APH1A encodes gamma-secretase subunit APH-1A, a multipass membrane protein and essential non-catalytic component of the gamma-secretase intramembrane protease complex. Together with a presenilin catalytic subunit, nicastrin, and PSENEN/PEN-2, APH1A supports complex assembly, stability, and activity toward membrane substrates including APP and Notch receptors. APH1A is enriched in endoplasmic-reticulum and cis-Golgi membranes and participates in regulated intramembrane proteolysis within membrane and endomembrane compartments.
| GO Term | Evidence | Action | Reason |
|---|---|---|---|
| GO:0070765 gamma-secretase complex | IBA GO_REF:0000033 | ACCEPT | Summary: APH1A is an established non-catalytic subunit of the gamma-secretase complex with presenilin, nicastrin, and PSENEN/PEN-2. Reason: The term aligns with APH1A function as a non-catalytic gamma-secretase subunit that supports complex assembly/activity and APP/Notch intramembrane processing. |
| GO:0034205 amyloid-beta formation | IBA GO_REF:0000033 | ACCEPT | Summary: APH1A-containing gamma-secretase participates in APP processing that generates amyloid-beta-related products. Reason: The term aligns with APH1A function as a non-catalytic gamma-secretase subunit that supports complex assembly/activity and APP/Notch intramembrane processing. |
| GO:0016485 protein processing | IBA GO_REF:0000033 | ACCEPT | Summary: This captures the core regulated intramembrane processing activity of the APH1A-containing gamma-secretase complex. Reason: The term aligns with APH1A function as a non-catalytic gamma-secretase subunit that supports complex assembly/activity and APP/Notch intramembrane processing. |
| GO:0030674 protein-macromolecule adaptor activity | IBA GO_REF:0000033 | ACCEPT | Summary: APH1A acts as a non-catalytic assembly/adaptor subunit that helps stabilize and organize active gamma-secretase complexes. Reason: The term aligns with APH1A function as a non-catalytic gamma-secretase subunit that supports complex assembly/activity and APP/Notch intramembrane processing. |
| GO:0007220 Notch receptor processing | IBA GO_REF:0000033 | ACCEPT | Summary: APH1A supports gamma-secretase-dependent Notch receptor processing and release of Notch intracellular domains. Reason: The term aligns with APH1A function as a non-catalytic gamma-secretase subunit that supports complex assembly/activity and APP/Notch intramembrane processing. |
| GO:0007219 Notch signaling pathway | IBA GO_REF:0000033 | ACCEPT | Summary: Notch signaling is a downstream pathway output of gamma-secretase-mediated Notch receptor processing. Reason: The term aligns with APH1A function as a non-catalytic gamma-secretase subunit that supports complex assembly/activity and APP/Notch intramembrane processing. |
| GO:0005789 endoplasmic reticulum membrane | IEA GO_REF:0000044 | ACCEPT | Summary: This membrane or endomembrane location is consistent with APH1A as a multipass gamma-secretase subunit, especially its ER/cis-Golgi localization. Reason: APH1A is a multipass membrane protein in the gamma-secretase complex; ER, Golgi, endosomal, and general membrane localizations are consistent with the curated biology. |
| GO:0006508 proteolysis | IEA GO_REF:0000117 | MODIFY | Summary: Generic proteolysis is too broad for APH1A; the supported process is gamma-secretase-dependent intramembrane processing of membrane substrates. Reason: Replace the broad proteolysis term with the more specific regulated intramembrane-processing terms supported for gamma-secretase. Proposed replacements: membrane protein intracellular domain proteolysis protein processing |
| GO:0016020 membrane | IEA GO_REF:0000002 | ACCEPT | Summary: This membrane or endomembrane location is consistent with APH1A as a multipass gamma-secretase subunit, especially its ER/cis-Golgi localization. Reason: APH1A is a multipass membrane protein in the gamma-secretase complex; ER, Golgi, endosomal, and general membrane localizations are consistent with the curated biology. |
| GO:0016485 protein processing | IEA GO_REF:0000120 | ACCEPT | Summary: This captures the core regulated intramembrane processing activity of the APH1A-containing gamma-secretase complex. Reason: The term aligns with APH1A function as a non-catalytic gamma-secretase subunit that supports complex assembly/activity and APP/Notch intramembrane processing. |
| GO:0032580 Golgi cisterna membrane | IEA GO_REF:0000044 | ACCEPT | Summary: This membrane or endomembrane location is consistent with APH1A as a multipass gamma-secretase subunit, especially its ER/cis-Golgi localization. Reason: APH1A is a multipass membrane protein in the gamma-secretase complex; ER, Golgi, endosomal, and general membrane localizations are consistent with the curated biology. |
| GO:0070765 gamma-secretase complex | IEA GO_REF:0000117 | ACCEPT | Summary: APH1A is an established non-catalytic subunit of the gamma-secretase complex with presenilin, nicastrin, and PSENEN/PEN-2. Reason: The term aligns with APH1A function as a non-catalytic gamma-secretase subunit that supports complex assembly/activity and APP/Notch intramembrane processing. |
| GO:0005515 protein binding | IPI PMID:12297508 Mammalian APH-1 interacts with presenilin and nicastrin and ... | MARK AS OVER ANNOTATED | Summary: The interaction evidence is compatible with APH1A complex membership, but generic protein binding is not an informative molecular function for this gene. Reason: Prefer complex membership and adaptor/activator terms over a broad protein-binding annotation. |
| GO:0005515 protein binding | IPI PMID:18201567 Cellular localization of Nicastrin affects amyloid beta spec... | MARK AS OVER ANNOTATED | Summary: The interaction evidence is compatible with APH1A complex membership, but generic protein binding is not an informative molecular function for this gene. Reason: Prefer complex membership and adaptor/activator terms over a broad protein-binding annotation. |
| GO:0005515 protein binding | IPI PMID:19376115 An alternative spliced mouse presenilin-2 mRNA encodes a nov... | MARK AS OVER ANNOTATED | Summary: The interaction evidence is compatible with APH1A complex membership, but generic protein binding is not an informative molecular function for this gene. Reason: Prefer complex membership and adaptor/activator terms over a broad protein-binding annotation. |
| GO:0005515 protein binding | IPI PMID:23864651 The identification of novel proteins that interact with the ... | MARK AS OVER ANNOTATED | Summary: The interaction evidence is compatible with APH1A complex membership, but generic protein binding is not an informative molecular function for this gene. Reason: Prefer complex membership and adaptor/activator terms over a broad protein-binding annotation. |
| GO:0005515 protein binding | IPI PMID:25394380 G206D Mutation of Presenilin-1 Reduces Pen2 Interaction, Inc... | MARK AS OVER ANNOTATED | Summary: The interaction evidence is compatible with APH1A complex membership, but generic protein binding is not an informative molecular function for this gene. Reason: Prefer complex membership and adaptor/activator terms over a broad protein-binding annotation. |
| GO:0005515 protein binding | IPI PMID:26280335 An atomic structure of human Ξ³-secretase. | MARK AS OVER ANNOTATED | Summary: The interaction evidence is compatible with APH1A complex membership, but generic protein binding is not an informative molecular function for this gene. Reason: Prefer complex membership and adaptor/activator terms over a broad protein-binding annotation. |
| GO:0005515 protein binding | IPI PMID:30559186 Bax inhibitor 1 is a Ξ³-secretase-independent presenilin-bind... | MARK AS OVER ANNOTATED | Summary: The interaction evidence is compatible with APH1A complex membership, but generic protein binding is not an informative molecular function for this gene. Reason: Prefer complex membership and adaptor/activator terms over a broad protein-binding annotation. |
| GO:0005515 protein binding | IPI PMID:32296183 A reference map of the human binary protein interactome. | MARK AS OVER ANNOTATED | Summary: The interaction evidence is compatible with APH1A complex membership, but generic protein binding is not an informative molecular function for this gene. Reason: Prefer complex membership and adaptor/activator terms over a broad protein-binding annotation. |
| GO:0005515 protein binding | IPI PMID:32814053 Interactome Mapping Provides a Network of Neurodegenerative ... | MARK AS OVER ANNOTATED | Summary: The interaction evidence is compatible with APH1A complex membership, but generic protein binding is not an informative molecular function for this gene. Reason: Prefer complex membership and adaptor/activator terms over a broad protein-binding annotation. |
| GO:0019899 enzyme binding | IEA GO_REF:0000107 | KEEP AS NON CORE | Summary: Broad enzyme binding is plausible for an APH1A gamma-secretase subunit but is less informative than adaptor/activator and complex-membership annotations. Reason: Retain as non-core because it may reflect real association with the presenilin protease but does not define APH1A primary molecular role. |
| GO:0061133 endopeptidase activator activity | IEA GO_REF:0000107 | ACCEPT | Summary: APH1A is required for normal gamma-secretase assembly and activity, supporting an endopeptidase activator role at the complex level. Reason: The term aligns with APH1A function as a non-catalytic gamma-secretase subunit that supports complex assembly/activity and APP/Notch intramembrane processing. |
| GO:0005789 endoplasmic reticulum membrane | EXP PMID:12522139 PEN-2 and APH-1 coordinately regulate proteolytic processing... | ACCEPT | Summary: This membrane or endomembrane location is consistent with APH1A as a multipass gamma-secretase subunit, especially its ER/cis-Golgi localization. Reason: APH1A is a multipass membrane protein in the gamma-secretase complex; ER, Golgi, endosomal, and general membrane localizations are consistent with the curated biology. |
| GO:0005789 endoplasmic reticulum membrane | NAS PMID:15274632 Purification and characterization of the human gamma-secreta... | ACCEPT | Summary: This membrane or endomembrane location is consistent with APH1A as a multipass gamma-secretase subunit, especially its ER/cis-Golgi localization. Reason: APH1A is a multipass membrane protein in the gamma-secretase complex; ER, Golgi, endosomal, and general membrane localizations are consistent with the curated biology. |
| GO:0005886 plasma membrane | IDA PMID:15274632 Purification and characterization of the human gamma-secreta... | KEEP AS NON CORE | Summary: Plasma-membrane annotations are plausible for gamma-secretase substrate events, but APH1A-specific steady-state localization is strongest for ER and cis-Golgi membranes. Reason: Retain as non-core because the site is biologically plausible for substrate processing without being the clearest APH1A-defining location. |
| GO:0007220 Notch receptor processing | NAS PMID:10206645 A presenilin-1-dependent gamma-secretase-like protease media... | ACCEPT | Summary: APH1A supports gamma-secretase-dependent Notch receptor processing and release of Notch intracellular domains. Reason: The term aligns with APH1A function as a non-catalytic gamma-secretase subunit that supports complex assembly/activity and APP/Notch intramembrane processing. |
| GO:0031293 membrane protein intracellular domain proteolysis | IDA PMID:15274632 Purification and characterization of the human gamma-secreta... | ACCEPT | Summary: This captures the core regulated intramembrane processing activity of the APH1A-containing gamma-secretase complex. Reason: The term aligns with APH1A function as a non-catalytic gamma-secretase subunit that supports complex assembly/activity and APP/Notch intramembrane processing. |
| GO:0042987 amyloid precursor protein catabolic process | IDA PMID:15274632 Purification and characterization of the human gamma-secreta... | ACCEPT | Summary: APH1A-containing gamma-secretase participates in APP processing that generates amyloid-beta-related products. Reason: The term aligns with APH1A function as a non-catalytic gamma-secretase subunit that supports complex assembly/activity and APP/Notch intramembrane processing. |
| GO:0070765 gamma-secretase complex | IPI PMID:26280335 An atomic structure of human Ξ³-secretase. | ACCEPT | Summary: APH1A is an established non-catalytic subunit of the gamma-secretase complex with presenilin, nicastrin, and PSENEN/PEN-2. Reason: The term aligns with APH1A function as a non-catalytic gamma-secretase subunit that supports complex assembly/activity and APP/Notch intramembrane processing. |
| GO:0000139 Golgi membrane | NAS PMID:15274632 Purification and characterization of the human gamma-secreta... | ACCEPT | Summary: This membrane or endomembrane location is consistent with APH1A as a multipass gamma-secretase subunit, especially its ER/cis-Golgi localization. Reason: APH1A is a multipass membrane protein in the gamma-secretase complex; ER, Golgi, endosomal, and general membrane localizations are consistent with the curated biology. |
| GO:0007220 Notch receptor processing | IMP PMID:12297508 Mammalian APH-1 interacts with presenilin and nicastrin and ... | ACCEPT | Summary: APH1A supports gamma-secretase-dependent Notch receptor processing and release of Notch intracellular domains. Reason: The term aligns with APH1A function as a non-catalytic gamma-secretase subunit that supports complex assembly/activity and APP/Notch intramembrane processing. |
| GO:0007220 Notch receptor processing | IDA PMID:27608597 Specific combinations of presenilins and Aph1s affect the su... | ACCEPT | Summary: APH1A supports gamma-secretase-dependent Notch receptor processing and release of Notch intracellular domains. Reason: The term aligns with APH1A function as a non-catalytic gamma-secretase subunit that supports complex assembly/activity and APP/Notch intramembrane processing. |
| GO:0016485 protein processing | IMP PMID:12297508 Mammalian APH-1 interacts with presenilin and nicastrin and ... | ACCEPT | Summary: This captures the core regulated intramembrane processing activity of the APH1A-containing gamma-secretase complex. Reason: The term aligns with APH1A function as a non-catalytic gamma-secretase subunit that supports complex assembly/activity and APP/Notch intramembrane processing. |
| GO:0016485 protein processing | IGI PMID:12763021 APH1, PEN2, and Nicastrin increase Abeta levels and gamma-se... | ACCEPT | Summary: This captures the core regulated intramembrane processing activity of the APH1A-containing gamma-secretase complex. Reason: The term aligns with APH1A function as a non-catalytic gamma-secretase subunit that supports complex assembly/activity and APP/Notch intramembrane processing. |
| GO:0016485 protein processing | IDA PMID:27608597 Specific combinations of presenilins and Aph1s affect the su... | ACCEPT | Summary: This captures the core regulated intramembrane processing activity of the APH1A-containing gamma-secretase complex. Reason: The term aligns with APH1A function as a non-catalytic gamma-secretase subunit that supports complex assembly/activity and APP/Notch intramembrane processing. |
| GO:0030674 protein-macromolecule adaptor activity | IMP PMID:12297508 Mammalian APH-1 interacts with presenilin and nicastrin and ... | ACCEPT | Summary: APH1A acts as a non-catalytic assembly/adaptor subunit that helps stabilize and organize active gamma-secretase complexes. Reason: The term aligns with APH1A function as a non-catalytic gamma-secretase subunit that supports complex assembly/activity and APP/Notch intramembrane processing. |
| GO:0034205 amyloid-beta formation | IMP PMID:12297508 Mammalian APH-1 interacts with presenilin and nicastrin and ... | ACCEPT | Summary: APH1A-containing gamma-secretase participates in APP processing that generates amyloid-beta-related products. Reason: The term aligns with APH1A function as a non-catalytic gamma-secretase subunit that supports complex assembly/activity and APP/Notch intramembrane processing. |
| GO:0034205 amyloid-beta formation | IGI PMID:12763021 APH1, PEN2, and Nicastrin increase Abeta levels and gamma-se... | ACCEPT | Summary: APH1A-containing gamma-secretase participates in APP processing that generates amyloid-beta-related products. Reason: The term aligns with APH1A function as a non-catalytic gamma-secretase subunit that supports complex assembly/activity and APP/Notch intramembrane processing. |
| GO:0034205 amyloid-beta formation | IDA PMID:27608597 Specific combinations of presenilins and Aph1s affect the su... | ACCEPT | Summary: APH1A-containing gamma-secretase participates in APP processing that generates amyloid-beta-related products. Reason: The term aligns with APH1A function as a non-catalytic gamma-secretase subunit that supports complex assembly/activity and APP/Notch intramembrane processing. |
| GO:0042987 amyloid precursor protein catabolic process | IGI PMID:12763021 APH1, PEN2, and Nicastrin increase Abeta levels and gamma-se... | ACCEPT | Summary: APH1A-containing gamma-secretase participates in APP processing that generates amyloid-beta-related products. Reason: The term aligns with APH1A function as a non-catalytic gamma-secretase subunit that supports complex assembly/activity and APP/Notch intramembrane processing. |
| GO:0042987 amyloid precursor protein catabolic process | IDA PMID:27608597 Specific combinations of presenilins and Aph1s affect the su... | ACCEPT | Summary: APH1A-containing gamma-secretase participates in APP processing that generates amyloid-beta-related products. Reason: The term aligns with APH1A function as a non-catalytic gamma-secretase subunit that supports complex assembly/activity and APP/Notch intramembrane processing. |
| GO:0061133 endopeptidase activator activity | IMP PMID:12297508 Mammalian APH-1 interacts with presenilin and nicastrin and ... | ACCEPT | Summary: APH1A is required for normal gamma-secretase assembly and activity, supporting an endopeptidase activator role at the complex level. Reason: The term aligns with APH1A function as a non-catalytic gamma-secretase subunit that supports complex assembly/activity and APP/Notch intramembrane processing. |
| GO:0061133 endopeptidase activator activity | IGI PMID:12763021 APH1, PEN2, and Nicastrin increase Abeta levels and gamma-se... | ACCEPT | Summary: APH1A is required for normal gamma-secretase assembly and activity, supporting an endopeptidase activator role at the complex level. Reason: The term aligns with APH1A function as a non-catalytic gamma-secretase subunit that supports complex assembly/activity and APP/Notch intramembrane processing. |
| GO:0070765 gamma-secretase complex | IDA PMID:12297508 Mammalian APH-1 interacts with presenilin and nicastrin and ... | ACCEPT | Summary: APH1A is an established non-catalytic subunit of the gamma-secretase complex with presenilin, nicastrin, and PSENEN/PEN-2. Reason: The term aligns with APH1A function as a non-catalytic gamma-secretase subunit that supports complex assembly/activity and APP/Notch intramembrane processing. |
| GO:0010008 endosome membrane | TAS Reactome:R-HSA-9010096 | ACCEPT | Summary: This membrane or endomembrane location is consistent with APH1A as a multipass gamma-secretase subunit, especially its ER/cis-Golgi localization. Reason: APH1A is a multipass membrane protein in the gamma-secretase complex; ER, Golgi, endosomal, and general membrane localizations are consistent with the curated biology. |
| GO:0016020 membrane | IDA PMID:25043039 Three-dimensional structure of human Ξ³-secretase. | ACCEPT | Summary: This membrane or endomembrane location is consistent with APH1A as a multipass gamma-secretase subunit, especially its ER/cis-Golgi localization. Reason: APH1A is a multipass membrane protein in the gamma-secretase complex; ER, Golgi, endosomal, and general membrane localizations are consistent with the curated biology. |
| GO:0016020 membrane | IDA PMID:26280335 An atomic structure of human Ξ³-secretase. | ACCEPT | Summary: This membrane or endomembrane location is consistent with APH1A as a multipass gamma-secretase subunit, especially its ER/cis-Golgi localization. Reason: APH1A is a multipass membrane protein in the gamma-secretase complex; ER, Golgi, endosomal, and general membrane localizations are consistent with the curated biology. |
| GO:0034205 amyloid-beta formation | IMP PMID:25043039 Three-dimensional structure of human Ξ³-secretase. | ACCEPT | Summary: APH1A-containing gamma-secretase participates in APP processing that generates amyloid-beta-related products. Reason: The term aligns with APH1A function as a non-catalytic gamma-secretase subunit that supports complex assembly/activity and APP/Notch intramembrane processing. |
| GO:0034205 amyloid-beta formation | IMP PMID:26280335 An atomic structure of human Ξ³-secretase. | ACCEPT | Summary: APH1A-containing gamma-secretase participates in APP processing that generates amyloid-beta-related products. Reason: The term aligns with APH1A function as a non-catalytic gamma-secretase subunit that supports complex assembly/activity and APP/Notch intramembrane processing. |
| GO:0042982 amyloid precursor protein metabolic process | IDA PMID:25043039 Three-dimensional structure of human Ξ³-secretase. | ACCEPT | Summary: APH1A-containing gamma-secretase participates in APP processing that generates amyloid-beta-related products. Reason: The term aligns with APH1A function as a non-catalytic gamma-secretase subunit that supports complex assembly/activity and APP/Notch intramembrane processing. |
| GO:0042982 amyloid precursor protein metabolic process | IDA PMID:26280335 An atomic structure of human Ξ³-secretase. | ACCEPT | Summary: APH1A-containing gamma-secretase participates in APP processing that generates amyloid-beta-related products. Reason: The term aligns with APH1A function as a non-catalytic gamma-secretase subunit that supports complex assembly/activity and APP/Notch intramembrane processing. |
| GO:0070765 gamma-secretase complex | IDA PMID:25043039 Three-dimensional structure of human Ξ³-secretase. | ACCEPT | Summary: APH1A is an established non-catalytic subunit of the gamma-secretase complex with presenilin, nicastrin, and PSENEN/PEN-2. Reason: The term aligns with APH1A function as a non-catalytic gamma-secretase subunit that supports complex assembly/activity and APP/Notch intramembrane processing. |
| GO:0070765 gamma-secretase complex | IDA PMID:26280335 An atomic structure of human Ξ³-secretase. | ACCEPT | Summary: APH1A is an established non-catalytic subunit of the gamma-secretase complex with presenilin, nicastrin, and PSENEN/PEN-2. Reason: The term aligns with APH1A function as a non-catalytic gamma-secretase subunit that supports complex assembly/activity and APP/Notch intramembrane processing. |
| GO:0016020 membrane | HDA PMID:19946888 Defining the membrane proteome of NK cells. | ACCEPT | Summary: This membrane or endomembrane location is consistent with APH1A as a multipass gamma-secretase subunit, especially its ER/cis-Golgi localization. Reason: APH1A is a multipass membrane protein in the gamma-secretase complex; ER, Golgi, endosomal, and general membrane localizations are consistent with the curated biology. |
| GO:0005886 plasma membrane | TAS Reactome:R-HSA-1251997 | KEEP AS NON CORE | Summary: Plasma-membrane annotations are plausible for gamma-secretase substrate events, but APH1A-specific steady-state localization is strongest for ER and cis-Golgi membranes. Reason: Retain as non-core because the site is biologically plausible for substrate processing without being the clearest APH1A-defining location. |
| GO:0005886 plasma membrane | TAS Reactome:R-HSA-193682 | KEEP AS NON CORE | Summary: Plasma-membrane annotations are plausible for gamma-secretase substrate events, but APH1A-specific steady-state localization is strongest for ER and cis-Golgi membranes. Reason: Retain as non-core because the site is biologically plausible for substrate processing without being the clearest APH1A-defining location. |
| GO:0005886 plasma membrane | TAS Reactome:R-HSA-205112 | KEEP AS NON CORE | Summary: Plasma-membrane annotations are plausible for gamma-secretase substrate events, but APH1A-specific steady-state localization is strongest for ER and cis-Golgi membranes. Reason: Retain as non-core because the site is biologically plausible for substrate processing without being the clearest APH1A-defining location. |
| GO:0005886 plasma membrane | TAS Reactome:R-HSA-2220988 | KEEP AS NON CORE | Summary: Plasma-membrane annotations are plausible for gamma-secretase substrate events, but APH1A-specific steady-state localization is strongest for ER and cis-Golgi membranes. Reason: Retain as non-core because the site is biologically plausible for substrate processing without being the clearest APH1A-defining location. |
| GO:0005886 plasma membrane | TAS Reactome:R-HSA-3928656 | KEEP AS NON CORE | Summary: Plasma-membrane annotations are plausible for gamma-secretase substrate events, but APH1A-specific steady-state localization is strongest for ER and cis-Golgi membranes. Reason: Retain as non-core because the site is biologically plausible for substrate processing without being the clearest APH1A-defining location. |
| GO:0005886 plasma membrane | TAS Reactome:R-HSA-9013361 | KEEP AS NON CORE | Summary: Plasma-membrane annotations are plausible for gamma-secretase substrate events, but APH1A-specific steady-state localization is strongest for ER and cis-Golgi membranes. Reason: Retain as non-core because the site is biologically plausible for substrate processing without being the clearest APH1A-defining location. |
| GO:0005886 plasma membrane | TAS Reactome:R-HSA-9017817 | KEEP AS NON CORE | Summary: Plasma-membrane annotations are plausible for gamma-secretase substrate events, but APH1A-specific steady-state localization is strongest for ER and cis-Golgi membranes. Reason: Retain as non-core because the site is biologically plausible for substrate processing without being the clearest APH1A-defining location. |
| GO:0005886 plasma membrane | TAS Reactome:R-HSA-9839376 | KEEP AS NON CORE | Summary: Plasma-membrane annotations are plausible for gamma-secretase substrate events, but APH1A-specific steady-state localization is strongest for ER and cis-Golgi membranes. Reason: Retain as non-core because the site is biologically plausible for substrate processing without being the clearest APH1A-defining location. |
| GO:0005886 plasma membrane | TAS Reactome:R-NUL-2197556 | KEEP AS NON CORE | Summary: Plasma-membrane annotations are plausible for gamma-secretase substrate events, but APH1A-specific steady-state localization is strongest for ER and cis-Golgi membranes. Reason: Retain as non-core because the site is biologically plausible for substrate processing without being the clearest APH1A-defining location. |
| GO:0005886 plasma membrane | TAS Reactome:R-NUL-9604300 | KEEP AS NON CORE | Summary: Plasma-membrane annotations are plausible for gamma-secretase substrate events, but APH1A-specific steady-state localization is strongest for ER and cis-Golgi membranes. Reason: Retain as non-core because the site is biologically plausible for substrate processing without being the clearest APH1A-defining location. |
| GO:0031293 membrane protein intracellular domain proteolysis | IMP PMID:12297508 Mammalian APH-1 interacts with presenilin and nicastrin and ... | ACCEPT | Summary: This captures the core regulated intramembrane processing activity of the APH1A-containing gamma-secretase complex. Reason: The term aligns with APH1A function as a non-catalytic gamma-secretase subunit that supports complex assembly/activity and APP/Notch intramembrane processing. |
| GO:0042987 amyloid precursor protein catabolic process | IMP PMID:12297508 Mammalian APH-1 interacts with presenilin and nicastrin and ... | ACCEPT | Summary: APH1A-containing gamma-secretase participates in APP processing that generates amyloid-beta-related products. Reason: The term aligns with APH1A function as a non-catalytic gamma-secretase subunit that supports complex assembly/activity and APP/Notch intramembrane processing. |
| GO:0005783 endoplasmic reticulum | IDA PMID:15274632 Purification and characterization of the human gamma-secreta... | ACCEPT | Summary: This membrane or endomembrane location is consistent with APH1A as a multipass gamma-secretase subunit, especially its ER/cis-Golgi localization. Reason: APH1A is a multipass membrane protein in the gamma-secretase complex; ER, Golgi, endosomal, and general membrane localizations are consistent with the curated biology. |
| GO:0005794 Golgi apparatus | IDA PMID:15274632 Purification and characterization of the human gamma-secreta... | ACCEPT | Summary: This membrane or endomembrane location is consistent with APH1A as a multipass gamma-secretase subunit, especially its ER/cis-Golgi localization. Reason: APH1A is a multipass membrane protein in the gamma-secretase complex; ER, Golgi, endosomal, and general membrane localizations are consistent with the curated biology. |
| GO:0006509 membrane protein ectodomain proteolysis | IDA PMID:15274632 Purification and characterization of the human gamma-secreta... | MODIFY | Summary: Gamma-secretase acts after ectodomain shedding and performs intramembrane cleavage; ectodomain proteolysis is not the best APH1A process label. Reason: Use an intramembrane substrate-processing term rather than ectodomain proteolysis for the APH1A-containing gamma-secretase complex. Proposed replacements: membrane protein intracellular domain proteolysis protein processing |
| GO:0007220 Notch receptor processing | TAS PMID:15274632 Purification and characterization of the human gamma-secreta... | ACCEPT | Summary: APH1A supports gamma-secretase-dependent Notch receptor processing and release of Notch intracellular domains. Reason: The term aligns with APH1A function as a non-catalytic gamma-secretase subunit that supports complex assembly/activity and APP/Notch intramembrane processing. |
| GO:0016485 protein processing | IDA PMID:15274632 Purification and characterization of the human gamma-secreta... | ACCEPT | Summary: This captures the core regulated intramembrane processing activity of the APH1A-containing gamma-secretase complex. Reason: The term aligns with APH1A function as a non-catalytic gamma-secretase subunit that supports complex assembly/activity and APP/Notch intramembrane processing. |
| GO:0042987 amyloid precursor protein catabolic process | TAS PMID:15274632 Purification and characterization of the human gamma-secreta... | ACCEPT | Summary: APH1A-containing gamma-secretase participates in APP processing that generates amyloid-beta-related products. Reason: The term aligns with APH1A function as a non-catalytic gamma-secretase subunit that supports complex assembly/activity and APP/Notch intramembrane processing. |
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Download this section (compressed HTML)Q: Which APH1A-containing gamma-secretase assemblies operate in ER/cis-Golgi compartments versus later endosomal or cell-surface substrate-processing compartments in human neural and glial cells?
Suggested experts: gamma-secretase complex experts, Notch and APP processing experts
Q: How should GO distinguish APH1A adaptor/assembly activity from APH1A contribution to presenilin catalytic activity within gamma-secretase?
Suggested experts: GO molecular-function curators, gamma-secretase structure-function experts
Experiment: Compare endogenous APH1A and APH1B knockout or isoform-rescue human neural cells for APP, Notch, and other gamma-secretase substrate cleavage in ER/Golgi, endosomal, and plasma-membrane-enriched fractions.
Hypothesis: APH1A-containing complexes have compartment- and substrate-specific roles that are not fully captured by generic gamma-secretase annotations.
Type: endogenous isoform-rescue substrate-processing assay
Experiment: Introduce APH1A interface mutations in endogenous cells and quantify presenilin maturation, nicastrin association, complex abundance, and substrate-specific cleavage products.
Hypothesis: APH1A primarily controls gamma-secretase assembly/stability and substrate-processing competence rather than catalysis directly.
Type: complex assembly and activity assay
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