PSENEN encodes PEN-2, a small multipass membrane protein and essential non-catalytic subunit of the gamma-secretase intramembrane protease complex. Together with a presenilin catalytic subunit, nicastrin, and APH1A or APH1B, PEN-2 promotes presenilin maturation/endoproteolysis, gamma-secretase complex stability and trafficking, and intramembrane cleavage of substrates including APP and Notch receptors. PEN-2 localizes primarily to endoplasmic-reticulum and cis-Golgi membranes, with evidence for cell-membrane and other membrane compartments; additional orthology-based evidence links PEN-2 to energy-stress signaling through V-ATPase/AMPK/TORC1 regulation.
| GO Term | Evidence | Action | Reason |
|---|---|---|---|
| GO:0007220 Notch receptor processing | IBA GO_REF:0000033 | ACCEPT | Summary: PSENEN supports gamma-secretase-dependent Notch receptor processing through its role in complex maturation and activity. Reason: The term aligns with PSENEN/PEN-2 function as an essential non-catalytic gamma-secretase subunit that promotes presenilin maturation, complex stability, trafficking, and APP/Notch substrate processing. |
| GO:0070765 gamma-secretase complex | IBA GO_REF:0000033 | ACCEPT | Summary: PSENEN/PEN-2 is an integral subunit of the four-component gamma-secretase complex with presenilin, nicastrin, and APH1. Reason: The term aligns with PSENEN/PEN-2 function as an essential non-catalytic gamma-secretase subunit that promotes presenilin maturation, complex stability, trafficking, and APP/Notch substrate processing. |
| GO:0005789 endoplasmic reticulum membrane | IEA GO_REF:0000044 | ACCEPT | Summary: This membrane or endomembrane location is consistent with PSENEN/PEN-2 as a multipass gamma-secretase subunit in ER, Golgi, cell-membrane, and substrate-processing compartments. Reason: PSENEN/PEN-2 is a multipass membrane gamma-secretase subunit with ER, cis-Golgi, cell-membrane, and general endomembrane localization evidence. |
| GO:0005886 plasma membrane | IEA GO_REF:0000044 | ACCEPT | Summary: This membrane or endomembrane location is consistent with PSENEN/PEN-2 as a multipass gamma-secretase subunit in ER, Golgi, cell-membrane, and substrate-processing compartments. Reason: PSENEN/PEN-2 is a multipass membrane gamma-secretase subunit with ER, cis-Golgi, cell-membrane, and general endomembrane localization evidence. |
| GO:0016020 membrane | IEA GO_REF:0000044 | ACCEPT | Summary: This membrane or endomembrane location is consistent with PSENEN/PEN-2 as a multipass gamma-secretase subunit in ER, Golgi, cell-membrane, and substrate-processing compartments. Reason: PSENEN/PEN-2 is a multipass membrane gamma-secretase subunit with ER, cis-Golgi, cell-membrane, and general endomembrane localization evidence. |
| GO:0032580 Golgi cisterna membrane | IEA GO_REF:0000044 | ACCEPT | Summary: This membrane or endomembrane location is consistent with PSENEN/PEN-2 as a multipass gamma-secretase subunit in ER, Golgi, cell-membrane, and substrate-processing compartments. Reason: PSENEN/PEN-2 is a multipass membrane gamma-secretase subunit with ER, cis-Golgi, cell-membrane, and general endomembrane localization evidence. |
| GO:0005515 protein binding | IPI PMID:15322109 Both the sequence and length of the C terminus of PEN-2 are ... | MARK AS OVER ANNOTATED | Summary: The interaction evidence is compatible with PSENEN complex/substrate associations, but generic protein binding is not an informative molecular function for this gene. Reason: Prefer gamma-secretase complex membership and endopeptidase-activator/contribution terms over broad protein-binding annotations. |
| GO:0005515 protein binding | IPI PMID:16641999 TMP21 is a presenilin complex component that modulates gamma... | MARK AS OVER ANNOTATED | Summary: The interaction evidence is compatible with PSENEN complex/substrate associations, but generic protein binding is not an informative molecular function for this gene. Reason: Prefer gamma-secretase complex membership and endopeptidase-activator/contribution terms over broad protein-binding annotations. |
| 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 PSENEN complex/substrate associations, but generic protein binding is not an informative molecular function for this gene. Reason: Prefer gamma-secretase complex membership and endopeptidase-activator/contribution terms over broad protein-binding annotations. |
| GO:0005515 protein binding | IPI PMID:23685131 Ferritin light chain interacts with PEN-2 and affects Ξ³-secr... | MARK AS OVER ANNOTATED | Summary: The interaction evidence is compatible with PSENEN complex/substrate associations, but generic protein binding is not an informative molecular function for this gene. Reason: Prefer gamma-secretase complex membership and endopeptidase-activator/contribution terms over broad protein-binding annotations. |
| 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 PSENEN complex/substrate associations, but generic protein binding is not an informative molecular function for this gene. Reason: Prefer gamma-secretase complex membership and endopeptidase-activator/contribution terms over broad protein-binding annotations. |
| 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 PSENEN complex/substrate associations, but generic protein binding is not an informative molecular function for this gene. Reason: Prefer gamma-secretase complex membership and endopeptidase-activator/contribution terms over broad protein-binding annotations. |
| 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 PSENEN complex/substrate associations, but generic protein binding is not an informative molecular function for this gene. Reason: Prefer gamma-secretase complex membership and endopeptidase-activator/contribution terms over broad protein-binding annotations. |
| GO:0016485 protein processing | IEA GO_REF:0000107 | ACCEPT | Summary: This captures regulated membrane-substrate processing by the PSENEN-containing gamma-secretase complex. Reason: The term aligns with PSENEN/PEN-2 function as an essential non-catalytic gamma-secretase subunit that promotes presenilin maturation, complex stability, trafficking, and APP/Notch substrate processing. |
| GO:0042149 cellular response to glucose starvation | IEA GO_REF:0000107 | KEEP AS NON CORE | Summary: This starvation/TORC1/AMPK-related annotation represents a plausible gamma-secretase-independent PSENEN role, but it is not the main PEN-2 function supported by the human gamma-secretase literature. Reason: Retain as non-core because this likely reflects a gamma-secretase-independent, energy-stress/V-ATPase/AMPK-related role transferred by orthology or automation, not the primary human PSENEN gamma-secretase function reviewed here. |
| GO:0042734 presynaptic membrane | IEA GO_REF:0000107 | KEEP AS NON CORE | Summary: Presynaptic membrane localization is plausible for some transferred annotations but is peripheral to the main ER/Golgi/cell-membrane gamma-secretase complex localization evidence. Reason: Retain as non-core because it may reflect a real context-specific localization without defining the primary PSENEN function. |
| GO:0061133 endopeptidase activator activity | IEA GO_REF:0000107 | ACCEPT | Summary: PSENEN/PEN-2 promotes presenilin endoproteolysis and gamma-secretase proteolytic activity, supporting an endopeptidase-activating role at the complex level. Reason: The term aligns with PSENEN/PEN-2 function as an essential non-catalytic gamma-secretase subunit that promotes presenilin maturation, complex stability, trafficking, and APP/Notch substrate processing. |
| GO:0070765 gamma-secretase complex | IEA GO_REF:0000107 | ACCEPT | Summary: PSENEN/PEN-2 is an integral subunit of the four-component gamma-secretase complex with presenilin, nicastrin, and APH1. Reason: The term aligns with PSENEN/PEN-2 function as an essential non-catalytic gamma-secretase subunit that promotes presenilin maturation, complex stability, trafficking, and APP/Notch substrate processing. |
| GO:0140678 molecular function inhibitor activity | IEA GO_REF:0000107 | KEEP AS NON CORE | Summary: This starvation/TORC1/AMPK-related annotation represents a plausible gamma-secretase-independent PSENEN role, but it is not the main PEN-2 function supported by the human gamma-secretase literature. Reason: Retain as non-core because this likely reflects a gamma-secretase-independent, energy-stress/V-ATPase/AMPK-related role transferred by orthology or automation, not the primary human PSENEN gamma-secretase function reviewed here. |
| GO:1904262 negative regulation of TORC1 signaling | IEA GO_REF:0000107 | KEEP AS NON CORE | Summary: This starvation/TORC1/AMPK-related annotation represents a plausible gamma-secretase-independent PSENEN role, but it is not the main PEN-2 function supported by the human gamma-secretase literature. Reason: Retain as non-core because this likely reflects a gamma-secretase-independent, energy-stress/V-ATPase/AMPK-related role transferred by orthology or automation, not the primary human PSENEN gamma-secretase function reviewed here. |
| GO:0042149 cellular response to glucose starvation | ISS GO_REF:0000024 | KEEP AS NON CORE | Summary: This starvation/TORC1/AMPK-related annotation represents a plausible gamma-secretase-independent PSENEN role, but it is not the main PEN-2 function supported by the human gamma-secretase literature. Reason: Retain as non-core because this likely reflects a gamma-secretase-independent, energy-stress/V-ATPase/AMPK-related role transferred by orthology or automation, not the primary human PSENEN gamma-secretase function reviewed here. |
| GO:0140678 molecular function inhibitor activity | ISS GO_REF:0000024 | KEEP AS NON CORE | Summary: This starvation/TORC1/AMPK-related annotation represents a plausible gamma-secretase-independent PSENEN role, but it is not the main PEN-2 function supported by the human gamma-secretase literature. Reason: Retain as non-core because this likely reflects a gamma-secretase-independent, energy-stress/V-ATPase/AMPK-related role transferred by orthology or automation, not the primary human PSENEN gamma-secretase function reviewed here. |
| GO:1904262 negative regulation of TORC1 signaling | ISS GO_REF:0000024 | KEEP AS NON CORE | Summary: This starvation/TORC1/AMPK-related annotation represents a plausible gamma-secretase-independent PSENEN role, but it is not the main PEN-2 function supported by the human gamma-secretase literature. Reason: Retain as non-core because this likely reflects a gamma-secretase-independent, energy-stress/V-ATPase/AMPK-related role transferred by orthology or automation, not the primary human PSENEN gamma-secretase function reviewed here. |
| 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 PSENEN/PEN-2 as a multipass gamma-secretase subunit in ER, Golgi, cell-membrane, and substrate-processing compartments. Reason: PSENEN/PEN-2 is a multipass membrane gamma-secretase subunit with ER, cis-Golgi, cell-membrane, and general endomembrane localization evidence. |
| GO:0005886 plasma membrane | IDA PMID:15274632 Purification and characterization of the human gamma-secreta... | ACCEPT | Summary: This membrane or endomembrane location is consistent with PSENEN/PEN-2 as a multipass gamma-secretase subunit in ER, Golgi, cell-membrane, and substrate-processing compartments. Reason: PSENEN/PEN-2 is a multipass membrane gamma-secretase subunit with ER, cis-Golgi, cell-membrane, and general endomembrane localization evidence. |
| GO:0007220 Notch receptor processing | NAS PMID:10206645 A presenilin-1-dependent gamma-secretase-like protease media... | ACCEPT | Summary: PSENEN supports gamma-secretase-dependent Notch receptor processing through its role in complex maturation and activity. Reason: The term aligns with PSENEN/PEN-2 function as an essential non-catalytic gamma-secretase subunit that promotes presenilin maturation, complex stability, trafficking, and APP/Notch substrate processing. |
| GO:0031293 membrane protein intracellular domain proteolysis | IDA PMID:15274632 Purification and characterization of the human gamma-secreta... | ACCEPT | Summary: This captures regulated membrane-substrate processing by the PSENEN-containing gamma-secretase complex. Reason: The term aligns with PSENEN/PEN-2 function as an essential non-catalytic gamma-secretase subunit that promotes presenilin maturation, complex stability, trafficking, and APP/Notch substrate processing. |
| GO:0042987 amyloid precursor protein catabolic process | IDA PMID:15274632 Purification and characterization of the human gamma-secreta... | ACCEPT | Summary: PSENEN-containing gamma-secretase participates in APP processing and amyloid-beta-related product formation. Reason: The term aligns with PSENEN/PEN-2 function as an essential non-catalytic gamma-secretase subunit that promotes presenilin maturation, complex stability, trafficking, and APP/Notch substrate processing. |
| GO:0070765 gamma-secretase complex | IPI PMID:26280335 An atomic structure of human Ξ³-secretase. | ACCEPT | Summary: PSENEN/PEN-2 is an integral subunit of the four-component gamma-secretase complex with presenilin, nicastrin, and APH1. Reason: The term aligns with PSENEN/PEN-2 function as an essential non-catalytic gamma-secretase subunit that promotes presenilin maturation, complex stability, trafficking, and APP/Notch substrate 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 PSENEN/PEN-2 as a multipass gamma-secretase subunit in ER, Golgi, cell-membrane, and substrate-processing compartments. Reason: PSENEN/PEN-2 is a multipass membrane gamma-secretase subunit with ER, cis-Golgi, cell-membrane, and general endomembrane localization evidence. |
| GO:0016485 protein processing | IMP PMID:12522139 PEN-2 and APH-1 coordinately regulate proteolytic processing... | ACCEPT | Summary: This captures regulated membrane-substrate processing by the PSENEN-containing gamma-secretase complex. Reason: The term aligns with PSENEN/PEN-2 function as an essential non-catalytic gamma-secretase subunit that promotes presenilin maturation, complex stability, trafficking, and APP/Notch substrate 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 PSENEN/PEN-2 as a multipass gamma-secretase subunit in ER, Golgi, cell-membrane, and substrate-processing compartments. Reason: PSENEN/PEN-2 is a multipass membrane gamma-secretase subunit with ER, cis-Golgi, cell-membrane, and general endomembrane localization evidence. |
| GO:0005789 endoplasmic reticulum membrane | EXP PMID:12639958 Membrane topology of gamma-secretase component PEN-2. | ACCEPT | Summary: This membrane or endomembrane location is consistent with PSENEN/PEN-2 as a multipass gamma-secretase subunit in ER, Golgi, cell-membrane, and substrate-processing compartments. Reason: PSENEN/PEN-2 is a multipass membrane gamma-secretase subunit with ER, cis-Golgi, cell-membrane, and general endomembrane localization evidence. |
| GO:0005886 plasma membrane | EXP PMID:24941111 Pen-2 is essential for Ξ³-secretase complex stability and tra... | ACCEPT | Summary: This membrane or endomembrane location is consistent with PSENEN/PEN-2 as a multipass gamma-secretase subunit in ER, Golgi, cell-membrane, and substrate-processing compartments. Reason: PSENEN/PEN-2 is a multipass membrane gamma-secretase subunit with ER, cis-Golgi, cell-membrane, and general endomembrane localization evidence. |
| GO:0016020 membrane | EXP PMID:12198112 PEN-2 is an integral component of the gamma-secretase comple... | ACCEPT | Summary: This membrane or endomembrane location is consistent with PSENEN/PEN-2 as a multipass gamma-secretase subunit in ER, Golgi, cell-membrane, and substrate-processing compartments. Reason: PSENEN/PEN-2 is a multipass membrane gamma-secretase subunit with ER, cis-Golgi, cell-membrane, and general endomembrane localization evidence. |
| GO:0016485 protein processing | IMP PMID:12660785 The role of presenilin cofactors in the gamma-secretase comp... | ACCEPT | Summary: This captures regulated membrane-substrate processing by the PSENEN-containing gamma-secretase complex. Reason: The term aligns with PSENEN/PEN-2 function as an essential non-catalytic gamma-secretase subunit that promotes presenilin maturation, complex stability, trafficking, and APP/Notch substrate processing. |
| GO:0016485 protein processing | IGI PMID:12763021 APH1, PEN2, and Nicastrin increase Abeta levels and gamma-se... | ACCEPT | Summary: This captures regulated membrane-substrate processing by the PSENEN-containing gamma-secretase complex. Reason: The term aligns with PSENEN/PEN-2 function as an essential non-catalytic gamma-secretase subunit that promotes presenilin maturation, complex stability, trafficking, and APP/Notch substrate processing. |
| GO:0019899 enzyme binding | IPI PMID:12522139 PEN-2 and APH-1 coordinately regulate proteolytic processing... | KEEP AS NON CORE | Summary: Broad enzyme binding is plausible for a PSENEN gamma-secretase subunit but is less informative than complex membership and activator/contribution terms. Reason: Retain as non-core because it may reflect real interaction with presenilin enzyme complexes without defining the primary PSENEN molecular role. |
| GO:0034205 amyloid-beta formation | IGI PMID:12763021 APH1, PEN2, and Nicastrin increase Abeta levels and gamma-se... | ACCEPT | Summary: PSENEN-containing gamma-secretase participates in APP processing and amyloid-beta-related product formation. Reason: The term aligns with PSENEN/PEN-2 function as an essential non-catalytic gamma-secretase subunit that promotes presenilin maturation, complex stability, trafficking, and APP/Notch substrate processing. |
| GO:0042987 amyloid precursor protein catabolic process | IMP PMID:12660785 The role of presenilin cofactors in the gamma-secretase comp... | ACCEPT | Summary: PSENEN-containing gamma-secretase participates in APP processing and amyloid-beta-related product formation. Reason: The term aligns with PSENEN/PEN-2 function as an essential non-catalytic gamma-secretase subunit that promotes presenilin maturation, complex stability, trafficking, and APP/Notch substrate processing. |
| GO:0042987 amyloid precursor protein catabolic process | IGI PMID:12763021 APH1, PEN2, and Nicastrin increase Abeta levels and gamma-se... | ACCEPT | Summary: PSENEN-containing gamma-secretase participates in APP processing and amyloid-beta-related product formation. Reason: The term aligns with PSENEN/PEN-2 function as an essential non-catalytic gamma-secretase subunit that promotes presenilin maturation, complex stability, trafficking, and APP/Notch substrate processing. |
| GO:0061133 endopeptidase activator activity | IMP PMID:12522139 PEN-2 and APH-1 coordinately regulate proteolytic processing... | ACCEPT | Summary: PSENEN/PEN-2 promotes presenilin endoproteolysis and gamma-secretase proteolytic activity, supporting an endopeptidase-activating role at the complex level. Reason: The term aligns with PSENEN/PEN-2 function as an essential non-catalytic gamma-secretase subunit that promotes presenilin maturation, complex stability, trafficking, and APP/Notch substrate processing. |
| GO:0061133 endopeptidase activator activity | IGI PMID:12763021 APH1, PEN2, and Nicastrin increase Abeta levels and gamma-se... | ACCEPT | Summary: PSENEN/PEN-2 promotes presenilin endoproteolysis and gamma-secretase proteolytic activity, supporting an endopeptidase-activating role at the complex level. Reason: The term aligns with PSENEN/PEN-2 function as an essential non-catalytic gamma-secretase subunit that promotes presenilin maturation, complex stability, trafficking, and APP/Notch substrate processing. |
| GO:0070765 gamma-secretase complex | IGI PMID:12763021 APH1, PEN2, and Nicastrin increase Abeta levels and gamma-se... | ACCEPT | Summary: PSENEN/PEN-2 is an integral subunit of the four-component gamma-secretase complex with presenilin, nicastrin, and APH1. Reason: The term aligns with PSENEN/PEN-2 function as an essential non-catalytic gamma-secretase subunit that promotes presenilin maturation, complex stability, trafficking, and APP/Notch substrate processing. |
| GO:0010950 positive regulation of endopeptidase activity | IMP PMID:12660785 The role of presenilin cofactors in the gamma-secretase comp... | ACCEPT | Summary: PSENEN/PEN-2 promotes presenilin endoproteolysis and gamma-secretase proteolytic activity, supporting an endopeptidase-activating role at the complex level. Reason: The term aligns with PSENEN/PEN-2 function as an essential non-catalytic gamma-secretase subunit that promotes presenilin maturation, complex stability, trafficking, and APP/Notch substrate processing. |
| GO:0034205 amyloid-beta formation | IMP PMID:12660785 The role of presenilin cofactors in the gamma-secretase comp... | ACCEPT | Summary: PSENEN-containing gamma-secretase participates in APP processing and amyloid-beta-related product formation. Reason: The term aligns with PSENEN/PEN-2 function as an essential non-catalytic gamma-secretase subunit that promotes presenilin maturation, complex stability, trafficking, and APP/Notch substrate processing. |
| GO:0010008 endosome membrane | TAS Reactome:R-HSA-9010096 | ACCEPT | Summary: This membrane or endomembrane location is consistent with PSENEN/PEN-2 as a multipass gamma-secretase subunit in ER, Golgi, cell-membrane, and substrate-processing compartments. Reason: PSENEN/PEN-2 is a multipass membrane gamma-secretase subunit with ER, cis-Golgi, cell-membrane, and general endomembrane localization evidence. |
| GO:0016020 membrane | IDA PMID:25043039 Three-dimensional structure of human Ξ³-secretase. | ACCEPT | Summary: This membrane or endomembrane location is consistent with PSENEN/PEN-2 as a multipass gamma-secretase subunit in ER, Golgi, cell-membrane, and substrate-processing compartments. Reason: PSENEN/PEN-2 is a multipass membrane gamma-secretase subunit with ER, cis-Golgi, cell-membrane, and general endomembrane localization evidence. |
| GO:0016020 membrane | IDA PMID:26280335 An atomic structure of human Ξ³-secretase. | ACCEPT | Summary: This membrane or endomembrane location is consistent with PSENEN/PEN-2 as a multipass gamma-secretase subunit in ER, Golgi, cell-membrane, and substrate-processing compartments. Reason: PSENEN/PEN-2 is a multipass membrane gamma-secretase subunit with ER, cis-Golgi, cell-membrane, and general endomembrane localization evidence. |
| GO:0034205 amyloid-beta formation | IMP PMID:25043039 Three-dimensional structure of human Ξ³-secretase. | ACCEPT | Summary: PSENEN-containing gamma-secretase participates in APP processing and amyloid-beta-related product formation. Reason: The term aligns with PSENEN/PEN-2 function as an essential non-catalytic gamma-secretase subunit that promotes presenilin maturation, complex stability, trafficking, and APP/Notch substrate processing. |
| GO:0034205 amyloid-beta formation | IMP PMID:26280335 An atomic structure of human Ξ³-secretase. | ACCEPT | Summary: PSENEN-containing gamma-secretase participates in APP processing and amyloid-beta-related product formation. Reason: The term aligns with PSENEN/PEN-2 function as an essential non-catalytic gamma-secretase subunit that promotes presenilin maturation, complex stability, trafficking, and APP/Notch substrate processing. |
| GO:0042982 amyloid precursor protein metabolic process | IDA PMID:25043039 Three-dimensional structure of human Ξ³-secretase. | ACCEPT | Summary: PSENEN-containing gamma-secretase participates in APP processing and amyloid-beta-related product formation. Reason: The term aligns with PSENEN/PEN-2 function as an essential non-catalytic gamma-secretase subunit that promotes presenilin maturation, complex stability, trafficking, and APP/Notch substrate processing. |
| GO:0042982 amyloid precursor protein metabolic process | IDA PMID:26280335 An atomic structure of human Ξ³-secretase. | ACCEPT | Summary: PSENEN-containing gamma-secretase participates in APP processing and amyloid-beta-related product formation. Reason: The term aligns with PSENEN/PEN-2 function as an essential non-catalytic gamma-secretase subunit that promotes presenilin maturation, complex stability, trafficking, and APP/Notch substrate processing. |
| GO:0070765 gamma-secretase complex | IDA PMID:25043039 Three-dimensional structure of human Ξ³-secretase. | ACCEPT | Summary: PSENEN/PEN-2 is an integral subunit of the four-component gamma-secretase complex with presenilin, nicastrin, and APH1. Reason: The term aligns with PSENEN/PEN-2 function as an essential non-catalytic gamma-secretase subunit that promotes presenilin maturation, complex stability, trafficking, and APP/Notch substrate processing. |
| GO:0070765 gamma-secretase complex | IDA PMID:26280335 An atomic structure of human Ξ³-secretase. | ACCEPT | Summary: PSENEN/PEN-2 is an integral subunit of the four-component gamma-secretase complex with presenilin, nicastrin, and APH1. Reason: The term aligns with PSENEN/PEN-2 function as an essential non-catalytic gamma-secretase subunit that promotes presenilin maturation, complex stability, trafficking, and APP/Notch substrate processing. |
| GO:0005886 plasma membrane | TAS Reactome:R-HSA-1251997 | ACCEPT | Summary: This membrane or endomembrane location is consistent with PSENEN/PEN-2 as a multipass gamma-secretase subunit in ER, Golgi, cell-membrane, and substrate-processing compartments. Reason: PSENEN/PEN-2 is a multipass membrane gamma-secretase subunit with ER, cis-Golgi, cell-membrane, and general endomembrane localization evidence. |
| GO:0005886 plasma membrane | TAS Reactome:R-HSA-193682 | ACCEPT | Summary: This membrane or endomembrane location is consistent with PSENEN/PEN-2 as a multipass gamma-secretase subunit in ER, Golgi, cell-membrane, and substrate-processing compartments. Reason: PSENEN/PEN-2 is a multipass membrane gamma-secretase subunit with ER, cis-Golgi, cell-membrane, and general endomembrane localization evidence. |
| GO:0005886 plasma membrane | TAS Reactome:R-HSA-205112 | ACCEPT | Summary: This membrane or endomembrane location is consistent with PSENEN/PEN-2 as a multipass gamma-secretase subunit in ER, Golgi, cell-membrane, and substrate-processing compartments. Reason: PSENEN/PEN-2 is a multipass membrane gamma-secretase subunit with ER, cis-Golgi, cell-membrane, and general endomembrane localization evidence. |
| GO:0005886 plasma membrane | TAS Reactome:R-HSA-2220988 | ACCEPT | Summary: This membrane or endomembrane location is consistent with PSENEN/PEN-2 as a multipass gamma-secretase subunit in ER, Golgi, cell-membrane, and substrate-processing compartments. Reason: PSENEN/PEN-2 is a multipass membrane gamma-secretase subunit with ER, cis-Golgi, cell-membrane, and general endomembrane localization evidence. |
| GO:0005886 plasma membrane | TAS Reactome:R-HSA-3928656 | ACCEPT | Summary: This membrane or endomembrane location is consistent with PSENEN/PEN-2 as a multipass gamma-secretase subunit in ER, Golgi, cell-membrane, and substrate-processing compartments. Reason: PSENEN/PEN-2 is a multipass membrane gamma-secretase subunit with ER, cis-Golgi, cell-membrane, and general endomembrane localization evidence. |
| GO:0005886 plasma membrane | TAS Reactome:R-HSA-9013361 | ACCEPT | Summary: This membrane or endomembrane location is consistent with PSENEN/PEN-2 as a multipass gamma-secretase subunit in ER, Golgi, cell-membrane, and substrate-processing compartments. Reason: PSENEN/PEN-2 is a multipass membrane gamma-secretase subunit with ER, cis-Golgi, cell-membrane, and general endomembrane localization evidence. |
| GO:0005886 plasma membrane | TAS Reactome:R-HSA-9017817 | ACCEPT | Summary: This membrane or endomembrane location is consistent with PSENEN/PEN-2 as a multipass gamma-secretase subunit in ER, Golgi, cell-membrane, and substrate-processing compartments. Reason: PSENEN/PEN-2 is a multipass membrane gamma-secretase subunit with ER, cis-Golgi, cell-membrane, and general endomembrane localization evidence. |
| GO:0005886 plasma membrane | TAS Reactome:R-HSA-9839376 | ACCEPT | Summary: This membrane or endomembrane location is consistent with PSENEN/PEN-2 as a multipass gamma-secretase subunit in ER, Golgi, cell-membrane, and substrate-processing compartments. Reason: PSENEN/PEN-2 is a multipass membrane gamma-secretase subunit with ER, cis-Golgi, cell-membrane, and general endomembrane localization evidence. |
| GO:0005886 plasma membrane | TAS Reactome:R-NUL-2197556 | ACCEPT | Summary: This membrane or endomembrane location is consistent with PSENEN/PEN-2 as a multipass gamma-secretase subunit in ER, Golgi, cell-membrane, and substrate-processing compartments. Reason: PSENEN/PEN-2 is a multipass membrane gamma-secretase subunit with ER, cis-Golgi, cell-membrane, and general endomembrane localization evidence. |
| GO:0005886 plasma membrane | TAS Reactome:R-NUL-9604300 | ACCEPT | Summary: This membrane or endomembrane location is consistent with PSENEN/PEN-2 as a multipass gamma-secretase subunit in ER, Golgi, cell-membrane, and substrate-processing compartments. Reason: PSENEN/PEN-2 is a multipass membrane gamma-secretase subunit with ER, cis-Golgi, cell-membrane, and general endomembrane localization evidence. |
| 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 PSENEN/PEN-2 as a multipass gamma-secretase subunit in ER, Golgi, cell-membrane, and substrate-processing compartments. Reason: PSENEN/PEN-2 is a multipass membrane gamma-secretase subunit with ER, cis-Golgi, cell-membrane, and general endomembrane localization evidence. |
| 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 PSENEN/PEN-2 as a multipass gamma-secretase subunit in ER, Golgi, cell-membrane, and substrate-processing compartments. Reason: PSENEN/PEN-2 is a multipass membrane gamma-secretase subunit with ER, cis-Golgi, cell-membrane, and general endomembrane localization evidence. |
| 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 PSENEN process label. Reason: Use intramembrane substrate-processing terms rather than ectodomain proteolysis for the PSENEN-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: PSENEN supports gamma-secretase-dependent Notch receptor processing through its role in complex maturation and activity. Reason: The term aligns with PSENEN/PEN-2 function as an essential non-catalytic gamma-secretase subunit that promotes presenilin maturation, complex stability, trafficking, and APP/Notch substrate processing. |
| GO:0016485 protein processing | IDA PMID:15274632 Purification and characterization of the human gamma-secreta... | ACCEPT | Summary: This captures regulated membrane-substrate processing by the PSENEN-containing gamma-secretase complex. Reason: The term aligns with PSENEN/PEN-2 function as an essential non-catalytic gamma-secretase subunit that promotes presenilin maturation, complex stability, trafficking, and APP/Notch substrate processing. |
| GO:0042987 amyloid precursor protein catabolic process | TAS PMID:15274632 Purification and characterization of the human gamma-secreta... | ACCEPT | Summary: PSENEN-containing gamma-secretase participates in APP processing and amyloid-beta-related product formation. Reason: The term aligns with PSENEN/PEN-2 function as an essential non-catalytic gamma-secretase subunit that promotes presenilin maturation, complex stability, trafficking, and APP/Notch substrate processing. |
Loading supporting contentβ¦
Download this section (compressed HTML)Q: How should GO represent PEN-2 promotion of presenilin endoproteolysis, complex stability, and trafficking without implying that PSENEN is the catalytic protease?
Suggested experts: GO molecular-function curators, gamma-secretase structure-function experts
Q: Which PSENEN energy-stress/V-ATPase/AMPK/TORC1 activities are direct human PEN-2 functions versus orthology-based or drug-response context?
Suggested experts: AMPK signaling experts, gamma-secretase complex experts
Experiment: Use endogenous PSENEN perturbation and rescue in human neural and epithelial cells to measure presenilin endoproteolysis, complex assembly, localization, and APP/Notch substrate cleavage side by side.
Hypothesis: PEN-2 primarily controls gamma-secretase activity by promoting presenilin maturation plus complex stability and trafficking rather than by acting as an independent protease.
Type: endogenous rescue and gamma-secretase maturation assay
Experiment: Test PSENEN-dependent metformin/V-ATPase/AMPK/TORC1 signaling in human cells with gamma-secretase catalytic inhibition and presenilin-complex assembly mutants.
Hypothesis: The reported energy-stress role of PEN-2 is separable from the canonical gamma-secretase substrate-processing role.
Type: separation-of-function energy-stress signaling assay
Loading supporting contentβ¦
Download this section (compressed HTML)Loading supporting contentβ¦
Download this section (compressed HTML)