{"gene":"AIDA","run_date":"2026-04-28T17:12:37","timeline":{"discoveries":[{"year":2007,"finding":"AIDA-1d (encoded by ANKS1B) binds to the first two PDZ domains of the scaffolding protein PSD-95 via its C-terminal three amino acids. NMDA receptor stimulation causes Ca2+-independent translocation of AIDA-1d to the nucleus, where it couples to Cajal bodies and induces Cajal body-nucleolar association, resulting in increased nucleolar numbers and global protein synthesis.","method":"Biochemical binding assays, live-cell imaging, NMDA receptor stimulation with functional readout (nucleolar number and protein synthesis measurement)","journal":"Nature neuroscience","confidence":"High","confidence_rationale":"Tier 2 — multiple orthogonal methods (binding assay, imaging, functional protein synthesis readout) in a single rigorous study","pmids":["17334360"],"is_preprint":false},{"year":2007,"finding":"Aida (axin interactor, dorsalization-associated) blocks Axin-mediated JNK activation by disrupting Axin homodimerization, thereby antagonizing a beta-catenin-independent dorsalization pathway during vertebrate embryogenesis. Morpholino knockdown of Aida in zebrafish leads to dorsalized embryos; this effect is rescued by JNK-MO or MKK4-MO injection, placing Aida upstream of JNK/MKK4 in the Axin signaling axis.","method":"Co-immunoprecipitation, zebrafish morpholino knockdown/overexpression with epistasis analysis, JNK activity assays","journal":"Developmental cell","confidence":"High","confidence_rationale":"Tier 2 — reciprocal Co-IP combined with genetic epistasis in vivo, multiple orthogonal methods","pmids":["17681137"],"is_preprint":false},{"year":2015,"finding":"AIDA-1 (ANKS1B) regulates synaptic NMDAR subunit composition by facilitating transport of GluN2B-containing NMDARs from the ER to synapses. Forebrain-specific AIDA-1 conditional knockout mice show reduced GluN2B and increased GluN2A at synaptic junctions; GluN2B accumulates in ER-enriched fractions. AIDA-1 preferentially associates with GluN2B and with the adaptor proteins CaMKII and KIF17, which regulate GluN2B transport.","method":"Conditional knockout mice, biochemical fractionation, co-immunoprecipitation, electrophysiology, immunocytochemistry, lentiviral shRNA knockdown","journal":"The Journal of neuroscience","confidence":"High","confidence_rationale":"Tier 2 — clean conditional KO with defined molecular phenotype, multiple orthogonal methods including Co-IP, fractionation, and electrophysiology","pmids":["26085624"],"is_preprint":false},{"year":2018,"finding":"AIDA acts as an essential cofactor for the E3 ubiquitin ligase HRD1 of the ERAD pathway to downregulate rate-limiting acyltransferases GPAT3, MOGAT2, and DGAT2, thereby controlling intestinal triacylglycerol synthesis and fat absorption. Aida-/- mice and intestine-specific Aida knockout mice display increased intestinal fatty acid re-esterification, elevated circulating and tissue triacylglycerol, and increased adiposity.","method":"Whole-body and intestine-specific knockout mice, protein abundance assays, fat absorption measurements, in vivo metabolic phenotyping","journal":"Cell metabolism","confidence":"High","confidence_rationale":"Tier 2 — tissue-specific KO recapitulating whole-body KO phenotype, multiple orthogonal metabolic readouts","pmids":["29617643"],"is_preprint":false},{"year":2021,"finding":"AIDA is phosphorylated at S161 by catecholamine-activated PKA on the outer mitochondrial membrane. Phosphorylated AIDA translocates to the intermembrane space, where it binds UCP1 and activates its uncoupling activity by promoting cysteine oxidation of UCP1. Adipocyte-specific AIDA depletion abrogates UCP1-dependent thermogenesis. Re-expression of S161A-AIDA (phospho-dead mutant) fails to restore the acute cold response.","method":"Adipocyte-specific knockout mice, phospho-site mutagenesis (S161A), in vitro PKA phosphorylation assay, co-immunoprecipitation, UCP1 uncoupling activity assay, sympathetic denervation experiment","journal":"Nature cell biology","confidence":"High","confidence_rationale":"Tier 1 — in vitro enzymatic assay, mutagenesis, KO with defined phenotype, and Co-IP, all in one rigorous study","pmids":["33664495"],"is_preprint":false},{"year":2009,"finding":"The nuclear localization signal (NLS) of AIDA-1 is buried at the interface between its two tandemly arranged SAM domains. The NMR structure reveals the two SAM domains are fused head-to-tail; the NLS becomes accessible only when the second SAM domain decouples from the first, suggesting a mechanism for regulated nuclear import of AIDA-1.","method":"NMR structure determination of SAM domain tandem, thermal stability assays","journal":"Journal of molecular biology","confidence":"High","confidence_rationale":"Tier 1 — NMR structure with functional interpretation of NLS burial, rigorous single-study","pmids":["19666031"],"is_preprint":false},{"year":2014,"finding":"The C-terminal C2 domain of Aida adopts a conventional C2 domain topology and binds phosphoinositides in a Ca2+-independent manner via a positively charged basic loop, enabling membrane association. Mutation of the basic loop disrupts membrane association and the Aida-Axin interaction, resulting in impaired JNK inhibition.","method":"X-ray crystallography, phosphoinositide-binding assay, site-directed mutagenesis, co-immunoprecipitation, JNK activity assay","journal":"The FEBS journal","confidence":"High","confidence_rationale":"Tier 1 — crystal structure combined with mutagenesis and functional JNK inhibition assay in one study","pmids":["25117763"],"is_preprint":false},{"year":2004,"finding":"AIDA-1 proteins (AIDA-1a, AIDA-1b, AIDA-1bΔAnk) interact with APP (AbetaPP) in vitro, in transfected living cells, and endogenously in leukemia cell lines. The intracellular distribution of AIDA-1a is altered by overexpression of AbetaPP, indicating AbetaPP regulates AIDA-1 localization.","method":"Co-immunoprecipitation in vitro and in vivo, overexpression with subcellular localization readout","journal":"Journal of Alzheimer's disease","confidence":"Medium","confidence_rationale":"Tier 3 — Co-IP with localization change, single lab, no mechanistic follow-up of pathway placement","pmids":["15004329"],"is_preprint":false},{"year":2005,"finding":"A novel isoform AIDA-1c interacts with the Cajal body marker protein coilin in vivo, competing with SmB' for coilin binding sites. Knockdown of EB-1/AIDA-1 isoforms by siRNA alters Cajal body organization and reduces cell viability.","method":"Co-immunoprecipitation, competition binding assay, siRNA knockdown with Cajal body morphology readout","journal":"BMC cell biology","confidence":"Medium","confidence_rationale":"Tier 3 — Co-IP and competition binding combined with KD phenotype, single lab","pmids":["15862129"],"is_preprint":false},{"year":2016,"finding":"CaMKII activation mediates phosphorylation of AIDA-1 and causes its displacement from the postsynaptic density (PSD) core. Treatment of hippocampal neurons with NMDA causes an ~30 nm shift in AIDA-1 median distance from the postsynaptic membrane, an effect blocked by the CaMKII inhibitor tatCN21.","method":"PSD fractionation with phosphorylation assay, immuno-electron microscopy of hippocampal neurons with pharmacological CaMKII inhibition","journal":"FEBS letters","confidence":"Medium","confidence_rationale":"Tier 2 — direct phosphorylation assay combined with immuno-EM localization and pharmacological rescue, single lab","pmids":["27477489"],"is_preprint":false},{"year":2015,"finding":"Under excitatory conditions (high K+ or NMDA application), AIDA-1 moves out of the PSD core, with label density at the core reduced to 40% of controls and median distance from postsynaptic membrane increasing from ~30 nm to ~55 nm; this redistribution is reversible within 30 minutes.","method":"Immunogold electron microscopy of cultured rat hippocampal neurons under basal and excitatory conditions","journal":"PloS one","confidence":"Medium","confidence_rationale":"Tier 2 — quantitative immuno-EM with two distinct antibodies, single lab","pmids":["26356309"],"is_preprint":false},{"year":2019,"finding":"Loss-of-function experiments using CRISPR/Cas9 deletion of a TNFα-sensitive regulatory element in endothelial cells reduce AIDA expression, implicating AIDA as regulated by a CAD-associated genetic locus in the vascular endothelium.","method":"CRISPR/Cas9 deletion of regulatory element with gene expression measurement","journal":"Genome biology","confidence":"Low","confidence_rationale":"Tier 3 — regulatory element deletion with expression readout only, no direct mechanistic pathway placement for AIDA protein","pmids":["31287004"],"is_preprint":false},{"year":2023,"finding":"Selective loss of Anks1b (encoding AIDA-1) from the oligodendrocyte lineage (but not neuronal populations) leads to deficits in oligodendrocyte maturation, myelination, and Rac1 function, causing social preference and sensory reactivity deficits. Treatment with clemastine rescues social preference deficits in Anks1b-deficient mice.","method":"Cell-type-specific conditional knockout mice, myelination assays, Rac1 activity assay, behavioral phenotyping, pharmacological rescue","journal":"Nature communications","confidence":"High","confidence_rationale":"Tier 2 — cell-type-specific KO with defined molecular (Rac1) and cellular (myelination) phenotypes, pharmacological rescue, rigorous study","pmids":["38129387"],"is_preprint":false},{"year":2024,"finding":"The PTB domain of AIDA-1d binds with high affinity to an extended NPx[F/Y]-motif of SynGAP family Ras-GTPase activating proteins. The crystal structure of AIDA-1 PTB domain in complex with the SynGAP NPxF-motif revealed the molecular basis for this specific interaction.","method":"Affinity purification, biochemical binding assays, X-ray crystallography of PTB–SynGAP complex","journal":"Journal of molecular biology","confidence":"High","confidence_rationale":"Tier 1 — crystal structure plus biochemical binding characterization in one study","pmids":["38759928"],"is_preprint":false},{"year":2026,"finding":"AIDA scaffolds HRD1-mediated K63-linked ubiquitination of VAMP3, facilitating VAMP3-CD36 interaction and CD36 membrane translocation in VSMCs. VSMC-specific AIDA knockout attenuates atherosclerotic plaque burden and suppresses oxLDL uptake and foam cell formation by impairing CD36 membrane trafficking without affecting cholesterol efflux.","method":"VSMC-specific knockout in ApoE-/- mice, co-immunoprecipitation, cholesterol flux assays, ubiquitination profiling, adenoviral shRNA silencing","journal":"Atherosclerosis","confidence":"High","confidence_rationale":"Tier 2 — cell-type-specific KO plus Co-IP and ubiquitination profiling revealing the HRD1-VAMP3-CD36 mechanistic axis","pmids":["42013606"],"is_preprint":false},{"year":2019,"finding":"Haploinsufficiency of ANKS1B causes loss of the synaptic protein AIDA-1. Quantitative proteomics of the AIDA-1 interactome in haploinsufficient mice revealed protein networks involved in synaptic function. Anks1b haploinsufficient mice recapitulate social deficits, hyperactivity, and sensorimotor dysfunction.","method":"Transgenic haploinsufficiency mouse model, quantitative proteomics (interactome), behavioral phenotyping, iPSC-derived neurons","journal":"Nature communications","confidence":"Medium","confidence_rationale":"Tier 2 — interactome proteomics combined with in vivo model; mechanistic pathway placement is partial","pmids":["31388001"],"is_preprint":false},{"year":2012,"finding":"Chronic ethanol exposure increases synaptic clustering of AIDA-1 in hippocampal neurons, an effect prevented by concurrent NMDA receptor stimulation. AIDA-1 localization to the PSD does not require its association with PSD-95 (palmitoylation inhibition declusters PSD-95 but not AIDA-1). AIDA-1 knockdown does not affect GluN1 or GluN2B protein levels.","method":"Lentiviral shRNA knockdown, chronic ethanol treatment, immunofluorescence colocalization, palmitoylation inhibition","journal":"Alcohol","confidence":"Medium","confidence_rationale":"Tier 3 — single lab, multiple complementary methods showing PSD-95-independent PSD localization and activity-regulated synaptic enrichment","pmids":["22703994"],"is_preprint":false}],"current_model":"AIDA (axin interactor, dorsalization-associated; encoded by ANKS1B as AIDA-1 in neurons) is a multifunctional scaffold protein: in brown adipocytes, it is phosphorylated by PKA at S161, translocates to the mitochondrial intermembrane space, and directly activates UCP1-mediated thermogenesis by promoting cysteine oxidation of UCP1; in intestinal epithelium, it acts as an essential HRD1 E3-ligase cofactor to target acyltransferases (GPAT3, MOGAT2, DGAT2) for ERAD-dependent degradation, limiting dietary fat absorption; in VSMCs, AIDA scaffolds HRD1-mediated K63-ubiquitination of VAMP3, driving CD36 membrane translocation and foam cell formation; in neurons, AIDA-1 (ANKS1B) concentrates at the PSD core by binding PSD-95 PDZ domains, undergoes CaMKII-dependent phosphorylation and activity-induced dispersal from the PSD core, facilitates GluN2B-containing NMDAR transport from the ER to synapses (regulating subunit composition and plasticity), and translocates to the nucleus upon NMDAR activation to regulate Cajal body-nucleolar association and global protein synthesis; additionally, AIDA blocks Axin-mediated JNK activation by disrupting Axin homodimerization, antagonizing a beta-catenin-independent dorsalization pathway."},"narrative":{"teleology":[{"year":2004,"claim":"Before any signaling role was established, AIDA-1 was shown to physically interact with APP, suggesting it participates in APP-associated protein complexes and raising the question of its broader interacting network.","evidence":"Co-immunoprecipitation in vitro and in living cells, with subcellular redistribution upon APP overexpression","pmids":["15004329"],"confidence":"Medium","gaps":["No downstream signaling consequence of the AIDA-1–APP interaction was defined","Single-lab observation without independent replication","Functional relevance to APP processing or Alzheimer's pathology not tested"]},{"year":2005,"claim":"AIDA-1 was linked to nuclear body organization through its interaction with the Cajal body marker coilin, establishing a nuclear role for this predominantly synaptic protein.","evidence":"Co-immunoprecipitation, competition binding with SmB', siRNA knockdown altering Cajal body morphology","pmids":["15862129"],"confidence":"Medium","gaps":["Mechanism by which AIDA-1 regulates Cajal body integrity not defined","Single-lab finding","Relationship to synaptic AIDA-1 function unclear"]},{"year":2007,"claim":"Two independent studies simultaneously established AIDA's dual identity: as a PSD-95-binding postsynaptic scaffold (AIDA-1d/ANKS1B) that undergoes NMDAR-triggered nuclear translocation to regulate Cajal body–nucleolar association and protein synthesis, and as a distinct protein (Aida) that inhibits Axin-mediated JNK signaling by disrupting Axin homodimerization during vertebrate dorsalization.","evidence":"Biochemical binding assays, live-cell imaging, and protein synthesis measurement for AIDA-1d; co-IP, zebrafish morpholino knockdown with JNK/MKK4 epistasis for Aida","pmids":["17334360","17681137"],"confidence":"High","gaps":["Signal that triggers SAM domain opening for nuclear import was unknown","Whether Aida's anti-JNK role operates in mammalian tissues was untested","Connection between the two gene products (ANKS1B vs. AIDA/C15orf29) was ambiguous"]},{"year":2009,"claim":"The NMR structure of the AIDA-1 tandem SAM domains revealed that the nuclear localization signal is buried at the SAM–SAM interface, providing a structural mechanism for how nuclear translocation is gated by conformational change.","evidence":"NMR structure determination of SAM domain tandem with thermal stability assays","pmids":["19666031"],"confidence":"High","gaps":["The upstream signal or post-translational modification that triggers SAM domain decoupling was not identified","No in vivo validation that SAM opening is required for nuclear import"]},{"year":2014,"claim":"Crystallography of Aida's C-terminal C2 domain showed it binds phosphoinositides Ca²⁺-independently via a basic loop, and mutagenesis demonstrated this membrane-binding surface is required for the Aida–Axin interaction and JNK inhibition, linking lipid binding to signaling scaffold function.","evidence":"X-ray crystallography, phosphoinositide-binding assay, site-directed mutagenesis, JNK activity assay","pmids":["25117763"],"confidence":"High","gaps":["Whether membrane recruitment is the proximate trigger for Axin interaction was not resolved","In vivo relevance of C2 domain lipid binding untested in mammalian systems"]},{"year":2015,"claim":"Two studies established that AIDA-1 undergoes activity-dependent redistribution within the PSD and is required for proper GluN2B-containing NMDAR trafficking from the ER to synapses, defining its core synaptic function as a subunit-selective NMDAR transport facilitator.","evidence":"Forebrain-specific conditional KO mice with biochemical fractionation and electrophysiology; immuno-gold EM of cultured hippocampal neurons under excitatory conditions","pmids":["26085624","26356309"],"confidence":"High","gaps":["Direct cargo-binding interface between AIDA-1 and GluN2B not structurally defined","Whether AIDA-1 acts as an adaptor on KIF17 vesicles or as a quality-control factor in the ER was unclear"]},{"year":2016,"claim":"CaMKII was identified as the kinase responsible for AIDA-1 phosphorylation and displacement from the PSD core, resolving the enzymatic basis of activity-dependent AIDA-1 redistribution.","evidence":"PSD fractionation with phosphorylation assay and immuno-EM with pharmacological CaMKII inhibition (tatCN21) in hippocampal neurons","pmids":["27477489"],"confidence":"Medium","gaps":["Specific phosphorylation site(s) on AIDA-1 targeted by CaMKII not identified","Functional consequence of CaMKII-dependent dispersal for synaptic plasticity not directly tested"]},{"year":2018,"claim":"AIDA was established as an essential HRD1 E3-ligase cofactor in intestinal epithelium, controlling dietary fat absorption by targeting acyltransferases (GPAT3, MOGAT2, DGAT2) for ERAD-dependent degradation — its first defined role outside the nervous system and in ubiquitin-dependent protein quality control.","evidence":"Whole-body and intestine-specific knockout mice with metabolic phenotyping and protein abundance measurements","pmids":["29617643"],"confidence":"High","gaps":["Structural basis for AIDA–HRD1 interaction not defined","Whether AIDA functions as a substrate adaptor or an allosteric activator of HRD1 was not distinguished"]},{"year":2019,"claim":"ANKS1B haploinsufficiency was shown to reduce AIDA-1 levels and produce neurodevelopmental phenotypes (social deficits, hyperactivity, sensorimotor dysfunction) in mice, with interactome proteomics delineating its synaptic protein network.","evidence":"Haploinsufficiency mouse model, quantitative interactome proteomics, behavioral phenotyping, iPSC-derived neurons","pmids":["31287004","31388001"],"confidence":"Medium","gaps":["Specific interactors driving behavioral phenotypes not isolated","Human genetic validation of ANKS1B haploinsufficiency as a neurodevelopmental syndrome was limited"]},{"year":2021,"claim":"PKA-dependent phosphorylation of AIDA at S161 was shown to drive its translocation to the mitochondrial intermembrane space where it directly activates UCP1 thermogenesis by promoting UCP1 cysteine oxidation, establishing AIDA as a signal-transducing activator of non-shivering thermogenesis.","evidence":"Adipocyte-specific KO mice, S161A phospho-dead mutagenesis, in vitro PKA assay, co-IP, UCP1 uncoupling activity assay, sympathetic denervation","pmids":["33664495"],"confidence":"High","gaps":["Identity of the cysteine residue(s) on UCP1 oxidized by AIDA not determined","How AIDA crosses the outer mitochondrial membrane upon phosphorylation was not resolved"]},{"year":2023,"claim":"Cell-type-specific loss of Anks1b in oligodendrocyte lineage cells revealed a non-neuronal role for AIDA-1 in oligodendrocyte maturation and myelination through Rac1, expanding its function beyond neurons and demonstrating that social and sensory deficits can arise from glial AIDA-1 loss.","evidence":"Oligodendrocyte-specific conditional KO mice, Rac1 activity assay, myelination analysis, behavioral rescue with clemastine","pmids":["38129387"],"confidence":"High","gaps":["Mechanism by which AIDA-1 regulates Rac1 activity in oligodendrocytes not defined","Whether neuronal and glial AIDA-1 functions are additive in behavioral phenotypes untested"]},{"year":2024,"claim":"The crystal structure of the AIDA-1 PTB domain bound to SynGAP's NPxF motif defined a high-affinity postsynaptic interaction, expanding the repertoire of AIDA-1's PSD binding partners beyond PSD-95.","evidence":"X-ray crystallography of PTB–SynGAP complex, affinity purification, biochemical binding assays","pmids":["38759928"],"confidence":"High","gaps":["Functional consequence of AIDA-1–SynGAP interaction for Ras-GAP signaling at synapses not tested","Whether this interaction competes with or complements PSD-95 binding unclear"]},{"year":2026,"claim":"In vascular smooth muscle cells, AIDA was shown to scaffold HRD1-mediated K63-ubiquitination of VAMP3, driving CD36 membrane translocation and foam cell formation, demonstrating that its HRD1 cofactor function extends to non-canonical (K63) ubiquitin linkages and atherosclerosis.","evidence":"VSMC-specific KO in ApoE⁻/⁻ mice, co-IP, ubiquitination profiling, cholesterol flux assays","pmids":["42013606"],"confidence":"High","gaps":["Whether AIDA determines HRD1 linkage-type specificity (K48 vs K63) or substrate specificity is unknown","Relevance to human atherosclerosis not validated"]},{"year":null,"claim":"Key unresolved questions include: how AIDA selects between ERAD degradation (K48) and non-degradative (K63) ubiquitin signaling in different tissues; the structural basis of the AIDA–HRD1 interface; the identity of UCP1 cysteine residues oxidized through AIDA; and whether the neuronal (ANKS1B/AIDA-1) and non-neuronal (AIDA/C15orf29) gene products share any mechanistic logic beyond scaffolding.","evidence":"","pmids":[],"confidence":"Low","gaps":["No structural model of AIDA–HRD1 complex","Ubiquitin linkage selectivity mechanism unknown","Relationship between the two distinct genes encoding 'AIDA' proteins mechanistically unresolved"]}],"mechanism_profile":{"molecular_activity":[{"term_id":"GO:0060090","term_label":"molecular adaptor activity","supporting_discovery_ids":[0,1,3,4,14]},{"term_id":"GO:0008289","term_label":"lipid binding","supporting_discovery_ids":[6]},{"term_id":"GO:0098772","term_label":"molecular function regulator activity","supporting_discovery_ids":[3,14]}],"localization":[{"term_id":"GO:0005634","term_label":"nucleus","supporting_discovery_ids":[0,5,8]},{"term_id":"GO:0005739","term_label":"mitochondrion","supporting_discovery_ids":[4]},{"term_id":"GO:0005886","term_label":"plasma membrane","supporting_discovery_ids":[6]},{"term_id":"GO:0005783","term_label":"endoplasmic reticulum","supporting_discovery_ids":[2]},{"term_id":"GO:0005829","term_label":"cytosol","supporting_discovery_ids":[1,3]}],"pathway":[{"term_id":"R-HSA-392499","term_label":"Metabolism of proteins","supporting_discovery_ids":[3,14]},{"term_id":"R-HSA-162582","term_label":"Signal Transduction","supporting_discovery_ids":[1,6]},{"term_id":"R-HSA-112316","term_label":"Neuronal System","supporting_discovery_ids":[0,2,9,10]},{"term_id":"R-HSA-1430728","term_label":"Metabolism","supporting_discovery_ids":[3,4]},{"term_id":"R-HSA-1643685","term_label":"Disease","supporting_discovery_ids":[14]}],"complexes":["HRD1/ERAD complex"],"partners":["PSD95","HRD1","AXIN1","UCP1","GLUN2B","VAMP3","SYNGAP1","CAMK2A"],"other_free_text":[]},"mechanistic_narrative":"AIDA functions as a multifunctional scaffold protein that couples signal-dependent phosphorylation to organelle-specific protein trafficking and ubiquitin-dependent quality control across diverse cell types. In brown adipocytes, PKA phosphorylates AIDA at S161, triggering its translocation to the mitochondrial intermembrane space where it directly activates UCP1-mediated thermogenesis by promoting UCP1 cysteine oxidation [PMID:33664495]; in intestinal epithelium and vascular smooth muscle cells, AIDA serves as an essential cofactor for the HRD1 E3 ubiquitin ligase, targeting acyltransferases (GPAT3, MOGAT2, DGAT2) for ERAD-dependent degradation to limit fat absorption [PMID:29617643] and scaffolding K63-ubiquitination of VAMP3 to drive CD36 membrane translocation and foam cell formation [PMID:42013606]. In neurons, the AIDA-1 isoform (encoded by ANKS1B) organizes postsynaptic signaling by binding PSD-95 PDZ domains, facilitating GluN2B-containing NMDAR transport from the ER to synapses, and undergoing CaMKII-dependent dispersal from the PSD core upon excitatory activity; NMDAR activation additionally triggers its nuclear translocation—governed by regulated unmasking of an NLS within its tandem SAM domains—where it promotes Cajal body–nucleolar association and global protein synthesis [PMID:17334360, PMID:26085624, PMID:19666031, PMID:27477489]. During embryogenesis, AIDA blocks Axin-mediated JNK activation by disrupting Axin homodimerization through its C2 domain, which binds phosphoinositides in a Ca²⁺-independent manner [PMID:17681137, PMID:25117763]."},"prefetch_data":{"uniprot":{"accession":"Q96BJ3","full_name":"Axin interactor, dorsalization-associated protein","aliases":["Axin interaction partner and dorsalization antagonist"],"length_aa":306,"mass_kda":35.0,"function":"Acts as a ventralizing factor during embryogenesis. Inhibits axin-mediated JNK activation by binding axin and disrupting axin homodimerization. This in turn antagonizes a Wnt/beta-catenin-independent dorsalization pathway activated by AXIN/JNK-signaling (By similarity)","subcellular_location":"","url":"https://www.uniprot.org/uniprotkb/Q96BJ3/entry"},"depmap":{"release":"DepMap","has_data":true,"is_common_essential":false,"resolved_as":"","url":"https://depmap.org/portal/gene/AIDA","classification":"Not Classified","n_dependent_lines":2,"n_total_lines":1208,"dependency_fraction":0.0016556291390728477},"opencell":{"profiled":false,"resolved_as":"","ensg_id":"","cell_line_id":"","localizations":[],"interactors":[],"url":"https://opencell.sf.czbiohub.org/search/AIDA","total_profiled":1310},"omim":[{"mim_id":"613163","title":"GABA-TRANSAMINASE DEFICIENCY; GABATD","url":"https://www.omim.org/entry/613163"},{"mim_id":"612375","title":"AXIN INTERACTOR, DORSALIZATION-ASSOCIATED; AIDA","url":"https://www.omim.org/entry/612375"},{"mim_id":"607815","title":"ANKYRIN REPEAT AND STERILE ALPHA MOTIF DOMAINS-CONTAINING PROTEIN 1B; ANKS1B","url":"https://www.omim.org/entry/607815"},{"mim_id":"606230","title":"SH3 AND MULTIPLE ANKYRIN REPEAT DOMAINS 3; SHANK3","url":"https://www.omim.org/entry/606230"},{"mim_id":"605279","title":"CARBOXYLESTERASE 3; CES3","url":"https://www.omim.org/entry/605279"}],"hpa":{"profiled":true,"resolved_as":"","reliability":"Approved","locations":[{"location":"Microtubules","reliability":"Approved"},{"location":"Primary cilium","reliability":"Approved"},{"location":"Cytokinetic bridge","reliability":"Additional"},{"location":"Basal body","reliability":"Additional"}],"tissue_specificity":"Low tissue specificity","tissue_distribution":"Detected in all","driving_tissues":[],"url":"https://www.proteinatlas.org/search/AIDA"},"hgnc":{"alias_symbol":["FLJ12806"],"prev_symbol":["C1orf80"]},"alphafold":{"accession":"Q96BJ3","domains":[{"cath_id":"1.20.120.360","chopping":"2-99","consensus_level":"high","plddt":88.9861,"start":2,"end":99},{"cath_id":"2.60.40.150","chopping":"166-304","consensus_level":"high","plddt":95.1148,"start":166,"end":304}],"viewer_url":"https://alphafold.ebi.ac.uk/entry/Q96BJ3","model_url":"https://alphafold.ebi.ac.uk/files/AF-Q96BJ3-F1-model_v6.cif","pae_url":"https://alphafold.ebi.ac.uk/files/AF-Q96BJ3-F1-predicted_aligned_error_v6.png","plddt_mean":85.75},"mouse_models":{"mgi_url":"https://www.informatics.jax.org/marker/summary?nomen=AIDA","jax_strain_url":"https://www.jax.org/strain/search?query=AIDA"},"sequence":{"accession":"Q96BJ3","fasta_url":"https://rest.uniprot.org/uniprotkb/Q96BJ3.fasta","uniprot_url":"https://www.uniprot.org/uniprotkb/Q96BJ3/entry","alphafold_viewer_url":"https://alphafold.ebi.ac.uk/entry/Q96BJ3"}},"corpus_meta":[{"pmid":"9242531","id":"PMC_9242531","title":"Molecular remission in PML/RAR alpha-positive acute promyelocytic leukemia by combined all-trans retinoic acid and idarubicin (AIDA) therapy. Gruppo Italiano-Malattie Ematologiche Maligne dell'Adulto and Associazione Italiana di Ematologia ed Oncologia Pediatrica Cooperative Groups.","date":"1997","source":"Blood","url":"https://pubmed.ncbi.nlm.nih.gov/9242531","citation_count":427,"is_preprint":false},{"pmid":"9680345","id":"PMC_9680345","title":"Early detection of relapse by prospective reverse transcriptase-polymerase chain reaction analysis of the PML/RARalpha fusion gene in patients with acute promyelocytic leukemia enrolled in the GIMEMA-AIEOP multicenter \"AIDA\" trial. 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Section F, Structural biology and crystallization communications","url":"https://pubmed.ncbi.nlm.nih.gov/24100572","citation_count":3,"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":"36804019","id":"PMC_36804019","title":"Acute promyelocytic leukemia in childhood and adolescence: treatment results of a modified AIDA protocol at a Brazilian center.","date":"2022","source":"Hematology, transfusion and cell therapy","url":"https://pubmed.ncbi.nlm.nih.gov/36804019","citation_count":2,"is_preprint":false},{"pmid":"34527082","id":"PMC_34527082","title":"Anakinra and canakinumab for patients with R92Q-associated autoinflammatory syndrome: a multicenter observational study from the AIDA Network.","date":"2021","source":"Therapeutic advances in musculoskeletal disease","url":"https://pubmed.ncbi.nlm.nih.gov/34527082","citation_count":2,"is_preprint":false},{"pmid":"20021103","id":"PMC_20021103","title":"Automated in vitro dermal absorption (AIDA): development of a cost-effective diffusion cell.","date":"2004","source":"Toxicology mechanisms and methods","url":"https://pubmed.ncbi.nlm.nih.gov/20021103","citation_count":1,"is_preprint":false},{"pmid":"19875354","id":"PMC_19875354","title":"Effect of the class I metabotropic glutamate receptor antagonist AIDA on certain behaviours in rats with experimental chronic hyperammonemia.","date":"2009","source":"Advances in medical sciences","url":"https://pubmed.ncbi.nlm.nih.gov/19875354","citation_count":1,"is_preprint":false},{"pmid":"42013606","id":"PMC_42013606","title":"Inhibiting AIDA suppresses VSMC-derived foam cell formation and atherosclerosis by hindering CD36 membrane translocation.","date":"2026","source":"Atherosclerosis","url":"https://pubmed.ncbi.nlm.nih.gov/42013606","citation_count":0,"is_preprint":false},{"pmid":"40969814","id":"PMC_40969814","title":"Development and implementation of the International AIDA Network Castleman's disease registry.","date":"2025","source":"Frontiers in medicine","url":"https://pubmed.ncbi.nlm.nih.gov/40969814","citation_count":0,"is_preprint":false},{"pmid":"41909650","id":"PMC_41909650","title":"Recurrent fever and association with severe organ involvement, mortality and treatment outcomes in VEXAS syndrome: data from the AIDA Network.","date":"2026","source":"Frontiers in immunology","url":"https://pubmed.ncbi.nlm.nih.gov/41909650","citation_count":0,"is_preprint":false},{"pmid":"37924480","id":"PMC_37924480","title":"Knowledge and Current Practices in Monogenic Uveitis: An International Survey by IUSG and AIDA Network.","date":"2023","source":"Ophthalmology and therapy","url":"https://pubmed.ncbi.nlm.nih.gov/37924480","citation_count":0,"is_preprint":false},{"pmid":"41133355","id":"PMC_41133355","title":"IL-1 targeting agents in Schnitzler syndrome: a multicentre, real-world study from the international AIDA Network Schnitzler Registry.","date":"2025","source":"Clinical and experimental rheumatology","url":"https://pubmed.ncbi.nlm.nih.gov/41133355","citation_count":0,"is_preprint":false},{"pmid":"41601749","id":"PMC_41601749","title":"Clinical and laboratory markers to distinguish VEXAS from Schnitzler's syndrome: data from the AIDA network registries.","date":"2026","source":"Frontiers in medicine","url":"https://pubmed.ncbi.nlm.nih.gov/41601749","citation_count":0,"is_preprint":false},{"pmid":"41619570","id":"PMC_41619570","title":"VEXAS syndrome and cancer: Insights about a possible \"Tip of the Iceberg\". Ambidirectional data from the international AIDA network registries.","date":"2026","source":"Seminars in arthritis and rheumatism","url":"https://pubmed.ncbi.nlm.nih.gov/41619570","citation_count":0,"is_preprint":false},{"pmid":"39740551","id":"PMC_39740551","title":"Insertional mutagenesis of AIDA or CYP720B1 in the green alga Chlamydomonas reinhardtii confers copper(II) tolerance and increased biomass.","date":"2024","source":"Journal of hazardous materials","url":"https://pubmed.ncbi.nlm.nih.gov/39740551","citation_count":0,"is_preprint":false},{"pmid":"41988190","id":"PMC_41988190","title":"Proteomic and experimental analyses reveal molecular signatures of flexural atopic dermatitis in antecubital and popliteal fossae and the therapeutic effect of Aida lotion.","date":"2026","source":"Frontiers in immunology","url":"https://pubmed.ncbi.nlm.nih.gov/41988190","citation_count":0,"is_preprint":false}],"cost":{"stage1":{"model":"claude-sonnet-4-6","input_tokens":52232,"output_tokens":4366,"usd":0.111093},"stage2":{"model":"claude-opus-4-6","input_tokens":7808,"output_tokens":3853,"usd":0.203047},"total_usd":0.31414,"stage1_batch_id":"msgbatch_01TqNM6p6FsoMBT2jzQTwKBr","stage2_batch_id":"msgbatch_01Ya473eco8sTHbvRymQaU8o","note":"batch pricing = 50% of standard"},"stage1_raw":"```json\n{\n  \"discoveries\": [\n    {\n      \"year\": 2007,\n      \"finding\": \"AIDA-1d (encoded by ANKS1B) binds to the first two PDZ domains of the scaffolding protein PSD-95 via its C-terminal three amino acids. NMDA receptor stimulation causes Ca2+-independent translocation of AIDA-1d to the nucleus, where it couples to Cajal bodies and induces Cajal body-nucleolar association, resulting in increased nucleolar numbers and global protein synthesis.\",\n      \"method\": \"Biochemical binding assays, live-cell imaging, NMDA receptor stimulation with functional readout (nucleolar number and protein synthesis measurement)\",\n      \"journal\": \"Nature neuroscience\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 — multiple orthogonal methods (binding assay, imaging, functional protein synthesis readout) in a single rigorous study\",\n      \"pmids\": [\"17334360\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2007,\n      \"finding\": \"Aida (axin interactor, dorsalization-associated) blocks Axin-mediated JNK activation by disrupting Axin homodimerization, thereby antagonizing a beta-catenin-independent dorsalization pathway during vertebrate embryogenesis. Morpholino knockdown of Aida in zebrafish leads to dorsalized embryos; this effect is rescued by JNK-MO or MKK4-MO injection, placing Aida upstream of JNK/MKK4 in the Axin signaling axis.\",\n      \"method\": \"Co-immunoprecipitation, zebrafish morpholino knockdown/overexpression with epistasis analysis, JNK activity assays\",\n      \"journal\": \"Developmental cell\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 — reciprocal Co-IP combined with genetic epistasis in vivo, multiple orthogonal methods\",\n      \"pmids\": [\"17681137\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2015,\n      \"finding\": \"AIDA-1 (ANKS1B) regulates synaptic NMDAR subunit composition by facilitating transport of GluN2B-containing NMDARs from the ER to synapses. Forebrain-specific AIDA-1 conditional knockout mice show reduced GluN2B and increased GluN2A at synaptic junctions; GluN2B accumulates in ER-enriched fractions. AIDA-1 preferentially associates with GluN2B and with the adaptor proteins CaMKII and KIF17, which regulate GluN2B transport.\",\n      \"method\": \"Conditional knockout mice, biochemical fractionation, co-immunoprecipitation, electrophysiology, immunocytochemistry, lentiviral shRNA knockdown\",\n      \"journal\": \"The Journal of neuroscience\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 — clean conditional KO with defined molecular phenotype, multiple orthogonal methods including Co-IP, fractionation, and electrophysiology\",\n      \"pmids\": [\"26085624\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2018,\n      \"finding\": \"AIDA acts as an essential cofactor for the E3 ubiquitin ligase HRD1 of the ERAD pathway to downregulate rate-limiting acyltransferases GPAT3, MOGAT2, and DGAT2, thereby controlling intestinal triacylglycerol synthesis and fat absorption. Aida-/- mice and intestine-specific Aida knockout mice display increased intestinal fatty acid re-esterification, elevated circulating and tissue triacylglycerol, and increased adiposity.\",\n      \"method\": \"Whole-body and intestine-specific knockout mice, protein abundance assays, fat absorption measurements, in vivo metabolic phenotyping\",\n      \"journal\": \"Cell metabolism\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 — tissue-specific KO recapitulating whole-body KO phenotype, multiple orthogonal metabolic readouts\",\n      \"pmids\": [\"29617643\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2021,\n      \"finding\": \"AIDA is phosphorylated at S161 by catecholamine-activated PKA on the outer mitochondrial membrane. Phosphorylated AIDA translocates to the intermembrane space, where it binds UCP1 and activates its uncoupling activity by promoting cysteine oxidation of UCP1. Adipocyte-specific AIDA depletion abrogates UCP1-dependent thermogenesis. Re-expression of S161A-AIDA (phospho-dead mutant) fails to restore the acute cold response.\",\n      \"method\": \"Adipocyte-specific knockout mice, phospho-site mutagenesis (S161A), in vitro PKA phosphorylation assay, co-immunoprecipitation, UCP1 uncoupling activity assay, sympathetic denervation experiment\",\n      \"journal\": \"Nature cell biology\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 — in vitro enzymatic assay, mutagenesis, KO with defined phenotype, and Co-IP, all in one rigorous study\",\n      \"pmids\": [\"33664495\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2009,\n      \"finding\": \"The nuclear localization signal (NLS) of AIDA-1 is buried at the interface between its two tandemly arranged SAM domains. The NMR structure reveals the two SAM domains are fused head-to-tail; the NLS becomes accessible only when the second SAM domain decouples from the first, suggesting a mechanism for regulated nuclear import of AIDA-1.\",\n      \"method\": \"NMR structure determination of SAM domain tandem, thermal stability assays\",\n      \"journal\": \"Journal of molecular biology\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 — NMR structure with functional interpretation of NLS burial, rigorous single-study\",\n      \"pmids\": [\"19666031\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2014,\n      \"finding\": \"The C-terminal C2 domain of Aida adopts a conventional C2 domain topology and binds phosphoinositides in a Ca2+-independent manner via a positively charged basic loop, enabling membrane association. Mutation of the basic loop disrupts membrane association and the Aida-Axin interaction, resulting in impaired JNK inhibition.\",\n      \"method\": \"X-ray crystallography, phosphoinositide-binding assay, site-directed mutagenesis, co-immunoprecipitation, JNK activity assay\",\n      \"journal\": \"The FEBS journal\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 — crystal structure combined with mutagenesis and functional JNK inhibition assay in one study\",\n      \"pmids\": [\"25117763\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2004,\n      \"finding\": \"AIDA-1 proteins (AIDA-1a, AIDA-1b, AIDA-1bΔAnk) interact with APP (AbetaPP) in vitro, in transfected living cells, and endogenously in leukemia cell lines. The intracellular distribution of AIDA-1a is altered by overexpression of AbetaPP, indicating AbetaPP regulates AIDA-1 localization.\",\n      \"method\": \"Co-immunoprecipitation in vitro and in vivo, overexpression with subcellular localization readout\",\n      \"journal\": \"Journal of Alzheimer's disease\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 3 — Co-IP with localization change, single lab, no mechanistic follow-up of pathway placement\",\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 in vivo, competing with SmB' for coilin binding sites. Knockdown of EB-1/AIDA-1 isoforms by siRNA alters Cajal body organization and reduces cell viability.\",\n      \"method\": \"Co-immunoprecipitation, competition binding assay, siRNA knockdown with Cajal body morphology readout\",\n      \"journal\": \"BMC cell biology\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 3 — Co-IP and competition binding combined with KD phenotype, single lab\",\n      \"pmids\": [\"15862129\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2016,\n      \"finding\": \"CaMKII activation mediates phosphorylation of AIDA-1 and causes its displacement from the postsynaptic density (PSD) core. Treatment of hippocampal neurons with NMDA causes an ~30 nm shift in AIDA-1 median distance from the postsynaptic membrane, an effect blocked by the CaMKII inhibitor tatCN21.\",\n      \"method\": \"PSD fractionation with phosphorylation assay, immuno-electron microscopy of hippocampal neurons with pharmacological CaMKII inhibition\",\n      \"journal\": \"FEBS letters\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 — direct phosphorylation assay combined with immuno-EM localization and pharmacological rescue, single lab\",\n      \"pmids\": [\"27477489\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2015,\n      \"finding\": \"Under excitatory conditions (high K+ or NMDA application), AIDA-1 moves out of the PSD core, with label density at the core reduced to 40% of controls and median distance from postsynaptic membrane increasing from ~30 nm to ~55 nm; this redistribution is reversible within 30 minutes.\",\n      \"method\": \"Immunogold electron microscopy of cultured rat hippocampal neurons under basal and excitatory conditions\",\n      \"journal\": \"PloS one\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 — quantitative immuno-EM with two distinct antibodies, single lab\",\n      \"pmids\": [\"26356309\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2019,\n      \"finding\": \"Loss-of-function experiments using CRISPR/Cas9 deletion of a TNFα-sensitive regulatory element in endothelial cells reduce AIDA expression, implicating AIDA as regulated by a CAD-associated genetic locus in the vascular endothelium.\",\n      \"method\": \"CRISPR/Cas9 deletion of regulatory element with gene expression measurement\",\n      \"journal\": \"Genome biology\",\n      \"confidence\": \"Low\",\n      \"confidence_rationale\": \"Tier 3 — regulatory element deletion with expression readout only, no direct mechanistic pathway placement for AIDA protein\",\n      \"pmids\": [\"31287004\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2023,\n      \"finding\": \"Selective loss of Anks1b (encoding AIDA-1) from the oligodendrocyte lineage (but not neuronal populations) leads to deficits in oligodendrocyte maturation, myelination, and Rac1 function, causing social preference and sensory reactivity deficits. Treatment with clemastine rescues social preference deficits in Anks1b-deficient mice.\",\n      \"method\": \"Cell-type-specific conditional knockout mice, myelination assays, Rac1 activity assay, behavioral phenotyping, pharmacological rescue\",\n      \"journal\": \"Nature communications\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 — cell-type-specific KO with defined molecular (Rac1) and cellular (myelination) phenotypes, pharmacological rescue, rigorous study\",\n      \"pmids\": [\"38129387\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2024,\n      \"finding\": \"The PTB domain of AIDA-1d binds with high affinity to an extended NPx[F/Y]-motif of SynGAP family Ras-GTPase activating proteins. The crystal structure of AIDA-1 PTB domain in complex with the SynGAP NPxF-motif revealed the molecular basis for this specific interaction.\",\n      \"method\": \"Affinity purification, biochemical binding assays, X-ray crystallography of PTB–SynGAP complex\",\n      \"journal\": \"Journal of molecular biology\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 — crystal structure plus biochemical binding characterization in one study\",\n      \"pmids\": [\"38759928\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2026,\n      \"finding\": \"AIDA scaffolds HRD1-mediated K63-linked ubiquitination of VAMP3, facilitating VAMP3-CD36 interaction and CD36 membrane translocation in VSMCs. VSMC-specific AIDA knockout attenuates atherosclerotic plaque burden and suppresses oxLDL uptake and foam cell formation by impairing CD36 membrane trafficking without affecting cholesterol efflux.\",\n      \"method\": \"VSMC-specific knockout in ApoE-/- mice, co-immunoprecipitation, cholesterol flux assays, ubiquitination profiling, adenoviral shRNA silencing\",\n      \"journal\": \"Atherosclerosis\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 — cell-type-specific KO plus Co-IP and ubiquitination profiling revealing the HRD1-VAMP3-CD36 mechanistic axis\",\n      \"pmids\": [\"42013606\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2019,\n      \"finding\": \"Haploinsufficiency of ANKS1B causes loss of the synaptic protein AIDA-1. Quantitative proteomics of the AIDA-1 interactome in haploinsufficient mice revealed protein networks involved in synaptic function. Anks1b haploinsufficient mice recapitulate social deficits, hyperactivity, and sensorimotor dysfunction.\",\n      \"method\": \"Transgenic haploinsufficiency mouse model, quantitative proteomics (interactome), behavioral phenotyping, iPSC-derived neurons\",\n      \"journal\": \"Nature communications\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 — interactome proteomics combined with in vivo model; mechanistic pathway placement is partial\",\n      \"pmids\": [\"31388001\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2012,\n      \"finding\": \"Chronic ethanol exposure increases synaptic clustering of AIDA-1 in hippocampal neurons, an effect prevented by concurrent NMDA receptor stimulation. AIDA-1 localization to the PSD does not require its association with PSD-95 (palmitoylation inhibition declusters PSD-95 but not AIDA-1). AIDA-1 knockdown does not affect GluN1 or GluN2B protein levels.\",\n      \"method\": \"Lentiviral shRNA knockdown, chronic ethanol treatment, immunofluorescence colocalization, palmitoylation inhibition\",\n      \"journal\": \"Alcohol\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 3 — single lab, multiple complementary methods showing PSD-95-independent PSD localization and activity-regulated synaptic enrichment\",\n      \"pmids\": [\"22703994\"],\n      \"is_preprint\": false\n    }\n  ],\n  \"current_model\": \"AIDA (axin interactor, dorsalization-associated; encoded by ANKS1B as AIDA-1 in neurons) is a multifunctional scaffold protein: in brown adipocytes, it is phosphorylated by PKA at S161, translocates to the mitochondrial intermembrane space, and directly activates UCP1-mediated thermogenesis by promoting cysteine oxidation of UCP1; in intestinal epithelium, it acts as an essential HRD1 E3-ligase cofactor to target acyltransferases (GPAT3, MOGAT2, DGAT2) for ERAD-dependent degradation, limiting dietary fat absorption; in VSMCs, AIDA scaffolds HRD1-mediated K63-ubiquitination of VAMP3, driving CD36 membrane translocation and foam cell formation; in neurons, AIDA-1 (ANKS1B) concentrates at the PSD core by binding PSD-95 PDZ domains, undergoes CaMKII-dependent phosphorylation and activity-induced dispersal from the PSD core, facilitates GluN2B-containing NMDAR transport from the ER to synapses (regulating subunit composition and plasticity), and translocates to the nucleus upon NMDAR activation to regulate Cajal body-nucleolar association and global protein synthesis; additionally, AIDA blocks Axin-mediated JNK activation by disrupting Axin homodimerization, antagonizing a beta-catenin-independent dorsalization pathway.\"\n}\n```","stage2_raw":"```json\n{\n  \"mechanistic_narrative\": \"AIDA functions as a multifunctional scaffold protein that couples signal-dependent phosphorylation to organelle-specific protein trafficking and ubiquitin-dependent quality control across diverse cell types. In brown adipocytes, PKA phosphorylates AIDA at S161, triggering its translocation to the mitochondrial intermembrane space where it directly activates UCP1-mediated thermogenesis by promoting UCP1 cysteine oxidation [PMID:33664495]; in intestinal epithelium and vascular smooth muscle cells, AIDA serves as an essential cofactor for the HRD1 E3 ubiquitin ligase, targeting acyltransferases (GPAT3, MOGAT2, DGAT2) for ERAD-dependent degradation to limit fat absorption [PMID:29617643] and scaffolding K63-ubiquitination of VAMP3 to drive CD36 membrane translocation and foam cell formation [PMID:42013606]. In neurons, the AIDA-1 isoform (encoded by ANKS1B) organizes postsynaptic signaling by binding PSD-95 PDZ domains, facilitating GluN2B-containing NMDAR transport from the ER to synapses, and undergoing CaMKII-dependent dispersal from the PSD core upon excitatory activity; NMDAR activation additionally triggers its nuclear translocation—governed by regulated unmasking of an NLS within its tandem SAM domains—where it promotes Cajal body–nucleolar association and global protein synthesis [PMID:17334360, PMID:26085624, PMID:19666031, PMID:27477489]. During embryogenesis, AIDA blocks Axin-mediated JNK activation by disrupting Axin homodimerization through its C2 domain, which binds phosphoinositides in a Ca²⁺-independent manner [PMID:17681137, PMID:25117763].\",\n  \"teleology\": [\n    {\n      \"year\": 2004,\n      \"claim\": \"Before any signaling role was established, AIDA-1 was shown to physically interact with APP, suggesting it participates in APP-associated protein complexes and raising the question of its broader interacting network.\",\n      \"evidence\": \"Co-immunoprecipitation in vitro and in living cells, with subcellular redistribution upon APP overexpression\",\n      \"pmids\": [\"15004329\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"No downstream signaling consequence of the AIDA-1–APP interaction was defined\", \"Single-lab observation without independent replication\", \"Functional relevance to APP processing or Alzheimer's pathology not tested\"]\n    },\n    {\n      \"year\": 2005,\n      \"claim\": \"AIDA-1 was linked to nuclear body organization through its interaction with the Cajal body marker coilin, establishing a nuclear role for this predominantly synaptic protein.\",\n      \"evidence\": \"Co-immunoprecipitation, competition binding with SmB', siRNA knockdown altering Cajal body morphology\",\n      \"pmids\": [\"15862129\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Mechanism by which AIDA-1 regulates Cajal body integrity not defined\", \"Single-lab finding\", \"Relationship to synaptic AIDA-1 function unclear\"]\n    },\n    {\n      \"year\": 2007,\n      \"claim\": \"Two independent studies simultaneously established AIDA's dual identity: as a PSD-95-binding postsynaptic scaffold (AIDA-1d/ANKS1B) that undergoes NMDAR-triggered nuclear translocation to regulate Cajal body–nucleolar association and protein synthesis, and as a distinct protein (Aida) that inhibits Axin-mediated JNK signaling by disrupting Axin homodimerization during vertebrate dorsalization.\",\n      \"evidence\": \"Biochemical binding assays, live-cell imaging, and protein synthesis measurement for AIDA-1d; co-IP, zebrafish morpholino knockdown with JNK/MKK4 epistasis for Aida\",\n      \"pmids\": [\"17334360\", \"17681137\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Signal that triggers SAM domain opening for nuclear import was unknown\", \"Whether Aida's anti-JNK role operates in mammalian tissues was untested\", \"Connection between the two gene products (ANKS1B vs. AIDA/C15orf29) was ambiguous\"]\n    },\n    {\n      \"year\": 2009,\n      \"claim\": \"The NMR structure of the AIDA-1 tandem SAM domains revealed that the nuclear localization signal is buried at the SAM–SAM interface, providing a structural mechanism for how nuclear translocation is gated by conformational change.\",\n      \"evidence\": \"NMR structure determination of SAM domain tandem with thermal stability assays\",\n      \"pmids\": [\"19666031\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"The upstream signal or post-translational modification that triggers SAM domain decoupling was not identified\", \"No in vivo validation that SAM opening is required for nuclear import\"]\n    },\n    {\n      \"year\": 2014,\n      \"claim\": \"Crystallography of Aida's C-terminal C2 domain showed it binds phosphoinositides Ca²⁺-independently via a basic loop, and mutagenesis demonstrated this membrane-binding surface is required for the Aida–Axin interaction and JNK inhibition, linking lipid binding to signaling scaffold function.\",\n      \"evidence\": \"X-ray crystallography, phosphoinositide-binding assay, site-directed mutagenesis, JNK activity assay\",\n      \"pmids\": [\"25117763\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Whether membrane recruitment is the proximate trigger for Axin interaction was not resolved\", \"In vivo relevance of C2 domain lipid binding untested in mammalian systems\"]\n    },\n    {\n      \"year\": 2015,\n      \"claim\": \"Two studies established that AIDA-1 undergoes activity-dependent redistribution within the PSD and is required for proper GluN2B-containing NMDAR trafficking from the ER to synapses, defining its core synaptic function as a subunit-selective NMDAR transport facilitator.\",\n      \"evidence\": \"Forebrain-specific conditional KO mice with biochemical fractionation and electrophysiology; immuno-gold EM of cultured hippocampal neurons under excitatory conditions\",\n      \"pmids\": [\"26085624\", \"26356309\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Direct cargo-binding interface between AIDA-1 and GluN2B not structurally defined\", \"Whether AIDA-1 acts as an adaptor on KIF17 vesicles or as a quality-control factor in the ER was unclear\"]\n    },\n    {\n      \"year\": 2016,\n      \"claim\": \"CaMKII was identified as the kinase responsible for AIDA-1 phosphorylation and displacement from the PSD core, resolving the enzymatic basis of activity-dependent AIDA-1 redistribution.\",\n      \"evidence\": \"PSD fractionation with phosphorylation assay and immuno-EM with pharmacological CaMKII inhibition (tatCN21) in hippocampal neurons\",\n      \"pmids\": [\"27477489\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Specific phosphorylation site(s) on AIDA-1 targeted by CaMKII not identified\", \"Functional consequence of CaMKII-dependent dispersal for synaptic plasticity not directly tested\"]\n    },\n    {\n      \"year\": 2018,\n      \"claim\": \"AIDA was established as an essential HRD1 E3-ligase cofactor in intestinal epithelium, controlling dietary fat absorption by targeting acyltransferases (GPAT3, MOGAT2, DGAT2) for ERAD-dependent degradation — its first defined role outside the nervous system and in ubiquitin-dependent protein quality control.\",\n      \"evidence\": \"Whole-body and intestine-specific knockout mice with metabolic phenotyping and protein abundance measurements\",\n      \"pmids\": [\"29617643\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Structural basis for AIDA–HRD1 interaction not defined\", \"Whether AIDA functions as a substrate adaptor or an allosteric activator of HRD1 was not distinguished\"]\n    },\n    {\n      \"year\": 2019,\n      \"claim\": \"ANKS1B haploinsufficiency was shown to reduce AIDA-1 levels and produce neurodevelopmental phenotypes (social deficits, hyperactivity, sensorimotor dysfunction) in mice, with interactome proteomics delineating its synaptic protein network.\",\n      \"evidence\": \"Haploinsufficiency mouse model, quantitative interactome proteomics, behavioral phenotyping, iPSC-derived neurons\",\n      \"pmids\": [\"31287004\", \"31388001\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Specific interactors driving behavioral phenotypes not isolated\", \"Human genetic validation of ANKS1B haploinsufficiency as a neurodevelopmental syndrome was limited\"]\n    },\n    {\n      \"year\": 2021,\n      \"claim\": \"PKA-dependent phosphorylation of AIDA at S161 was shown to drive its translocation to the mitochondrial intermembrane space where it directly activates UCP1 thermogenesis by promoting UCP1 cysteine oxidation, establishing AIDA as a signal-transducing activator of non-shivering thermogenesis.\",\n      \"evidence\": \"Adipocyte-specific KO mice, S161A phospho-dead mutagenesis, in vitro PKA assay, co-IP, UCP1 uncoupling activity assay, sympathetic denervation\",\n      \"pmids\": [\"33664495\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Identity of the cysteine residue(s) on UCP1 oxidized by AIDA not determined\", \"How AIDA crosses the outer mitochondrial membrane upon phosphorylation was not resolved\"]\n    },\n    {\n      \"year\": 2023,\n      \"claim\": \"Cell-type-specific loss of Anks1b in oligodendrocyte lineage cells revealed a non-neuronal role for AIDA-1 in oligodendrocyte maturation and myelination through Rac1, expanding its function beyond neurons and demonstrating that social and sensory deficits can arise from glial AIDA-1 loss.\",\n      \"evidence\": \"Oligodendrocyte-specific conditional KO mice, Rac1 activity assay, myelination analysis, behavioral rescue with clemastine\",\n      \"pmids\": [\"38129387\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Mechanism by which AIDA-1 regulates Rac1 activity in oligodendrocytes not defined\", \"Whether neuronal and glial AIDA-1 functions are additive in behavioral phenotypes untested\"]\n    },\n    {\n      \"year\": 2024,\n      \"claim\": \"The crystal structure of the AIDA-1 PTB domain bound to SynGAP's NPxF motif defined a high-affinity postsynaptic interaction, expanding the repertoire of AIDA-1's PSD binding partners beyond PSD-95.\",\n      \"evidence\": \"X-ray crystallography of PTB–SynGAP complex, affinity purification, biochemical binding assays\",\n      \"pmids\": [\"38759928\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Functional consequence of AIDA-1–SynGAP interaction for Ras-GAP signaling at synapses not tested\", \"Whether this interaction competes with or complements PSD-95 binding unclear\"]\n    },\n    {\n      \"year\": 2026,\n      \"claim\": \"In vascular smooth muscle cells, AIDA was shown to scaffold HRD1-mediated K63-ubiquitination of VAMP3, driving CD36 membrane translocation and foam cell formation, demonstrating that its HRD1 cofactor function extends to non-canonical (K63) ubiquitin linkages and atherosclerosis.\",\n      \"evidence\": \"VSMC-specific KO in ApoE⁻/⁻ mice, co-IP, ubiquitination profiling, cholesterol flux assays\",\n      \"pmids\": [\"42013606\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Whether AIDA determines HRD1 linkage-type specificity (K48 vs K63) or substrate specificity is unknown\", \"Relevance to human atherosclerosis not validated\"]\n    },\n    {\n      \"year\": null,\n      \"claim\": \"Key unresolved questions include: how AIDA selects between ERAD degradation (K48) and non-degradative (K63) ubiquitin signaling in different tissues; the structural basis of the AIDA–HRD1 interface; the identity of UCP1 cysteine residues oxidized through AIDA; and whether the neuronal (ANKS1B/AIDA-1) and non-neuronal (AIDA/C15orf29) gene products share any mechanistic logic beyond scaffolding.\",\n      \"evidence\": \"\",\n      \"pmids\": [],\n      \"confidence\": \"Low\",\n      \"gaps\": [\"No structural model of AIDA–HRD1 complex\", \"Ubiquitin linkage selectivity mechanism unknown\", \"Relationship between the two distinct genes encoding 'AIDA' proteins mechanistically unresolved\"]\n    }\n  ],\n  \"mechanism_profile\": {\n    \"molecular_activity\": [\n      {\"term_id\": \"GO:0060090\", \"supporting_discovery_ids\": [0, 1, 3, 4, 14]},\n      {\"term_id\": \"GO:0008289\", \"supporting_discovery_ids\": [6]},\n      {\"term_id\": \"GO:0098772\", \"supporting_discovery_ids\": [3, 14]}\n    ],\n    \"localization\": [\n      {\"term_id\": \"GO:0005634\", \"supporting_discovery_ids\": [0, 5, 8]},\n      {\"term_id\": \"GO:0005739\", \"supporting_discovery_ids\": [4]},\n      {\"term_id\": \"GO:0005886\", \"supporting_discovery_ids\": [6]},\n      {\"term_id\": \"GO:0005783\", \"supporting_discovery_ids\": [2]},\n      {\"term_id\": \"GO:0005829\", \"supporting_discovery_ids\": [1, 3]}\n    ],\n    \"pathway\": [\n      {\"term_id\": \"R-HSA-392499\", \"supporting_discovery_ids\": [3, 14]},\n      {\"term_id\": \"R-HSA-162582\", \"supporting_discovery_ids\": [1, 6]},\n      {\"term_id\": \"R-HSA-112316\", \"supporting_discovery_ids\": [0, 2, 9, 10]},\n      {\"term_id\": \"R-HSA-1430728\", \"supporting_discovery_ids\": [3, 4]},\n      {\"term_id\": \"R-HSA-1643685\", \"supporting_discovery_ids\": [14]}\n    ],\n    \"complexes\": [\n      \"HRD1/ERAD complex\"\n    ],\n    \"partners\": [\n      \"PSD95\",\n      \"HRD1\",\n      \"AXIN1\",\n      \"UCP1\",\n      \"GluN2B\",\n      \"VAMP3\",\n      \"SYNGAP1\",\n      \"CAMK2A\"\n    ],\n    \"other_free_text\": []\n  }\n}\n```"}