ADAM10 notes

Review status

• First-pass review completed on 2026-06-19.
• just fetch-gene-pmids human ADAM10 completed successfully; all 44 PMID-backed publication caches were present after refresh.
• Falcon deep research was attempted with timeout 180 just deep-research-falcon human ADAM10 --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 ADAM10 passes cleanly.

Functional synthesis

ADAM10 is a type I membrane zinc metalloprotease and broad ectodomain sheddase. A tetraspanin-regulation study gives the cleanest high-level statement of the core function: PMID:26686862 It also captures two central substrate axes: APP PMID:26686862 and Notch PMID:26686862.

ADAM10 alpha-secretase biology is directly relevant to Alzheimer mechanisms. A full-text cached paper states PMID:33731436 and frames reduced ADAM10 activity as a shift toward beta-secretase processing. Synaptic trafficking work adds that ADAM10 resides in postsynaptic compartments and that its surface removal affects activity: PMID:23676497.

ADAM10's substrate range is much broader than APP. L1 processing supports cell-surface/Golgi/vesicle cleavage: PMID:12475894 Fractalkine/CX3CL1 processing supports constitutive shedding: PMID:12714508 TREM2 shedding, TNF-family and FasL processing, cadherin/junction substrates, and tetraspanin-dependent substrate selectivity were retained as substrate-specific consequences of the same sheddase function rather than separate core functions.

The S. aureus alpha-toxin pore annotations are biologically supported as pathogen exploitation of junctional ADAM10, not normal evolved host function: PMID:30463011 These were retained as non-core.

Annotation decisions

• Accepted metalloendopeptidase, metallopeptidase, endopeptidase, proteolysis, membrane-protein ectodomain proteolysis, constitutive ectodomain proteolysis, signaling receptor ligand precursor processing, APP catabolic processing, negative amyloid-beta formation regulation, Notch signaling, EGFR-ligand maturation, and core membrane/Golgi/synaptic/tetraspanin-domain locations.
• Modified negative regulation of amyloid precursor protein biosynthetic process to APP catabolic processing and negative regulation of amyloid-beta formation; ADAM10 cleaves APP rather than regulating APP biosynthesis.
• Removed metallodipeptidase activity because ADAM10 is an endopeptidase/sheddase, not a dipeptidase.
• Marked generic protein binding annotations as over-annotated.
• Kept immune, adhesion, chemokine, TNF, FasL, TREM2, synaptic-organization, developmental, granule, exosome, and S. aureus alpha-toxin pore annotations as non-core substrate/context outputs.

Final action distribution: 88 ACCEPT, 42 KEEP_AS_NON_CORE, 19 MARK_AS_OVER_ANNOTATED, 1 MODIFY, 1 REMOVE.

Knowledge gaps and experiments

• The major curation challenge is representing ADAM10 substrate specificity without turning every downstream substrate phenotype into a core function.
• Useful experiments would combine endogenous ADAM10 variant knock-ins with substrate-specific reporters for APP, Notch, cadherins, TREM2, CX3CL1, and TNF-family substrates across defined tetraspanin backgrounds.
• For Alzheimer biology, the highest-value assay is compartment-resolved measurement of ADAM10 maturation, synaptic/cell-surface retention, APP alpha-cleavage, and amyloid-beta suppression in human neurons.

2026-06-20 Second-Pass Review Notes

Second-pass audit confirmed the existing action calls. No annotation actions were
changed. The single REMOVE call remains appropriate for GO:0070573
metallodipeptidase activity, because ADAM10 is a membrane
metalloendopeptidase/sheddase and not a dipeptidase.

The YAML now records reference_review metadata for the main evidence anchors:
PMID:26686862 for broad ectodomain shedding, APP cleavage, Notch S2 cleavage,
and tetraspanin compartmentalization; PMID:33731436 for APP alpha-secretase
cleavage; PMID:23676497 for synaptic ADAM10 endocytosis; PMID:12475894 for L1
cleavage at cell-surface/Golgi-vesicle contexts; and PMID:30463011 for
S. aureus alpha-toxin exploitation of junctional ADAM10.

The core review remains substrate-aware but conservative: ADAM10's evolved core
function is regulated membrane-protein ectodomain shedding. Substrate-specific
outputs should be retained when directly supported, but broad downstream
developmental, immune, synaptic, pathogen, or cancer phenotypes should not be
promoted above that sheddase mechanism.