{"gene":"ANKS1B","run_date":"2026-06-09T22:02:43","timeline":{"discoveries":[{"year":2007,"finding":"AIDA-1d binds to the first two PDZ domains of the scaffolding protein PSD-95 via its C-terminal three amino acids; stimulation of NMDA receptors results in Ca2+-independent translocation of AIDA-1d to the nucleus, where it couples to Cajal bodies and induces Cajal body-nucleolar association; long-term neuronal stimulation results in an AIDA-1-dependent increase in nucleolar numbers and protein synthesis.","method":"Co-immunoprecipitation, subcellular fractionation, immunofluorescence, neuronal stimulation assays","journal":"Nature neuroscience","confidence":"High","confidence_rationale":"Tier 2 / Strong — reciprocal binding demonstrated, multiple orthogonal methods (Co-IP, imaging, functional protein synthesis readout), replicated across stimulation paradigms","pmids":["17334360"],"is_preprint":false},{"year":2009,"finding":"AIDA-1 contains two SAM domains in a head-to-tail orientation separated by a 15-aa linker; the nuclear localization signal is buried at the SAM-SAM domain interface; differential thermal stability of the two SAM domains suggests the second SAM domain decouples from the first to expose the NLS and facilitate nuclear import.","method":"NMR structure determination, thermal stability assays","journal":"Journal of molecular biology","confidence":"High","confidence_rationale":"Tier 1 / Moderate — NMR structure with functional interpretation of NLS burial, single lab but structural data with mechanistic validation","pmids":["19666031"],"is_preprint":false},{"year":2004,"finding":"AIDA-1 proteins (isoforms AIDA-1a, AIDA-1b, AIDA-1bΔAnk) interact with the intracellular domain of amyloid precursor protein (AbetaPP) in vitro, in living cells, and endogenously in leukemia cell lines; the intracellular localization of AIDA-1a can be modified by overexpression of AbetaPP.","method":"Co-immunoprecipitation, in vitro binding assay, transfection/overexpression with subcellular localization imaging","journal":"Journal of Alzheimer's disease : JAD","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — reciprocal Co-IP in multiple contexts (in vitro, cell lines, endogenous), localization change tied to binding partner, single lab","pmids":["15004329"],"is_preprint":false},{"year":2005,"finding":"A novel isoform AIDA-1c interacts with the Cajal body marker protein coilin; AIDA-1c competes with SmB' for coilin binding sites but does not bind SMN; siRNA knockdown of EB-1/AIDA-1 isoforms altered Cajal body organization and reduced cell viability.","method":"Co-immunoprecipitation, competition binding assays, siRNA knockdown, immunofluorescence","journal":"BMC cell biology","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — Co-IP with competition assay, functional knockdown phenotype, single lab with two orthogonal methods","pmids":["15862129"],"is_preprint":false},{"year":2015,"finding":"AIDA-1 (encoded by ANKS1B) regulates synaptic NMDA receptor subunit composition: forebrain-specific AIDA-1 conditional knockout mice exhibit reduced GluN2B-mediated and increased GluN2A-mediated synaptic transmission; GluN2B accumulates in ER-enriched fractions in AIDA-1 cKO mice; AIDA-1 preferentially associates with GluN2B, CASK, and KIF17, which regulate transport of GluN2B-containing NMDARs from the ER to synapses; NMDAR-dependent but not mGluR-dependent plasticity is impaired in AIDA-1 cKO mice.","method":"Conditional knockout mouse, electrophysiology, biochemical fractionation, Co-immunoprecipitation, lentiviral shRNA knockdown, immunocytochemistry","journal":"The Journal of neuroscience","confidence":"High","confidence_rationale":"Tier 2 / Strong — conditional KO with multiple orthogonal methods (electrophysiology, fractionation, Co-IP, imaging), mechanistic pathway (ER export) defined","pmids":["26085624"],"is_preprint":false},{"year":2015,"finding":"Under basal conditions, AIDA-1 concentrates within the electron-dense core of the postsynaptic density (~30 nm from postsynaptic membrane); under excitatory conditions (high K+ or NMDA application), AIDA-1 label density at the PSD core is reduced to 40% of controls and median distance increases to ~55 nm; this redistribution is reversible within 30 minutes.","method":"Immunogold electron microscopy with two antibodies recognizing different epitopes, pharmacological stimulation","journal":"PloS one","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — direct subcellular localization by immuno-EM with quantification, two antibodies, functional context established","pmids":["26356309"],"is_preprint":false},{"year":2016,"finding":"CaMKII mediates phosphorylation of AIDA-1 upon activation; NMDA treatment causes an ~30 nm shift in median distance of AIDA-1 from the postsynaptic membrane, an effect blocked by the CaMKII inhibitor tatCN21; CaMKII-mediated displacement of AIDA-1 from the PSD core is mechanistically similar to that of SynGAP.","method":"Phosphorylation assay with PSD fractions, immuno-electron microscopy, pharmacological inhibition of CaMKII","journal":"FEBS letters","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — kinase-substrate assay combined with immuno-EM and pharmacological rescue, single lab","pmids":["27477489"],"is_preprint":false},{"year":2015,"finding":"ANKS1B was identified as a novel binding partner of KRIT1 (CCM1) by yeast two-hybrid screen; silencing ANKS1B in primary human endothelial cells increased endothelial permeability, while forced ANKS1B expression reduced permeability; this effect was independent of Rho kinase activity and presence of KRIT1; silencing had no significant effect on proliferation, migration, or sprouting angiogenesis.","method":"Yeast two-hybrid screen, siRNA knockdown, overexpression, permeability assays, pharmacological inhibition","journal":"PloS one","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — Y2H identification followed by functional KD and OE with specific phenotype, single lab","pmids":["26698571"],"is_preprint":false},{"year":2019,"finding":"AIDA-1 interactome identified by quantitative proteomics from patient-derived iPSC neurons and transgenic mouse model; Anks1b haploinsufficiency leads to loss of AIDA-1 at synapses, recapitulating neurodevelopmental phenotypes (social deficits, hyperactivity, sensorimotor dysfunction) in mice; protein networks involved in synaptic function were identified as AIDA-1 binding partners.","method":"Quantitative proteomics (interactome), patient-derived iPSC neurons, transgenic haploinsufficiency mouse model, behavioral assays","journal":"Nature communications","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — quantitative proteomics interactome with mouse model validation, multiple phenotypic readouts, single lab","pmids":["31388001"],"is_preprint":false},{"year":2023,"finding":"Anks1b-deficient mice display deficits in oligodendrocyte maturation, myelination, and Rac1 function; selective loss of Anks1b from the oligodendrocyte lineage (but not neuronal populations) leads to deficits in social preference and sensory reactivity; clemastine (an oligodendrocyte precursor maturation promoter) rescues social preference deficits in Anks1b-deficient mice.","method":"Cell type-specific conditional knockout (oligodendrocyte lineage vs. neuronal), myelination assays, Rac1 activity assay, behavioral assays, pharmacological rescue","journal":"Nature communications","confidence":"High","confidence_rationale":"Tier 2 / Strong — cell-type specific conditional KO with epistasis-like dissection, pharmacological rescue, multiple orthogonal methods and readouts","pmids":["38129387"],"is_preprint":false},{"year":2024,"finding":"The PTB domain of AIDA-1 binds to an extended NPx[F/Y]-motif of SynGAP family Ras-GTPase activating proteins with high affinity; crystal structure of the AIDA-1 PTB domain in complex with the SynGAP NPxF-motif revealed the molecular basis of this specific interaction.","method":"Affinity purification, biochemical binding assays, crystal structure determination","journal":"Journal of molecular biology","confidence":"High","confidence_rationale":"Tier 1 / Moderate — crystal structure with biochemical validation (affinity purification and binding assays), single lab but two orthogonal methods","pmids":["38759928"],"is_preprint":false},{"year":2012,"finding":"Chronic ethanol exposure enhances synaptic clustering of AIDA-1 in hippocampal neurons; concurrent NMDA receptor stimulation prevents this ethanol-induced synaptic accumulation; the association of AIDA-1 with PSD-95 is not required for its localization to the PSD (negative finding: PSD-95 declustering did not affect AIDA-1 synaptic distribution); AIDA-1 knockdown did not affect protein expression levels of GluN1 or GluN2B NMDA receptor subunits (negative finding).","method":"Lentiviral shRNA knockdown, immunofluorescence, pharmacological treatments (ethanol, AP-V, NMDA, palmitoylation inhibitor)","journal":"Alcohol (Fayetteville, N.Y.)","confidence":"Low","confidence_rationale":"Tier 3 / Weak — single lab, primarily imaging-based with pharmacological manipulation, no mechanistic pathway placement beyond observation","pmids":["22703994"],"is_preprint":false},{"year":2026,"finding":"Ischemia induces ANKS1B lactylation at the conserved K1222 site, which targets ANKS1B for ubiquitin-proteasome-mediated degradation; ANKS1B regulates ER export of GluN2B; lactylation-driven ANKS1B loss leads to GluN2B retention in the ER; a lactylation-resistant mutant (ANKS1B-K1222R) prevented degradation and restored GluN2B surface trafficking but exacerbated excitotoxic Ca2+ overload and neuronal death.","method":"Proteomics, OGD/R cell model, site-directed mutagenesis (K1222R), ubiquitin-proteasome pathway assays, Ca2+ imaging, cell death assays","journal":"Biochemical and biophysical research communications","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — mutagenesis with functional rescue/loss readouts, multiple orthogonal methods, single lab","pmids":["41564684"],"is_preprint":false},{"year":2026,"finding":"ANKS1B in the nucleus accumbens interacts with the histone acetyltransferase CBP to control H3K27 acetylation; this complex epigenetically represses the transcription factor FoxO3; ANKS1B downregulation after extended cocaine use leads to escalated cocaine intake via this CBP-FoxO3 pathway; manipulating ANKS1B selectively influences escalation of cocaine intake and cocaine-seeking behavior.","method":"Co-immunoprecipitation, ChIP assay (H3K27ac), viral vector-mediated ANKS1B manipulation, cocaine self-administration rat model","journal":"Advanced science","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — Co-IP for complex, ChIP for epigenetic modification, in vivo behavioral model with genetic manipulation, single lab","pmids":["42228033"],"is_preprint":false}],"current_model":"AIDA-1 (ANKS1B) is a postsynaptic scaffold protein that localizes to the PSD core under basal conditions and undergoes CaMKII-mediated phosphorylation and displacement from the PSD core upon NMDA receptor activation; it facilitates anterograde transport of GluN2B-containing NMDARs from the ER to synapses by associating with GluN2B, CASK, and KIF17, thereby controlling synaptic NMDAR subunit composition and NMDAR-dependent plasticity; its PTB domain binds SynGAP family RasGAPs via NPx[F/Y] motifs; upon synaptic activation, an N-terminal fragment translocates to the nucleus where it couples to Cajal bodies via coilin interaction to regulate nucleolar assembly and global protein synthesis; in oligodendrocytes, ANKS1B controls Rac1-dependent maturation and myelination relevant to social behavior; in the nucleus accumbens, it interacts with CBP to regulate H3K27 acetylation and FoxO3-dependent transcription; during ischemia, lactylation at K1222 targets ANKS1B for proteasomal degradation, reducing GluN2B surface trafficking as a neuroprotective feedback mechanism."},"narrative":{"mechanistic_narrative":"ANKS1B (AIDA-1) is a multidomain postsynaptic scaffold protein that couples NMDA receptor activity to synaptic composition, gene expression, and global protein synthesis [PMID:17334360, PMID:26085624]. At the synapse it concentrates within the electron-dense core of the postsynaptic density under basal conditions and is displaced toward the periphery upon NMDA receptor activation through CaMKII-mediated phosphorylation, in a manner mechanistically parallel to SynGAP [PMID:26356309, PMID:27477489]. It preferentially associates with GluN2B together with CASK and KIF17 to drive anterograde transport of GluN2B-containing NMDARs from the ER to synapses, thereby setting the synaptic GluN2B/GluN2A balance and enabling NMDAR-dependent plasticity; loss of AIDA-1 causes ER retention of GluN2B and impaired plasticity [PMID:26085624]. Its PTB domain binds SynGAP-family RasGAPs through an extended NPx[F/Y] motif, a recognition mode defined at atomic resolution [PMID:38759928]. Upon NMDAR stimulation an N-terminal fragment translocates to the nucleus — gated by an NLS buried at a tandem SAM-SAM domain interface that is exposed by domain decoupling — where it engages the Cajal body protein coilin to promote Cajal body-nucleolar association, nucleolar biogenesis, and protein synthesis [PMID:17334360, PMID:19666031, PMID:15862129]. Beyond neurons, ANKS1B functions in the oligodendrocyte lineage to control Rac1-dependent maturation and myelination underlying social behavior [PMID:38129387], and in the nucleus accumbens it forms a complex with the acetyltransferase CBP to regulate H3K27 acetylation and FoxO3-dependent transcription relevant to addiction-related behavior [PMID:42228033]. ANKS1B haploinsufficiency produces neurodevelopmental phenotypes including social deficits, hyperactivity, and sensorimotor dysfunction [PMID:31388001].","teleology":[{"year":2004,"claim":"Establishing ANKS1B's first molecular partner addressed whether the protein had a defined binding function, linking it to amyloid precursor protein biology.","evidence":"Co-IP and in vitro binding of multiple AIDA-1 isoforms to the AbetaPP intracellular domain, with localization shifts on AbetaPP overexpression","pmids":["15004329"],"confidence":"Medium","gaps":["Functional consequence of the AbetaPP interaction in neurons unresolved","Binding mapped to isoforms but not to a specific domain","Single lab"]},{"year":2005,"claim":"Identifying coilin binding placed an ANKS1B isoform in the nuclear Cajal body compartment, hinting at a role beyond cytoplasmic scaffolding.","evidence":"Co-IP, competition binding against SmB', siRNA knockdown altering Cajal body organization in cells","pmids":["15862129"],"confidence":"Medium","gaps":["Mechanism linking coilin binding to nucleolar function not yet defined","Physiological trigger for nuclear targeting unknown at this stage"]},{"year":2007,"claim":"Connecting synaptic NMDAR activity to nuclear translocation defined ANKS1B as a synapse-to-nucleus messenger controlling protein synthesis capacity.","evidence":"Co-IP with PSD-95 PDZ domains, subcellular fractionation, and stimulation-induced nuclear coupling to Cajal bodies with increased nucleolar number and protein synthesis","pmids":["17334360"],"confidence":"High","gaps":["Identity of the translocating cleavage fragment and the cleavage mechanism not established","Transcriptional/translational targets downstream of nucleolar expansion undefined"]},{"year":2009,"claim":"Resolving the tandem SAM domain structure explained how nuclear import is gated, by burying the NLS at the SAM-SAM interface.","evidence":"NMR structure determination with differential thermal stability analysis of the two SAM domains","pmids":["19666031"],"confidence":"High","gaps":["Direct demonstration that SAM decoupling triggers import in cells not shown","Signal that drives domain decoupling unidentified"]},{"year":2015,"claim":"Conditional knockout work established the core synaptic function: control of NMDAR subunit composition via ER-to-synapse transport of GluN2B.","evidence":"Forebrain AIDA-1 cKO mice analyzed by electrophysiology, fractionation, and Co-IP with GluN2B/CASK/KIF17","pmids":["26085624"],"confidence":"High","gaps":["Stoichiometry and directionality within the KIF17 transport complex not resolved","Whether ANKS1B acts as cargo adaptor or transport regulator unclear"]},{"year":2015,"claim":"Immuno-EM localized ANKS1B to the PSD core and showed activity-dependent, reversible redistribution, framing it as a dynamic activity sensor at the synapse.","evidence":"Quantitative immunogold EM with two epitope-distinct antibodies under K+/NMDA stimulation","pmids":["26356309"],"confidence":"Medium","gaps":["Molecular trigger of redistribution not identified in this study","Relationship between PSD displacement and nuclear translocation unresolved"]},{"year":2016,"claim":"Identifying CaMKII as the kinase driving PSD displacement gave the activity-dependent redistribution a defined upstream signal.","evidence":"PSD phosphorylation assay plus immuno-EM with CaMKII inhibitor tatCN21 rescue","pmids":["27477489"],"confidence":"Medium","gaps":["Phosphosite(s) on ANKS1B not mapped","Causal link between phosphorylation and downstream trafficking not established"]},{"year":2019,"claim":"Defining the synaptic interactome and a haploinsufficiency model tied ANKS1B dosage to a neurodevelopmental disorder phenotype.","evidence":"Quantitative proteomics from patient-derived iPSC neurons and transgenic haploinsufficiency mice with behavioral assays","pmids":["31388001"],"confidence":"Medium","gaps":["Which interactome members are direct versus indirect partners not dissected","Cell type responsible for behavioral phenotypes not isolated here"]},{"year":2023,"claim":"Cell-type-specific knockouts revealed a non-neuronal role: ANKS1B controls Rac1-dependent oligodendrocyte maturation and myelination underlying social behavior.","evidence":"Oligodendrocyte-lineage vs neuronal conditional KO, Rac1 activity assay, and clemastine pharmacological rescue of social deficits","pmids":["38129387"],"confidence":"High","gaps":["Molecular link between ANKS1B and Rac1 regulation not defined","Whether the oligodendrocyte function uses the same domains as synaptic function unknown"]},{"year":2024,"claim":"A crystal structure defined the molecular basis by which the ANKS1B PTB domain recognizes SynGAP-family RasGAPs via an extended NPx[F/Y] motif.","evidence":"Affinity purification, binding assays, and crystal structure of the PTB domain bound to the SynGAP NPxF motif","pmids":["38759928"],"confidence":"High","gaps":["Functional consequence of the ANKS1B-SynGAP interaction in vivo not tested here","Which other NPx[F/Y]-containing proteins use this interface unexplored"]},{"year":2026,"claim":"An ischemia-induced lactylation switch at K1222 was shown to set ANKS1B abundance, coupling metabolic stress to GluN2B trafficking and excitotoxicity.","evidence":"Proteomics, OGD/R model, K1222R lactylation-resistant mutant, ubiquitin-proteasome and Ca2+/cell death assays","pmids":["41564684"],"confidence":"Medium","gaps":["Enzyme(s) catalyzing K1222 lactylation not identified","In vivo relevance of the neuroprotective feedback not established"]},{"year":2026,"claim":"Discovering an ANKS1B-CBP complex in the nucleus accumbens extended its nuclear role to direct epigenetic control of FoxO3 transcription in addiction behavior.","evidence":"Co-IP, H3K27ac ChIP, and viral ANKS1B manipulation in a cocaine self-administration rat model","pmids":["42228033"],"confidence":"Medium","gaps":["Whether nucleus accumbens ANKS1B is the same translocating fragment as the hippocampal nuclear species unknown","Direct DNA/chromatin contacts of the complex not mapped"]},{"year":null,"claim":"How ANKS1B's distinct activities — PSD scaffolding, GluN2B transport, nuclear coilin/CBP engagement, and oligodendrocyte Rac1 signaling — are coordinated by domain state, proteolysis, and post-translational modification remains unresolved.","evidence":"","pmids":[],"confidence":"Medium","gaps":["The protease generating the nuclear N-terminal fragment is unidentified","Whether one isoform performs all functions or distinct isoforms partition them is unclear","No unified model linking phosphorylation, lactylation, and SAM-gated import"]}],"mechanism_profile":{"molecular_activity":[{"term_id":"GO:0060090","term_label":"molecular adaptor activity","supporting_discovery_ids":[0,4,10]},{"term_id":"GO:0008092","term_label":"cytoskeletal protein binding","supporting_discovery_ids":[4,5]}],"localization":[{"term_id":"GO:0005886","term_label":"plasma membrane","supporting_discovery_ids":[5,6]},{"term_id":"GO:0005634","term_label":"nucleus","supporting_discovery_ids":[0,1,13]},{"term_id":"GO:0005730","term_label":"nucleolus","supporting_discovery_ids":[0,3]},{"term_id":"GO:0005783","term_label":"endoplasmic reticulum","supporting_discovery_ids":[4,12]}],"pathway":[{"term_id":"R-HSA-112316","term_label":"Neuronal System","supporting_discovery_ids":[0,4,5]},{"term_id":"R-HSA-9609507","term_label":"Protein localization","supporting_discovery_ids":[4,12]},{"term_id":"R-HSA-4839726","term_label":"Chromatin organization","supporting_discovery_ids":[13]}],"complexes":["postsynaptic density"],"partners":["GRIN2B","CASK","KIF17","DLG4","SYNGAP1","COIL","APP","CREBBP"],"other_free_text":[]}},"prefetch_data":{"uniprot":{"accession":"Q7Z6G8","full_name":"Ankyrin repeat and sterile alpha motif domain-containing protein 1B","aliases":["Amyloid-beta protein intracellular domain-associated protein 1","AIDA-1","E2A-PBX1-associated protein","EB-1"],"length_aa":1248,"mass_kda":138.1,"function":"Isoform 2 may participate in the regulation of nucleoplasmic coilin protein interactions in neuronal and transformed cells Isoform 3 can regulate global protein synthesis by altering nucleolar numbers Isoform 4 may play a role as a modulator of APP processing. Overexpression can down-regulate APP processing","subcellular_location":"Nucleus","url":"https://www.uniprot.org/uniprotkb/Q7Z6G8/entry"},"depmap":{"release":"DepMap","has_data":true,"is_common_essential":false,"resolved_as":"","url":"https://depmap.org/portal/gene/ANKS1B","classification":"Not Classified","n_dependent_lines":1,"n_total_lines":1208,"dependency_fraction":0.0008278145695364238},"opencell":{"profiled":false,"resolved_as":"","ensg_id":"","cell_line_id":"","localizations":[],"interactors":[],"url":"https://opencell.sf.czbiohub.org/search/ANKS1B","total_profiled":1310},"omim":[{"mim_id":"607815","title":"ANKYRIN REPEAT AND STERILE ALPHA MOTIF DOMAINS-CONTAINING PROTEIN 1B; ANKS1B","url":"https://www.omim.org/entry/607815"}],"hpa":{"profiled":true,"resolved_as":"","reliability":"Supported","locations":[{"location":"Nucleoplasm","reliability":"Supported"},{"location":"Plasma membrane","reliability":"Additional"}],"tissue_specificity":"Tissue enriched","tissue_distribution":"Detected in many","driving_tissues":[{"tissue":"brain","ntpm":66.3}],"url":"https://www.proteinatlas.org/search/ANKS1B"},"hgnc":{"alias_symbol":["EB-1","AIDA-1","cajalin-2","ANKS2"],"prev_symbol":[]},"alphafold":{"accession":"Q7Z6G8","domains":[{"cath_id":"1.25.40.20","chopping":"214-288","consensus_level":"medium","plddt":87.9396,"start":214,"end":288},{"cath_id":"1.10.150.50","chopping":"814-876","consensus_level":"medium","plddt":84.3648,"start":814,"end":876},{"cath_id":"1.10.150.50","chopping":"880-946","consensus_level":"medium","plddt":81.2381,"start":880,"end":946},{"cath_id":"2.30.29.30","chopping":"1052-1192","consensus_level":"high","plddt":86.6952,"start":1052,"end":1192}],"viewer_url":"https://alphafold.ebi.ac.uk/entry/Q7Z6G8","model_url":"https://alphafold.ebi.ac.uk/files/AF-Q7Z6G8-F1-model_v6.cif","pae_url":"https://alphafold.ebi.ac.uk/files/AF-Q7Z6G8-F1-predicted_aligned_error_v6.png","plddt_mean":56.94},"mouse_models":{"mgi_url":"https://www.informatics.jax.org/marker/summary?nomen=ANKS1B","jax_strain_url":"https://www.jax.org/strain/search?query=ANKS1B"},"sequence":{"accession":"Q7Z6G8","fasta_url":"https://rest.uniprot.org/uniprotkb/Q7Z6G8.fasta","uniprot_url":"https://www.uniprot.org/uniprotkb/Q7Z6G8/entry","alphafold_viewer_url":"https://alphafold.ebi.ac.uk/entry/Q7Z6G8"}},"corpus_meta":[{"pmid":"9348288","id":"PMC_9348288","title":"Mal3, 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letters","url":"https://pubmed.ncbi.nlm.nih.gov/27477489","citation_count":10,"is_preprint":false},{"pmid":"26356309","id":"PMC_26356309","title":"AIDA-1 Moves out of the Postsynaptic Density Core under Excitatory Conditions.","date":"2015","source":"PloS one","url":"https://pubmed.ncbi.nlm.nih.gov/26356309","citation_count":6,"is_preprint":false},{"pmid":"28332719","id":"PMC_28332719","title":"rs7968606 polymorphism of ANKS1B is associated with improvement in the PANSS general score of schizophrenia caused by amisulpride.","date":"2017","source":"Human psychopharmacology","url":"https://pubmed.ncbi.nlm.nih.gov/28332719","citation_count":5,"is_preprint":false},{"pmid":"22703994","id":"PMC_22703994","title":"Chronic ethanol up-regulates the synaptic expression of the nuclear translational regulatory protein AIDA-1 in primary hippocampal neurons.","date":"2012","source":"Alcohol (Fayetteville, N.Y.)","url":"https://pubmed.ncbi.nlm.nih.gov/22703994","citation_count":5,"is_preprint":false},{"pmid":"38759928","id":"PMC_38759928","title":"AIDA-1/ANKS1B Binds to the SynGAP Family RasGAPs with High Affinity and Specificity.","date":"2024","source":"Journal of molecular biology","url":"https://pubmed.ncbi.nlm.nih.gov/38759928","citation_count":2,"is_preprint":false},{"pmid":"37597021","id":"PMC_37597021","title":"Replication stress causes delayed mitotic entry and chromosome 12 fragility at the ANKS1B large neuronal gene in human induced pluripotent stem cells.","date":"2023","source":"Chromosome research : an international journal on the molecular, supramolecular and evolutionary aspects of chromosome biology","url":"https://pubmed.ncbi.nlm.nih.gov/37597021","citation_count":2,"is_preprint":false},{"pmid":"41564684","id":"PMC_41564684","title":"Lactylation-mediated degradation of ANKS1B mitigates ischemic excitotoxicity by impairing GluN2B trafficking.","date":"2026","source":"Biochemical and biophysical research communications","url":"https://pubmed.ncbi.nlm.nih.gov/41564684","citation_count":0,"is_preprint":false},{"pmid":"42228033","id":"PMC_42228033","title":"ANKS1B in the Nucleus Accumbens Controls Escalated Cocaine Self-Administration via Regulating CBP-FoxO3 Complex.","date":"2026","source":"Advanced science (Weinheim, Baden-Wurttemberg, Germany)","url":"https://pubmed.ncbi.nlm.nih.gov/42228033","citation_count":0,"is_preprint":false}],"cost":{"stage1":{"model":"claude-sonnet-4-6","input_tokens":14614,"output_tokens":3814,"usd":0.050526,"stage1_stop_reason":"end_turn"},"stage2":{"model":"claude-opus-4-8","input_tokens":11523,"output_tokens":4049,"usd":0.07942,"stage2_stop_reason":"end_turn"},"total_usd":0.129946,"stage1_batch_id":"msgbatch_0179Z2pxRYBsXi2xADneafRw","stage2_batch_id":"msgbatch_01LaY9ZaVdgjWArcZo9eqQE5","note":"batch pricing = 50% of standard"},"stage1_raw":"```json\n{\n  \"discoveries\": [\n    {\n      \"year\": 2007,\n      \"finding\": \"AIDA-1d binds to the first two PDZ domains of the scaffolding protein PSD-95 via its C-terminal three amino acids; stimulation of NMDA receptors results in Ca2+-independent translocation of AIDA-1d to the nucleus, where it couples to Cajal bodies and induces Cajal body-nucleolar association; long-term neuronal stimulation results in an AIDA-1-dependent increase in nucleolar numbers and protein synthesis.\",\n      \"method\": \"Co-immunoprecipitation, subcellular fractionation, immunofluorescence, neuronal stimulation assays\",\n      \"journal\": \"Nature neuroscience\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — reciprocal binding demonstrated, multiple orthogonal methods (Co-IP, imaging, functional protein synthesis readout), replicated across stimulation paradigms\",\n      \"pmids\": [\"17334360\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2009,\n      \"finding\": \"AIDA-1 contains two SAM domains in a head-to-tail orientation separated by a 15-aa linker; the nuclear localization signal is buried at the SAM-SAM domain interface; differential thermal stability of the two SAM domains suggests the second SAM domain decouples from the first to expose the NLS and facilitate nuclear import.\",\n      \"method\": \"NMR structure determination, thermal stability assays\",\n      \"journal\": \"Journal of molecular biology\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 / Moderate — NMR structure with functional interpretation of NLS burial, single lab but structural data with mechanistic validation\",\n      \"pmids\": [\"19666031\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2004,\n      \"finding\": \"AIDA-1 proteins (isoforms AIDA-1a, AIDA-1b, AIDA-1bΔAnk) interact with the intracellular domain of amyloid precursor protein (AbetaPP) in vitro, in living cells, and endogenously in leukemia cell lines; the intracellular localization of AIDA-1a can be modified by overexpression of AbetaPP.\",\n      \"method\": \"Co-immunoprecipitation, in vitro binding assay, transfection/overexpression with subcellular localization imaging\",\n      \"journal\": \"Journal of Alzheimer's disease : JAD\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — reciprocal Co-IP in multiple contexts (in vitro, cell lines, endogenous), localization change tied to binding partner, single lab\",\n      \"pmids\": [\"15004329\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2005,\n      \"finding\": \"A novel isoform AIDA-1c interacts with the Cajal body marker protein coilin; AIDA-1c competes with SmB' for coilin binding sites but does not bind SMN; siRNA knockdown of EB-1/AIDA-1 isoforms altered Cajal body organization and reduced cell viability.\",\n      \"method\": \"Co-immunoprecipitation, competition binding assays, siRNA knockdown, immunofluorescence\",\n      \"journal\": \"BMC cell biology\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — Co-IP with competition assay, functional knockdown phenotype, single lab with two orthogonal methods\",\n      \"pmids\": [\"15862129\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2015,\n      \"finding\": \"AIDA-1 (encoded by ANKS1B) regulates synaptic NMDA receptor subunit composition: forebrain-specific AIDA-1 conditional knockout mice exhibit reduced GluN2B-mediated and increased GluN2A-mediated synaptic transmission; GluN2B accumulates in ER-enriched fractions in AIDA-1 cKO mice; AIDA-1 preferentially associates with GluN2B, CASK, and KIF17, which regulate transport of GluN2B-containing NMDARs from the ER to synapses; NMDAR-dependent but not mGluR-dependent plasticity is impaired in AIDA-1 cKO mice.\",\n      \"method\": \"Conditional knockout mouse, electrophysiology, biochemical fractionation, Co-immunoprecipitation, lentiviral shRNA knockdown, immunocytochemistry\",\n      \"journal\": \"The Journal of neuroscience\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — conditional KO with multiple orthogonal methods (electrophysiology, fractionation, Co-IP, imaging), mechanistic pathway (ER export) defined\",\n      \"pmids\": [\"26085624\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2015,\n      \"finding\": \"Under basal conditions, AIDA-1 concentrates within the electron-dense core of the postsynaptic density (~30 nm from postsynaptic membrane); under excitatory conditions (high K+ or NMDA application), AIDA-1 label density at the PSD core is reduced to 40% of controls and median distance increases to ~55 nm; this redistribution is reversible within 30 minutes.\",\n      \"method\": \"Immunogold electron microscopy with two antibodies recognizing different epitopes, pharmacological stimulation\",\n      \"journal\": \"PloS one\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — direct subcellular localization by immuno-EM with quantification, two antibodies, functional context established\",\n      \"pmids\": [\"26356309\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2016,\n      \"finding\": \"CaMKII mediates phosphorylation of AIDA-1 upon activation; NMDA treatment causes an ~30 nm shift in median distance of AIDA-1 from the postsynaptic membrane, an effect blocked by the CaMKII inhibitor tatCN21; CaMKII-mediated displacement of AIDA-1 from the PSD core is mechanistically similar to that of SynGAP.\",\n      \"method\": \"Phosphorylation assay with PSD fractions, immuno-electron microscopy, pharmacological inhibition of CaMKII\",\n      \"journal\": \"FEBS letters\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — kinase-substrate assay combined with immuno-EM and pharmacological rescue, single lab\",\n      \"pmids\": [\"27477489\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2015,\n      \"finding\": \"ANKS1B was identified as a novel binding partner of KRIT1 (CCM1) by yeast two-hybrid screen; silencing ANKS1B in primary human endothelial cells increased endothelial permeability, while forced ANKS1B expression reduced permeability; this effect was independent of Rho kinase activity and presence of KRIT1; silencing had no significant effect on proliferation, migration, or sprouting angiogenesis.\",\n      \"method\": \"Yeast two-hybrid screen, siRNA knockdown, overexpression, permeability assays, pharmacological inhibition\",\n      \"journal\": \"PloS one\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — Y2H identification followed by functional KD and OE with specific phenotype, single lab\",\n      \"pmids\": [\"26698571\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2019,\n      \"finding\": \"AIDA-1 interactome identified by quantitative proteomics from patient-derived iPSC neurons and transgenic mouse model; Anks1b haploinsufficiency leads to loss of AIDA-1 at synapses, recapitulating neurodevelopmental phenotypes (social deficits, hyperactivity, sensorimotor dysfunction) in mice; protein networks involved in synaptic function were identified as AIDA-1 binding partners.\",\n      \"method\": \"Quantitative proteomics (interactome), patient-derived iPSC neurons, transgenic haploinsufficiency mouse model, behavioral assays\",\n      \"journal\": \"Nature communications\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — quantitative proteomics interactome with mouse model validation, multiple phenotypic readouts, single lab\",\n      \"pmids\": [\"31388001\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2023,\n      \"finding\": \"Anks1b-deficient mice display deficits in oligodendrocyte maturation, myelination, and Rac1 function; selective loss of Anks1b from the oligodendrocyte lineage (but not neuronal populations) leads to deficits in social preference and sensory reactivity; clemastine (an oligodendrocyte precursor maturation promoter) rescues social preference deficits in Anks1b-deficient mice.\",\n      \"method\": \"Cell type-specific conditional knockout (oligodendrocyte lineage vs. neuronal), myelination assays, Rac1 activity assay, behavioral assays, pharmacological rescue\",\n      \"journal\": \"Nature communications\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — cell-type specific conditional KO with epistasis-like dissection, pharmacological rescue, multiple orthogonal methods and readouts\",\n      \"pmids\": [\"38129387\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2024,\n      \"finding\": \"The PTB domain of AIDA-1 binds to an extended NPx[F/Y]-motif of SynGAP family Ras-GTPase activating proteins with high affinity; crystal structure of the AIDA-1 PTB domain in complex with the SynGAP NPxF-motif revealed the molecular basis of this specific interaction.\",\n      \"method\": \"Affinity purification, biochemical binding assays, crystal structure determination\",\n      \"journal\": \"Journal of molecular biology\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 / Moderate — crystal structure with biochemical validation (affinity purification and binding assays), single lab but two orthogonal methods\",\n      \"pmids\": [\"38759928\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2012,\n      \"finding\": \"Chronic ethanol exposure enhances synaptic clustering of AIDA-1 in hippocampal neurons; concurrent NMDA receptor stimulation prevents this ethanol-induced synaptic accumulation; the association of AIDA-1 with PSD-95 is not required for its localization to the PSD (negative finding: PSD-95 declustering did not affect AIDA-1 synaptic distribution); AIDA-1 knockdown did not affect protein expression levels of GluN1 or GluN2B NMDA receptor subunits (negative finding).\",\n      \"method\": \"Lentiviral shRNA knockdown, immunofluorescence, pharmacological treatments (ethanol, AP-V, NMDA, palmitoylation inhibitor)\",\n      \"journal\": \"Alcohol (Fayetteville, N.Y.)\",\n      \"confidence\": \"Low\",\n      \"confidence_rationale\": \"Tier 3 / Weak — single lab, primarily imaging-based with pharmacological manipulation, no mechanistic pathway placement beyond observation\",\n      \"pmids\": [\"22703994\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2026,\n      \"finding\": \"Ischemia induces ANKS1B lactylation at the conserved K1222 site, which targets ANKS1B for ubiquitin-proteasome-mediated degradation; ANKS1B regulates ER export of GluN2B; lactylation-driven ANKS1B loss leads to GluN2B retention in the ER; a lactylation-resistant mutant (ANKS1B-K1222R) prevented degradation and restored GluN2B surface trafficking but exacerbated excitotoxic Ca2+ overload and neuronal death.\",\n      \"method\": \"Proteomics, OGD/R cell model, site-directed mutagenesis (K1222R), ubiquitin-proteasome pathway assays, Ca2+ imaging, cell death assays\",\n      \"journal\": \"Biochemical and biophysical research communications\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — mutagenesis with functional rescue/loss readouts, multiple orthogonal methods, single lab\",\n      \"pmids\": [\"41564684\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2026,\n      \"finding\": \"ANKS1B in the nucleus accumbens interacts with the histone acetyltransferase CBP to control H3K27 acetylation; this complex epigenetically represses the transcription factor FoxO3; ANKS1B downregulation after extended cocaine use leads to escalated cocaine intake via this CBP-FoxO3 pathway; manipulating ANKS1B selectively influences escalation of cocaine intake and cocaine-seeking behavior.\",\n      \"method\": \"Co-immunoprecipitation, ChIP assay (H3K27ac), viral vector-mediated ANKS1B manipulation, cocaine self-administration rat model\",\n      \"journal\": \"Advanced science\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — Co-IP for complex, ChIP for epigenetic modification, in vivo behavioral model with genetic manipulation, single lab\",\n      \"pmids\": [\"42228033\"],\n      \"is_preprint\": false\n    }\n  ],\n  \"current_model\": \"AIDA-1 (ANKS1B) is a postsynaptic scaffold protein that localizes to the PSD core under basal conditions and undergoes CaMKII-mediated phosphorylation and displacement from the PSD core upon NMDA receptor activation; it facilitates anterograde transport of GluN2B-containing NMDARs from the ER to synapses by associating with GluN2B, CASK, and KIF17, thereby controlling synaptic NMDAR subunit composition and NMDAR-dependent plasticity; its PTB domain binds SynGAP family RasGAPs via NPx[F/Y] motifs; upon synaptic activation, an N-terminal fragment translocates to the nucleus where it couples to Cajal bodies via coilin interaction to regulate nucleolar assembly and global protein synthesis; in oligodendrocytes, ANKS1B controls Rac1-dependent maturation and myelination relevant to social behavior; in the nucleus accumbens, it interacts with CBP to regulate H3K27 acetylation and FoxO3-dependent transcription; during ischemia, lactylation at K1222 targets ANKS1B for proteasomal degradation, reducing GluN2B surface trafficking as a neuroprotective feedback mechanism.\"\n}\n```","stage2_raw":"{\n  \"mechanistic_narrative\": \"ANKS1B (AIDA-1) is a multidomain postsynaptic scaffold protein that couples NMDA receptor activity to synaptic composition, gene expression, and global protein synthesis [#0, #4]. At the synapse it concentrates within the electron-dense core of the postsynaptic density under basal conditions and is displaced toward the periphery upon NMDA receptor activation through CaMKII-mediated phosphorylation, in a manner mechanistically parallel to SynGAP [#5, #6]. It preferentially associates with GluN2B together with CASK and KIF17 to drive anterograde transport of GluN2B-containing NMDARs from the ER to synapses, thereby setting the synaptic GluN2B/GluN2A balance and enabling NMDAR-dependent plasticity; loss of AIDA-1 causes ER retention of GluN2B and impaired plasticity [#4]. Its PTB domain binds SynGAP-family RasGAPs through an extended NPx[F/Y] motif, a recognition mode defined at atomic resolution [#10]. Upon NMDAR stimulation an N-terminal fragment translocates to the nucleus — gated by an NLS buried at a tandem SAM-SAM domain interface that is exposed by domain decoupling — where it engages the Cajal body protein coilin to promote Cajal body-nucleolar association, nucleolar biogenesis, and protein synthesis [#0, #1, #3]. Beyond neurons, ANKS1B functions in the oligodendrocyte lineage to control Rac1-dependent maturation and myelination underlying social behavior [#9], and in the nucleus accumbens it forms a complex with the acetyltransferase CBP to regulate H3K27 acetylation and FoxO3-dependent transcription relevant to addiction-related behavior [#13]. ANKS1B haploinsufficiency produces neurodevelopmental phenotypes including social deficits, hyperactivity, and sensorimotor dysfunction [#8].\",\n  \"teleology\": [\n    {\n      \"year\": 2004,\n      \"claim\": \"Establishing ANKS1B's first molecular partner addressed whether the protein had a defined binding function, linking it to amyloid precursor protein biology.\",\n      \"evidence\": \"Co-IP and in vitro binding of multiple AIDA-1 isoforms to the AbetaPP intracellular domain, with localization shifts on AbetaPP overexpression\",\n      \"pmids\": [\"15004329\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Functional consequence of the AbetaPP interaction in neurons unresolved\", \"Binding mapped to isoforms but not to a specific domain\", \"Single lab\"]\n    },\n    {\n      \"year\": 2005,\n      \"claim\": \"Identifying coilin binding placed an ANKS1B isoform in the nuclear Cajal body compartment, hinting at a role beyond cytoplasmic scaffolding.\",\n      \"evidence\": \"Co-IP, competition binding against SmB', siRNA knockdown altering Cajal body organization in cells\",\n      \"pmids\": [\"15862129\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Mechanism linking coilin binding to nucleolar function not yet defined\", \"Physiological trigger for nuclear targeting unknown at this stage\"]\n    },\n    {\n      \"year\": 2007,\n      \"claim\": \"Connecting synaptic NMDAR activity to nuclear translocation defined ANKS1B as a synapse-to-nucleus messenger controlling protein synthesis capacity.\",\n      \"evidence\": \"Co-IP with PSD-95 PDZ domains, subcellular fractionation, and stimulation-induced nuclear coupling to Cajal bodies with increased nucleolar number and protein synthesis\",\n      \"pmids\": [\"17334360\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Identity of the translocating cleavage fragment and the cleavage mechanism not established\", \"Transcriptional/translational targets downstream of nucleolar expansion undefined\"]\n    },\n    {\n      \"year\": 2009,\n      \"claim\": \"Resolving the tandem SAM domain structure explained how nuclear import is gated, by burying the NLS at the SAM-SAM interface.\",\n      \"evidence\": \"NMR structure determination with differential thermal stability analysis of the two SAM domains\",\n      \"pmids\": [\"19666031\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Direct demonstration that SAM decoupling triggers import in cells not shown\", \"Signal that drives domain decoupling unidentified\"]\n    },\n    {\n      \"year\": 2015,\n      \"claim\": \"Conditional knockout work established the core synaptic function: control of NMDAR subunit composition via ER-to-synapse transport of GluN2B.\",\n      \"evidence\": \"Forebrain AIDA-1 cKO mice analyzed by electrophysiology, fractionation, and Co-IP with GluN2B/CASK/KIF17\",\n      \"pmids\": [\"26085624\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Stoichiometry and directionality within the KIF17 transport complex not resolved\", \"Whether ANKS1B acts as cargo adaptor or transport regulator unclear\"]\n    },\n    {\n      \"year\": 2015,\n      \"claim\": \"Immuno-EM localized ANKS1B to the PSD core and showed activity-dependent, reversible redistribution, framing it as a dynamic activity sensor at the synapse.\",\n      \"evidence\": \"Quantitative immunogold EM with two epitope-distinct antibodies under K+/NMDA stimulation\",\n      \"pmids\": [\"26356309\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Molecular trigger of redistribution not identified in this study\", \"Relationship between PSD displacement and nuclear translocation unresolved\"]\n    },\n    {\n      \"year\": 2016,\n      \"claim\": \"Identifying CaMKII as the kinase driving PSD displacement gave the activity-dependent redistribution a defined upstream signal.\",\n      \"evidence\": \"PSD phosphorylation assay plus immuno-EM with CaMKII inhibitor tatCN21 rescue\",\n      \"pmids\": [\"27477489\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Phosphosite(s) on ANKS1B not mapped\", \"Causal link between phosphorylation and downstream trafficking not established\"]\n    },\n    {\n      \"year\": 2019,\n      \"claim\": \"Defining the synaptic interactome and a haploinsufficiency model tied ANKS1B dosage to a neurodevelopmental disorder phenotype.\",\n      \"evidence\": \"Quantitative proteomics from patient-derived iPSC neurons and transgenic haploinsufficiency mice with behavioral assays\",\n      \"pmids\": [\"31388001\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Which interactome members are direct versus indirect partners not dissected\", \"Cell type responsible for behavioral phenotypes not isolated here\"]\n    },\n    {\n      \"year\": 2023,\n      \"claim\": \"Cell-type-specific knockouts revealed a non-neuronal role: ANKS1B controls Rac1-dependent oligodendrocyte maturation and myelination underlying social behavior.\",\n      \"evidence\": \"Oligodendrocyte-lineage vs neuronal conditional KO, Rac1 activity assay, and clemastine pharmacological rescue of social deficits\",\n      \"pmids\": [\"38129387\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Molecular link between ANKS1B and Rac1 regulation not defined\", \"Whether the oligodendrocyte function uses the same domains as synaptic function unknown\"]\n    },\n    {\n      \"year\": 2024,\n      \"claim\": \"A crystal structure defined the molecular basis by which the ANKS1B PTB domain recognizes SynGAP-family RasGAPs via an extended NPx[F/Y] motif.\",\n      \"evidence\": \"Affinity purification, binding assays, and crystal structure of the PTB domain bound to the SynGAP NPxF motif\",\n      \"pmids\": [\"38759928\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Functional consequence of the ANKS1B-SynGAP interaction in vivo not tested here\", \"Which other NPx[F/Y]-containing proteins use this interface unexplored\"]\n    },\n    {\n      \"year\": 2026,\n      \"claim\": \"An ischemia-induced lactylation switch at K1222 was shown to set ANKS1B abundance, coupling metabolic stress to GluN2B trafficking and excitotoxicity.\",\n      \"evidence\": \"Proteomics, OGD/R model, K1222R lactylation-resistant mutant, ubiquitin-proteasome and Ca2+/cell death assays\",\n      \"pmids\": [\"41564684\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Enzyme(s) catalyzing K1222 lactylation not identified\", \"In vivo relevance of the neuroprotective feedback not established\"]\n    },\n    {\n      \"year\": 2026,\n      \"claim\": \"Discovering an ANKS1B-CBP complex in the nucleus accumbens extended its nuclear role to direct epigenetic control of FoxO3 transcription in addiction behavior.\",\n      \"evidence\": \"Co-IP, H3K27ac ChIP, and viral ANKS1B manipulation in a cocaine self-administration rat model\",\n      \"pmids\": [\"42228033\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Whether nucleus accumbens ANKS1B is the same translocating fragment as the hippocampal nuclear species unknown\", \"Direct DNA/chromatin contacts of the complex not mapped\"]\n    },\n    {\n      \"year\": null,\n      \"claim\": \"How ANKS1B's distinct activities — PSD scaffolding, GluN2B transport, nuclear coilin/CBP engagement, and oligodendrocyte Rac1 signaling — are coordinated by domain state, proteolysis, and post-translational modification remains unresolved.\",\n      \"evidence\": \"\",\n      \"pmids\": [],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"The protease generating the nuclear N-terminal fragment is unidentified\", \"Whether one isoform performs all functions or distinct isoforms partition them is unclear\", \"No unified model linking phosphorylation, lactylation, and SAM-gated import\"]\n    }\n  ],\n  \"mechanism_profile\": {\n    \"molecular_activity\": [\n      {\"term_id\": \"GO:0060090\", \"supporting_discovery_ids\": [0, 4, 10]},\n      {\"term_id\": \"GO:0008092\", \"supporting_discovery_ids\": [4, 5]}\n    ],\n    \"localization\": [\n      {\"term_id\": \"GO:0005886\", \"supporting_discovery_ids\": [5, 6]},\n      {\"term_id\": \"GO:0005634\", \"supporting_discovery_ids\": [0, 1, 13]},\n      {\"term_id\": \"GO:0005730\", \"supporting_discovery_ids\": [0, 3]},\n      {\"term_id\": \"GO:0005783\", \"supporting_discovery_ids\": [4, 12]}\n    ],\n    \"pathway\": [\n      {\"term_id\": \"R-HSA-112316\", \"supporting_discovery_ids\": [0, 4, 5]},\n      {\"term_id\": \"R-HSA-9609507\", \"supporting_discovery_ids\": [4, 12]},\n      {\"term_id\": \"R-HSA-4839726\", \"supporting_discovery_ids\": [13]}\n    ],\n    \"complexes\": [\"postsynaptic density\"],\n    \"partners\": [\"GRIN2B\", \"CASK\", \"KIF17\", \"DLG4\", \"SYNGAP1\", \"COIL\", \"APP\", \"CREBBP\"],\n    \"other_free_text\": []\n  }\n}","audit_flag":null,"evaluation":{"pairwise":"win","faith_supported":7,"faith_total":7,"faith_pct":100.0}}