon human PSEN2 --fallback perplexity-lite
stayed silent and timed out without writing an artifact. Publication caching was
refreshed separately with just fetch-gene-pmids human PSEN2 and confirmed all
18 PSEN2 review PMIDs were already cached. Per project instructions, no
provider-named deep-research file was written manually.

Core biology: PSEN2 encodes presenilin-2, a catalytic presenilin isoform in the
gamma-secretase complex. Gamma-secretase cleaves membrane substrates including
APP and Notch PMID:15274632. Direct PSEN2 mutagenesis supports the catalytic annotation:
the two PS2 transmembrane aspartates are critical for gamma-secretase activity
PMID:10652302.

Substrate biology: PSEN2 participates in APP processing and Notch signaling.
The D366A catalytic-site mutation caused deficits in APP proteolytic processing
PMID:10497236 and also impaired Notch signaling
PMID:10497236.

PSEN2-specific localization: compared with PSEN1, PSEN2-containing
gamma-secretase has strong late endosome/lysosome enrichment. The Cell paper
identifies a PSEN2 sorting motif that directs the complex to late
endosomes/lysosomes through AP-1 PMID:27293189 and
states that PSEN2 selectively cleaves substrates in those compartments
PMID:27293189. This supports accepting late endosome/lysosome annotations as
core localization context and treating repeated pathway-level plasma membrane
annotations cautiously.

Calcium and MAM biology: PSEN2 has evidence for ER-mitochondria calcium
coupling and membrane-contact effects PMID:21285369. For GO review,
calcium ion homeostasis, regulation of mitochondrial calcium import, and
mitochondria-associated ER membrane-contact annotations were retained as
non-core rather than promoted into the core function.

Knowledge gaps to curate:

  • Which endogenous PSEN2 gamma-secretase complexes and APH1 isoform
    combinations define normal in-vivo PSEN2 substrate specificity across tissues?
  • Which PSEN2 locations represent mature active gamma-secretase complexes, and
    which represent holoprotein trafficking, overexpression, or interactor-specific
    localization contexts?
  • Which calcium-homeostasis and ER-mitochondria contact phenotypes reflect
    conserved normal PSEN2 biology rather than mutant, overexpression, stress, or
    disease-model context?

Review update: completed first-pass review of all 79 seeded GO annotations.
Final action distribution after validation: 40 ACCEPT, 24 KEEP_AS_NON_CORE, 11
MARK_AS_OVER_ANNOTATED, and 4 UNDECIDED. just validate human PSEN2 passes
cleanly.

2026-06-20 Second-Pass Review Notes

Second-pass audit confirmed the core PSEN2 framing: PSEN2 is a catalytic
presenilin isoform in gamma-secretase complexes, with PSEN2-specific
late-endosome/lysosome enrichment and substrate specificity. The YAML now records
manual reference_review metadata for PMID:15274632, PMID:10497236,
PMID:10652302, PMID:27293189, and PMID:21285369.

No annotation actions were changed in this pass. The four remaining UNDECIDED
annotations are response to hypoxia and three electronically inferred synaptic
location terms. The local evidence supports PSEN2 endolysosomal localization in
neuronal contexts, but not specific synaptic vesicle, presynaptic membrane, or
synaptic membrane localization; these should remain UNDECIDED pending stronger
direct evidence.

📄 View Raw YAML

 
id: P49810
gene_symbol: PSEN2
product_type: PROTEIN
status: COMPLETE
taxon:
  id: NCBITaxon:9606
  label: Homo sapiens
description: 'Presenilin-2 is a multi-pass membrane aspartyl protease subunit of gamma-secretase complexes.
  After endoproteolytic maturation, PSEN2 N- and C-terminal fragments assemble with nicastrin, APH1, and
  PEN2 to cleave type I membrane-protein substrates, including APP-derived C-terminal fragments and Notch
  receptor substrates. PSEN2-containing complexes are distinguished from PSEN1 complexes by stronger late
  endosome/lysosome enrichment mediated by an AP-1-dependent N-terminal sorting motif, which shapes substrate
  access and intracellular amyloid-beta generation. Additional evidence links PSEN2 to endoplasmic-reticulum/mitochondrial
  calcium coupling and membrane-contact site biology, but these activities are secondary to its gamma-secretase
  catalytic role.'
alternative_products:
- name: '1'
  id: P49810-1
- name: '2'
  id: P49810-2
  sequence_note: VSP_005194
- name: '3'
  id: P49810-3
  sequence_note: VSP_043648
existing_annotations:
- term:
    id: GO:0007219
    label: Notch signaling pathway
  evidence_type: IBA
  original_reference_id: GO_REF:0000033
  qualifier: involved_in
  review:
    summary: PSEN2-containing gamma-secretase can mediate Notch receptor cleavage/signaling, 
      although substrate preference varies by presenilin and APH1 isoform composition.
    action: ACCEPT
    reason: Experimental PSEN2 catalytic-site mutation impairs Notch signaling, and gamma-secretase 
      biology includes Notch receptor substrate cleavage. Subunit-composition differences should be 
      noted but do not negate the annotation.
    supported_by:
    - reference_id: PMID:15274632
      supporting_text: This enzyme cleaves many type I membrane proteins, including the amyloid 
        beta-protein (Abeta) precursor (APP) and the Notch receptor.
    - reference_id: PMID:10497236
      supporting_text: the PS2 D366A mutation not only blocks gamma-secretase activity but also 
        inactivates PS2 activity in Notch signaling by inhibiting the proteolytic release of the 
        cytoplasmic Notch1 domain.
    - reference_id: PMID:27608597
      supporting_text: 'PS2/Aph1b had a clear substrate specificity: APP-Gal4, but not Notch-Gal4, was
        cleaved.'
- term:
    id: GO:0042500
    label: aspartic endopeptidase activity, intramembrane cleaving
  evidence_type: IBA
  original_reference_id: GO_REF:0000033
  qualifier: enables
  review:
    summary: PSEN2 provides the catalytic presenilin aspartyl protease activity within 
      PSEN2-containing gamma-secretase complexes.
    action: ACCEPT
    reason: Mutational, biochemical, and structural evidence supports PSEN2 as a catalytic 
      intramembrane-cleaving aspartyl protease subunit of gamma-secretase.
    supported_by:
    - reference_id: PMID:10652302
      supporting_text: Here, we show that the two TM aspartates in PS2 are also critical for 
        gamma-secretase activity, providing further evidence that PS2 is functionally homologous to 
        PS1.
    - reference_id: PMID:10497236
      supporting_text: Cells expressing the PS2 D366A mutation exhibit significant deficits in 
        proteolytic processing of beta-amyloid precursor protein indicating a defect in 
        gamma-secretase activity.
    - reference_id: PMID:27293189
      supporting_text: The catalytic activity of the complex is provided by the PSEN1 or PSEN2 
        subunit isoforms, while three additional subunits, APH1A or B/C, nicastrin (NCT), and PEN-2 
        are needed to build a functional enzyme
- term:
    id: GO:0055074
    label: calcium ion homeostasis
  evidence_type: IBA
  original_reference_id: GO_REF:0000033
  qualifier: involved_in
  review:
    summary: PSEN2 has evidence for roles in cellular calcium handling, especially ER-mitochondria 
      calcium coupling, but this is secondary to the gamma-secretase catalytic role.
    action: KEEP_AS_NON_CORE
    reason: The annotation is biologically plausible and supported, but calcium ion homeostasis 
      should be retained as non-core until normal in-vivo physiology is separated from mutant, 
      overexpression, and disease-context phenotypes.
    supported_by:
    - reference_id: PMID:21285369
      supporting_text: we show that overexpression or down-regulation of PS2, but not of presenilin 
        1 (PS1), modulates the Ca(2+) shuttling between ER and mitochondria
- term:
    id: GO:0016485
    label: protein processing
  evidence_type: IBA
  original_reference_id: GO_REF:0000033
  qualifier: involved_in
  review:
    summary: PSEN2 participates in protein processing through gamma-secretase substrate cleavage, 
      but this term is broad relative to the more informative intramembrane proteolysis annotations.
    action: KEEP_AS_NON_CORE
    reason: Retain as a true broad process context, while treating specific membrane-protein 
      ectodomain proteolysis, APP processing, and Notch receptor processing as the informative core 
      annotations.
    supported_by:
    - reference_id: PMID:15274632
      supporting_text: This enzyme cleaves many type I membrane proteins, including the amyloid 
        beta-protein (Abeta) precursor (APP) and the Notch receptor.
    - reference_id: PMID:27608597
      supporting_text: The γ-secretase complex comprises presenilin (PS), nicastrin (NCT), anterior 
        pharynx-defective 1 (Aph1), and presenilin enhancer 2 (Pen2).
- term:
    id: GO:0006509
    label: membrane protein ectodomain proteolysis
  evidence_type: IBA
  original_reference_id: GO_REF:0000033
  qualifier: involved_in
  review:
    summary: PSEN2/gamma-secretase cleaves membrane-protein substrates after ectodomain shedding, 
      including APP and Notch receptor fragments.
    action: ACCEPT
    reason: This process annotation reflects the general regulated intramembrane proteolysis 
      activity of PSEN2-containing gamma-secretase complexes.
    supported_by:
    - reference_id: PMID:15274632
      supporting_text: This enzyme cleaves many type I membrane proteins, including the amyloid 
        beta-protein (Abeta) precursor (APP) and the Notch receptor.
    - reference_id: PMID:27293189
      supporting_text: The catalytic activity of the complex is provided by the PSEN1 or PSEN2 
        subunit isoforms, while three additional subunits, APH1A or B/C, nicastrin (NCT), and PEN-2 
        are needed to build a functional enzyme
    - reference_id: PMID:27293189
      supporting_text: sub-compartmentalization of the different γ-secretases and their substrates 
        provides specificity as well as spatial and temporal control of their proteolytic 
        activities.
- term:
    id: GO:0034205
    label: amyloid-beta formation
  evidence_type: IBA
  original_reference_id: GO_REF:0000033
  qualifier: involved_in
  review:
    summary: PSEN2-containing gamma-secretase cleaves APP-derived substrates and contributes to 
      amyloid-beta formation, especially an intracellular late endosomal/lysosomal pool.
    action: ACCEPT
    reason: APP/Aβ production is a core substrate-processing output of PSEN2 gamma-secretase 
      activity, with PSEN2 localization shaping the intracellular Aβ pool.
    supported_by:
    - reference_id: PMID:15274632
      supporting_text: This enzyme cleaves many type I membrane proteins, including the amyloid 
        beta-protein (Abeta) precursor (APP) and the Notch receptor.
    - reference_id: PMID:10497236
      supporting_text: Cells expressing the PS2 D366A mutation exhibit significant deficits in 
        proteolytic processing of beta-amyloid precursor protein indicating a defect in 
        gamma-secretase activity.
    - reference_id: PMID:27293189
      supporting_text: PSEN2 selectively cleaves late endosomal/lysosomal localized substrates and 
        generates the prominent pool of intracellular Aβ that contains longer Aβ
- term:
    id: GO:0070765
    label: gamma-secretase complex
  evidence_type: IBA
  original_reference_id: GO_REF:0000033
  qualifier: part_of
  review:
    summary: PSEN2 is a presenilin subunit of mature gamma-secretase complexes with nicastrin, APH1,
      and PEN2.
    action: ACCEPT
    reason: The complex annotation is central to PSEN2 biology because presenilin-containing 
      gamma-secretase complexes perform the substrate-cleavage reactions attributed to PSEN2.
    supported_by:
    - reference_id: PMID:15274632
      supporting_text: Extensive mass spectrometry of the purified proteins strongly suggests that 
        PS-NTF/CTF, mNCT, Aph-1, and Pen-2 are the components of active gamma-secretase.
    - reference_id: PMID:12297508
      supporting_text: Presenilin and nicastrin are essential components of the gamma-secretase 
        complex that is required for the intramembrane proteolysis of an increasing number of 
        membrane proteins including the amyloid-beta precursor protein (APP) and Notch.
    - reference_id: PMID:36272978
      supporting_text: A γ-secretase complex comprises APH-1, Pen-2, nicastrin and the catalytic 
        subunit presenilin
- term:
    id: GO:0000139
    label: Golgi membrane
  evidence_type: IEA
  original_reference_id: GO_REF:0000044
  qualifier: located_in
  review:
    summary: PSEN2 is a multi-pass membrane protein detected in secretory-pathway compartments, 
      including ER and Golgi, while mature PSEN2 complexes are especially enriched later in the 
      endolysosomal route.
    action: ACCEPT
    reason: ER/Golgi localization is supported by presenilin localization studies and is compatible 
      with gamma-secretase maturation and trafficking before PSEN2 enrichment in late 
      endosome/lysosome compartments.
    supported_by:
    - reference_id: PMID:8574969
      supporting_text: Immunochemical analyses indicate that PS1 and PS2 are similar in size and 
        localized to similar intracellular compartments (endoplasmic reticulum and Golgi complex).
    - reference_id: PMID:27293189
      supporting_text: identified a unique motif in PSEN2 that directs this γ-secretase to late 
        endosomes/lysosomes via a phosphorylation-dependent interaction with the AP-1 adaptor 
        complex.
- term:
    id: GO:0000776
    label: kinetochore
  evidence_type: IEA
  original_reference_id: GO_REF:0000117
  qualifier: located_in
  review:
    summary: Older experimental literature reported presenilin localization to nuclear membrane, 
      interphase kinetochore, and centrosome structures, but these locations are not central to 
      current PSEN2 gamma-secretase biology.
    action: KEEP_AS_NON_CORE
    reason: Do not remove curator-supported or electronically propagated location annotations from 
      incomplete evidence, but treat them as non-core because the evidence does not establish a 
      primary PSEN2 function at these structures.
    supported_by:
    - reference_id: PMID:9298903
      supporting_text: We have localized the presenilins to the nuclear membrane, its associated 
        interphase kinetochores, and the centrosomes-all subcellular structures involved in cell 
        cycle regulation and mitosis.
- term:
    id: GO:0005765
    label: lysosomal membrane
  evidence_type: IEA
  original_reference_id: GO_REF:0000044
  qualifier: located_in
  review:
    summary: PSEN2-containing gamma-secretase is strongly enriched in late endosomal and lysosomal 
      compartments.
    action: ACCEPT
    reason: Multiple experiments support PSEN2 late endosome/lysosome enrichment, and this 
      localization helps explain PSEN2 substrate specificity and intracellular Aβ production.
    supported_by:
    - reference_id: PMID:27293189
      supporting_text: identified a unique motif in PSEN2 that directs this γ-secretase to late 
        endosomes/lysosomes via a phosphorylation-dependent interaction with the AP-1 adaptor 
        complex.
    - reference_id: PMID:27293189
      supporting_text: This more restricted localization of PSEN2 is conserved in a wide range of 
        cell lines, in primary neurons, and in brain.
    - reference_id: PMID:27293189
      supporting_text: PSEN2 selectively cleaves late endosomal/lysosomal localized substrates and 
        generates the prominent pool of intracellular Aβ that contains longer Aβ
- term:
    id: GO:0005789
    label: endoplasmic reticulum membrane
  evidence_type: IEA
  original_reference_id: GO_REF:0000044
  qualifier: located_in
  review:
    summary: PSEN2 is a multi-pass membrane protein detected in secretory-pathway compartments, 
      including ER and Golgi, while mature PSEN2 complexes are especially enriched later in the 
      endolysosomal route.
    action: ACCEPT
    reason: ER/Golgi localization is supported by presenilin localization studies and is compatible 
      with gamma-secretase maturation and trafficking before PSEN2 enrichment in late 
      endosome/lysosome compartments.
    supported_by:
    - reference_id: PMID:8574969
      supporting_text: Immunochemical analyses indicate that PS1 and PS2 are similar in size and 
        localized to similar intracellular compartments (endoplasmic reticulum and Golgi complex).
    - reference_id: PMID:27293189
      supporting_text: identified a unique motif in PSEN2 that directs this γ-secretase to late 
        endosomes/lysosomes via a phosphorylation-dependent interaction with the AP-1 adaptor 
        complex.
- term:
    id: GO:0006509
    label: membrane protein ectodomain proteolysis
  evidence_type: IEA
  original_reference_id: GO_REF:0000117
  qualifier: involved_in
  review:
    summary: PSEN2/gamma-secretase cleaves membrane-protein substrates after ectodomain shedding, 
      including APP and Notch receptor fragments.
    action: ACCEPT
    reason: This process annotation reflects the general regulated intramembrane proteolysis 
      activity of PSEN2-containing gamma-secretase complexes.
    supported_by:
    - reference_id: PMID:15274632
      supporting_text: This enzyme cleaves many type I membrane proteins, including the amyloid 
        beta-protein (Abeta) precursor (APP) and the Notch receptor.
    - reference_id: PMID:27293189
      supporting_text: The catalytic activity of the complex is provided by the PSEN1 or PSEN2 
        subunit isoforms, while three additional subunits, APH1A or B/C, nicastrin (NCT), and PEN-2 
        are needed to build a functional enzyme
    - reference_id: PMID:27293189
      supporting_text: sub-compartmentalization of the different γ-secretases and their substrates 
        provides specificity as well as spatial and temporal control of their proteolytic 
        activities.
- term:
    id: GO:0007220
    label: Notch receptor processing
  evidence_type: IEA
  original_reference_id: GO_REF:0000117
  qualifier: involved_in
  review:
    summary: PSEN2-containing gamma-secretase can mediate Notch receptor cleavage/signaling, 
      although substrate preference varies by presenilin and APH1 isoform composition.
    action: ACCEPT
    reason: Experimental PSEN2 catalytic-site mutation impairs Notch signaling, and gamma-secretase 
      biology includes Notch receptor substrate cleavage. Subunit-composition differences should be 
      noted but do not negate the annotation.
    supported_by:
    - reference_id: PMID:15274632
      supporting_text: This enzyme cleaves many type I membrane proteins, including the amyloid 
        beta-protein (Abeta) precursor (APP) and the Notch receptor.
    - reference_id: PMID:10497236
      supporting_text: the PS2 D366A mutation not only blocks gamma-secretase activity but also 
        inactivates PS2 activity in Notch signaling by inhibiting the proteolytic release of the 
        cytoplasmic Notch1 domain.
    - reference_id: PMID:27608597
      supporting_text: 'PS2/Aph1b had a clear substrate specificity: APP-Gal4, but not Notch-Gal4, was
        cleaved.'
- term:
    id: GO:0016020
    label: membrane
  evidence_type: IEA
  original_reference_id: GO_REF:0000002
  qualifier: located_in
  review:
    summary: PSEN2 is a multi-pass membrane protein, but the generic membrane term is too broad for 
      curation value.
    action: MARK_AS_OVER_ANNOTATED
    reason: More specific ER, Golgi, late endosome/lysosome membrane, and gamma-secretase complex 
      annotations capture the relevant localization and function.
    supported_by:
    - reference_id: PMID:8574969
      supporting_text: Immunochemical analyses indicate that PS1 and PS2 are similar in size and 
        localized to similar intracellular compartments (endoplasmic reticulum and Golgi complex).
    - reference_id: PMID:27293189
      supporting_text: identified a unique motif in PSEN2 that directs this γ-secretase to late 
        endosomes/lysosomes via a phosphorylation-dependent interaction with the AP-1 adaptor 
        complex.
- term:
    id: GO:0016485
    label: protein processing
  evidence_type: IEA
  original_reference_id: GO_REF:0000120
  qualifier: involved_in
  review:
    summary: PSEN2 participates in protein processing through gamma-secretase substrate cleavage, 
      but this term is broad relative to the more informative intramembrane proteolysis annotations.
    action: KEEP_AS_NON_CORE
    reason: Retain as a true broad process context, while treating specific membrane-protein 
      ectodomain proteolysis, APP processing, and Notch receptor processing as the informative core 
      annotations.
    supported_by:
    - reference_id: PMID:15274632
      supporting_text: This enzyme cleaves many type I membrane proteins, including the amyloid 
        beta-protein (Abeta) precursor (APP) and the Notch receptor.
    - reference_id: PMID:27608597
      supporting_text: The γ-secretase complex comprises presenilin (PS), nicastrin (NCT), anterior 
        pharynx-defective 1 (Aph1), and presenilin enhancer 2 (Pen2).
- term:
    id: GO:0031902
    label: late endosome membrane
  evidence_type: IEA
  original_reference_id: GO_REF:0000044
  qualifier: located_in
  review:
    summary: PSEN2-containing gamma-secretase is strongly enriched in late endosomal and lysosomal 
      compartments.
    action: ACCEPT
    reason: Multiple experiments support PSEN2 late endosome/lysosome enrichment, and this 
      localization helps explain PSEN2 substrate specificity and intracellular Aβ production.
    supported_by:
    - reference_id: PMID:27293189
      supporting_text: identified a unique motif in PSEN2 that directs this γ-secretase to late 
        endosomes/lysosomes via a phosphorylation-dependent interaction with the AP-1 adaptor 
        complex.
    - reference_id: PMID:27293189
      supporting_text: This more restricted localization of PSEN2 is conserved in a wide range of 
        cell lines, in primary neurons, and in brain.
    - reference_id: PMID:27293189
      supporting_text: PSEN2 selectively cleaves late endosomal/lysosomal localized substrates and 
        generates the prominent pool of intracellular Aβ that contains longer Aβ
- term:
    id: GO:0031965
    label: nuclear membrane
  evidence_type: IEA
  original_reference_id: GO_REF:0000117
  qualifier: located_in
  review:
    summary: Older experimental literature reported presenilin localization to nuclear membrane, 
      interphase kinetochore, and centrosome structures, but these locations are not central to 
      current PSEN2 gamma-secretase biology.
    action: KEEP_AS_NON_CORE
    reason: Do not remove curator-supported or electronically propagated location annotations from 
      incomplete evidence, but treat them as non-core because the evidence does not establish a 
      primary PSEN2 function at these structures.
    supported_by:
    - reference_id: PMID:9298903
      supporting_text: We have localized the presenilins to the nuclear membrane, its associated 
        interphase kinetochores, and the centrosomes-all subcellular structures involved in cell 
        cycle regulation and mitosis.
- term:
    id: GO:0035556
    label: intracellular signal transduction
  evidence_type: IEA
  original_reference_id: GO_REF:0000002
  qualifier: involved_in
  review:
    summary: Intracellular signal transduction is too broad to describe PSEN2 function precisely.
    action: MARK_AS_OVER_ANNOTATED
    reason: PSEN2 affects signaling through specific gamma-secretase-mediated substrate processing 
      and calcium-related phenotypes; the generic signaling term obscures those mechanisms.
- term:
    id: GO:0042500
    label: aspartic endopeptidase activity, intramembrane cleaving
  evidence_type: IEA
  original_reference_id: GO_REF:0000002
  qualifier: enables
  review:
    summary: PSEN2 provides the catalytic presenilin aspartyl protease activity within 
      PSEN2-containing gamma-secretase complexes.
    action: ACCEPT
    reason: Mutational, biochemical, and structural evidence supports PSEN2 as a catalytic 
      intramembrane-cleaving aspartyl protease subunit of gamma-secretase.
    supported_by:
    - reference_id: PMID:10652302
      supporting_text: Here, we show that the two TM aspartates in PS2 are also critical for 
        gamma-secretase activity, providing further evidence that PS2 is functionally homologous to 
        PS1.
    - reference_id: PMID:10497236
      supporting_text: Cells expressing the PS2 D366A mutation exhibit significant deficits in 
        proteolytic processing of beta-amyloid precursor protein indicating a defect in 
        gamma-secretase activity.
    - reference_id: PMID:27293189
      supporting_text: The catalytic activity of the complex is provided by the PSEN1 or PSEN2 
        subunit isoforms, while three additional subunits, APH1A or B/C, nicastrin (NCT), and PEN-2 
        are needed to build a functional enzyme
- term:
    id: GO:0042987
    label: amyloid precursor protein catabolic process
  evidence_type: IEA
  original_reference_id: GO_REF:0000002
  qualifier: involved_in
  review:
    summary: PSEN2 participates in APP catabolism as the catalytic presenilin isoform in 
      gamma-secretase complexes that process APP C-terminal fragments.
    action: ACCEPT
    reason: The annotation captures a specific and well-supported substrate class of 
      PSEN2/gamma-secretase, rather than a generic disease association.
    supported_by:
    - reference_id: PMID:15274632
      supporting_text: This enzyme cleaves many type I membrane proteins, including the amyloid 
        beta-protein (Abeta) precursor (APP) and the Notch receptor.
    - reference_id: PMID:10497236
      supporting_text: Cells expressing the PS2 D366A mutation exhibit significant deficits in 
        proteolytic processing of beta-amyloid precursor protein indicating a defect in 
        gamma-secretase activity.
    - reference_id: PMID:27293189
      supporting_text: PSEN2 selectively cleaves late endosomal/lysosomal localized substrates and 
        generates the prominent pool of intracellular Aβ that contains longer Aβ
- term:
    id: GO:0005515
    label: protein binding
  evidence_type: IPI
  original_reference_id: PMID:21163940
  qualifier: enables
  review:
    summary: Generic protein binding annotation for PSEN2. The reported interactions may be real, 
      but GO:0005515 is not informative about PSEN2 molecular function.
    action: MARK_AS_OVER_ANNOTATED
    reason: Mark as over-annotated because specific curatable biology is gamma-secretase complex 
      membership, substrate cleavage, AP-1-dependent trafficking, or calcium-coupled interactions 
      rather than generic protein binding.
- term:
    id: GO:0005515
    label: protein binding
  evidence_type: IPI
  original_reference_id: PMID:32814053
  qualifier: enables
  review:
    summary: Generic protein binding annotation for PSEN2. The reported interactions may be real, 
      but GO:0005515 is not informative about PSEN2 molecular function.
    action: MARK_AS_OVER_ANNOTATED
    reason: Mark as over-annotated because specific curatable biology is gamma-secretase complex 
      membership, substrate cleavage, AP-1-dependent trafficking, or calcium-coupled interactions 
      rather than generic protein binding.
- term:
    id: GO:0005515
    label: protein binding
  evidence_type: IPI
  original_reference_id: PMID:9223340
  qualifier: enables
  review:
    summary: Generic protein binding annotation for PSEN2. The reported interactions may be real, 
      but GO:0005515 is not informative about PSEN2 molecular function.
    action: MARK_AS_OVER_ANNOTATED
    reason: Mark as over-annotated because specific curatable biology is gamma-secretase complex 
      membership, substrate cleavage, AP-1-dependent trafficking, or calcium-coupled interactions 
      rather than generic protein binding.
    supported_by:
    - reference_id: PMID:9223340
      supporting_text: wt and mutant PS1 and PS2 proteins form complexes with APP in living cells
- term:
    id: GO:0001666
    label: response to hypoxia
  evidence_type: IEA
  original_reference_id: GO_REF:0000107
  qualifier: involved_in
  review:
    summary: Response-to-hypoxia is electronically inferred and not supported by the PSEN2 
      literature reviewed here.
    action: UNDECIDED
    reason: No cached publication evidence was found that establishes hypoxia response as a PSEN2 
      function; retain as undecided rather than removing an electronic transfer without a full 
      provenance review.
- term:
    id: GO:0005769
    label: early endosome
  evidence_type: IEA
  original_reference_id: GO_REF:0000107
  qualifier: located_in
  review:
    summary: Early endosome localization is consistent with AP-1-dependent PSEN2 routing toward late
      endosome/lysosome compartments, but it is not the best-supported mature steady-state 
      compartment.
    action: KEEP_AS_NON_CORE
    reason: Retain as trafficking context rather than core localization because the strongest 
      evidence emphasizes late endosome/lysosome enrichment.
    supported_by:
    - reference_id: PMID:27293189
      supporting_text: identified a unique motif in PSEN2 that directs this γ-secretase to late 
        endosomes/lysosomes via a phosphorylation-dependent interaction with the AP-1 adaptor 
        complex.
- term:
    id: GO:0008021
    label: synaptic vesicle
  evidence_type: IEA
  original_reference_id: GO_REF:0000107
  qualifier: located_in
  review:
    summary: Synaptic-compartment annotations are plausible in neuronal contexts but are only 
      electronically inferred here and not directly established by the cached PSEN2 evidence.
    action: UNDECIDED
    reason: The local evidence supports neuronal somatodendritic endolysosomal PSEN2, but not this 
      specific synaptic vesicle/presynaptic/synaptic membrane localization. Leave undecided pending 
      stronger direct evidence.
    supported_by:
    - reference_id: PMID:27293189
      supporting_text: This more restricted localization of PSEN2 is conserved in a wide range of 
        cell lines, in primary neurons, and in brain.
- term:
    id: GO:0042734
    label: presynaptic membrane
  evidence_type: IEA
  original_reference_id: GO_REF:0000107
  qualifier: is_active_in
  review:
    summary: Synaptic-compartment annotations are plausible in neuronal contexts but are only 
      electronically inferred here and not directly established by the cached PSEN2 evidence.
    action: UNDECIDED
    reason: The local evidence supports neuronal somatodendritic endolysosomal PSEN2, but not this 
      specific synaptic vesicle/presynaptic/synaptic membrane localization. Leave undecided pending 
      stronger direct evidence.
    supported_by:
    - reference_id: PMID:27293189
      supporting_text: This more restricted localization of PSEN2 is conserved in a wide range of 
        cell lines, in primary neurons, and in brain.
- term:
    id: GO:0097060
    label: synaptic membrane
  evidence_type: IEA
  original_reference_id: GO_REF:0000107
  qualifier: located_in
  review:
    summary: Synaptic-compartment annotations are plausible in neuronal contexts but are only 
      electronically inferred here and not directly established by the cached PSEN2 evidence.
    action: UNDECIDED
    reason: The local evidence supports neuronal somatodendritic endolysosomal PSEN2, but not this 
      specific synaptic vesicle/presynaptic/synaptic membrane localization. Leave undecided pending 
      stronger direct evidence.
    supported_by:
    - reference_id: PMID:27293189
      supporting_text: This more restricted localization of PSEN2 is conserved in a wide range of 
        cell lines, in primary neurons, and in brain.
- term:
    id: GO:0000139
    label: Golgi membrane
  evidence_type: EXP
  original_reference_id: PMID:8574969
  qualifier: located_in
  review:
    summary: PSEN2 is a multi-pass membrane protein detected in secretory-pathway compartments, 
      including ER and Golgi, while mature PSEN2 complexes are especially enriched later in the 
      endolysosomal route.
    action: ACCEPT
    reason: ER/Golgi localization is supported by presenilin localization studies and is compatible 
      with gamma-secretase maturation and trafficking before PSEN2 enrichment in late 
      endosome/lysosome compartments.
    supported_by:
    - reference_id: PMID:8574969
      supporting_text: Immunochemical analyses indicate that PS1 and PS2 are similar in size and 
        localized to similar intracellular compartments (endoplasmic reticulum and Golgi complex).
    - reference_id: PMID:27293189
      supporting_text: identified a unique motif in PSEN2 that directs this γ-secretase to late 
        endosomes/lysosomes via a phosphorylation-dependent interaction with the AP-1 adaptor 
        complex.
- term:
    id: GO:0005765
    label: lysosomal membrane
  evidence_type: EXP
  original_reference_id: PMID:27293189
  qualifier: located_in
  review:
    summary: PSEN2-containing gamma-secretase is strongly enriched in late endosomal and lysosomal 
      compartments.
    action: ACCEPT
    reason: Multiple experiments support PSEN2 late endosome/lysosome enrichment, and this 
      localization helps explain PSEN2 substrate specificity and intracellular Aβ production.
    supported_by:
    - reference_id: PMID:27293189
      supporting_text: identified a unique motif in PSEN2 that directs this γ-secretase to late 
        endosomes/lysosomes via a phosphorylation-dependent interaction with the AP-1 adaptor 
        complex.
    - reference_id: PMID:27293189
      supporting_text: This more restricted localization of PSEN2 is conserved in a wide range of 
        cell lines, in primary neurons, and in brain.
    - reference_id: PMID:27293189
      supporting_text: PSEN2 selectively cleaves late endosomal/lysosomal localized substrates and 
        generates the prominent pool of intracellular Aβ that contains longer Aβ
- term:
    id: GO:0005789
    label: endoplasmic reticulum membrane
  evidence_type: EXP
  original_reference_id: PMID:8574969
  qualifier: located_in
  review:
    summary: PSEN2 is a multi-pass membrane protein detected in secretory-pathway compartments, 
      including ER and Golgi, while mature PSEN2 complexes are especially enriched later in the 
      endolysosomal route.
    action: ACCEPT
    reason: ER/Golgi localization is supported by presenilin localization studies and is compatible 
      with gamma-secretase maturation and trafficking before PSEN2 enrichment in late 
      endosome/lysosome compartments.
    supported_by:
    - reference_id: PMID:8574969
      supporting_text: Immunochemical analyses indicate that PS1 and PS2 are similar in size and 
        localized to similar intracellular compartments (endoplasmic reticulum and Golgi complex).
    - reference_id: PMID:27293189
      supporting_text: identified a unique motif in PSEN2 that directs this γ-secretase to late 
        endosomes/lysosomes via a phosphorylation-dependent interaction with the AP-1 adaptor 
        complex.
- term:
    id: GO:0031902
    label: late endosome membrane
  evidence_type: EXP
  original_reference_id: PMID:27293189
  qualifier: located_in
  review:
    summary: PSEN2-containing gamma-secretase is strongly enriched in late endosomal and lysosomal 
      compartments.
    action: ACCEPT
    reason: Multiple experiments support PSEN2 late endosome/lysosome enrichment, and this 
      localization helps explain PSEN2 substrate specificity and intracellular Aβ production.
    supported_by:
    - reference_id: PMID:27293189
      supporting_text: identified a unique motif in PSEN2 that directs this γ-secretase to late 
        endosomes/lysosomes via a phosphorylation-dependent interaction with the AP-1 adaptor 
        complex.
    - reference_id: PMID:27293189
      supporting_text: This more restricted localization of PSEN2 is conserved in a wide range of 
        cell lines, in primary neurons, and in brain.
    - reference_id: PMID:27293189
      supporting_text: PSEN2 selectively cleaves late endosomal/lysosomal localized substrates and 
        generates the prominent pool of intracellular Aβ that contains longer Aβ
- term:
    id: GO:0044233
    label: mitochondria-associated endoplasmic reticulum membrane contact site
  evidence_type: ISS
  original_reference_id: GO_REF:0000024
  qualifier: located_in
  review:
    summary: PSEN2 has evidence connecting it to ER-mitochondria membrane-contact biology and 
      calcium cross-talk.
    action: KEEP_AS_NON_CORE
    reason: The location/interaction context is relevant to PSEN2 calcium biology, but it should 
      remain non-core relative to gamma-secretase complex localization and protease activity.
    supported_by:
    - reference_id: PMID:21285369
      supporting_text: This effect is not caused by a direct PS2 action on mitochondrial 
        Ca(2+)-uptake machinery but rather by an increased physical interaction between ER and 
        mitochondria
- term:
    id: GO:0005515
    label: protein binding
  evidence_type: IPI
  original_reference_id: PMID:27293189
  qualifier: enables
  review:
    summary: Generic protein binding annotation for PSEN2. The reported interactions may be real, 
      but GO:0005515 is not informative about PSEN2 molecular function.
    action: MARK_AS_OVER_ANNOTATED
    reason: Mark as over-annotated because specific curatable biology is gamma-secretase complex 
      membership, substrate cleavage, AP-1-dependent trafficking, or calcium-coupled interactions 
      rather than generic protein binding.
    supported_by:
    - reference_id: PMID:27293189
      supporting_text: identified a unique motif in PSEN2 that directs this γ-secretase to late 
        endosomes/lysosomes via a phosphorylation-dependent interaction with the AP-1 adaptor 
        complex.
- term:
    id: GO:0005764
    label: lysosome
  evidence_type: IDA
  original_reference_id: PMID:27293189
  qualifier: located_in
  review:
    summary: PSEN2-containing gamma-secretase is strongly enriched in late endosomal and lysosomal 
      compartments.
    action: ACCEPT
    reason: Multiple experiments support PSEN2 late endosome/lysosome enrichment, and this 
      localization helps explain PSEN2 substrate specificity and intracellular Aβ production.
    supported_by:
    - reference_id: PMID:27293189
      supporting_text: identified a unique motif in PSEN2 that directs this γ-secretase to late 
        endosomes/lysosomes via a phosphorylation-dependent interaction with the AP-1 adaptor 
        complex.
    - reference_id: PMID:27293189
      supporting_text: This more restricted localization of PSEN2 is conserved in a wide range of 
        cell lines, in primary neurons, and in brain.
    - reference_id: PMID:27293189
      supporting_text: PSEN2 selectively cleaves late endosomal/lysosomal localized substrates and 
        generates the prominent pool of intracellular Aβ that contains longer Aβ
- term:
    id: GO:0005770
    label: late endosome
  evidence_type: IDA
  original_reference_id: PMID:27293189
  qualifier: located_in
  review:
    summary: PSEN2-containing gamma-secretase is strongly enriched in late endosomal and lysosomal 
      compartments.
    action: ACCEPT
    reason: Multiple experiments support PSEN2 late endosome/lysosome enrichment, and this 
      localization helps explain PSEN2 substrate specificity and intracellular Aβ production.
    supported_by:
    - reference_id: PMID:27293189
      supporting_text: identified a unique motif in PSEN2 that directs this γ-secretase to late 
        endosomes/lysosomes via a phosphorylation-dependent interaction with the AP-1 adaptor 
        complex.
    - reference_id: PMID:27293189
      supporting_text: This more restricted localization of PSEN2 is conserved in a wide range of 
        cell lines, in primary neurons, and in brain.
    - reference_id: PMID:27293189
      supporting_text: PSEN2 selectively cleaves late endosomal/lysosomal localized substrates and 
        generates the prominent pool of intracellular Aβ that contains longer Aβ
- term:
    id: GO:0034205
    label: amyloid-beta formation
  evidence_type: IDA
  original_reference_id: PMID:27293189
  qualifier: involved_in
  review:
    summary: PSEN2-containing gamma-secretase cleaves APP-derived substrates and contributes to 
      amyloid-beta formation, especially an intracellular late endosomal/lysosomal pool.
    action: ACCEPT
    reason: APP/Aβ production is a core substrate-processing output of PSEN2 gamma-secretase 
      activity, with PSEN2 localization shaping the intracellular Aβ pool.
    supported_by:
    - reference_id: PMID:15274632
      supporting_text: This enzyme cleaves many type I membrane proteins, including the amyloid 
        beta-protein (Abeta) precursor (APP) and the Notch receptor.
    - reference_id: PMID:10497236
      supporting_text: Cells expressing the PS2 D366A mutation exhibit significant deficits in 
        proteolytic processing of beta-amyloid precursor protein indicating a defect in 
        gamma-secretase activity.
    - reference_id: PMID:27293189
      supporting_text: PSEN2 selectively cleaves late endosomal/lysosomal localized substrates and 
        generates the prominent pool of intracellular Aβ that contains longer Aβ
- term:
    id: GO:0034205
    label: amyloid-beta formation
  evidence_type: IDA
  original_reference_id: PMID:36272978
  qualifier: involved_in
  review:
    summary: PSEN2-containing gamma-secretase cleaves APP-derived substrates and contributes to 
      amyloid-beta formation, especially an intracellular late endosomal/lysosomal pool.
    action: ACCEPT
    reason: APP/Aβ production is a core substrate-processing output of PSEN2 gamma-secretase 
      activity, with PSEN2 localization shaping the intracellular Aβ pool.
    supported_by:
    - reference_id: PMID:15274632
      supporting_text: This enzyme cleaves many type I membrane proteins, including the amyloid 
        beta-protein (Abeta) precursor (APP) and the Notch receptor.
    - reference_id: PMID:10497236
      supporting_text: Cells expressing the PS2 D366A mutation exhibit significant deficits in 
        proteolytic processing of beta-amyloid precursor protein indicating a defect in 
        gamma-secretase activity.
    - reference_id: PMID:27293189
      supporting_text: PSEN2 selectively cleaves late endosomal/lysosomal localized substrates and 
        generates the prominent pool of intracellular Aβ that contains longer Aβ
- term:
    id: GO:0035333
    label: Notch receptor processing, ligand-dependent
  evidence_type: IDA
  original_reference_id: PMID:27293189
  qualifier: involved_in
  review:
    summary: PSEN2-containing gamma-secretase can mediate Notch receptor cleavage/signaling, 
      although substrate preference varies by presenilin and APH1 isoform composition.
    action: ACCEPT
    reason: Experimental PSEN2 catalytic-site mutation impairs Notch signaling, and gamma-secretase 
      biology includes Notch receptor substrate cleavage. Subunit-composition differences should be 
      noted but do not negate the annotation.
    supported_by:
    - reference_id: PMID:15274632
      supporting_text: This enzyme cleaves many type I membrane proteins, including the amyloid 
        beta-protein (Abeta) precursor (APP) and the Notch receptor.
    - reference_id: PMID:10497236
      supporting_text: the PS2 D366A mutation not only blocks gamma-secretase activity but also 
        inactivates PS2 activity in Notch signaling by inhibiting the proteolytic release of the 
        cytoplasmic Notch1 domain.
    - reference_id: PMID:27608597
      supporting_text: 'PS2/Aph1b had a clear substrate specificity: APP-Gal4, but not Notch-Gal4, was
        cleaved.'
- term:
    id: GO:0042500
    label: aspartic endopeptidase activity, intramembrane cleaving
  evidence_type: IDA
  original_reference_id: PMID:27293189
  qualifier: enables
  review:
    summary: PSEN2 provides the catalytic presenilin aspartyl protease activity within 
      PSEN2-containing gamma-secretase complexes.
    action: ACCEPT
    reason: Mutational, biochemical, and structural evidence supports PSEN2 as a catalytic 
      intramembrane-cleaving aspartyl protease subunit of gamma-secretase.
    supported_by:
    - reference_id: PMID:10652302
      supporting_text: Here, we show that the two TM aspartates in PS2 are also critical for 
        gamma-secretase activity, providing further evidence that PS2 is functionally homologous to 
        PS1.
    - reference_id: PMID:10497236
      supporting_text: Cells expressing the PS2 D366A mutation exhibit significant deficits in 
        proteolytic processing of beta-amyloid precursor protein indicating a defect in 
        gamma-secretase activity.
    - reference_id: PMID:27293189
      supporting_text: The catalytic activity of the complex is provided by the PSEN1 or PSEN2 
        subunit isoforms, while three additional subunits, APH1A or B/C, nicastrin (NCT), and PEN-2 
        are needed to build a functional enzyme
- term:
    id: GO:0042500
    label: aspartic endopeptidase activity, intramembrane cleaving
  evidence_type: IDA
  original_reference_id: PMID:36272978
  qualifier: enables
  review:
    summary: PSEN2 provides the catalytic presenilin aspartyl protease activity within 
      PSEN2-containing gamma-secretase complexes.
    action: ACCEPT
    reason: Mutational, biochemical, and structural evidence supports PSEN2 as a catalytic 
      intramembrane-cleaving aspartyl protease subunit of gamma-secretase.
    supported_by:
    - reference_id: PMID:10652302
      supporting_text: Here, we show that the two TM aspartates in PS2 are also critical for 
        gamma-secretase activity, providing further evidence that PS2 is functionally homologous to 
        PS1.
    - reference_id: PMID:10497236
      supporting_text: Cells expressing the PS2 D366A mutation exhibit significant deficits in 
        proteolytic processing of beta-amyloid precursor protein indicating a defect in 
        gamma-secretase activity.
    - reference_id: PMID:27293189
      supporting_text: The catalytic activity of the complex is provided by the PSEN1 or PSEN2 
        subunit isoforms, while three additional subunits, APH1A or B/C, nicastrin (NCT), and PEN-2 
        are needed to build a functional enzyme
- term:
    id: GO:0070765
    label: gamma-secretase complex
  evidence_type: IDA
  original_reference_id: PMID:36272978
  qualifier: part_of
  review:
    summary: PSEN2 is a presenilin subunit of mature gamma-secretase complexes with nicastrin, APH1,
      and PEN2.
    action: ACCEPT
    reason: The complex annotation is central to PSEN2 biology because presenilin-containing 
      gamma-secretase complexes perform the substrate-cleavage reactions attributed to PSEN2.
    supported_by:
    - reference_id: PMID:15274632
      supporting_text: Extensive mass spectrometry of the purified proteins strongly suggests that 
        PS-NTF/CTF, mNCT, Aph-1, and Pen-2 are the components of active gamma-secretase.
    - reference_id: PMID:12297508
      supporting_text: Presenilin and nicastrin are essential components of the gamma-secretase 
        complex that is required for the intramembrane proteolysis of an increasing number of 
        membrane proteins including the amyloid-beta precursor protein (APP) and Notch.
    - reference_id: PMID:36272978
      supporting_text: A γ-secretase complex comprises APH-1, Pen-2, nicastrin and the catalytic 
        subunit presenilin
- term:
    id: GO:0034205
    label: amyloid-beta formation
  evidence_type: IDA
  original_reference_id: PMID:10497236
  qualifier: involved_in
  review:
    summary: PSEN2-containing gamma-secretase cleaves APP-derived substrates and contributes to 
      amyloid-beta formation, especially an intracellular late endosomal/lysosomal pool.
    action: ACCEPT
    reason: APP/Aβ production is a core substrate-processing output of PSEN2 gamma-secretase 
      activity, with PSEN2 localization shaping the intracellular Aβ pool.
    supported_by:
    - reference_id: PMID:15274632
      supporting_text: This enzyme cleaves many type I membrane proteins, including the amyloid 
        beta-protein (Abeta) precursor (APP) and the Notch receptor.
    - reference_id: PMID:10497236
      supporting_text: Cells expressing the PS2 D366A mutation exhibit significant deficits in 
        proteolytic processing of beta-amyloid precursor protein indicating a defect in 
        gamma-secretase activity.
    - reference_id: PMID:27293189
      supporting_text: PSEN2 selectively cleaves late endosomal/lysosomal localized substrates and 
        generates the prominent pool of intracellular Aβ that contains longer Aβ
- term:
    id: GO:0034205
    label: amyloid-beta formation
  evidence_type: IDA
  original_reference_id: PMID:10652302
  qualifier: involved_in
  review:
    summary: PSEN2-containing gamma-secretase cleaves APP-derived substrates and contributes to 
      amyloid-beta formation, especially an intracellular late endosomal/lysosomal pool.
    action: ACCEPT
    reason: APP/Aβ production is a core substrate-processing output of PSEN2 gamma-secretase 
      activity, with PSEN2 localization shaping the intracellular Aβ pool.
    supported_by:
    - reference_id: PMID:15274632
      supporting_text: This enzyme cleaves many type I membrane proteins, including the amyloid 
        beta-protein (Abeta) precursor (APP) and the Notch receptor.
    - reference_id: PMID:10497236
      supporting_text: Cells expressing the PS2 D366A mutation exhibit significant deficits in 
        proteolytic processing of beta-amyloid precursor protein indicating a defect in 
        gamma-secretase activity.
    - reference_id: PMID:27293189
      supporting_text: PSEN2 selectively cleaves late endosomal/lysosomal localized substrates and 
        generates the prominent pool of intracellular Aβ that contains longer Aβ
- term:
    id: GO:0034205
    label: amyloid-beta formation
  evidence_type: IDA
  original_reference_id: PMID:16752394
  qualifier: involved_in
  review:
    summary: PSEN2-containing gamma-secretase cleaves APP-derived substrates and contributes to 
      amyloid-beta formation, especially an intracellular late endosomal/lysosomal pool.
    action: ACCEPT
    reason: APP/Aβ production is a core substrate-processing output of PSEN2 gamma-secretase 
      activity, with PSEN2 localization shaping the intracellular Aβ pool.
    supported_by:
    - reference_id: PMID:15274632
      supporting_text: This enzyme cleaves many type I membrane proteins, including the amyloid 
        beta-protein (Abeta) precursor (APP) and the Notch receptor.
    - reference_id: PMID:10497236
      supporting_text: Cells expressing the PS2 D366A mutation exhibit significant deficits in 
        proteolytic processing of beta-amyloid precursor protein indicating a defect in 
        gamma-secretase activity.
    - reference_id: PMID:27293189
      supporting_text: PSEN2 selectively cleaves late endosomal/lysosomal localized substrates and 
        generates the prominent pool of intracellular Aβ that contains longer Aβ
- term:
    id: GO:0035333
    label: Notch receptor processing, ligand-dependent
  evidence_type: IDA
  original_reference_id: PMID:10497236
  qualifier: involved_in
  review:
    summary: PSEN2-containing gamma-secretase can mediate Notch receptor cleavage/signaling, 
      although substrate preference varies by presenilin and APH1 isoform composition.
    action: ACCEPT
    reason: Experimental PSEN2 catalytic-site mutation impairs Notch signaling, and gamma-secretase 
      biology includes Notch receptor substrate cleavage. Subunit-composition differences should be 
      noted but do not negate the annotation.
    supported_by:
    - reference_id: PMID:15274632
      supporting_text: This enzyme cleaves many type I membrane proteins, including the amyloid 
        beta-protein (Abeta) precursor (APP) and the Notch receptor.
    - reference_id: PMID:10497236
      supporting_text: the PS2 D366A mutation not only blocks gamma-secretase activity but also 
        inactivates PS2 activity in Notch signaling by inhibiting the proteolytic release of the 
        cytoplasmic Notch1 domain.
    - reference_id: PMID:27608597
      supporting_text: 'PS2/Aph1b had a clear substrate specificity: APP-Gal4, but not Notch-Gal4, was
        cleaved.'
- term:
    id: GO:0042500
    label: aspartic endopeptidase activity, intramembrane cleaving
  evidence_type: IDA
  original_reference_id: PMID:10497236
  qualifier: enables
  review:
    summary: PSEN2 provides the catalytic presenilin aspartyl protease activity within 
      PSEN2-containing gamma-secretase complexes.
    action: ACCEPT
    reason: Mutational, biochemical, and structural evidence supports PSEN2 as a catalytic 
      intramembrane-cleaving aspartyl protease subunit of gamma-secretase.
    supported_by:
    - reference_id: PMID:10652302
      supporting_text: Here, we show that the two TM aspartates in PS2 are also critical for 
        gamma-secretase activity, providing further evidence that PS2 is functionally homologous to 
        PS1.
    - reference_id: PMID:10497236
      supporting_text: Cells expressing the PS2 D366A mutation exhibit significant deficits in 
        proteolytic processing of beta-amyloid precursor protein indicating a defect in 
        gamma-secretase activity.
    - reference_id: PMID:27293189
      supporting_text: The catalytic activity of the complex is provided by the PSEN1 or PSEN2 
        subunit isoforms, while three additional subunits, APH1A or B/C, nicastrin (NCT), and PEN-2 
        are needed to build a functional enzyme
- term:
    id: GO:0042500
    label: aspartic endopeptidase activity, intramembrane cleaving
  evidence_type: IDA
  original_reference_id: PMID:10652302
  qualifier: enables
  review:
    summary: PSEN2 provides the catalytic presenilin aspartyl protease activity within 
      PSEN2-containing gamma-secretase complexes.
    action: ACCEPT
    reason: Mutational, biochemical, and structural evidence supports PSEN2 as a catalytic 
      intramembrane-cleaving aspartyl protease subunit of gamma-secretase.
    supported_by:
    - reference_id: PMID:10652302
      supporting_text: Here, we show that the two TM aspartates in PS2 are also critical for 
        gamma-secretase activity, providing further evidence that PS2 is functionally homologous to 
        PS1.
    - reference_id: PMID:10497236
      supporting_text: Cells expressing the PS2 D366A mutation exhibit significant deficits in 
        proteolytic processing of beta-amyloid precursor protein indicating a defect in 
        gamma-secretase activity.
    - reference_id: PMID:27293189
      supporting_text: The catalytic activity of the complex is provided by the PSEN1 or PSEN2 
        subunit isoforms, while three additional subunits, APH1A or B/C, nicastrin (NCT), and PEN-2 
        are needed to build a functional enzyme
- term:
    id: GO:0042500
    label: aspartic endopeptidase activity, intramembrane cleaving
  evidence_type: IDA
  original_reference_id: PMID:16752394
  qualifier: enables
  review:
    summary: PSEN2 provides the catalytic presenilin aspartyl protease activity within 
      PSEN2-containing gamma-secretase complexes.
    action: ACCEPT
    reason: Mutational, biochemical, and structural evidence supports PSEN2 as a catalytic 
      intramembrane-cleaving aspartyl protease subunit of gamma-secretase.
    supported_by:
    - reference_id: PMID:10652302
      supporting_text: Here, we show that the two TM aspartates in PS2 are also critical for 
        gamma-secretase activity, providing further evidence that PS2 is functionally homologous to 
        PS1.
    - reference_id: PMID:10497236
      supporting_text: Cells expressing the PS2 D366A mutation exhibit significant deficits in 
        proteolytic processing of beta-amyloid precursor protein indicating a defect in 
        gamma-secretase activity.
    - reference_id: PMID:27293189
      supporting_text: The catalytic activity of the complex is provided by the PSEN1 or PSEN2 
        subunit isoforms, while three additional subunits, APH1A or B/C, nicastrin (NCT), and PEN-2 
        are needed to build a functional enzyme
- term:
    id: GO:0016485
    label: protein processing
  evidence_type: IDA
  original_reference_id: PMID:27608597
  qualifier: involved_in
  review:
    summary: PSEN2 participates in protein processing through gamma-secretase substrate cleavage, 
      but this term is broad relative to the more informative intramembrane proteolysis annotations.
    action: KEEP_AS_NON_CORE
    reason: Retain as a true broad process context, while treating specific membrane-protein 
      ectodomain proteolysis, APP processing, and Notch receptor processing as the informative core 
      annotations.
    supported_by:
    - reference_id: PMID:15274632
      supporting_text: This enzyme cleaves many type I membrane proteins, including the amyloid 
        beta-protein (Abeta) precursor (APP) and the Notch receptor.
    - reference_id: PMID:27608597
      supporting_text: The γ-secretase complex comprises presenilin (PS), nicastrin (NCT), anterior 
        pharynx-defective 1 (Aph1), and presenilin enhancer 2 (Pen2).
- term:
    id: GO:0034205
    label: amyloid-beta formation
  evidence_type: IDA
  original_reference_id: PMID:27608597
  qualifier: involved_in
  review:
    summary: PSEN2-containing gamma-secretase cleaves APP-derived substrates and contributes to 
      amyloid-beta formation, especially an intracellular late endosomal/lysosomal pool.
    action: ACCEPT
    reason: APP/Aβ production is a core substrate-processing output of PSEN2 gamma-secretase 
      activity, with PSEN2 localization shaping the intracellular Aβ pool.
    supported_by:
    - reference_id: PMID:15274632
      supporting_text: This enzyme cleaves many type I membrane proteins, including the amyloid 
        beta-protein (Abeta) precursor (APP) and the Notch receptor.
    - reference_id: PMID:10497236
      supporting_text: Cells expressing the PS2 D366A mutation exhibit significant deficits in 
        proteolytic processing of beta-amyloid precursor protein indicating a defect in 
        gamma-secretase activity.
    - reference_id: PMID:27293189
      supporting_text: PSEN2 selectively cleaves late endosomal/lysosomal localized substrates and 
        generates the prominent pool of intracellular Aβ that contains longer Aβ
- term:
    id: GO:0042987
    label: amyloid precursor protein catabolic process
  evidence_type: IDA
  original_reference_id: PMID:27608597
  qualifier: involved_in
  review:
    summary: PSEN2 participates in APP catabolism as the catalytic presenilin isoform in 
      gamma-secretase complexes that process APP C-terminal fragments.
    action: ACCEPT
    reason: The annotation captures a specific and well-supported substrate class of 
      PSEN2/gamma-secretase, rather than a generic disease association.
    supported_by:
    - reference_id: PMID:15274632
      supporting_text: This enzyme cleaves many type I membrane proteins, including the amyloid 
        beta-protein (Abeta) precursor (APP) and the Notch receptor.
    - reference_id: PMID:10497236
      supporting_text: Cells expressing the PS2 D366A mutation exhibit significant deficits in 
        proteolytic processing of beta-amyloid precursor protein indicating a defect in 
        gamma-secretase activity.
    - reference_id: PMID:27293189
      supporting_text: PSEN2 selectively cleaves late endosomal/lysosomal localized substrates and 
        generates the prominent pool of intracellular Aβ that contains longer Aβ
- term:
    id: GO:0070765
    label: gamma-secretase complex
  evidence_type: IDA
  original_reference_id: PMID:12297508
  qualifier: part_of
  review:
    summary: PSEN2 is a presenilin subunit of mature gamma-secretase complexes with nicastrin, APH1,
      and PEN2.
    action: ACCEPT
    reason: The complex annotation is central to PSEN2 biology because presenilin-containing 
      gamma-secretase complexes perform the substrate-cleavage reactions attributed to PSEN2.
    supported_by:
    - reference_id: PMID:15274632
      supporting_text: Extensive mass spectrometry of the purified proteins strongly suggests that 
        PS-NTF/CTF, mNCT, Aph-1, and Pen-2 are the components of active gamma-secretase.
    - reference_id: PMID:12297508
      supporting_text: Presenilin and nicastrin are essential components of the gamma-secretase 
        complex that is required for the intramembrane proteolysis of an increasing number of 
        membrane proteins including the amyloid-beta precursor protein (APP) and Notch.
    - reference_id: PMID:36272978
      supporting_text: A γ-secretase complex comprises APH-1, Pen-2, nicastrin and the catalytic 
        subunit presenilin
- term:
    id: GO:0110097
    label: regulation of calcium import into the mitochondrion
  evidence_type: IMP
  original_reference_id: PMID:21285369
  qualifier: involved_in
  review:
    summary: PSEN2 modulates ER-mitochondria calcium transfer in cellular and neuronal culture 
      systems.
    action: KEEP_AS_NON_CORE
    reason: This is a supported PSEN2-associated phenotype, but it is best curated as non-core 
      relative to gamma-secretase activity until its normal in-vivo physiological scope is clearer.
    supported_by:
    - reference_id: PMID:21285369
      supporting_text: we show that overexpression or down-regulation of PS2, but not of presenilin 
        1 (PS1), modulates the Ca(2+) shuttling between ER and mitochondria
    - reference_id: PMID:21285369
      supporting_text: This effect is not caused by a direct PS2 action on mitochondrial 
        Ca(2+)-uptake machinery but rather by an increased physical interaction between ER and 
        mitochondria
- term:
    id: GO:0005886
    label: plasma membrane
  evidence_type: TAS
  original_reference_id: Reactome:R-HSA-1251997
  qualifier: located_in
  review:
    summary: Plasma membrane localization is a plausible gamma-secretase context, but PSEN2 is much 
      less abundant at the cell surface than PSEN1 in later comparative studies.
    action: KEEP_AS_NON_CORE
    reason: Retain the location as non-core context while treating late endosome/lysosome enrichment
      as the characteristic PSEN2 localization supported by the strongest PSEN2-specific evidence.
    supported_by:
    - reference_id: PMID:27293189
      supporting_text: identified a unique motif in PSEN2 that directs this γ-secretase to late 
        endosomes/lysosomes via a phosphorylation-dependent interaction with the AP-1 adaptor 
        complex.
- term:
    id: GO:0005886
    label: plasma membrane
  evidence_type: TAS
  original_reference_id: Reactome:R-HSA-193682
  qualifier: located_in
  review:
    summary: Plasma membrane localization is a plausible gamma-secretase context, but PSEN2 is much 
      less abundant at the cell surface than PSEN1 in later comparative studies.
    action: KEEP_AS_NON_CORE
    reason: Retain the location as non-core context while treating late endosome/lysosome enrichment
      as the characteristic PSEN2 localization supported by the strongest PSEN2-specific evidence.
    supported_by:
    - reference_id: PMID:27293189
      supporting_text: identified a unique motif in PSEN2 that directs this γ-secretase to late 
        endosomes/lysosomes via a phosphorylation-dependent interaction with the AP-1 adaptor 
        complex.
- term:
    id: GO:0005886
    label: plasma membrane
  evidence_type: TAS
  original_reference_id: Reactome:R-HSA-205112
  qualifier: located_in
  review:
    summary: Plasma membrane localization is a plausible gamma-secretase context, but PSEN2 is much 
      less abundant at the cell surface than PSEN1 in later comparative studies.
    action: KEEP_AS_NON_CORE
    reason: Retain the location as non-core context while treating late endosome/lysosome enrichment
      as the characteristic PSEN2 localization supported by the strongest PSEN2-specific evidence.
    supported_by:
    - reference_id: PMID:27293189
      supporting_text: identified a unique motif in PSEN2 that directs this γ-secretase to late 
        endosomes/lysosomes via a phosphorylation-dependent interaction with the AP-1 adaptor 
        complex.
- term:
    id: GO:0005886
    label: plasma membrane
  evidence_type: TAS
  original_reference_id: Reactome:R-HSA-2220988
  qualifier: located_in
  review:
    summary: Plasma membrane localization is a plausible gamma-secretase context, but PSEN2 is much 
      less abundant at the cell surface than PSEN1 in later comparative studies.
    action: KEEP_AS_NON_CORE
    reason: Retain the location as non-core context while treating late endosome/lysosome enrichment
      as the characteristic PSEN2 localization supported by the strongest PSEN2-specific evidence.
    supported_by:
    - reference_id: PMID:27293189
      supporting_text: identified a unique motif in PSEN2 that directs this γ-secretase to late 
        endosomes/lysosomes via a phosphorylation-dependent interaction with the AP-1 adaptor 
        complex.
- term:
    id: GO:0005886
    label: plasma membrane
  evidence_type: TAS
  original_reference_id: Reactome:R-HSA-3928656
  qualifier: located_in
  review:
    summary: Plasma membrane localization is a plausible gamma-secretase context, but PSEN2 is much 
      less abundant at the cell surface than PSEN1 in later comparative studies.
    action: KEEP_AS_NON_CORE
    reason: Retain the location as non-core context while treating late endosome/lysosome enrichment
      as the characteristic PSEN2 localization supported by the strongest PSEN2-specific evidence.
    supported_by:
    - reference_id: PMID:27293189
      supporting_text: identified a unique motif in PSEN2 that directs this γ-secretase to late 
        endosomes/lysosomes via a phosphorylation-dependent interaction with the AP-1 adaptor 
        complex.
- term:
    id: GO:0005886
    label: plasma membrane
  evidence_type: TAS
  original_reference_id: Reactome:R-HSA-9013361
  qualifier: located_in
  review:
    summary: Plasma membrane localization is a plausible gamma-secretase context, but PSEN2 is much 
      less abundant at the cell surface than PSEN1 in later comparative studies.
    action: KEEP_AS_NON_CORE
    reason: Retain the location as non-core context while treating late endosome/lysosome enrichment
      as the characteristic PSEN2 localization supported by the strongest PSEN2-specific evidence.
    supported_by:
    - reference_id: PMID:27293189
      supporting_text: identified a unique motif in PSEN2 that directs this γ-secretase to late 
        endosomes/lysosomes via a phosphorylation-dependent interaction with the AP-1 adaptor 
        complex.
- term:
    id: GO:0005886
    label: plasma membrane
  evidence_type: TAS
  original_reference_id: Reactome:R-HSA-9017817
  qualifier: located_in
  review:
    summary: Plasma membrane localization is a plausible gamma-secretase context, but PSEN2 is much 
      less abundant at the cell surface than PSEN1 in later comparative studies.
    action: KEEP_AS_NON_CORE
    reason: Retain the location as non-core context while treating late endosome/lysosome enrichment
      as the characteristic PSEN2 localization supported by the strongest PSEN2-specific evidence.
    supported_by:
    - reference_id: PMID:27293189
      supporting_text: identified a unique motif in PSEN2 that directs this γ-secretase to late 
        endosomes/lysosomes via a phosphorylation-dependent interaction with the AP-1 adaptor 
        complex.
- term:
    id: GO:0005886
    label: plasma membrane
  evidence_type: TAS
  original_reference_id: Reactome:R-HSA-9839376
  qualifier: located_in
  review:
    summary: Plasma membrane localization is a plausible gamma-secretase context, but PSEN2 is much 
      less abundant at the cell surface than PSEN1 in later comparative studies.
    action: KEEP_AS_NON_CORE
    reason: Retain the location as non-core context while treating late endosome/lysosome enrichment
      as the characteristic PSEN2 localization supported by the strongest PSEN2-specific evidence.
    supported_by:
    - reference_id: PMID:27293189
      supporting_text: identified a unique motif in PSEN2 that directs this γ-secretase to late 
        endosomes/lysosomes via a phosphorylation-dependent interaction with the AP-1 adaptor 
        complex.
- term:
    id: GO:0005886
    label: plasma membrane
  evidence_type: TAS
  original_reference_id: Reactome:R-NUL-2197556
  qualifier: located_in
  review:
    summary: Plasma membrane localization is a plausible gamma-secretase context, but PSEN2 is much 
      less abundant at the cell surface than PSEN1 in later comparative studies.
    action: KEEP_AS_NON_CORE
    reason: Retain the location as non-core context while treating late endosome/lysosome enrichment
      as the characteristic PSEN2 localization supported by the strongest PSEN2-specific evidence.
    supported_by:
    - reference_id: PMID:27293189
      supporting_text: identified a unique motif in PSEN2 that directs this γ-secretase to late 
        endosomes/lysosomes via a phosphorylation-dependent interaction with the AP-1 adaptor 
        complex.
- term:
    id: GO:0005886
    label: plasma membrane
  evidence_type: TAS
  original_reference_id: Reactome:R-NUL-9604300
  qualifier: located_in
  review:
    summary: Plasma membrane localization is a plausible gamma-secretase context, but PSEN2 is much 
      less abundant at the cell surface than PSEN1 in later comparative studies.
    action: KEEP_AS_NON_CORE
    reason: Retain the location as non-core context while treating late endosome/lysosome enrichment
      as the characteristic PSEN2 localization supported by the strongest PSEN2-specific evidence.
    supported_by:
    - reference_id: PMID:27293189
      supporting_text: identified a unique motif in PSEN2 that directs this γ-secretase to late 
        endosomes/lysosomes via a phosphorylation-dependent interaction with the AP-1 adaptor 
        complex.
- term:
    id: GO:0016020
    label: membrane
  evidence_type: HDA
  original_reference_id: PMID:19946888
  qualifier: located_in
  review:
    summary: PSEN2 is a multi-pass membrane protein, but the generic membrane term is too broad for 
      curation value.
    action: MARK_AS_OVER_ANNOTATED
    reason: More specific ER, Golgi, late endosome/lysosome membrane, and gamma-secretase complex 
      annotations capture the relevant localization and function.
    supported_by:
    - reference_id: PMID:8574969
      supporting_text: Immunochemical analyses indicate that PS1 and PS2 are similar in size and 
        localized to similar intracellular compartments (endoplasmic reticulum and Golgi complex).
    - reference_id: PMID:27293189
      supporting_text: identified a unique motif in PSEN2 that directs this γ-secretase to late 
        endosomes/lysosomes via a phosphorylation-dependent interaction with the AP-1 adaptor 
        complex.
- term:
    id: GO:0005515
    label: protein binding
  evidence_type: IPI
  original_reference_id: PMID:10748169
  qualifier: enables
  review:
    summary: Generic protein binding annotation for PSEN2. The reported interactions may be real, 
      but GO:0005515 is not informative about PSEN2 molecular function.
    action: MARK_AS_OVER_ANNOTATED
    reason: Mark as over-annotated because specific curatable biology is gamma-secretase complex 
      membership, substrate cleavage, AP-1-dependent trafficking, or calcium-coupled interactions 
      rather than generic protein binding.
    supported_by:
    - reference_id: PMID:10748169
      supporting_text: the large hydrophilic loop region of presenilin 2 (PS2) with sorcin, a 
        penta-EF-hand Ca(2+)-binding protein
- term:
    id: GO:0000776
    label: kinetochore
  evidence_type: IDA
  original_reference_id: PMID:9298903
  qualifier: located_in
  review:
    summary: Older experimental literature reported presenilin localization to nuclear membrane, 
      interphase kinetochore, and centrosome structures, but these locations are not central to 
      current PSEN2 gamma-secretase biology.
    action: KEEP_AS_NON_CORE
    reason: Do not remove curator-supported or electronically propagated location annotations from 
      incomplete evidence, but treat them as non-core because the evidence does not establish a 
      primary PSEN2 function at these structures.
    supported_by:
    - reference_id: PMID:9298903
      supporting_text: We have localized the presenilins to the nuclear membrane, its associated 
        interphase kinetochores, and the centrosomes-all subcellular structures involved in cell 
        cycle regulation and mitosis.
- term:
    id: GO:0005637
    label: nuclear inner membrane
  evidence_type: IDA
  original_reference_id: PMID:9298903
  qualifier: located_in
  review:
    summary: Older experimental literature reported presenilin localization to nuclear membrane, 
      interphase kinetochore, and centrosome structures, but these locations are not central to 
      current PSEN2 gamma-secretase biology.
    action: KEEP_AS_NON_CORE
    reason: Do not remove curator-supported or electronically propagated location annotations from 
      incomplete evidence, but treat them as non-core because the evidence does not establish a 
      primary PSEN2 function at these structures.
    supported_by:
    - reference_id: PMID:9298903
      supporting_text: We have localized the presenilins to the nuclear membrane, its associated 
        interphase kinetochores, and the centrosomes-all subcellular structures involved in cell 
        cycle regulation and mitosis.
- term:
    id: GO:0005813
    label: centrosome
  evidence_type: IDA
  original_reference_id: PMID:9298903
  qualifier: located_in
  review:
    summary: Older experimental literature reported presenilin localization to nuclear membrane, 
      interphase kinetochore, and centrosome structures, but these locations are not central to 
      current PSEN2 gamma-secretase biology.
    action: KEEP_AS_NON_CORE
    reason: Do not remove curator-supported or electronically propagated location annotations from 
      incomplete evidence, but treat them as non-core because the evidence does not establish a 
      primary PSEN2 function at these structures.
    supported_by:
    - reference_id: PMID:9298903
      supporting_text: We have localized the presenilins to the nuclear membrane, its associated 
        interphase kinetochores, and the centrosomes-all subcellular structures involved in cell 
        cycle regulation and mitosis.
- term:
    id: GO:0032991
    label: protein-containing complex
  evidence_type: IDA
  original_reference_id: PMID:9632714
  qualifier: part_of
  review:
    summary: PSEN2 forms higher-order membrane protein complexes, but GO:0032991 is much less 
      informative than gamma-secretase complex membership.
    action: MARK_AS_OVER_ANNOTATED
    reason: Retain the idea that PSEN2 is complex-associated, but this broad cellular-component term
      should not substitute for the specific gamma-secretase complex annotation.
    supported_by:
    - reference_id: PMID:9632714
      supporting_text: PS2 forms similar but independent complexes.
- term:
    id: GO:0005515
    label: protein binding
  evidence_type: IPI
  original_reference_id: PMID:10366599
  qualifier: enables
  review:
    summary: Generic protein binding annotation for PSEN2. The reported interactions may be real, 
      but GO:0005515 is not informative about PSEN2 molecular function.
    action: MARK_AS_OVER_ANNOTATED
    reason: Mark as over-annotated because specific curatable biology is gamma-secretase complex 
      membership, substrate cleavage, AP-1-dependent trafficking, or calcium-coupled interactions 
      rather than generic protein binding.
    supported_by:
    - reference_id: PMID:10366599
      supporting_text: human PS2 protein interacts with a recently discovered calcium-binding 
        protein which we refer to as calmyrin
- term:
    id: GO:0005515
    label: protein binding
  evidence_type: IPI
  original_reference_id: PMID:12297508
  qualifier: enables
  review:
    summary: Generic protein binding annotation for PSEN2. The reported interactions may be real, 
      but GO:0005515 is not informative about PSEN2 molecular function.
    action: MARK_AS_OVER_ANNOTATED
    reason: Mark as over-annotated because specific curatable biology is gamma-secretase complex 
      membership, substrate cleavage, AP-1-dependent trafficking, or calcium-coupled interactions 
      rather than generic protein binding.
    supported_by:
    - reference_id: PMID:12297508
      supporting_text: Presenilin and nicastrin are essential components of the gamma-secretase 
        complex that is required for the intramembrane proteolysis of an increasing number of 
        membrane proteins including the amyloid-beta precursor protein (APP) and Notch.
- term:
    id: GO:0005783
    label: endoplasmic reticulum
  evidence_type: IDA
  original_reference_id: PMID:15274632
  qualifier: located_in
  review:
    summary: PSEN2 is a multi-pass membrane protein detected in secretory-pathway compartments, 
      including ER and Golgi, while mature PSEN2 complexes are especially enriched later in the 
      endolysosomal route.
    action: ACCEPT
    reason: ER/Golgi localization is supported by presenilin localization studies and is compatible 
      with gamma-secretase maturation and trafficking before PSEN2 enrichment in late 
      endosome/lysosome compartments.
    supported_by:
    - reference_id: PMID:8574969
      supporting_text: Immunochemical analyses indicate that PS1 and PS2 are similar in size and 
        localized to similar intracellular compartments (endoplasmic reticulum and Golgi complex).
    - reference_id: PMID:27293189
      supporting_text: identified a unique motif in PSEN2 that directs this γ-secretase to late 
        endosomes/lysosomes via a phosphorylation-dependent interaction with the AP-1 adaptor 
        complex.
- term:
    id: GO:0005794
    label: Golgi apparatus
  evidence_type: IDA
  original_reference_id: PMID:15274632
  qualifier: located_in
  review:
    summary: PSEN2 is a multi-pass membrane protein detected in secretory-pathway compartments, 
      including ER and Golgi, while mature PSEN2 complexes are especially enriched later in the 
      endolysosomal route.
    action: ACCEPT
    reason: ER/Golgi localization is supported by presenilin localization studies and is compatible 
      with gamma-secretase maturation and trafficking before PSEN2 enrichment in late 
      endosome/lysosome compartments.
    supported_by:
    - reference_id: PMID:8574969
      supporting_text: Immunochemical analyses indicate that PS1 and PS2 are similar in size and 
        localized to similar intracellular compartments (endoplasmic reticulum and Golgi complex).
    - reference_id: PMID:27293189
      supporting_text: identified a unique motif in PSEN2 that directs this γ-secretase to late 
        endosomes/lysosomes via a phosphorylation-dependent interaction with the AP-1 adaptor 
        complex.
- term:
    id: GO:0005886
    label: plasma membrane
  evidence_type: IDA
  original_reference_id: PMID:15274632
  qualifier: located_in
  review:
    summary: Plasma membrane localization is a plausible gamma-secretase context, but PSEN2 is much 
      less abundant at the cell surface than PSEN1 in later comparative studies.
    action: KEEP_AS_NON_CORE
    reason: Retain the location as non-core context while treating late endosome/lysosome enrichment
      as the characteristic PSEN2 localization supported by the strongest PSEN2-specific evidence.
    supported_by:
    - reference_id: PMID:27293189
      supporting_text: identified a unique motif in PSEN2 that directs this γ-secretase to late 
        endosomes/lysosomes via a phosphorylation-dependent interaction with the AP-1 adaptor 
        complex.
- term:
    id: GO:0006509
    label: membrane protein ectodomain proteolysis
  evidence_type: IDA
  original_reference_id: PMID:15274632
  qualifier: involved_in
  review:
    summary: PSEN2/gamma-secretase cleaves membrane-protein substrates after ectodomain shedding, 
      including APP and Notch receptor fragments.
    action: ACCEPT
    reason: This process annotation reflects the general regulated intramembrane proteolysis 
      activity of PSEN2-containing gamma-secretase complexes.
    supported_by:
    - reference_id: PMID:15274632
      supporting_text: This enzyme cleaves many type I membrane proteins, including the amyloid 
        beta-protein (Abeta) precursor (APP) and the Notch receptor.
    - reference_id: PMID:27293189
      supporting_text: The catalytic activity of the complex is provided by the PSEN1 or PSEN2 
        subunit isoforms, while three additional subunits, APH1A or B/C, nicastrin (NCT), and PEN-2 
        are needed to build a functional enzyme
    - reference_id: PMID:27293189
      supporting_text: sub-compartmentalization of the different γ-secretases and their substrates 
        provides specificity as well as spatial and temporal control of their proteolytic 
        activities.
- term:
    id: GO:0007220
    label: Notch receptor processing
  evidence_type: TAS
  original_reference_id: PMID:15274632
  qualifier: involved_in
  review:
    summary: PSEN2-containing gamma-secretase can mediate Notch receptor cleavage/signaling, 
      although substrate preference varies by presenilin and APH1 isoform composition.
    action: ACCEPT
    reason: Experimental PSEN2 catalytic-site mutation impairs Notch signaling, and gamma-secretase 
      biology includes Notch receptor substrate cleavage. Subunit-composition differences should be 
      noted but do not negate the annotation.
    supported_by:
    - reference_id: PMID:15274632
      supporting_text: This enzyme cleaves many type I membrane proteins, including the amyloid 
        beta-protein (Abeta) precursor (APP) and the Notch receptor.
    - reference_id: PMID:10497236
      supporting_text: the PS2 D366A mutation not only blocks gamma-secretase activity but also 
        inactivates PS2 activity in Notch signaling by inhibiting the proteolytic release of the 
        cytoplasmic Notch1 domain.
    - reference_id: PMID:27608597
      supporting_text: 'PS2/Aph1b had a clear substrate specificity: APP-Gal4, but not Notch-Gal4, was
        cleaved.'
- term:
    id: GO:0016485
    label: protein processing
  evidence_type: IDA
  original_reference_id: PMID:15274632
  qualifier: involved_in
  review:
    summary: PSEN2 participates in protein processing through gamma-secretase substrate cleavage, 
      but this term is broad relative to the more informative intramembrane proteolysis annotations.
    action: KEEP_AS_NON_CORE
    reason: Retain as a true broad process context, while treating specific membrane-protein 
      ectodomain proteolysis, APP processing, and Notch receptor processing as the informative core 
      annotations.
    supported_by:
    - reference_id: PMID:15274632
      supporting_text: This enzyme cleaves many type I membrane proteins, including the amyloid 
        beta-protein (Abeta) precursor (APP) and the Notch receptor.
    - reference_id: PMID:27608597
      supporting_text: The γ-secretase complex comprises presenilin (PS), nicastrin (NCT), anterior 
        pharynx-defective 1 (Aph1), and presenilin enhancer 2 (Pen2).
- term:
    id: GO:0042987
    label: amyloid precursor protein catabolic process
  evidence_type: TAS
  original_reference_id: PMID:15274632
  qualifier: involved_in
  review:
    summary: PSEN2 participates in APP catabolism as the catalytic presenilin isoform in 
      gamma-secretase complexes that process APP C-terminal fragments.
    action: ACCEPT
    reason: The annotation captures a specific and well-supported substrate class of 
      PSEN2/gamma-secretase, rather than a generic disease association.
    supported_by:
    - reference_id: PMID:15274632
      supporting_text: This enzyme cleaves many type I membrane proteins, including the amyloid 
        beta-protein (Abeta) precursor (APP) and the Notch receptor.
    - reference_id: PMID:10497236
      supporting_text: Cells expressing the PS2 D366A mutation exhibit significant deficits in 
        proteolytic processing of beta-amyloid precursor protein indicating a defect in 
        gamma-secretase activity.
    - reference_id: PMID:27293189
      supporting_text: PSEN2 selectively cleaves late endosomal/lysosomal localized substrates and 
        generates the prominent pool of intracellular Aβ that contains longer Aβ
references:
- id: GO_REF:0000002
  title: Gene Ontology annotation through association of InterPro records with GO terms
  findings: []
- id: GO_REF:0000024
  title: Manual transfer of experimentally-verified manual GO annotation data to orthologs by 
    curator judgment of sequence similarity
  findings: []
- 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:10366599
  title: A myristoylated calcium-binding protein that preferentially interacts with the Alzheimer's 
    disease presenilin 2 protein.
  findings: []
- id: PMID:10497236
  title: A loss of function mutation of presenilin-2 interferes with amyloid beta-peptide production
    and notch signaling.
  findings: []
  reference_review:
    relevance: HIGH
    correctness: VERIFIED
    review_notes: Cached abstract/title verified; supports PSEN2 catalytic-site
      dependence for APP processing and Notch signaling.
- id: PMID:10652302
  title: The transmembrane aspartates in presenilin 1 and 2 are obligatory for gamma-secretase 
    activity and amyloid beta-protein generation.
  findings: []
  reference_review:
    relevance: HIGH
    correctness: VERIFIED
    review_notes: Cached abstract/title verified; supports the PSEN2 transmembrane
      aspartates as required for gamma-secretase activity and amyloid-beta generation.
- id: PMID:10748169
  title: Presenilin 2 interacts with sorcin, a modulator of the ryanodine receptor.
  findings: []
- 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: []
- id: PMID:15274632
  title: Purification and characterization of the human gamma-secretase complex.
  findings: []
  reference_review:
    relevance: HIGH
    correctness: VERIFIED
    review_notes: Cached abstract/title verified; supports gamma-secretase complex
      composition and APP/Notch substrate cleavage used for PSEN2 core-function
      synthesis.
- id: PMID:16752394
  title: Mean age-of-onset of familial alzheimer disease caused by presenilin mutations correlates 
    with both increased Abeta42 and decreased Abeta40.
  findings: []
- id: PMID:19946888
  title: Defining the membrane proteome of NK cells.
  findings: []
- id: PMID:21163940
  title: Interactome mapping suggests new mechanistic details underlying Alzheimer's disease.
  findings: []
- id: PMID:21285369
  title: Presenilin 2 modulates endoplasmic reticulum (ER)-mitochondria interactions and Ca2+ 
    cross-talk.
  findings: []
  reference_review:
    relevance: MEDIUM
    correctness: VERIFIED
    review_notes: Cached abstract/title verified; supports PSEN2 ER-mitochondria
      calcium-coupling biology, treated as non-core pending stronger normal in-vivo
      evidence.
- id: PMID:27293189
  title: Restricted Location of PSEN2/γ-Secretase Determines Substrate Specificity and Generates an 
    Intracellular Aβ Pool.
  findings: []
  reference_review:
    relevance: HIGH
    correctness: VERIFIED
    review_notes: Cached full text verified; directly supports AP-1-dependent
      late endosome/lysosome enrichment and PSEN2 substrate specificity.
- id: PMID:27608597
  title: Specific combinations of presenilins and Aph1s affect the substrate specificity and 
    activity of γ-secretase.
  findings: []
- id: PMID:32814053
  title: Interactome Mapping Provides a Network of Neurodegenerative Disease Proteins and Uncovers 
    Widespread Protein Aggregation in Affected Brains.
  findings: []
- id: PMID:36272978
  title: Molecular basis for isoform-selective inhibition of presenilin-1 by MRK-560.
  findings: []
- id: PMID:8574969
  title: 'Alzheimer-associated presenilins 1 and 2: neuronal expression in brain and localization to intracellular
    membranes in mammalian cells.'
  findings: []
- id: PMID:9223340
  title: 'Interaction between amyloid precursor protein and presenilins in mammalian cells: implications
    for the pathogenesis of Alzheimer disease.'
  findings: []
- id: PMID:9298903
  title: Alzheimer presenilins in the nuclear membrane, interphase kinetochores, and centrosomes 
    suggest a role in chromosome segregation.
  findings: []
- id: PMID:9632714
  title: The presenilin 1 protein is a component of a high molecular weight intracellular complex 
    that contains beta-catenin.
  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-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:0042500
    label: aspartic endopeptidase activity, intramembrane cleaving
  description: PSEN2 is a catalytic presenilin isoform in mature gamma-secretase complexes. It 
    cleaves membrane-protein substrates including APP-derived C-terminal fragments and Notch 
    receptor substrates, with PSEN2 complexes showing prominent late endosome/lysosome enrichment 
    that shapes substrate specificity and intracellular amyloid-beta generation.
  directly_involved_in:
  - id: GO:0006509
    label: membrane protein ectodomain proteolysis
  - id: GO:0042987
    label: amyloid precursor protein catabolic process
  - id: GO:0034205
    label: amyloid-beta formation
  - id: GO:0007220
    label: Notch receptor processing
  - id: GO:0007219
    label: Notch signaling pathway
  locations:
  - id: GO:0005789
    label: endoplasmic reticulum membrane
  - id: GO:0000139
    label: Golgi membrane
  - id: GO:0031902
    label: late endosome membrane
  - id: GO:0005765
    label: lysosomal membrane
  in_complex:
    id: GO:0070765
    label: gamma-secretase complex
  supported_by:
  - reference_id: PMID:15274632
    supporting_text: This enzyme cleaves many type I membrane proteins, including the amyloid 
      beta-protein (Abeta) precursor (APP) and the Notch receptor.
  - reference_id: PMID:15274632
    supporting_text: Extensive mass spectrometry of the purified proteins strongly suggests that 
      PS-NTF/CTF, mNCT, Aph-1, and Pen-2 are the components of active gamma-secretase.
  - reference_id: PMID:10652302
    supporting_text: Here, we show that the two TM aspartates in PS2 are also critical for 
      gamma-secretase activity, providing further evidence that PS2 is functionally homologous to 
      PS1.
  - reference_id: PMID:27293189
    supporting_text: PSEN2 selectively cleaves late endosomal/lysosomal localized substrates and 
      generates the prominent pool of intracellular Aβ that contains longer Aβ
proposed_new_terms: []
suggested_questions:
- question: Which endogenous PSEN2-containing gamma-secretase complexes and APH1 isoform 
    combinations define normal in-vivo PSEN2 substrate specificity across neuronal and non-neuronal 
    tissues?
  experts:
  - gamma-secretase biology experts
  - GO membrane proteolysis curators
- question: Which PSEN2 late endosome/lysosome and ER/Golgi annotations correspond to mature active 
    gamma-secretase complexes versus holoprotein trafficking or overexpression contexts?
  experts:
  - cell biology curators
  - endolysosomal trafficking experts
- question: Should PSEN2 ER-mitochondria calcium-coupling phenotypes be curated as conserved normal 
    PSEN2 biology, or retained as context-dependent non-core phenotypes pending stronger in-vivo 
    evidence?
  experts:
  - calcium signaling experts
  - neurobiology curators
suggested_experiments:
- description: Use endogenous tagging of PSEN2, APH1 isoforms, and active-substrate reporters in 
    physiologic human neuronal and glial models to map active PSEN2 gamma-secretase by compartment.
  hypothesis: Only a subset of PSEN2-positive ER/Golgi/endolysosomal compartments contain mature 
    complexes responsible for APP and Notch substrate cleavage.
  experiment_type: endogenous tagging/substrate reporter imaging
- description: Compare wild-type PSEN2, catalytically inactive PSEN2, and AP-1-sorting-motif PSEN2 
    mutants in knock-in cells or animal models under baseline non-disease conditions.
  hypothesis: AP-1-dependent late endosome/lysosome localization is a normal determinant of PSEN2 
    substrate specificity, not only a disease-model artifact.
  experiment_type: knock-in cell biology and substrate proteomics
- description: Measure ER-mitochondria contact dynamics and calcium transfer in endogenous PSEN2 
    knock-in models while separating catalytic-site, holoprotein, and sorting-motif effects.
  hypothesis: PSEN2 calcium-coupling phenotypes are mechanistically separable from gamma-secretase 
    catalytic activity and may depend on PSEN2 localization or maturation state.
  experiment_type: calcium imaging and organelle-contact analysis