APH1B

UniProt ID: Q8WW43
Organism: Homo sapiens
Review Status: COMPLETE
📝 Provide Detailed Feedback

Gene Description

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.

Existing Annotations Review

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.
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.

Core Functions

APH1B is a non-catalytic APH-1 paralog that helps assemble or stabilize a subset of presenilin/nicastrin/PSENEN gamma-secretase complexes, enabling presenilin-dependent intramembrane cleavage of APP, Notch receptors, and related membrane substrates with substrate preferences that depend on the presenilin/APH1 combination.

Molecular Function:
protein-macromolecule adaptor activity
Directly Involved In:
membrane protein intracellular domain proteolysis Notch receptor processing amyloid precursor protein catabolic process amyloid-beta formation protein processing
Cellular Locations:
membrane plasma membrane endosome membrane Golgi membrane endoplasmic reticulum membrane
In Complex:
gamma-secretase complex
Supporting Evidence:
  • PMID:12763021
    APH1a, APH1b, PEN2, and Nicastrin proteins, which are part of the gamma-secretase complex with PS1
  • PMID:12763021
    these components are essential for gamma-secretase activity
  • PMID:15715652
    Functional gamma-secretase activity can be reconstituted from four proteins--presenilin, nicastrin, Pen-2 and Aph-1
  • PMID:15715652
    Aph-1 is present at the cell surface, presumably in active gamma-secretase complexes
  • PMID:27608597
    Aph1 has two isoforms, Aph1a and Aph1b
  • PMID:27608597
    PS2/Aph1b had a clear substrate specificity: APP-Gal4, but not Notch-Gal4, was cleaved

References

GO_REF:0000002
Gene Ontology annotation through association of InterPro records with GO terms
GO_REF:0000033
Annotation inferences using phylogenetic trees
GO_REF:0000054
Gene Ontology annotation based on curation of intracellular localizations of expressed fusion proteins in living cells
GO_REF:0000117
Electronic Gene Ontology annotations created by ARBA machine learning models
GO_REF:0000120
Combined Automated Annotation using Multiple IEA Methods
PMID:10206645
A presenilin-1-dependent gamma-secretase-like protease mediates release of Notch intracellular domain.
PMID:12297508
Mammalian APH-1 interacts with presenilin and nicastrin and is required for intramembrane proteolysis of amyloid-beta precursor protein and Notch.
PMID:12763021
APH1, PEN2, and Nicastrin increase Abeta levels and gamma-secretase activity.
PMID:15274632
Purification and characterization of the human gamma-secretase complex.
PMID:15715652
Aph-1 interacts at the cell surface with proteins in the active gamma-secretase complex and membrane-tethered Notch.
PMID:27608597
Specific combinations of presenilins and Aph1s affect the substrate specificity and activity of γ-secretase.
PMID:32296183
A reference map of the human binary protein interactome.
PMID:32814053
Interactome Mapping Provides a Network of Neurodegenerative Disease Proteins and Uncovers Widespread Protein Aggregation in Affected Brains.
Reactome:R-HSA-1251997
Cleavage of ERBB4m80 by gamma-scretase complex
Reactome:R-HSA-193682
gamma-secretase cleaves the p75NTR transmembrane domain
Reactome:R-HSA-205112
gamma-secretase cleaves p75NTR, releasing NRIF and TRAF6
Reactome:R-HSA-2220988
NEXT1 PEST domain mutants are cleaved to produce NICD1 PEST domain mutants
Reactome:R-HSA-3928656
gamma-secretase cleaves EPHB2
Reactome:R-HSA-9010096
Gamma-secretase cleaves APP(672-770) to APP(672-711) and APP(672-713)
Reactome:R-HSA-9013361
NEXT3 is cleaved to produce NICD3
Reactome:R-HSA-9017817
Gamma-secretase cleaves YBX1:NOTCH3
Reactome:R-HSA-9839376
TGFBR3(784-851) degradation
Reactome:R-NUL-2197556
Gamma-secretase complex cleaves mNEXT2
Reactome:R-NUL-9604300
Gamma-secretase cleaves Notch4

Suggested Questions for Experts

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

Suggested Experiments

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

📚 Additional Documentation

Notes

(APH1B-notes.md)

APH1B curation notes

2026-06-19

  • Deep-research attempt with just deep-research-falcon human APH1B --fallback perplexity-lite timed out after 180 seconds with no generated research artifact, so this manual review uses cached UniProt, GOA, and publication evidence.
  • APH1B encodes gamma-secretase subunit APH-1B, a multipass membrane protein and probable non-catalytic component of a subset of gamma-secretase complexes. UniProt frames APH1B as less abundant than APH1A-containing complexes and as a stabilizing cofactor for presenilin-containing complexes.
  • APH1B-specific support comes from papers that discuss Aph1 isoforms and defined complex combinations. One abstract states that genes encoding "APH1a, APH1b, PEN2, and Nicastrin proteins" are part of the gamma-secretase complex with PS1 and that RNAi evidence indicates these components are essential for activity [PMID:12763021 "APH1a, APH1b, PEN2, and Nicastrin proteins, which are part of the gamma-secretase complex with PS1"; PMID:12763021 "these components are essential for gamma-secretase activity"].
  • APH1B-containing complexes have substrate/complex-combination nuance. A defined-complex study states that "Aph1 has two isoforms, Aph1a and Aph1b" and reports different APP/Notch cleavage behavior across PS/Aph1 combinations [PMID:27608597 "Aph1 has two isoforms, Aph1a and Aph1b"; PMID:27608597 "PS2/Aph1b had a clear substrate specificity: APP-Gal4, but not Notch-Gal4, was cleaved"].
  • Cell-surface/plasma-membrane annotations are plausible for APH1B because the cached Aph-1 localization abstract says Aph-1 is present at the cell surface, presumably in active gamma-secretase complexes PMID:15715652.
  • APH1B should not be curated as an independent protease. Its core molecular role is adaptor/assembly/stabilizing contribution to the presenilin/nicastrin/PEN-2 gamma-secretase complex, with contribution to intramembrane aspartyl endopeptidase activity.
  • Generic protein binding annotations reflect real interaction data but are less informative than gamma-secretase complex membership and APH1B adaptor/activator terms, so I marked them as over-annotated.

2026-06-20 second-pass audit

The second-pass audit added manual reference_review metadata for APH1B-relevant gamma-secretase references, emphasizing direct APH1B/APH1-isoform evidence where available and family-level APH-1 complex evidence where not isoform-specific. No annotation action changes were needed: APH1B remains curated as an APH-1 paralog in a subset of gamma-secretase complexes, with its strongest distinction being substrate-preference context rather than independent catalytic activity.

📄 View Raw YAML

 
id: Q8WW43
gene_symbol: APH1B
product_type: PROTEIN
status: COMPLETE
taxon:
  id: NCBITaxon:9606
  label: Homo sapiens
description: '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.'
alternative_products:
- name: '1'
  id: Q8WW43-1
- name: '2'
  id: Q8WW43-2
  sequence_note: VSP_042945
existing_annotations:
- term:
    id: GO:0070765
    label: gamma-secretase complex
  evidence_type: IBA
  original_reference_id: GO_REF:0000033
  qualifier: part_of
  review:
    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.
    action: ACCEPT
    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.
- term:
    id: GO:0034205
    label: amyloid-beta formation
  evidence_type: IBA
  original_reference_id: GO_REF:0000033
  qualifier: involved_in
  review:
    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.
    action: ACCEPT
    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.
- term:
    id: GO:0016485
    label: protein processing
  evidence_type: IBA
  original_reference_id: GO_REF:0000033
  qualifier: involved_in
  review:
    summary: This captures gamma-secretase-dependent processing of membrane protein 
      substrates by complexes that can include APH1B.
    action: ACCEPT
    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.
- term:
    id: GO:0030674
    label: protein-macromolecule adaptor activity
  evidence_type: IBA
  original_reference_id: GO_REF:0000033
  qualifier: enables
  review:
    summary: APH1B is best interpreted as a non-catalytic adaptor/assembly subunit 
      within gamma-secretase complexes rather than as the catalytic protease.
    action: ACCEPT
    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.
- term:
    id: GO:0007220
    label: Notch receptor processing
  evidence_type: IBA
  original_reference_id: GO_REF:0000033
  qualifier: involved_in
  review:
    summary: APH1B-containing gamma-secretase complexes can support Notch receptor 
      processing, although substrate preference varies by presenilin/APH1 combination.
    action: ACCEPT
    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.
- term:
    id: GO:0007219
    label: Notch signaling pathway
  evidence_type: IBA
  original_reference_id: GO_REF:0000033
  qualifier: involved_in
  review:
    summary: Notch signaling is a downstream pathway output of gamma-secretase-mediated 
      Notch receptor processing.
    action: ACCEPT
    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.
- term:
    id: GO:0006508
    label: proteolysis
  evidence_type: IEA
  original_reference_id: GO_REF:0000117
  qualifier: involved_in
  review:
    summary: Generic proteolysis is too broad for APH1B; the supported process is 
      gamma-secretase-dependent intramembrane processing of membrane substrates.
    action: MODIFY
    proposed_replacement_terms:
    - id: GO:0031293
      label: membrane protein intracellular domain proteolysis
    - id: GO:0016485
      label: protein processing
    reason: Replace the broad proteolysis term with regulated intramembrane 
      substrate-processing terms supported for gamma-secretase.
- term:
    id: GO:0016020
    label: membrane
  evidence_type: IEA
  original_reference_id: GO_REF:0000120
  qualifier: located_in
  review:
    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.
    action: ACCEPT
    reason: APH1B is a multipass membrane protein in gamma-secretase complexes; 
      membrane, cell-surface, and endomembrane locations are consistent with the curated
      biology.
- term:
    id: GO:0016485
    label: protein processing
  evidence_type: IEA
  original_reference_id: GO_REF:0000002
  qualifier: involved_in
  review:
    summary: This captures gamma-secretase-dependent processing of membrane protein 
      substrates by complexes that can include APH1B.
    action: ACCEPT
    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.
- term:
    id: GO:0070765
    label: gamma-secretase complex
  evidence_type: IEA
  original_reference_id: GO_REF:0000117
  qualifier: part_of
  review:
    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.
    action: ACCEPT
    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.
- term:
    id: GO:0005515
    label: protein binding
  evidence_type: IPI
  original_reference_id: PMID:15715652
  qualifier: enables
  review:
    summary: The interaction evidence is compatible with APH1B 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 adaptor/activator terms over a
      broad protein-binding annotation.
- 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 APH1B 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 adaptor/activator terms over a
      broad protein-binding annotation.
- 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 APH1B 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 adaptor/activator terms over a
      broad protein-binding annotation.
- 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 APH1B as a 
      multipass gamma-secretase subunit; cell-surface Aph-1 localization is also 
      directly reported.
    action: ACCEPT
    reason: APH1B is a multipass membrane protein in gamma-secretase complexes; 
      membrane, cell-surface, and endomembrane locations are consistent with the curated
      biology.
- 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 APH1B as a 
      multipass gamma-secretase subunit; cell-surface Aph-1 localization is also 
      directly reported.
    action: ACCEPT
    reason: APH1B is a multipass membrane protein in gamma-secretase complexes; 
      membrane, cell-surface, and endomembrane locations are consistent with the curated
      biology.
- term:
    id: GO:0007220
    label: Notch receptor processing
  evidence_type: NAS
  original_reference_id: PMID:10206645
  qualifier: involved_in
  review:
    summary: APH1B-containing gamma-secretase complexes can support Notch receptor 
      processing, although substrate preference varies by presenilin/APH1 combination.
    action: ACCEPT
    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.
- term:
    id: GO:0007220
    label: Notch receptor processing
  evidence_type: IDA
  original_reference_id: PMID:27608597
  qualifier: involved_in
  review:
    summary: APH1B-containing gamma-secretase complexes can support Notch receptor 
      processing, although substrate preference varies by presenilin/APH1 combination.
    action: ACCEPT
    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.
- term:
    id: GO:0016485
    label: protein processing
  evidence_type: IGI
  original_reference_id: PMID:12763021
  qualifier: involved_in
  review:
    summary: This captures gamma-secretase-dependent processing of membrane protein 
      substrates by complexes that can include APH1B.
    action: ACCEPT
    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.
- term:
    id: GO:0016485
    label: protein processing
  evidence_type: IDA
  original_reference_id: PMID:27608597
  qualifier: involved_in
  review:
    summary: This captures gamma-secretase-dependent processing of membrane protein 
      substrates by complexes that can include APH1B.
    action: ACCEPT
    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.
- term:
    id: GO:0030674
    label: protein-macromolecule adaptor activity
  evidence_type: IMP
  original_reference_id: PMID:12297508
  qualifier: enables
  review:
    summary: APH1B is best interpreted as a non-catalytic adaptor/assembly subunit 
      within gamma-secretase complexes rather than as the catalytic protease.
    action: ACCEPT
    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.
- term:
    id: GO:0034205
    label: amyloid-beta formation
  evidence_type: IGI
  original_reference_id: PMID:12763021
  qualifier: involved_in
  review:
    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.
    action: ACCEPT
    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.
- term:
    id: GO:0034205
    label: amyloid-beta formation
  evidence_type: IDA
  original_reference_id: PMID:27608597
  qualifier: involved_in
  review:
    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.
    action: ACCEPT
    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.
- term:
    id: GO:0042987
    label: amyloid precursor protein catabolic process
  evidence_type: IGI
  original_reference_id: PMID:12763021
  qualifier: involved_in
  review:
    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.
    action: ACCEPT
    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.
- term:
    id: GO:0042987
    label: amyloid precursor protein catabolic process
  evidence_type: IDA
  original_reference_id: PMID:27608597
  qualifier: involved_in
  review:
    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.
    action: ACCEPT
    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.
- term:
    id: GO:0061133
    label: endopeptidase activator activity
  evidence_type: IMP
  original_reference_id: PMID:12297508
  qualifier: enables
  review:
    summary: APH1B supports presenilin-containing gamma-secretase complex activity, 
      consistent with a non-catalytic endopeptidase activator role at the complex level.
    action: ACCEPT
    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.
- term:
    id: GO:0061133
    label: endopeptidase activator activity
  evidence_type: IGI
  original_reference_id: PMID:12763021
  qualifier: enables
  review:
    summary: APH1B supports presenilin-containing gamma-secretase complex activity, 
      consistent with a non-catalytic endopeptidase activator role at the complex level.
    action: ACCEPT
    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.
- term:
    id: GO:0070765
    label: gamma-secretase complex
  evidence_type: IDA
  original_reference_id: PMID:12297508
  qualifier: part_of
  review:
    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.
    action: ACCEPT
    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.
- term:
    id: GO:0070765
    label: gamma-secretase complex
  evidence_type: IGI
  original_reference_id: PMID:12763021
  qualifier: part_of
  review:
    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.
    action: ACCEPT
    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.
- 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 APH1B as a 
      multipass gamma-secretase subunit; cell-surface Aph-1 localization is also 
      directly reported.
    action: ACCEPT
    reason: APH1B is a multipass membrane protein in gamma-secretase complexes; 
      membrane, cell-surface, and endomembrane locations are consistent with the curated
      biology.
- 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 APH1B as a 
      multipass gamma-secretase subunit; cell-surface Aph-1 localization is also 
      directly reported.
    action: ACCEPT
    reason: APH1B is a multipass membrane protein in gamma-secretase complexes; 
      membrane, cell-surface, and endomembrane locations are consistent with the curated
      biology.
- 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 APH1B as a 
      multipass gamma-secretase subunit; cell-surface Aph-1 localization is also 
      directly reported.
    action: ACCEPT
    reason: APH1B is a multipass membrane protein in gamma-secretase complexes; 
      membrane, cell-surface, and endomembrane locations are consistent with the curated
      biology.
- 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 APH1B as a 
      multipass gamma-secretase subunit; cell-surface Aph-1 localization is also 
      directly reported.
    action: ACCEPT
    reason: APH1B is a multipass membrane protein in gamma-secretase complexes; 
      membrane, cell-surface, and endomembrane locations are consistent with the curated
      biology.
- 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 APH1B as a 
      multipass gamma-secretase subunit; cell-surface Aph-1 localization is also 
      directly reported.
    action: ACCEPT
    reason: APH1B is a multipass membrane protein in gamma-secretase complexes; 
      membrane, cell-surface, and endomembrane locations are consistent with the curated
      biology.
- 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 APH1B as a 
      multipass gamma-secretase subunit; cell-surface Aph-1 localization is also 
      directly reported.
    action: ACCEPT
    reason: APH1B is a multipass membrane protein in gamma-secretase complexes; 
      membrane, cell-surface, and endomembrane locations are consistent with the curated
      biology.
- 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 APH1B as a 
      multipass gamma-secretase subunit; cell-surface Aph-1 localization is also 
      directly reported.
    action: ACCEPT
    reason: APH1B is a multipass membrane protein in gamma-secretase complexes; 
      membrane, cell-surface, and endomembrane locations are consistent with the curated
      biology.
- 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 APH1B as a 
      multipass gamma-secretase subunit; cell-surface Aph-1 localization is also 
      directly reported.
    action: ACCEPT
    reason: APH1B is a multipass membrane protein in gamma-secretase complexes; 
      membrane, cell-surface, and endomembrane locations are consistent with the curated
      biology.
- 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 APH1B as a 
      multipass gamma-secretase subunit; cell-surface Aph-1 localization is also 
      directly reported.
    action: ACCEPT
    reason: APH1B is a multipass membrane protein in gamma-secretase complexes; 
      membrane, cell-surface, and endomembrane locations are consistent with the curated
      biology.
- 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 APH1B as a 
      multipass gamma-secretase subunit; cell-surface Aph-1 localization is also 
      directly reported.
    action: ACCEPT
    reason: APH1B is a multipass membrane protein in gamma-secretase complexes; 
      membrane, cell-surface, and endomembrane locations are consistent with the curated
      biology.
- 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 APH1B as a 
      multipass gamma-secretase subunit; cell-surface Aph-1 localization is also 
      directly reported.
    action: ACCEPT
    reason: APH1B is a multipass membrane protein in gamma-secretase complexes; 
      membrane, cell-surface, and endomembrane locations are consistent with the curated
      biology.
- term:
    id: GO:0030133
    label: transport vesicle
  evidence_type: IDA
  original_reference_id: GO_REF:0000054
  qualifier: located_in
  review:
    summary: Transport-vesicle localization is plausible from intracellular-localization
      curation but is peripheral to APH1B primary gamma-secretase complex function.
    action: KEEP_AS_NON_CORE
    reason: Retain as non-core because it may reflect a real location without defining 
      the main APH1B molecular role.
- term:
    id: GO:0016485
    label: protein processing
  evidence_type: IDA
  original_reference_id: PMID:12297508
  qualifier: acts_upstream_of_or_within
  review:
    summary: This captures gamma-secretase-dependent processing of membrane protein 
      substrates by complexes that can include APH1B.
    action: ACCEPT
    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.
- term:
    id: GO:0005515
    label: protein binding
  evidence_type: IPI
  original_reference_id: PMID:12297508
  qualifier: enables
  review:
    summary: The interaction evidence is compatible with APH1B 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 adaptor/activator terms over a
      broad protein-binding annotation.
- term:
    id: GO:0016020
    label: membrane
  evidence_type: IDA
  original_reference_id: PMID:12297508
  qualifier: located_in
  review:
    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.
    action: ACCEPT
    reason: APH1B is a multipass membrane protein in gamma-secretase complexes; 
      membrane, cell-surface, and endomembrane locations are consistent with the curated
      biology.
references:
- id: GO_REF:0000002
  title: Gene Ontology annotation through association of InterPro records with GO terms
  findings: []
- id: GO_REF:0000033
  title: Annotation inferences using phylogenetic trees
  findings: []
- id: GO_REF:0000054
  title: Gene Ontology annotation based on curation of intracellular localizations of 
    expressed fusion proteins in living cells
  findings: []
- id: GO_REF:0000117
  title: Electronic Gene Ontology annotations created by ARBA machine learning models
  findings: []
- id: GO_REF:0000120
  title: Combined Automated Annotation using Multiple IEA Methods
  findings: []
- id: PMID:10206645
  title: A presenilin-1-dependent gamma-secretase-like protease mediates release of 
    Notch intracellular domain.
  findings: []
- id: PMID:12297508
  title: Mammalian APH-1 interacts with presenilin and nicastrin and is required for 
    intramembrane proteolysis of amyloid-beta precursor protein and Notch.
  findings: []
  reference_review:
    relevance: HIGH
    correctness: VERIFIED
    review_notes: Cached abstract supports mammalian APH-1 association with 
      presenilin/nicastrin and requirement for APP and Notch intramembrane 
      proteolysis; it is relevant family-level evidence for APH1B.
- 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 explicitly includes APH1b among 
      gamma-secretase complex genes and supports APH1/PEN2/nicastrin effects on
      Abeta levels and gamma-secretase activity.
- id: PMID:15274632
  title: Purification and characterization of the human gamma-secretase complex.
  findings: []
  reference_review:
    relevance: MEDIUM
    correctness: VERIFIED
    review_notes: Cached abstract identifies APH-1 with presenilin, nicastrin,
      and Pen-2 as active human gamma-secretase components, though it is not 
      APH1B-isoform specific.
- id: PMID:15715652
  title: Aph-1 interacts at the cell surface with proteins in the active gamma-secretase
    complex and membrane-tethered Notch.
  findings: []
- id: PMID:27608597
  title: Specific combinations of presenilins and Aph1s affect the substrate specificity
    and activity of γ-secretase.
  findings: []
  reference_review:
    relevance: HIGH
    correctness: VERIFIED
    review_notes: Cached abstract directly discusses APH1B-containing 
      gamma-secretase combinations and their APP/Notch substrate specificity.
- 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:0030674
    label: protein-macromolecule adaptor activity
  contributes_to_molecular_function:
    id: GO:0042500
    label: aspartic endopeptidase activity, intramembrane cleaving
  description: APH1B is a non-catalytic APH-1 paralog that helps assemble or stabilize a
    subset of presenilin/nicastrin/PSENEN gamma-secretase complexes, enabling 
    presenilin-dependent intramembrane cleavage of APP, Notch receptors, and related 
    membrane substrates with substrate preferences that depend on the presenilin/APH1 
    combination.
  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
  locations:
  - id: GO:0016020
    label: membrane
  - id: GO:0005886
    label: plasma membrane
  - id: GO:0010008
    label: endosome membrane
  - id: GO:0000139
    label: Golgi membrane
  - id: GO:0005789
    label: endoplasmic reticulum membrane
  in_complex:
    id: GO:0070765
    label: gamma-secretase complex
  supported_by:
  - reference_id: PMID:12763021
    supporting_text: APH1a, APH1b, PEN2, and Nicastrin proteins, which are part of the 
      gamma-secretase complex with PS1
  - reference_id: PMID:12763021
    supporting_text: these components are essential for gamma-secretase activity
  - reference_id: PMID:15715652
    supporting_text: Functional gamma-secretase activity can be reconstituted from four 
      proteins--presenilin, nicastrin, Pen-2 and Aph-1
  - reference_id: PMID:15715652
    supporting_text: Aph-1 is present at the cell surface, presumably in active 
      gamma-secretase complexes
  - reference_id: PMID:27608597
    supporting_text: Aph1 has two isoforms, Aph1a and Aph1b
  - reference_id: PMID:27608597
    supporting_text: 'PS2/Aph1b had a clear substrate specificity: APP-Gal4, but not Notch-Gal4,
      was cleaved'
proposed_new_terms: []
suggested_questions:
- question: Which endogenous human cell types assemble APH1B-containing gamma-secretase 
    complexes at meaningful abundance, and how do those complexes differ from 
    APH1A-containing complexes?
  experts:
  - gamma-secretase complex experts
  - single-cell proteomics experts
- question: Should GO capture APH1B-specific substrate preference or only the shared 
    gamma-secretase complex functions that apply across APH1 paralogs?
  experts:
  - GO molecular-function curators
  - APP and Notch processing experts
suggested_experiments:
- description: 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.
  experiment_type: endogenous tagging and isoform-rescue substrate-processing assay
- description: 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.
  experiment_type: defined gamma-secretase complex reconstitution assay