NCSTN notes

Review status

• First-pass review completed on 2026-06-19.
• just fetch-gene human NCSTN created local UniProt, GOA, publication, and PANTHER-family evidence files; just fetch-gene-pmids human NCSTN confirmed all 25 PMID-backed publication caches were present.
• Falcon deep research was attempted with timeout 180 just deep-research-falcon human NCSTN --fallback perplexity-lite, but the process timed out and no provider deep-research artifact was written. These notes rely on cached UniProt, GOA, and publication files.
• just validate human NCSTN passes cleanly.

Functional synthesis

NCSTN encodes nicastrin, an essential non-catalytic subunit of the gamma-secretase complex. The original nicastrin paper supports its presenilin association: PMID:10993067 and its role in intramembrane proteolysis: PMID:10993067.

Structural work supports the four-subunit complex model: PMID:25043039 and the substrate-recruitment framing for nicastrin's extracellular domain: PMID:25043039.

NCSTN should therefore be curated as an adaptor/activator/substrate-recognition component that contributes to complex-level intramembrane aspartyl endopeptidase activity, not as an independently catalytic peptidase. APH1/PEN2/nicastrin perturbation studies support the broader complex function in APP and Notch processing: PMID:12297508.

Annotation decisions

• Accepted gamma-secretase complex membership, protein-macromolecule adaptor activity, endopeptidase activator activity, contribution to intramembrane aspartyl endopeptidase activity, APP catabolic/metabolic process, amyloid-beta formation, Notch receptor processing, membrane-protein intracellular domain proteolysis, protein processing, and core ER/Golgi/endosomal/plasma-membrane locations.
• Modified broad endopeptidase activity, peptidase activity, proteolysis, and membrane protein ectodomain proteolysis annotations toward complex-level intramembrane proteolysis/protein-processing terms.
• Marked generic protein binding annotations as over-annotated.
• Kept melanosome, focal adhesion, extracellular exosome, azurophil granule membrane, sarcolemma, synaptic membrane/vesicle, cerebellum development, ATPase binding, and growth-factor receptor binding as non-core.

Final action distribution: 73 ACCEPT, 12 KEEP_AS_NON_CORE, 10 MARK_AS_OVER_ANNOTATED, 4 MODIFY.

Knowledge gaps and experiments

• The key ontology/curation issue is how to represent NCSTN substrate recruitment separately from presenilin catalytic activity.
• Useful experiments would use endogenous NCSTN extracellular-domain mutants to separate complex assembly, substrate recruitment, APP cleavage, and Notch cleavage.
• Compartment-resolved gamma-secretase assays would clarify which NCSTN-containing pools process APP versus Notch in vivo.

2026-06-20 second-pass audit

The second-pass audit added manual reference_review metadata for the core NCSTN/gamma-secretase papers supporting nicastrin complex membership, APP/Notch proteolysis, and structural placement. No annotation action changes were needed: NCSTN remains curated as a non-catalytic substrate-recruitment/adaptor component of the presenilin-containing gamma-secretase complex, with broad peptidase terms modified toward complex-level intramembrane proteolysis and generic interaction/localization terms kept non-core or over-annotated.