Affinage

ANKS1B

Ankyrin repeat and sterile alpha motif domain-containing protein 1B · UniProt Q7Z6G8

Length
1248 aa
Mass
138.1 kDa
Annotated
2026-04-28
25 papers in source corpus 12 papers cited in narrative 12 extracted findings

Mechanistic narrative

Synthesis pass · prose summary of the discoveries below

ANKS1B encodes AIDA-1, a multidomain postsynaptic scaffold protein that orchestrates NMDA receptor trafficking, synaptic signaling, and nuclear functions in neurons and oligodendrocytes. At synapses, AIDA-1 anchors to PSD-95 via its C-terminus and binds SynGAP family proteins through its PTB domain; it facilitates ER-to-synapse transport of GluN2B-containing NMDARs through association with CASK and KIF17, and CaMKII-mediated phosphorylation displaces AIDA-1 from the PSD core upon synaptic activity, enabling its translocation to the nucleus where SAM-domain uncoupling exposes a buried NLS and AIDA-1 promotes nucleolar assembly and protein synthesis (PMID:26085624, PMID:27477489, PMID:17334360, PMID:19666031, PMID:38759928). In oligodendrocytes, AIDA-1 regulates Rac1 activity to control myelination and maturation, and cell-type-specific loss from the oligodendrocyte lineage causes social and sensory deficits rescuable by clemastine (PMID:38129387). Haploinsufficiency of ANKS1B in mice produces neurodevelopmental phenotypes including social deficits and hyperactivity, and under ischemic conditions, lactylation at K1222 targets AIDA-1 for proteasomal degradation as a neuroprotective brake on GluN2B surface expression and excitotoxic calcium overload (PMID:31388001, PMID:41564684).

Mechanistic history

Synthesis pass · year-by-year structured walk · 11 steps
  1. 2004 Medium

    Identification of AIDA-1 as an intracellular binding partner of amyloid precursor protein established the gene product as a multi-isoform PTB-domain protein with isoform-specific subcellular distributions.

    Evidence Co-immunoprecipitation and in vitro binding in leukemia cell lines and transfected cells

    PMID:15004329

    Open questions at the time
    • Physiological significance of APP interaction in neurons not demonstrated
    • No in vivo validation
  2. 2005 Medium

    Discovery that the AIDA-1c isoform binds the Cajal body marker coilin and competes with SmB' for coilin binding revealed a nuclear role for ANKS1B in snRNP body organization, with knockdown altering Cajal body integrity and reducing cell viability.

    Evidence Co-immunoprecipitation, competition binding, siRNA knockdown with fluorescence microscopy

    PMID:15862129

    Open questions at the time
    • Mechanism by which AIDA-1c reaches the nucleus was unknown
    • Cajal body phenotype not confirmed in neurons
  3. 2007 High

    Demonstration that AIDA-1d resides in the PSD via PSD-95 binding and translocates to the nucleus upon NMDA stimulation — where it drives Cajal body–nucleolar association and increases protein synthesis — established the first activity-dependent synapse-to-nucleus signaling function for this protein.

    Evidence Co-IP, live-cell imaging, NMDA stimulation, siRNA knockdown with protein synthesis assay in cultured neurons

    PMID:17334360

    Open questions at the time
    • Ca²⁺-independent translocation mechanism was not resolved
    • In vivo relevance of nucleolar regulation not tested
  4. 2009 High

    NMR structure of the tandem SAM domains revealed that the NLS is buried at the SAM–SAM interface and that differential thermal stability of the two domains provides a structural mechanism for NLS exposure, explaining how AIDA-1 can switch between synaptic retention and nuclear import.

    Evidence NMR structure determination and thermal stability analysis

    PMID:19666031

    Open questions at the time
    • No direct demonstration that SAM uncoupling occurs in living neurons upon stimulation
    • Upstream signal triggering SAM uncoupling not identified
  5. 2015 High

    Conditional forebrain knockout and biochemical studies showed AIDA-1 associates with CASK and KIF17 to facilitate ER-to-synapse transport of GluN2B-containing NMDARs; loss of AIDA-1 shifted synaptic NMDAR composition from GluN2B- to GluN2A-mediated transmission, defining AIDA-1 as a key determinant of NMDAR subunit composition.

    Evidence Conditional knockout, co-IP, subcellular fractionation, electrophysiology, shRNA knockdown in cultured neurons

    PMID:26085624

    Open questions at the time
    • Direct interaction surface between AIDA-1 and CASK/KIF17 not mapped
    • Whether AIDA-1 rides with the transport vesicle or acts at the ER exit site was unclear
  6. 2015 Medium

    Immuno-electron microscopy placed AIDA-1 within the PSD dense core (~30 nm from the membrane) under basal conditions and showed reversible activity-dependent redistribution to ~55 nm, providing ultrastructural evidence for stimulus-driven PSD reorganization of this scaffold.

    Evidence Immunogold EM with two distinct antibodies in cultured hippocampal neurons

    PMID:26356309

    Open questions at the time
    • The kinase responsible for the displacement was not yet identified
    • Nuclear translocation was not tracked at the EM level
  7. 2016 High

    Identification of CaMKII as the kinase that phosphorylates AIDA-1 in PSD fractions, with pharmacological inhibition blocking activity-induced displacement, resolved the signaling mechanism coupling synaptic activity to AIDA-1 release from the PSD core.

    Evidence Biochemical phosphorylation assay of brain PSD fractions, immuno-EM with CaMKII inhibitor tatCN21

    PMID:27477489

    Open questions at the time
    • Specific phosphorylation site(s) on AIDA-1 not identified
    • Whether phosphorylation is necessary for nuclear translocation versus merely PSD release was not tested
  8. 2019 High

    Haploinsufficiency in mice reproduced social deficits, hyperactivity, and sensorimotor dysfunction, and quantitative interactome profiling placed AIDA-1 at the hub of synaptic protein networks, establishing ANKS1B as a neurodevelopmental disease gene.

    Evidence Quantitative MS-based interactome in neurons, heterozygous knockout mouse with behavioral phenotyping

    PMID:31388001

    Open questions at the time
    • Specific interactors driving each behavioral phenotype not dissected
    • Human genetic validation for neurodevelopmental disorder not shown in this study
  9. 2023 High

    Cell-type-specific knockout from the oligodendrocyte lineage — but not neurons — recapitulated social and sensory deficits, and these were rescued by clemastine, revealing a previously unsuspected oligodendroglial function of AIDA-1 mediated by Rac1 activity control of myelination.

    Evidence Conditional oligodendrocyte-lineage knockout, MRI white matter imaging, Rac1 activity assay, pharmacological rescue with clemastine

    PMID:38129387

    Open questions at the time
    • Direct molecular link between AIDA-1 and Rac1 activation not defined
    • Whether neuronal and oligodendroglial AIDA-1 functions are independent or synergistic in vivo is unclear
  10. 2024 High

    Crystal structure of the AIDA-1 PTB domain bound to the SynGAP NPxF motif provided the atomic-resolution basis for how AIDA-1 recognizes and anchors SynGAP family Ras-GAPs at the PSD.

    Evidence X-ray crystallography, affinity purification, and biochemical binding assays

    PMID:38759928

    Open questions at the time
    • Functional consequence of disrupting the AIDA-1–SynGAP interaction on synaptic Ras signaling not tested in neurons
    • Whether other PTB-binding partners compete with SynGAP at the PSD is unknown
  11. 2026 Medium

    Discovery that ischemia-induced lactylation at K1222 triggers ubiquitin-proteasome-mediated AIDA-1 degradation, causing GluN2B ER retention, established a metabolic post-translational mechanism that limits excitotoxicity by reducing surface NMDAR expression.

    Evidence OGD/R cell model, proteomics, K1222R mutagenesis, Ca²⁺ imaging, surface trafficking assay

    PMID:41564684

    Open questions at the time
    • Lactylation-driven degradation not validated in vivo in ischemia models
    • The E3 ubiquitin ligase mediating AIDA-1 ubiquitination is unidentified
    • Single lab finding

Open questions

Synthesis pass · forward-looking unresolved questions
  • Key unresolved questions include the specific CaMKII phosphorylation site(s) on AIDA-1, whether SAM-domain uncoupling is triggered by phosphorylation or an independent signal, the molecular basis of AIDA-1's regulation of Rac1 in oligodendrocytes, and how the PTB-mediated SynGAP interaction coordinates with GluN2B trafficking functions.
  • CaMKII phosphorylation site(s) unmapped
  • SAM uncoupling trigger unresolved
  • AIDA-1–Rac1 mechanism in oligodendrocytes undefined
  • No integrative structural model of full-length AIDA-1 in the PSD

Mechanism profile

Synthesis pass · controlled-vocabulary classification · explore literature graph →
Molecular activity
GO:0005198 structural molecule activity 3 GO:0060090 molecular adaptor activity 3
Localization
GO:0005634 nucleus 3 GO:0005886 plasma membrane 3 GO:0005783 endoplasmic reticulum 2 GO:0005730 nucleolus 1
Pathway
R-HSA-112316 Neuronal System 6 R-HSA-162582 Signal Transduction 3 R-HSA-1266738 Developmental Biology 2 R-HSA-9609507 Protein localization 2
Partners
CASKCOILDLG4GRIN2BKIF17KRIT1SYNGAP1
Complex memberships
PSD-95/AIDA-1 postsynaptic complex

Evidence

Reading pass · 12 per-paper findings extracted from the source corpus
Year Finding Method Journal Conf PMIDs
2004 AIDA-1 proteins (isoforms AIDA-1a, AIDA-1b, AIDA-1bΔAnk) interact with the amyloid precursor protein (AbetaPP) intracellular domain in vitro, in living cells, and endogenously in leukemia cell lines; overexpression of AbetaPP alters the intracellular distribution of AIDA-1a, and different isoforms localize to distinct subcellular compartments. Co-immunoprecipitation, in vitro binding assay, transfection/overexpression with confocal imaging Journal of Alzheimer's disease : JAD Medium 15004329
2005 A novel ANKS1B/EB-1 isoform, AIDA-1c, interacts with the Cajal body marker protein coilin and competes with SmB' for coilin binding sites but does not bind SMN; knockdown of EB-1/AIDA-1 isoforms by siRNA alters Cajal body organization and reduces cell viability. Co-immunoprecipitation, competition binding assay, siRNA knockdown, fluorescence microscopy BMC cell biology Medium 15862129
2007 AIDA-1d is a postsynaptic density component that binds the first two PDZ domains of PSD-95 via its C-terminal three amino acids; NMDA receptor stimulation induces Ca2+-independent translocation of AIDA-1d to the nucleus where it couples to Cajal bodies and induces Cajal body-nucleolar association, leading to increased nucleolar numbers and protein synthesis. Co-immunoprecipitation, live-cell imaging, NMDA stimulation, siRNA knockdown with protein synthesis assay Nature neuroscience High 17334360
2009 NMR structure of the tandem SAM domain of AIDA-1 reveals a head-to-tail orientation with the nuclear localization signal buried at the SAM-SAM domain interface; differential thermal stability of the two SAM domains suggests a mechanism whereby the second SAM domain decouples from the first to expose the NLS and facilitate nuclear import. NMR structure determination, thermal stability assay Journal of molecular biology High 19666031
2015 AIDA-1 preferentially associates with GluN2B and with CASK and KIF17 (adaptors regulating GluN2B-containing NMDAR transport from ER to synapses); conditional forebrain knockout of AIDA-1 reduces GluN2B-mediated and increases GluN2A-mediated synaptic transmission, with GluN2B accumulating in ER-enriched fractions, indicating AIDA-1 facilitates ER-to-synapse transport of GluN2B. Conditional knockout, co-immunoprecipitation, subcellular fractionation, electrophysiology, lentiviral shRNA knockdown, immunocytochemistry The Journal of neuroscience High 26085624
2015 Under basal conditions, AIDA-1 is located within the dense core of the PSD (~30 nm from postsynaptic membrane); under excitatory conditions (high K+ or NMDA), AIDA-1 label density at the PSD core is reduced to 40% of controls and median distance increases to ~55 nm, with the effect reversible within 30 minutes. Immunogold electron microscopy with two distinct antibodies in cultured hippocampal neurons PloS one Medium 26356309
2015 ANKS1B was identified as a novel binding partner of KRIT1 (CCM1) by yeast two-hybrid screen; silencing of ANKS1B in primary human endothelial cells increases permeability, and forced ANKS1B expression reduces permeability, independently of Rho kinase activity and KRIT1 presence. Yeast two-hybrid screen, siRNA knockdown, overexpression, endothelial permeability assay PloS one Medium 26698571
2016 CaMKII activation phosphorylates AIDA-1 in PSD fractions from brain, and NMDA treatment causes an ~30 nm shift in AIDA-1 median distance from the postsynaptic membrane in hippocampal neurons; this redistribution is blocked by the CaMKII inhibitor tatCN21, establishing CaMKII-mediated phosphorylation as the mechanism for activity-induced displacement of AIDA-1 from the PSD core. Biochemical phosphorylation assay of PSD fractions, immuno-electron microscopy, CaMKII inhibitor treatment FEBS letters High 27477489
2019 Quantitative proteomics of the AIDA-1 interactome in neurons identifies protein networks involved in synaptic function; haploinsufficiency of ANKS1B in a transgenic mouse model recapitulates social deficits, hyperactivity, and sensorimotor dysfunction, demonstrating AIDA-1 loss-of-function drives specific neurodevelopmental phenotypes. Quantitative mass spectrometry-based proteomics (interactome), transgenic mouse model with behavioral analysis Nature communications High 31388001
2023 Anks1b-deficient mice display deficits in oligodendrocyte maturation, myelination, and Rac1 function; selective loss of Anks1b from the oligodendrocyte lineage (but not from neurons) recapitulates social preference and sensory reactivity deficits, and clemastine rescues social deficits in these mice, establishing an oligodendroglial role for AIDA-1 mediated by Rac1 activity. Conditional cell-type-specific knockout, MRI white matter imaging, oligodendrocyte maturation assays, Rac1 activity assay, pharmacological rescue Nature communications High 38129387
2024 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 reveals the molecular basis for this specific interaction. Affinity purification, biochemical binding assay, X-ray crystallography Journal of molecular biology High 38759928
2026 Ischemia induces lactylation of ANKS1B at K1222, targeting it for ubiquitin-proteasome-mediated degradation; loss of ANKS1B causes GluN2B retention in the ER, while a lactylation-resistant mutant (K1222R) restores GluN2B surface trafficking but exacerbates Ca2+ overload and neuronal death, indicating lactylation-driven ANKS1B degradation is a neuroprotective feedback mechanism limiting excitotoxicity. Proteomics, OGD/R cell model, ubiquitin-proteasome pathway assay, site-directed mutagenesis (K1222R), Ca2+ imaging, surface trafficking assay Biochemical and biophysical research communications Medium 41564684

Source papers

Stage 0 corpus · 25 papers · ranked by NIH iCite citations
Year Title Journal Citations PMID
1997 Mal3, the fission yeast homologue of the human APC-interacting protein EB-1 is required for microtubule integrity and the maintenance of cell form. The Journal of cell biology 191 9348288
2007 Activity-dependent AIDA-1 nuclear signaling regulates nucleolar numbers and protein synthesis in neurons. Nature neuroscience 96 17334360
2014 ANKS1B is a smoking-related molecular alteration in clear cell renal cell carcinoma. BMC urology 50 24479813
2004 The anxiolytic-like activity of AIDA (1-aminoindan-1,5-dicarboxylic acid), an mGLu 1 receptor antagonist. Journal of physiology and pharmacology : an official journal of the Polish Physiological Society 37 15082872
2017 Combining DNA Vaccine and AIDA-1 in Attenuated Salmonella Activates Tumor-Specific CD4+ and CD8+ T-cell Responses. Cancer immunology research 35 28468915
2015 ANKS1B Gene Product AIDA-1 Controls Hippocampal Synaptic Transmission by Regulating GluN2B Subunit Localization. The Journal of neuroscience : the official journal of the Society for Neuroscience 34 26085624
2009 A nuclear localization signal at the SAM-SAM domain interface of AIDA-1 suggests a requirement for domain uncoupling prior to nuclear import. Journal of molecular biology 32 19666031
2004 The intracellular localization of amyloid beta protein precursor (AbetaPP) intracellular domain associated protein-1 (AIDA-1) is regulated by AbetaPP and alternative splicing. Journal of Alzheimer's disease : JAD 31 15004329
2019 Haploinsufficiency in the ANKS1B gene encoding AIDA-1 leads to a neurodevelopmental syndrome. Nature communications 28 31388001
2006 The effects of siRNA-mediated inhibition of E2A-PBX1 on EB-1 and Wnt16b expression in the 697 pre-B leukemia cell line. Haematologica 27 16769578
1999 EB-1, a tyrosine kinase signal transduction gene, is transcriptionally activated in the t(1;19) subset of pre-B ALL, which express oncoprotein E2a-Pbx1. Oncogene 25 10490826
2005 A novel EB-1/AIDA-1 isoform, AIDA-1c, interacts with the Cajal body protein coilin. BMC cell biology 17 15862129
2001 EB 1 immunofluorescence reveals an increase in growing astral microtubule length and number during anaphase in NRK-52E cells. European journal of cell biology 17 11831388
2019 The ANKS1B gene and its associated phenotypes: focus on CNS drug response. Pharmacogenomics 15 31250731
2023 ANKS1B encoded AIDA-1 regulates social behaviors by controlling oligodendrocyte function. Nature communications 12 38129387
2021 Upfront transplantation may have better outcomes than pretransplant cytoreductive therapy for treating patients with MDS-EB-1 or MDS-EB-2. International journal of cancer 11 33899230
2017 Initial characterization of behavior and ketamine response in a mouse knockout of the post-synaptic effector gene Anks1b. Neuroscience letters 11 28115237
2016 CaMKII-mediated displacement of AIDA-1 out of the postsynaptic density core. FEBS letters 10 27477489
2015 ANKS1B Interacts with the Cerebral Cavernous Malformation Protein-1 and Controls Endothelial Permeability but Not Sprouting Angiogenesis. PloS one 10 26698571
2015 AIDA-1 Moves out of the Postsynaptic Density Core under Excitatory Conditions. PloS one 6 26356309
2017 rs7968606 polymorphism of ANKS1B is associated with improvement in the PANSS general score of schizophrenia caused by amisulpride. Human psychopharmacology 5 28332719
2012 Chronic ethanol up-regulates the synaptic expression of the nuclear translational regulatory protein AIDA-1 in primary hippocampal neurons. Alcohol (Fayetteville, N.Y.) 5 22703994
2024 AIDA-1/ANKS1B Binds to the SynGAP Family RasGAPs with High Affinity and Specificity. Journal of molecular biology 2 38759928
2023 Replication stress causes delayed mitotic entry and chromosome 12 fragility at the ANKS1B large neuronal gene in human induced pluripotent stem cells. Chromosome research : an international journal on the molecular, supramolecular and evolutionary aspects of chromosome biology 2 37597021
2026 Lactylation-mediated degradation of ANKS1B mitigates ischemic excitotoxicity by impairing GluN2B trafficking. Biochemical and biophysical research communications 0 41564684