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 γ-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 γ-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 γ-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 γ-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 γ-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 γ-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 γ-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 γ-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 γ-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 γ-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 γ-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 γ-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.
|
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
just deep-research-falcon human PSENEN --fallback perplexity-lite timed out after 180 seconds with no generated research artifact, so this manual review uses cached UniProt, GOA, and publication evidence.protein binding and broad enzyme binding annotations are less informative than complex membership and endopeptidase-activator/contribution terms. I marked generic protein binding as over-annotated and kept enzyme binding as non-core.The second-pass audit added manual reference_review metadata for PEN-2/PSENEN papers supporting integral gamma-secretase complex membership, presenilin endoproteolysis, complex stability, and purified/structural complex composition. No annotation action changes were needed: PSENEN remains curated as a small non-catalytic gamma-secretase subunit required for presenilin maturation and complex activity, while broad stress-response transfers remain non-core.
id: Q9NZ42
gene_symbol: PSENEN
product_type: PROTEIN
status: COMPLETE
taxon:
id: NCBITaxon:9606
label: Homo sapiens
description: '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.'
existing_annotations:
- term:
id: GO:0007220
label: Notch receptor processing
evidence_type: IBA
original_reference_id: GO_REF:0000033
qualifier: involved_in
review:
summary: PSENEN supports gamma-secretase-dependent Notch receptor processing through
its role in complex maturation and activity.
action: ACCEPT
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.
- term:
id: GO:0070765
label: gamma-secretase complex
evidence_type: IBA
original_reference_id: GO_REF:0000033
qualifier: part_of
review:
summary: PSENEN/PEN-2 is an integral subunit of the four-component gamma-secretase
complex with presenilin, nicastrin, and APH1.
action: ACCEPT
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.
- term:
id: GO:0005789
label: endoplasmic reticulum membrane
evidence_type: IEA
original_reference_id: GO_REF:0000044
qualifier: located_in
review:
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.
action: ACCEPT
reason: PSENEN/PEN-2 is a multipass membrane gamma-secretase subunit with ER,
cis-Golgi, cell-membrane, and general endomembrane localization evidence.
- term:
id: GO:0005886
label: plasma membrane
evidence_type: IEA
original_reference_id: GO_REF:0000044
qualifier: located_in
review:
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.
action: ACCEPT
reason: PSENEN/PEN-2 is a multipass membrane gamma-secretase subunit with ER,
cis-Golgi, cell-membrane, and general endomembrane localization evidence.
- term:
id: GO:0016020
label: membrane
evidence_type: IEA
original_reference_id: GO_REF:0000044
qualifier: located_in
review:
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.
action: ACCEPT
reason: PSENEN/PEN-2 is a multipass membrane gamma-secretase subunit with ER,
cis-Golgi, cell-membrane, and general endomembrane localization evidence.
- term:
id: GO:0032580
label: Golgi cisterna membrane
evidence_type: IEA
original_reference_id: GO_REF:0000044
qualifier: located_in
review:
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.
action: ACCEPT
reason: PSENEN/PEN-2 is a multipass membrane gamma-secretase subunit with ER,
cis-Golgi, cell-membrane, and general endomembrane localization evidence.
- term:
id: GO:0005515
label: protein binding
evidence_type: IPI
original_reference_id: PMID:15322109
qualifier: enables
review:
summary: The interaction evidence is compatible with PSENEN complex/substrate
associations, but generic protein binding is not an informative molecular function
for this gene.
action: MARK_AS_OVER_ANNOTATED
reason: Prefer gamma-secretase complex membership and
endopeptidase-activator/contribution terms over broad protein-binding annotations.
- term:
id: GO:0005515
label: protein binding
evidence_type: IPI
original_reference_id: PMID:16641999
qualifier: enables
review:
summary: The interaction evidence is compatible with PSENEN complex/substrate
associations, but generic protein binding is not an informative molecular function
for this gene.
action: MARK_AS_OVER_ANNOTATED
reason: Prefer gamma-secretase complex membership and
endopeptidase-activator/contribution terms over broad protein-binding annotations.
- term:
id: GO:0005515
label: protein binding
evidence_type: IPI
original_reference_id: PMID:18201567
qualifier: enables
review:
summary: The interaction evidence is compatible with PSENEN complex/substrate
associations, but generic protein binding is not an informative molecular function
for this gene.
action: MARK_AS_OVER_ANNOTATED
reason: Prefer gamma-secretase complex membership and
endopeptidase-activator/contribution terms over broad protein-binding annotations.
- term:
id: GO:0005515
label: protein binding
evidence_type: IPI
original_reference_id: PMID:23685131
qualifier: enables
review:
summary: The interaction evidence is compatible with PSENEN complex/substrate
associations, but generic protein binding is not an informative molecular function
for this gene.
action: MARK_AS_OVER_ANNOTATED
reason: Prefer gamma-secretase complex membership and
endopeptidase-activator/contribution terms over broad protein-binding annotations.
- term:
id: GO:0005515
label: protein binding
evidence_type: IPI
original_reference_id: PMID:30559186
qualifier: enables
review:
summary: The interaction evidence is compatible with PSENEN complex/substrate
associations, but generic protein binding is not an informative molecular function
for this gene.
action: MARK_AS_OVER_ANNOTATED
reason: Prefer gamma-secretase complex membership and
endopeptidase-activator/contribution terms over broad protein-binding annotations.
- term:
id: GO:0005515
label: protein binding
evidence_type: IPI
original_reference_id: PMID:32296183
qualifier: enables
review:
summary: The interaction evidence is compatible with PSENEN complex/substrate
associations, but generic protein binding is not an informative molecular function
for this gene.
action: MARK_AS_OVER_ANNOTATED
reason: Prefer gamma-secretase complex membership and
endopeptidase-activator/contribution terms over broad protein-binding annotations.
- term:
id: GO:0005515
label: protein binding
evidence_type: IPI
original_reference_id: PMID:32814053
qualifier: enables
review:
summary: The interaction evidence is compatible with PSENEN complex/substrate
associations, but generic protein binding is not an informative molecular function
for this gene.
action: MARK_AS_OVER_ANNOTATED
reason: Prefer gamma-secretase complex membership and
endopeptidase-activator/contribution terms over broad protein-binding annotations.
- term:
id: GO:0016485
label: protein processing
evidence_type: IEA
original_reference_id: GO_REF:0000107
qualifier: involved_in
review:
summary: This captures regulated membrane-substrate processing by the
PSENEN-containing gamma-secretase complex.
action: ACCEPT
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.
- term:
id: GO:0042149
label: cellular response to glucose starvation
evidence_type: IEA
original_reference_id: GO_REF:0000107
qualifier: involved_in
review:
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.
action: KEEP_AS_NON_CORE
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.
- term:
id: GO:0042734
label: presynaptic membrane
evidence_type: IEA
original_reference_id: GO_REF:0000107
qualifier: is_active_in
review:
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.
action: KEEP_AS_NON_CORE
reason: Retain as non-core because it may reflect a real context-specific
localization without defining the primary PSENEN function.
- term:
id: GO:0061133
label: endopeptidase activator activity
evidence_type: IEA
original_reference_id: GO_REF:0000107
qualifier: enables
review:
summary: PSENEN/PEN-2 promotes presenilin endoproteolysis and gamma-secretase
proteolytic activity, supporting an endopeptidase-activating role at the complex
level.
action: ACCEPT
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.
- term:
id: GO:0070765
label: gamma-secretase complex
evidence_type: IEA
original_reference_id: GO_REF:0000107
qualifier: part_of
review:
summary: PSENEN/PEN-2 is an integral subunit of the four-component gamma-secretase
complex with presenilin, nicastrin, and APH1.
action: ACCEPT
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.
- term:
id: GO:0140678
label: molecular function inhibitor activity
evidence_type: IEA
original_reference_id: GO_REF:0000107
qualifier: enables
review:
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.
action: KEEP_AS_NON_CORE
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.
- term:
id: GO:1904262
label: negative regulation of TORC1 signaling
evidence_type: IEA
original_reference_id: GO_REF:0000107
qualifier: involved_in
review:
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.
action: KEEP_AS_NON_CORE
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.
- term:
id: GO:0042149
label: cellular response to glucose starvation
evidence_type: ISS
original_reference_id: GO_REF:0000024
qualifier: involved_in
review:
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.
action: KEEP_AS_NON_CORE
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.
- term:
id: GO:0140678
label: molecular function inhibitor activity
evidence_type: ISS
original_reference_id: GO_REF:0000024
qualifier: enables
review:
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.
action: KEEP_AS_NON_CORE
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.
- term:
id: GO:1904262
label: negative regulation of TORC1 signaling
evidence_type: ISS
original_reference_id: GO_REF:0000024
qualifier: involved_in
review:
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.
action: KEEP_AS_NON_CORE
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.
- term:
id: GO:0005789
label: endoplasmic reticulum membrane
evidence_type: NAS
original_reference_id: PMID:15274632
qualifier: located_in
review:
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.
action: ACCEPT
reason: PSENEN/PEN-2 is a multipass membrane gamma-secretase subunit with ER,
cis-Golgi, cell-membrane, and general endomembrane localization evidence.
- term:
id: GO:0005886
label: plasma membrane
evidence_type: IDA
original_reference_id: PMID:15274632
qualifier: located_in
review:
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.
action: ACCEPT
reason: PSENEN/PEN-2 is a multipass membrane gamma-secretase subunit with ER,
cis-Golgi, cell-membrane, and general endomembrane localization evidence.
- term:
id: GO:0007220
label: Notch receptor processing
evidence_type: NAS
original_reference_id: PMID:10206645
qualifier: involved_in
review:
summary: PSENEN supports gamma-secretase-dependent Notch receptor processing through
its role in complex maturation and activity.
action: ACCEPT
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.
- term:
id: GO:0031293
label: membrane protein intracellular domain proteolysis
evidence_type: IDA
original_reference_id: PMID:15274632
qualifier: involved_in
review:
summary: This captures regulated membrane-substrate processing by the
PSENEN-containing gamma-secretase complex.
action: ACCEPT
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.
- term:
id: GO:0042987
label: amyloid precursor protein catabolic process
evidence_type: IDA
original_reference_id: PMID:15274632
qualifier: involved_in
review:
summary: PSENEN-containing gamma-secretase participates in APP processing and
amyloid-beta-related product formation.
action: ACCEPT
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.
- term:
id: GO:0070765
label: gamma-secretase complex
evidence_type: IPI
original_reference_id: PMID:26280335
qualifier: part_of
review:
summary: PSENEN/PEN-2 is an integral subunit of the four-component gamma-secretase
complex with presenilin, nicastrin, and APH1.
action: ACCEPT
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.
- term:
id: GO:0000139
label: Golgi membrane
evidence_type: NAS
original_reference_id: PMID:15274632
qualifier: located_in
review:
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.
action: ACCEPT
reason: PSENEN/PEN-2 is a multipass membrane gamma-secretase subunit with ER,
cis-Golgi, cell-membrane, and general endomembrane localization evidence.
- term:
id: GO:0016485
label: protein processing
evidence_type: IMP
original_reference_id: PMID:12522139
qualifier: involved_in
review:
summary: This captures regulated membrane-substrate processing by the
PSENEN-containing gamma-secretase complex.
action: ACCEPT
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.
- term:
id: GO:0005789
label: endoplasmic reticulum membrane
evidence_type: EXP
original_reference_id: PMID:12522139
qualifier: located_in
review:
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.
action: ACCEPT
reason: PSENEN/PEN-2 is a multipass membrane gamma-secretase subunit with ER,
cis-Golgi, cell-membrane, and general endomembrane localization evidence.
- term:
id: GO:0005789
label: endoplasmic reticulum membrane
evidence_type: EXP
original_reference_id: PMID:12639958
qualifier: located_in
review:
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.
action: ACCEPT
reason: PSENEN/PEN-2 is a multipass membrane gamma-secretase subunit with ER,
cis-Golgi, cell-membrane, and general endomembrane localization evidence.
- term:
id: GO:0005886
label: plasma membrane
evidence_type: EXP
original_reference_id: PMID:24941111
qualifier: located_in
review:
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.
action: ACCEPT
reason: PSENEN/PEN-2 is a multipass membrane gamma-secretase subunit with ER,
cis-Golgi, cell-membrane, and general endomembrane localization evidence.
- term:
id: GO:0016020
label: membrane
evidence_type: EXP
original_reference_id: PMID:12198112
qualifier: located_in
review:
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.
action: ACCEPT
reason: PSENEN/PEN-2 is a multipass membrane gamma-secretase subunit with ER,
cis-Golgi, cell-membrane, and general endomembrane localization evidence.
- term:
id: GO:0016485
label: protein processing
evidence_type: IMP
original_reference_id: PMID:12660785
qualifier: involved_in
review:
summary: This captures regulated membrane-substrate processing by the
PSENEN-containing gamma-secretase complex.
action: ACCEPT
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.
- term:
id: GO:0016485
label: protein processing
evidence_type: IGI
original_reference_id: PMID:12763021
qualifier: involved_in
review:
summary: This captures regulated membrane-substrate processing by the
PSENEN-containing gamma-secretase complex.
action: ACCEPT
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.
- term:
id: GO:0019899
label: enzyme binding
evidence_type: IPI
original_reference_id: PMID:12522139
qualifier: enables
review:
summary: Broad enzyme binding is plausible for a PSENEN gamma-secretase subunit but
is less informative than complex membership and activator/contribution terms.
action: KEEP_AS_NON_CORE
reason: Retain as non-core because it may reflect real interaction with presenilin
enzyme complexes without defining the primary PSENEN molecular role.
- term:
id: GO:0034205
label: amyloid-beta formation
evidence_type: IGI
original_reference_id: PMID:12763021
qualifier: involved_in
review:
summary: PSENEN-containing gamma-secretase participates in APP processing and
amyloid-beta-related product formation.
action: ACCEPT
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.
- term:
id: GO:0042987
label: amyloid precursor protein catabolic process
evidence_type: IMP
original_reference_id: PMID:12660785
qualifier: involved_in
review:
summary: PSENEN-containing gamma-secretase participates in APP processing and
amyloid-beta-related product formation.
action: ACCEPT
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.
- term:
id: GO:0042987
label: amyloid precursor protein catabolic process
evidence_type: IGI
original_reference_id: PMID:12763021
qualifier: involved_in
review:
summary: PSENEN-containing gamma-secretase participates in APP processing and
amyloid-beta-related product formation.
action: ACCEPT
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.
- term:
id: GO:0061133
label: endopeptidase activator activity
evidence_type: IMP
original_reference_id: PMID:12522139
qualifier: enables
review:
summary: PSENEN/PEN-2 promotes presenilin endoproteolysis and gamma-secretase
proteolytic activity, supporting an endopeptidase-activating role at the complex
level.
action: ACCEPT
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.
- term:
id: GO:0061133
label: endopeptidase activator activity
evidence_type: IGI
original_reference_id: PMID:12763021
qualifier: enables
review:
summary: PSENEN/PEN-2 promotes presenilin endoproteolysis and gamma-secretase
proteolytic activity, supporting an endopeptidase-activating role at the complex
level.
action: ACCEPT
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.
- term:
id: GO:0070765
label: gamma-secretase complex
evidence_type: IGI
original_reference_id: PMID:12763021
qualifier: part_of
review:
summary: PSENEN/PEN-2 is an integral subunit of the four-component gamma-secretase
complex with presenilin, nicastrin, and APH1.
action: ACCEPT
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.
- term:
id: GO:0010950
label: positive regulation of endopeptidase activity
evidence_type: IMP
original_reference_id: PMID:12660785
qualifier: involved_in
review:
summary: PSENEN/PEN-2 promotes presenilin endoproteolysis and gamma-secretase
proteolytic activity, supporting an endopeptidase-activating role at the complex
level.
action: ACCEPT
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.
- term:
id: GO:0034205
label: amyloid-beta formation
evidence_type: IMP
original_reference_id: PMID:12660785
qualifier: involved_in
review:
summary: PSENEN-containing gamma-secretase participates in APP processing and
amyloid-beta-related product formation.
action: ACCEPT
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.
- term:
id: GO:0010008
label: endosome membrane
evidence_type: TAS
original_reference_id: Reactome:R-HSA-9010096
qualifier: located_in
review:
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.
action: ACCEPT
reason: PSENEN/PEN-2 is a multipass membrane gamma-secretase subunit with ER,
cis-Golgi, cell-membrane, and general endomembrane localization evidence.
- term:
id: GO:0016020
label: membrane
evidence_type: IDA
original_reference_id: PMID:25043039
qualifier: located_in
review:
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.
action: ACCEPT
reason: PSENEN/PEN-2 is a multipass membrane gamma-secretase subunit with ER,
cis-Golgi, cell-membrane, and general endomembrane localization evidence.
- term:
id: GO:0016020
label: membrane
evidence_type: IDA
original_reference_id: PMID:26280335
qualifier: located_in
review:
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.
action: ACCEPT
reason: PSENEN/PEN-2 is a multipass membrane gamma-secretase subunit with ER,
cis-Golgi, cell-membrane, and general endomembrane localization evidence.
- term:
id: GO:0034205
label: amyloid-beta formation
evidence_type: IMP
original_reference_id: PMID:25043039
qualifier: involved_in
review:
summary: PSENEN-containing gamma-secretase participates in APP processing and
amyloid-beta-related product formation.
action: ACCEPT
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.
- term:
id: GO:0034205
label: amyloid-beta formation
evidence_type: IMP
original_reference_id: PMID:26280335
qualifier: involved_in
review:
summary: PSENEN-containing gamma-secretase participates in APP processing and
amyloid-beta-related product formation.
action: ACCEPT
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.
- term:
id: GO:0042982
label: amyloid precursor protein metabolic process
evidence_type: IDA
original_reference_id: PMID:25043039
qualifier: involved_in
review:
summary: PSENEN-containing gamma-secretase participates in APP processing and
amyloid-beta-related product formation.
action: ACCEPT
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.
- term:
id: GO:0042982
label: amyloid precursor protein metabolic process
evidence_type: IDA
original_reference_id: PMID:26280335
qualifier: involved_in
review:
summary: PSENEN-containing gamma-secretase participates in APP processing and
amyloid-beta-related product formation.
action: ACCEPT
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.
- term:
id: GO:0070765
label: gamma-secretase complex
evidence_type: IDA
original_reference_id: PMID:25043039
qualifier: part_of
review:
summary: PSENEN/PEN-2 is an integral subunit of the four-component gamma-secretase
complex with presenilin, nicastrin, and APH1.
action: ACCEPT
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.
- term:
id: GO:0070765
label: gamma-secretase complex
evidence_type: IDA
original_reference_id: PMID:26280335
qualifier: part_of
review:
summary: PSENEN/PEN-2 is an integral subunit of the four-component gamma-secretase
complex with presenilin, nicastrin, and APH1.
action: ACCEPT
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.
- term:
id: GO:0005886
label: plasma membrane
evidence_type: TAS
original_reference_id: Reactome:R-HSA-1251997
qualifier: located_in
review:
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.
action: ACCEPT
reason: PSENEN/PEN-2 is a multipass membrane gamma-secretase subunit with ER,
cis-Golgi, cell-membrane, and general endomembrane localization evidence.
- term:
id: GO:0005886
label: plasma membrane
evidence_type: TAS
original_reference_id: Reactome:R-HSA-193682
qualifier: located_in
review:
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.
action: ACCEPT
reason: PSENEN/PEN-2 is a multipass membrane gamma-secretase subunit with ER,
cis-Golgi, cell-membrane, and general endomembrane localization evidence.
- term:
id: GO:0005886
label: plasma membrane
evidence_type: TAS
original_reference_id: Reactome:R-HSA-205112
qualifier: located_in
review:
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.
action: ACCEPT
reason: PSENEN/PEN-2 is a multipass membrane gamma-secretase subunit with ER,
cis-Golgi, cell-membrane, and general endomembrane localization evidence.
- term:
id: GO:0005886
label: plasma membrane
evidence_type: TAS
original_reference_id: Reactome:R-HSA-2220988
qualifier: located_in
review:
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.
action: ACCEPT
reason: PSENEN/PEN-2 is a multipass membrane gamma-secretase subunit with ER,
cis-Golgi, cell-membrane, and general endomembrane localization evidence.
- term:
id: GO:0005886
label: plasma membrane
evidence_type: TAS
original_reference_id: Reactome:R-HSA-3928656
qualifier: located_in
review:
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.
action: ACCEPT
reason: PSENEN/PEN-2 is a multipass membrane gamma-secretase subunit with ER,
cis-Golgi, cell-membrane, and general endomembrane localization evidence.
- term:
id: GO:0005886
label: plasma membrane
evidence_type: TAS
original_reference_id: Reactome:R-HSA-9013361
qualifier: located_in
review:
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.
action: ACCEPT
reason: PSENEN/PEN-2 is a multipass membrane gamma-secretase subunit with ER,
cis-Golgi, cell-membrane, and general endomembrane localization evidence.
- term:
id: GO:0005886
label: plasma membrane
evidence_type: TAS
original_reference_id: Reactome:R-HSA-9017817
qualifier: located_in
review:
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.
action: ACCEPT
reason: PSENEN/PEN-2 is a multipass membrane gamma-secretase subunit with ER,
cis-Golgi, cell-membrane, and general endomembrane localization evidence.
- term:
id: GO:0005886
label: plasma membrane
evidence_type: TAS
original_reference_id: Reactome:R-HSA-9839376
qualifier: located_in
review:
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.
action: ACCEPT
reason: PSENEN/PEN-2 is a multipass membrane gamma-secretase subunit with ER,
cis-Golgi, cell-membrane, and general endomembrane localization evidence.
- term:
id: GO:0005886
label: plasma membrane
evidence_type: TAS
original_reference_id: Reactome:R-NUL-2197556
qualifier: located_in
review:
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.
action: ACCEPT
reason: PSENEN/PEN-2 is a multipass membrane gamma-secretase subunit with ER,
cis-Golgi, cell-membrane, and general endomembrane localization evidence.
- term:
id: GO:0005886
label: plasma membrane
evidence_type: TAS
original_reference_id: Reactome:R-NUL-9604300
qualifier: located_in
review:
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.
action: ACCEPT
reason: PSENEN/PEN-2 is a multipass membrane gamma-secretase subunit with ER,
cis-Golgi, cell-membrane, and general endomembrane localization evidence.
- term:
id: GO:0005783
label: endoplasmic reticulum
evidence_type: IDA
original_reference_id: PMID:15274632
qualifier: located_in
review:
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.
action: ACCEPT
reason: PSENEN/PEN-2 is a multipass membrane gamma-secretase subunit with ER,
cis-Golgi, cell-membrane, and general endomembrane localization evidence.
- term:
id: GO:0005794
label: Golgi apparatus
evidence_type: IDA
original_reference_id: PMID:15274632
qualifier: located_in
review:
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.
action: ACCEPT
reason: PSENEN/PEN-2 is a multipass membrane gamma-secretase subunit with ER,
cis-Golgi, cell-membrane, and general endomembrane localization evidence.
- term:
id: GO:0006509
label: membrane protein ectodomain proteolysis
evidence_type: IDA
original_reference_id: PMID:15274632
qualifier: involved_in
review:
summary: Gamma-secretase acts after ectodomain shedding and performs intramembrane
cleavage; ectodomain proteolysis is not the best PSENEN process label.
action: MODIFY
proposed_replacement_terms:
- id: GO:0031293
label: membrane protein intracellular domain proteolysis
- id: GO:0016485
label: protein processing
reason: Use intramembrane substrate-processing terms rather than ectodomain
proteolysis for the PSENEN-containing gamma-secretase complex.
- term:
id: GO:0007220
label: Notch receptor processing
evidence_type: TAS
original_reference_id: PMID:15274632
qualifier: involved_in
review:
summary: PSENEN supports gamma-secretase-dependent Notch receptor processing through
its role in complex maturation and activity.
action: ACCEPT
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.
- term:
id: GO:0016485
label: protein processing
evidence_type: IDA
original_reference_id: PMID:15274632
qualifier: involved_in
review:
summary: This captures regulated membrane-substrate processing by the
PSENEN-containing gamma-secretase complex.
action: ACCEPT
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.
- term:
id: GO:0042987
label: amyloid precursor protein catabolic process
evidence_type: TAS
original_reference_id: PMID:15274632
qualifier: involved_in
review:
summary: PSENEN-containing gamma-secretase participates in APP processing and
amyloid-beta-related product formation.
action: ACCEPT
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.
references:
- id: GO_REF:0000024
title: Manual transfer of experimentally-verified manual GO annotation data to
orthologs by curator judgment of sequence similarity
findings: []
- id: GO_REF:0000033
title: Annotation inferences using phylogenetic trees
findings: []
- id: GO_REF:0000044
title: Gene Ontology annotation based on UniProtKB/Swiss-Prot Subcellular Location
vocabulary mapping, accompanied by conservative changes to GO terms applied by
UniProt
findings: []
- id: GO_REF:0000107
title: Automatic transfer of experimentally verified manual GO annotation data to
orthologs using Ensembl Compara
findings: []
- id: PMID:10206645
title: A presenilin-1-dependent gamma-secretase-like protease mediates release of
Notch intracellular domain.
findings: []
- id: PMID:12198112
title: PEN-2 is an integral component of the gamma-secretase complex required for
coordinated expression of presenilin and nicastrin.
findings: []
reference_review:
relevance: HIGH
correctness: VERIFIED
review_notes: Cached abstract directly identifies PEN-2 as an integral
gamma-secretase component required for coordinated presenilin/nicastrin
complex expression.
- id: PMID:12522139
title: PEN-2 and APH-1 coordinately regulate proteolytic processing of presenilin 1.
findings: []
reference_review:
relevance: HIGH
correctness: VERIFIED
review_notes: Cached abstract supports PEN-2 interaction with presenilin 1
holoprotein and a direct role in presenilin endoproteolysis.
- id: PMID:12639958
title: Membrane topology of gamma-secretase component PEN-2.
findings: []
- id: PMID:12660785
title: The role of presenilin cofactors in the gamma-secretase complex.
findings: []
reference_review:
relevance: HIGH
correctness: VERIFIED
review_notes: Cached abstract supports PEN-2 requirement for presenilin
endoproteolysis and conferring gamma-secretase activity to the complex.
- id: PMID:12763021
title: APH1, PEN2, and Nicastrin increase Abeta levels and gamma-secretase activity.
findings: []
reference_review:
relevance: HIGH
correctness: VERIFIED
review_notes: Cached abstract includes PEN2 as a gamma-secretase complex
component and supports its contribution to Abeta levels and
gamma-secretase activity.
- id: PMID:15274632
title: Purification and characterization of the human gamma-secretase complex.
findings: []
reference_review:
relevance: HIGH
correctness: VERIFIED
review_notes: Cached abstract identifies Pen-2 with presenilin, nicastrin,
and APH-1 as components of purified active human gamma-secretase.
- id: PMID:15322109
title: Both the sequence and length of the C terminus of PEN-2 are critical for
intermolecular interactions and function of presenilin complexes.
findings: []
- id: PMID:16641999
title: TMP21 is a presenilin complex component that modulates gamma-secretase but not
epsilon-secretase activity.
findings: []
- id: PMID:18201567
title: Cellular localization of Nicastrin affects amyloid beta species production.
findings: []
- id: PMID:23685131
title: Ferritin light chain interacts with PEN-2 and affects γ-secretase activity.
findings: []
- id: PMID:24941111
title: Pen-2 is essential for γ-secretase complex stability and trafficking but
partially dispensable for endoproteolysis.
findings: []
- id: PMID:25043039
title: Three-dimensional structure of human γ-secretase.
findings: []
reference_review:
relevance: HIGH
correctness: VERIFIED
review_notes: Cached full-text record supports the four-subunit human
gamma-secretase structural model containing Pen-2/PSENEN.
- id: PMID:26280335
title: An atomic structure of human γ-secretase.
findings: []
reference_review:
relevance: HIGH
correctness: VERIFIED
review_notes: Cached full-text record supports atomic gamma-secretase
structure and membrane-embedded complex organization including PSENEN.
- id: PMID:30559186
title: Bax inhibitor 1 is a γ-secretase-independent presenilin-binding protein.
findings: []
- id: PMID:32296183
title: A reference map of the human binary protein interactome.
findings: []
- id: PMID:32814053
title: Interactome Mapping Provides a Network of Neurodegenerative Disease Proteins
and Uncovers Widespread Protein Aggregation in Affected Brains.
findings: []
- id: Reactome:R-HSA-1251997
title: Cleavage of ERBB4m80 by gamma-scretase complex
findings: []
- id: Reactome:R-HSA-193682
title: gamma-secretase cleaves the p75NTR transmembrane domain
findings: []
- id: Reactome:R-HSA-205112
title: gamma-secretase cleaves p75NTR, releasing NRIF and TRAF6
findings: []
- id: Reactome:R-HSA-2220988
title: NEXT1 PEST domain mutants are cleaved to produce NICD1 PEST domain mutants
findings: []
- id: Reactome:R-HSA-3928656
title: gamma-secretase cleaves EPHB2
findings: []
- id: Reactome:R-HSA-9010096
title: Gamma-secretase cleaves APP(672-770) to APP(672-711) and APP(672-713)
findings: []
- id: Reactome:R-HSA-9013361
title: NEXT3 is cleaved to produce NICD3
findings: []
- id: Reactome:R-HSA-9017817
title: Gamma-secretase cleaves YBX1:NOTCH3
findings: []
- id: Reactome:R-HSA-9839376
title: TGFBR3(784-851) degradation
findings: []
- id: Reactome:R-NUL-2197556
title: Gamma-secretase complex cleaves mNEXT2
findings: []
- id: Reactome:R-NUL-9604300
title: Gamma-secretase cleaves Notch4
findings: []
core_functions:
- molecular_function:
id: GO:0061133
label: endopeptidase activator activity
contributes_to_molecular_function:
id: GO:0042500
label: aspartic endopeptidase activity, intramembrane cleaving
description: PSENEN/PEN-2 is an essential non-catalytic gamma-secretase subunit that
promotes presenilin endoproteolysis, stabilizes and traffics the assembled complex,
and enables presenilin-dependent intramembrane cleavage of APP, Notch receptors, and
related membrane substrates.
directly_involved_in:
- id: GO:0031293
label: membrane protein intracellular domain proteolysis
- id: GO:0007220
label: Notch receptor processing
- id: GO:0042987
label: amyloid precursor protein catabolic process
- id: GO:0034205
label: amyloid-beta formation
- id: GO:0016485
label: protein processing
- id: GO:0010950
label: positive regulation of endopeptidase activity
locations:
- id: GO:0005789
label: endoplasmic reticulum membrane
- id: GO:0032580
label: Golgi cisterna membrane
- id: GO:0000139
label: Golgi membrane
- id: GO:0005886
label: plasma membrane
- id: GO:0010008
label: endosome membrane
- id: GO:0016020
label: membrane
in_complex:
id: GO:0070765
label: gamma-secretase complex
supported_by:
- reference_id: PMID:12198112
supporting_text: a critical component of PS1/gamma-secretase and PS2/gamma-secretase
complexes
- reference_id: PMID:12198112
supporting_text: PEN-2 is an integral gamma-secretase complex component
- reference_id: PMID:12522139
supporting_text: Down-regulation of PEN-2 expression by small interfering RNA
(siRNA) abolishes the endoproteolysis of PS1
- reference_id: PMID:12660785
supporting_text: PEN-2 is required for endoproteolytic processing of presenilin and
conferring gamma-secretase activity to the complex
- reference_id: PMID:24941111
supporting_text: Pen-2 may also stabilize the complex prior to PS1 endoproteolysis,
allowing time for full assembly and proper trafficking
- reference_id: PMID:25043039
supporting_text: 'The γ-secretase complex consists of four components: presenilin, Pen-2,
Aph-1, and Nicastrin'
proposed_new_terms: []
suggested_questions:
- question: How should GO represent PEN-2 promotion of presenilin endoproteolysis,
complex stability, and trafficking without implying that PSENEN is the catalytic
protease?
experts:
- GO molecular-function curators
- gamma-secretase structure-function experts
- question: Which PSENEN energy-stress/V-ATPase/AMPK/TORC1 activities are direct human
PEN-2 functions versus orthology-based or drug-response context?
experts:
- AMPK signaling experts
- gamma-secretase complex experts
suggested_experiments:
- description: 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.
experiment_type: endogenous rescue and gamma-secretase maturation assay
- description: 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.
experiment_type: separation-of-function energy-stress signaling assay