APH1B encodes gamma-secretase subunit APH-1B, a multipass membrane protein and non-catalytic APH-1 paralog incorporated into a subset of gamma-secretase complexes. Together with a presenilin catalytic subunit, nicastrin, and PSENEN/PEN-2, APH1B supports complex assembly or stabilization and contributes to regulated intramembrane proteolysis of membrane substrates including APP and Notch receptors. APH1B-containing complexes appear less abundant than APH1A-containing complexes and can differ in substrate preference depending on the presenilin/APH1 subunit combination.
| GO Term | Evidence | Action | Reason |
|---|---|---|---|
| GO:0070765 gamma-secretase complex | IBA GO_REF:0000033 | ACCEPT | Summary: APH1B is a non-catalytic APH-1 paralog that can substitute for APH1A in defined gamma-secretase complexes with presenilin, nicastrin, and PSENEN/PEN-2. Reason: The term aligns with APH1B function as a non-catalytic gamma-secretase subunit that supports a subset of presenilin-containing complexes and APP/Notch substrate processing. |
| GO:0034205 amyloid-beta formation | IBA GO_REF:0000033 | ACCEPT | Summary: APH1B-containing gamma-secretase complexes participate in APP cleavage and amyloid-beta-related product formation, with substrate effects depending on the presenilin/APH1 combination. Reason: The term aligns with APH1B function as a non-catalytic gamma-secretase subunit that supports a subset of presenilin-containing complexes and APP/Notch substrate processing. |
| GO:0016485 protein processing | IBA GO_REF:0000033 | ACCEPT | Summary: This captures gamma-secretase-dependent processing of membrane protein substrates by complexes that can include APH1B. Reason: The term aligns with APH1B function as a non-catalytic gamma-secretase subunit that supports a subset of presenilin-containing complexes and APP/Notch substrate processing. |
| GO:0030674 protein-macromolecule adaptor activity | IBA GO_REF:0000033 | ACCEPT | Summary: APH1B is best interpreted as a non-catalytic adaptor/assembly subunit within gamma-secretase complexes rather than as the catalytic protease. Reason: The term aligns with APH1B function as a non-catalytic gamma-secretase subunit that supports a subset of presenilin-containing complexes and APP/Notch substrate processing. |
| GO:0007220 Notch receptor processing | IBA GO_REF:0000033 | ACCEPT | Summary: APH1B-containing gamma-secretase complexes can support Notch receptor processing, although substrate preference varies by presenilin/APH1 combination. Reason: The term aligns with APH1B function as a non-catalytic gamma-secretase subunit that supports a subset of presenilin-containing complexes and APP/Notch substrate processing. |
| GO:0007219 Notch signaling pathway | IBA GO_REF:0000033 | ACCEPT | Summary: Notch signaling is a downstream pathway output of gamma-secretase-mediated Notch receptor processing. Reason: The term aligns with APH1B function as a non-catalytic gamma-secretase subunit that supports a subset of presenilin-containing complexes and APP/Notch substrate processing. |
| GO:0006508 proteolysis | IEA GO_REF:0000117 | MODIFY | Summary: Generic proteolysis is too broad for APH1B; the supported process is gamma-secretase-dependent intramembrane processing of membrane substrates. Reason: Replace the broad proteolysis term with regulated intramembrane substrate-processing terms supported for gamma-secretase. Proposed replacements: membrane protein intracellular domain proteolysis protein processing |
| GO:0016020 membrane | IEA GO_REF:0000120 | ACCEPT | Summary: This membrane or endomembrane location is consistent with APH1B as a multipass gamma-secretase subunit; cell-surface Aph-1 localization is also directly reported. Reason: APH1B is a multipass membrane protein in gamma-secretase complexes; membrane, cell-surface, and endomembrane locations are consistent with the curated biology. |
| GO:0016485 protein processing | IEA GO_REF:0000002 | ACCEPT | Summary: This captures gamma-secretase-dependent processing of membrane protein substrates by complexes that can include APH1B. Reason: The term aligns with APH1B function as a non-catalytic gamma-secretase subunit that supports a subset of presenilin-containing complexes and APP/Notch substrate processing. |
| GO:0070765 gamma-secretase complex | IEA GO_REF:0000117 | ACCEPT | Summary: APH1B is a non-catalytic APH-1 paralog that can substitute for APH1A in defined gamma-secretase complexes with presenilin, nicastrin, and PSENEN/PEN-2. Reason: The term aligns with APH1B function as a non-catalytic gamma-secretase subunit that supports a subset of presenilin-containing complexes and APP/Notch substrate processing. |
| GO:0005515 protein binding | IPI PMID:15715652 Aph-1 interacts at the cell surface with proteins in the act... | MARK AS OVER ANNOTATED | Summary: The interaction evidence is compatible with APH1B complex/substrate associations, but generic protein binding is not an informative molecular function for this gene. Reason: Prefer gamma-secretase complex membership and adaptor/activator terms over a broad protein-binding annotation. |
| GO:0005515 protein binding | IPI PMID:32296183 A reference map of the human binary protein interactome. | MARK AS OVER ANNOTATED | Summary: The interaction evidence is compatible with APH1B complex/substrate associations, but generic protein binding is not an informative molecular function for this gene. Reason: Prefer gamma-secretase complex membership and adaptor/activator terms over a broad protein-binding annotation. |
| GO:0005515 protein binding | IPI PMID:32814053 Interactome Mapping Provides a Network of Neurodegenerative ... | MARK AS OVER ANNOTATED | Summary: The interaction evidence is compatible with APH1B complex/substrate associations, but generic protein binding is not an informative molecular function for this gene. Reason: Prefer gamma-secretase complex membership and adaptor/activator terms over a broad protein-binding annotation. |
| 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 APH1B as a multipass gamma-secretase subunit; cell-surface Aph-1 localization is also directly reported. Reason: APH1B is a multipass membrane protein in gamma-secretase complexes; membrane, cell-surface, and endomembrane locations are consistent with the curated biology. |
| GO:0005789 endoplasmic reticulum membrane | NAS PMID:15274632 Purification and characterization of the human gamma-secreta... | ACCEPT | Summary: This membrane or endomembrane location is consistent with APH1B as a multipass gamma-secretase subunit; cell-surface Aph-1 localization is also directly reported. Reason: APH1B is a multipass membrane protein in gamma-secretase complexes; membrane, cell-surface, and endomembrane locations are consistent with the curated biology. |
| GO:0007220 Notch receptor processing | NAS PMID:10206645 A presenilin-1-dependent gamma-secretase-like protease media... | ACCEPT | Summary: APH1B-containing gamma-secretase complexes can support Notch receptor processing, although substrate preference varies by presenilin/APH1 combination. Reason: The term aligns with APH1B function as a non-catalytic gamma-secretase subunit that supports a subset of presenilin-containing complexes and APP/Notch substrate processing. |
| GO:0007220 Notch receptor processing | IDA PMID:27608597 Specific combinations of presenilins and Aph1s affect the su... | ACCEPT | Summary: APH1B-containing gamma-secretase complexes can support Notch receptor processing, although substrate preference varies by presenilin/APH1 combination. Reason: The term aligns with APH1B function as a non-catalytic gamma-secretase subunit that supports a subset of presenilin-containing complexes 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 gamma-secretase-dependent processing of membrane protein substrates by complexes that can include APH1B. Reason: The term aligns with APH1B function as a non-catalytic gamma-secretase subunit that supports a subset of presenilin-containing complexes and APP/Notch substrate processing. |
| GO:0016485 protein processing | IDA PMID:27608597 Specific combinations of presenilins and Aph1s affect the su... | ACCEPT | Summary: This captures gamma-secretase-dependent processing of membrane protein substrates by complexes that can include APH1B. Reason: The term aligns with APH1B function as a non-catalytic gamma-secretase subunit that supports a subset of presenilin-containing complexes and APP/Notch substrate processing. |
| GO:0030674 protein-macromolecule adaptor activity | IMP PMID:12297508 Mammalian APH-1 interacts with presenilin and nicastrin and ... | ACCEPT | Summary: APH1B is best interpreted as a non-catalytic adaptor/assembly subunit within gamma-secretase complexes rather than as the catalytic protease. Reason: The term aligns with APH1B function as a non-catalytic gamma-secretase subunit that supports a subset of presenilin-containing complexes and APP/Notch substrate processing. |
| GO:0034205 amyloid-beta formation | IGI PMID:12763021 APH1, PEN2, and Nicastrin increase Abeta levels and gamma-se... | ACCEPT | Summary: APH1B-containing gamma-secretase complexes participate in APP cleavage and amyloid-beta-related product formation, with substrate effects depending on the presenilin/APH1 combination. Reason: The term aligns with APH1B function as a non-catalytic gamma-secretase subunit that supports a subset of presenilin-containing complexes and APP/Notch substrate processing. |
| GO:0034205 amyloid-beta formation | IDA PMID:27608597 Specific combinations of presenilins and Aph1s affect the su... | ACCEPT | Summary: APH1B-containing gamma-secretase complexes participate in APP cleavage and amyloid-beta-related product formation, with substrate effects depending on the presenilin/APH1 combination. Reason: The term aligns with APH1B function as a non-catalytic gamma-secretase subunit that supports a subset of presenilin-containing complexes 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: APH1B-containing gamma-secretase complexes participate in APP cleavage and amyloid-beta-related product formation, with substrate effects depending on the presenilin/APH1 combination. Reason: The term aligns with APH1B function as a non-catalytic gamma-secretase subunit that supports a subset of presenilin-containing complexes and APP/Notch substrate processing. |
| GO:0042987 amyloid precursor protein catabolic process | IDA PMID:27608597 Specific combinations of presenilins and Aph1s affect the su... | ACCEPT | Summary: APH1B-containing gamma-secretase complexes participate in APP cleavage and amyloid-beta-related product formation, with substrate effects depending on the presenilin/APH1 combination. Reason: The term aligns with APH1B function as a non-catalytic gamma-secretase subunit that supports a subset of presenilin-containing complexes and APP/Notch substrate processing. |
| GO:0061133 endopeptidase activator activity | IMP PMID:12297508 Mammalian APH-1 interacts with presenilin and nicastrin and ... | ACCEPT | Summary: APH1B supports presenilin-containing gamma-secretase complex activity, consistent with a non-catalytic endopeptidase activator role at the complex level. Reason: The term aligns with APH1B function as a non-catalytic gamma-secretase subunit that supports a subset of presenilin-containing complexes 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: APH1B supports presenilin-containing gamma-secretase complex activity, consistent with a non-catalytic endopeptidase activator role at the complex level. Reason: The term aligns with APH1B function as a non-catalytic gamma-secretase subunit that supports a subset of presenilin-containing complexes and APP/Notch substrate processing. |
| GO:0070765 gamma-secretase complex | IDA PMID:12297508 Mammalian APH-1 interacts with presenilin and nicastrin and ... | ACCEPT | Summary: APH1B is a non-catalytic APH-1 paralog that can substitute for APH1A in defined gamma-secretase complexes with presenilin, nicastrin, and PSENEN/PEN-2. Reason: The term aligns with APH1B function as a non-catalytic gamma-secretase subunit that supports a subset of presenilin-containing complexes 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: APH1B is a non-catalytic APH-1 paralog that can substitute for APH1A in defined gamma-secretase complexes with presenilin, nicastrin, and PSENEN/PEN-2. Reason: The term aligns with APH1B function as a non-catalytic gamma-secretase subunit that supports a subset of presenilin-containing complexes and APP/Notch substrate processing. |
| GO:0010008 endosome membrane | TAS Reactome:R-HSA-9010096 | ACCEPT | Summary: This membrane or endomembrane location is consistent with APH1B as a multipass gamma-secretase subunit; cell-surface Aph-1 localization is also directly reported. Reason: APH1B is a multipass membrane protein in gamma-secretase complexes; membrane, cell-surface, and endomembrane locations are consistent with the curated biology. |
| GO:0005886 plasma membrane | TAS Reactome:R-HSA-1251997 | ACCEPT | Summary: This membrane or endomembrane location is consistent with APH1B as a multipass gamma-secretase subunit; cell-surface Aph-1 localization is also directly reported. Reason: APH1B is a multipass membrane protein in gamma-secretase complexes; membrane, cell-surface, and endomembrane locations are consistent with the curated biology. |
| GO:0005886 plasma membrane | TAS Reactome:R-HSA-193682 | ACCEPT | Summary: This membrane or endomembrane location is consistent with APH1B as a multipass gamma-secretase subunit; cell-surface Aph-1 localization is also directly reported. Reason: APH1B is a multipass membrane protein in gamma-secretase complexes; membrane, cell-surface, and endomembrane locations are consistent with the curated biology. |
| GO:0005886 plasma membrane | TAS Reactome:R-HSA-205112 | ACCEPT | Summary: This membrane or endomembrane location is consistent with APH1B as a multipass gamma-secretase subunit; cell-surface Aph-1 localization is also directly reported. Reason: APH1B is a multipass membrane protein in gamma-secretase complexes; membrane, cell-surface, and endomembrane locations are consistent with the curated biology. |
| GO:0005886 plasma membrane | TAS Reactome:R-HSA-2220988 | ACCEPT | Summary: This membrane or endomembrane location is consistent with APH1B as a multipass gamma-secretase subunit; cell-surface Aph-1 localization is also directly reported. Reason: APH1B is a multipass membrane protein in gamma-secretase complexes; membrane, cell-surface, and endomembrane locations are consistent with the curated biology. |
| GO:0005886 plasma membrane | TAS Reactome:R-HSA-3928656 | ACCEPT | Summary: This membrane or endomembrane location is consistent with APH1B as a multipass gamma-secretase subunit; cell-surface Aph-1 localization is also directly reported. Reason: APH1B is a multipass membrane protein in gamma-secretase complexes; membrane, cell-surface, and endomembrane locations are consistent with the curated biology. |
| GO:0005886 plasma membrane | TAS Reactome:R-HSA-9013361 | ACCEPT | Summary: This membrane or endomembrane location is consistent with APH1B as a multipass gamma-secretase subunit; cell-surface Aph-1 localization is also directly reported. Reason: APH1B is a multipass membrane protein in gamma-secretase complexes; membrane, cell-surface, and endomembrane locations are consistent with the curated biology. |
| GO:0005886 plasma membrane | TAS Reactome:R-HSA-9017817 | ACCEPT | Summary: This membrane or endomembrane location is consistent with APH1B as a multipass gamma-secretase subunit; cell-surface Aph-1 localization is also directly reported. Reason: APH1B is a multipass membrane protein in gamma-secretase complexes; membrane, cell-surface, and endomembrane locations are consistent with the curated biology. |
| GO:0005886 plasma membrane | TAS Reactome:R-HSA-9839376 | ACCEPT | Summary: This membrane or endomembrane location is consistent with APH1B as a multipass gamma-secretase subunit; cell-surface Aph-1 localization is also directly reported. Reason: APH1B is a multipass membrane protein in gamma-secretase complexes; membrane, cell-surface, and endomembrane locations are consistent with the curated biology. |
| GO:0005886 plasma membrane | TAS Reactome:R-NUL-2197556 | ACCEPT | Summary: This membrane or endomembrane location is consistent with APH1B as a multipass gamma-secretase subunit; cell-surface Aph-1 localization is also directly reported. Reason: APH1B is a multipass membrane protein in gamma-secretase complexes; membrane, cell-surface, and endomembrane locations are consistent with the curated biology. |
| GO:0005886 plasma membrane | TAS Reactome:R-NUL-9604300 | ACCEPT | Summary: This membrane or endomembrane location is consistent with APH1B as a multipass gamma-secretase subunit; cell-surface Aph-1 localization is also directly reported. Reason: APH1B is a multipass membrane protein in gamma-secretase complexes; membrane, cell-surface, and endomembrane locations are consistent with the curated biology. |
| GO:0030133 transport vesicle | IDA GO_REF:0000054 | KEEP AS NON CORE | Summary: Transport-vesicle localization is plausible from intracellular-localization curation but is peripheral to APH1B primary gamma-secretase complex function. Reason: Retain as non-core because it may reflect a real location without defining the main APH1B molecular role. |
| GO:0016485 protein processing | IDA PMID:12297508 Mammalian APH-1 interacts with presenilin and nicastrin and ... | ACCEPT | Summary: This captures gamma-secretase-dependent processing of membrane protein substrates by complexes that can include APH1B. Reason: The term aligns with APH1B function as a non-catalytic gamma-secretase subunit that supports a subset of presenilin-containing complexes and APP/Notch substrate processing. |
| GO:0005515 protein binding | IPI PMID:12297508 Mammalian APH-1 interacts with presenilin and nicastrin and ... | MARK AS OVER ANNOTATED | Summary: The interaction evidence is compatible with APH1B complex/substrate associations, but generic protein binding is not an informative molecular function for this gene. Reason: Prefer gamma-secretase complex membership and adaptor/activator terms over a broad protein-binding annotation. |
| GO:0016020 membrane | IDA PMID:12297508 Mammalian APH-1 interacts with presenilin and nicastrin and ... | ACCEPT | Summary: This membrane or endomembrane location is consistent with APH1B as a multipass gamma-secretase subunit; cell-surface Aph-1 localization is also directly reported. Reason: APH1B is a multipass membrane protein in gamma-secretase complexes; membrane, cell-surface, and endomembrane locations are consistent with the curated biology. |
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Download this section (compressed HTML)Q: Which endogenous human cell types assemble APH1B-containing gamma-secretase complexes at meaningful abundance, and how do those complexes differ from APH1A-containing complexes?
Suggested experts: gamma-secretase complex experts, single-cell proteomics experts
Q: Should GO capture APH1B-specific substrate preference or only the shared gamma-secretase complex functions that apply across APH1 paralogs?
Suggested experts: GO molecular-function curators, APP and Notch processing experts
Experiment: Use endogenous APH1B tagging and APH1A/APH1B isoform rescue in human neural and glial cells to quantify complex abundance, compartment localization, and APP/Notch substrate cleavage products.
Hypothesis: APH1B-containing gamma-secretase complexes are lower abundance but have distinct compartment or substrate preferences compared with APH1A-containing complexes.
Type: endogenous tagging and isoform-rescue substrate-processing assay
Experiment: Reconstitute matched PSEN1-APH1B and PSEN2-APH1B complexes with nicastrin and PSENEN and compare cleavage of APP, Notch, and other transmembrane substrates.
Hypothesis: APH1B effects on APP and Notch processing depend strongly on the presenilin paralog incorporated into gamma-secretase.
Type: defined gamma-secretase complex reconstitution assay
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