ID: hyp-SDA-2026-04-09-gap-debate-20260409-2
Hypothesis
p300/CBP-dependent K280 acetylation nucleates pathogenic tau conformers
Acetylation at Lys-280 within the microtubule-binding repeat domain converts tau into an aggregation-competent state by simultaneously disrupting microtubule binding and creating a β-sheet nucleation interface that templates unmodified tau.
EvidencePending (0%)📖 5 cit🗣 1 debates✓ 5 support✗ 1 oppose
✓ All Quality Gates Passed
🧪 Overview
Acetylation at Lys-280 within the microtubule-binding repeat domain converts tau into an aggregation-competent state by simultaneously disrupting microtubule binding and creating a β-sheet nucleation interface that templates unmodified tau.
🧬 Mechanism
🔗 Mechanism from KG for EP300
Auto-built from this analysis's top knowledge-graph edges.
graph TD
tau_protein["tau_protein"] -->|undergoes| post_translational_modifi["post_translational_modifications"]
post_translational_modifi_1["post_translational_modifications"] -->|contributes to| pathological_tau["pathological_tau"]
pathological_tau_2["pathological_tau"] -->|causes| neurodegeneration["neurodegeneration"]
CASP2["CASP2"] -->|causes| TAU_Aggregation["TAU Aggregation"]
CASP3["CASP3"] -->|causes| TAU_Aggregation_3["TAU Aggregation"]
EP300["EP300"] -->|causes| K280_acetylated_tau["K280 acetylated tau"]
D421_truncation["D421 truncation"] -->|biomarker for| Alzheimer_s_disease["Alzheimer's_disease"]
K280_acetylation["K280 acetylation"] -->|associated with| Alzheimer_s_disease_4["Alzheimer's_disease"]
CASP2_5["CASP2"] -->|causes| Neurofibrillary_Tangle_Fo["Neurofibrillary Tangle Formation"]
EP300_6["EP300"] -->|regulates| TAU_Acetylation["TAU Acetylation"]
post_translational_modifi_7["post_translational_modifications"] -->|causes| pathological_tau_8["pathological_tau"]
sess_SDA_2026_04_09_gap_d["sess_SDA-2026-04-09-gap-debate-20260409-201742-1e8eb3bd_20260412-091129"] -->|causal extracted| processed["processed"]
style tau_protein fill:#4fc3f7,stroke:#333,color:#000
style post_translational_modifi fill:#81c784,stroke:#333,color:#000
style post_translational_modifi_1 fill:#81c784,stroke:#333,color:#000
style pathological_tau fill:#4fc3f7,stroke:#333,color:#000
style pathological_tau_2 fill:#4fc3f7,stroke:#333,color:#000
style neurodegeneration fill:#ef5350,stroke:#333,color:#000
style CASP2 fill:#ce93d8,stroke:#333,color:#000
style TAU_Aggregation fill:#4fc3f7,stroke:#333,color:#000
style CASP3 fill:#ce93d8,stroke:#333,color:#000
style TAU_Aggregation_3 fill:#4fc3f7,stroke:#333,color:#000
style EP300 fill:#ce93d8,stroke:#333,color:#000
style K280_acetylated_tau fill:#4fc3f7,stroke:#333,color:#000
style D421_truncation fill:#4fc3f7,stroke:#333,color:#000
style Alzheimer_s_disease fill:#ef5350,stroke:#333,color:#000
style K280_acetylation fill:#4fc3f7,stroke:#333,color:#000
style Alzheimer_s_disease_4 fill:#ef5350,stroke:#333,color:#000
style CASP2_5 fill:#ce93d8,stroke:#333,color:#000
style Neurofibrillary_Tangle_Fo fill:#4fc3f7,stroke:#333,color:#000
style EP300_6 fill:#ce93d8,stroke:#333,color:#000
style TAU_Acetylation fill:#4fc3f7,stroke:#333,color:#000
style post_translational_modifi_7 fill:#4fc3f7,stroke:#333,color:#000
style pathological_tau_8 fill:#4fc3f7,stroke:#333,color:#000
style sess_SDA_2026_04_09_gap_d fill:#4fc3f7,stroke:#333,color:#000
style processed fill:#4fc3f7,stroke:#333,color:#000⚖️ Evidence
⚖️ Evidence Matrix5 supports0 contradicts
Supports
SIRT6-CBP-dependent nuclear Tau accumulation and its role in protein synthesis.
Supports
Promoting tau secretion and propagation by hyperactive p300/CBP via autophagy-lysosomal pathway in tauopathy.
Supports
Identification of a reciprocal negative feedback loop between tau-modifying proteins MARK2 kinase and CBP acetyltransferase.
Supports
Decoding tau acetylation in Alzheimer's disease and tauopathies: from site-specific mechanisms to therapeutic horizons.
📖 Linked Papers
No linked papers recorded for this hypothesis yet.
🏥 Translation
🧬 3D Protein Structure — EP300
No curated PDB or AlphaFold mapping for EP300 yet. Search RCSB →
💉 Clinical Trials
No clinical trials data linked to this hypothesis yet.
No curated ClinVar variants loaded for this hypothesis.
Run scripts/backfill_clinvar_variants.py to fetch P/LP/VUS variants.
No DepMap CRISPR Chronos data found for EP300.
Run python3 scripts/backfill_hypothesis_depmap.py to populate.
🏆 Tournament
🏆 Arenas / Elo
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📊 Market Indicators
7d Trend
↔
Stable
7d Momentum
▲ 0.0%
Volatility
Medium
0.0449
Events (7d)
0
Price History
▲7.2%💾 Resource Usage
LLM Tokens
17,312
$0.0625
Total Cost
$0.0625
🔮 Predictions
🔎 Predictions vs Observations2 predictions · 0 with recorded observations
| Prediction | Predicted | Observed | Status | Conf |
|---|---|---|---|---|
| IF primary neurons from tau transgenic mice are treated with the p300/CBP inhibitor A-485 (1 μM for 7 days) or express a K280R non-acetylatable tau mutant, THEN phospho-tau solubility will increase by | Reduced accumulation of Sarkosyl-insoluble, aggregated tau in neurons | — no observation — | pending | 0.75 |
| IF pre-formed fibrils composed of K280-acetylated tau (ac-Tau, at 1:10 seed:substrate ratio) are added to solutions of unmodified full-length 2N4R wild-type tau (25 μM), THEN wild-type tau aggregation | Accelerated ThT-positive aggregation kinetics of unmodified tau seeded by K280-acetylated tau | — no observation — | pending | 0.82 |
🔮 Falsifiable Predictions (2)
pendingconf 82%
IF pre-formed fibrils composed of K280-acetylated tau (ac-Tau, at 1:10 seed:substrate ratio) are added to solutions of unmodified full-length 2N4R wild-type tau (25 μM), THEN wild-type tau aggregation will reach 50% ThT fluorescence by ≤48 hours versus ≥96 hours for untreated or non-acetyl seed cont
Predicted outcome: Accelerated ThT-positive aggregation kinetics of unmodified tau seeded by K280-acetylated tau
Falsification: K280-acetylated tau seeds fail to accelerate wild-type tau aggregation (ThT curves superimposable with non-seeded or non-acetyl-seeded controls), disproving the nucleation interface hypothesis.
pendingconf 75%
IF primary neurons from tau transgenic mice are treated with the p300/CBP inhibitor A-485 (1 μM for 7 days) or express a K280R non-acetylatable tau mutant, THEN phospho-tau solubility will increase by ≥40% and Sarkosyl-insoluble tau aggregates will decrease by ≥60% compared to vehicle-treated or wil
Predicted outcome: Reduced accumulation of Sarkosyl-insoluble, aggregated tau in neurons
Falsification: No significant difference in tau aggregation between p300-inhibited/K280R mutant neurons and controls (i.e., <20% change in insoluble tau), indicating K280 acetylation is not required for aggregation.
▸Metadatasource: v1_phase_c_backfill · origin_type: debate_synthesis
| source | v1_phase_c_backfill |
| origin_type | debate_synthesis |
| _schema_version | 1 |
📊 Evidence Profile
Evidence Balance
+0%
Certainty
0%
Debates
0
Incoming
0
Outgoing
0
0 supporting
0 contradicting
0 neutral
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