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.
| 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 Ξ³-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 Ξ³-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/AΞ² production is a core substrate-processing output of PSEN2 gamma-secretase activity, with PSEN2 localization shaping the intracellular AΞ² 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 AΞ² that contains longer AΞ² |
| 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 Ξ³-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 Ξ³-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 AΞ² production. Supporting Evidence: PMID:27293189 identified a unique motif in PSEN2 that directs this Ξ³-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 AΞ² that contains longer AΞ² |
| 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 Ξ³-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 Ξ³-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 Ξ³-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 Ξ³-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 AΞ² production. Supporting Evidence: PMID:27293189 identified a unique motif in PSEN2 that directs this Ξ³-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 AΞ² that contains longer AΞ² |
| 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 AΞ² that contains longer AΞ² |
| 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 Ξ³-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 Ξ³-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/Ξ³-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 AΞ² production. Supporting Evidence: PMID:27293189 identified a unique motif in PSEN2 that directs this Ξ³-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 AΞ² that contains longer AΞ² |
| 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 Ξ³-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/Ξ³-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 AΞ² production. Supporting Evidence: PMID:27293189 identified a unique motif in PSEN2 that directs this Ξ³-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 AΞ² that contains longer AΞ² |
| 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/Ξ³-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 Ξ³-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/Ξ³-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 AΞ² production. Supporting Evidence: PMID:27293189 identified a unique motif in PSEN2 that directs this Ξ³-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 AΞ² that contains longer AΞ² |
| GO:0005770 late endosome | IDA PMID:27293189 Restricted Location of PSEN2/Ξ³-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 AΞ² production. Supporting Evidence: PMID:27293189 identified a unique motif in PSEN2 that directs this Ξ³-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 AΞ² that contains longer AΞ² |
| GO:0034205 amyloid-beta formation | IDA PMID:27293189 Restricted Location of PSEN2/Ξ³-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/AΞ² production is a core substrate-processing output of PSEN2 gamma-secretase activity, with PSEN2 localization shaping the intracellular AΞ² 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 AΞ² that contains longer AΞ² |
| 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/AΞ² production is a core substrate-processing output of PSEN2 gamma-secretase activity, with PSEN2 localization shaping the intracellular AΞ² 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 AΞ² that contains longer AΞ² |
| GO:0035333 Notch receptor processing, ligand-dependent | IDA PMID:27293189 Restricted Location of PSEN2/Ξ³-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/Ξ³-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 Ξ³-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/AΞ² production is a core substrate-processing output of PSEN2 gamma-secretase activity, with PSEN2 localization shaping the intracellular AΞ² 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 AΞ² that contains longer AΞ² |
| 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/AΞ² production is a core substrate-processing output of PSEN2 gamma-secretase activity, with PSEN2 localization shaping the intracellular AΞ² 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 AΞ² that contains longer AΞ² |
| 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/AΞ² production is a core substrate-processing output of PSEN2 gamma-secretase activity, with PSEN2 localization shaping the intracellular AΞ² 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 AΞ² that contains longer AΞ² |
| 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 Ξ³-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/AΞ² production is a core substrate-processing output of PSEN2 gamma-secretase activity, with PSEN2 localization shaping the intracellular AΞ² 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 AΞ² that contains longer AΞ² |
| 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 AΞ² that contains longer AΞ² |
| 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 Ξ³-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 Ξ³-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 Ξ³-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 Ξ³-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 Ξ³-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 Ξ³-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 Ξ³-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 Ξ³-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 Ξ³-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 Ξ³-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 Ξ³-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 Ξ³-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 Ξ³-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 Ξ³-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 Ξ³-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 Ξ³-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 Ξ³-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 AΞ² that contains longer AΞ² |
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Download this section (compressed HTML)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
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
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