Affinage

ANKS1B

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

Length
1248 aa
Mass
138.1 kDa
Annotated
2026-06-09
26 papers in source corpus 14 papers cited in narrative 14 extracted findings
Cross-family judge vs UniProt: Affinage preferred faithfulness: 7/7 claims corpus-supported (100%)

Mechanistic narrative

Synthesis pass · prose summary of the discoveries below

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).

Mechanistic history

Synthesis pass · year-by-year structured walk · 12 steps
  1. 2004 Medium

    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

    PMID:15004329

    Open questions at the time
    • Functional consequence of the AbetaPP interaction in neurons unresolved
    • Binding mapped to isoforms but not to a specific domain
    • Single lab
  2. 2005 Medium

    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

    PMID:15862129

    Open questions at the time
    • Mechanism linking coilin binding to nucleolar function not yet defined
    • Physiological trigger for nuclear targeting unknown at this stage
  3. 2007 High

    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

    PMID:17334360

    Open questions at the time
    • Identity of the translocating cleavage fragment and the cleavage mechanism not established
    • Transcriptional/translational targets downstream of nucleolar expansion undefined
  4. 2009 High

    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

    PMID:19666031

    Open questions at the time
    • Direct demonstration that SAM decoupling triggers import in cells not shown
    • Signal that drives domain decoupling unidentified
  5. 2015 High

    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

    PMID:26085624

    Open questions at the time
    • Stoichiometry and directionality within the KIF17 transport complex not resolved
    • Whether ANKS1B acts as cargo adaptor or transport regulator unclear
  6. 2015 Medium

    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

    PMID:26356309

    Open questions at the time
    • Molecular trigger of redistribution not identified in this study
    • Relationship between PSD displacement and nuclear translocation unresolved
  7. 2016 Medium

    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

    PMID:27477489

    Open questions at the time
    • Phosphosite(s) on ANKS1B not mapped
    • Causal link between phosphorylation and downstream trafficking not established
  8. 2019 Medium

    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

    PMID:31388001

    Open questions at the time
    • Which interactome members are direct versus indirect partners not dissected
    • Cell type responsible for behavioral phenotypes not isolated here
  9. 2023 High

    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

    PMID:38129387

    Open questions at the time
    • Molecular link between ANKS1B and Rac1 regulation not defined
    • Whether the oligodendrocyte function uses the same domains as synaptic function unknown
  10. 2024 High

    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

    PMID:38759928

    Open questions at the time
    • Functional consequence of the ANKS1B-SynGAP interaction in vivo not tested here
    • Which other NPx[F/Y]-containing proteins use this interface unexplored
  11. 2026 Medium

    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

    PMID:41564684

    Open questions at the time
    • Enzyme(s) catalyzing K1222 lactylation not identified
    • In vivo relevance of the neuroprotective feedback not established
  12. 2026 Medium

    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

    PMID:42228033

    Open questions at the time
    • Whether nucleus accumbens ANKS1B is the same translocating fragment as the hippocampal nuclear species unknown
    • Direct DNA/chromatin contacts of the complex not mapped

Open questions

Synthesis pass · forward-looking unresolved questions
  • 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.
  • 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

Synthesis pass · controlled-vocabulary classification · explore literature graph →
Molecular activity
GO:0060090 molecular adaptor activity 3 GO:0008092 cytoskeletal protein binding 2
Localization
GO:0005634 nucleus 3 GO:0005730 nucleolus 2 GO:0005783 endoplasmic reticulum 2 GO:0005886 plasma membrane 2
Pathway
R-HSA-112316 Neuronal System 3 R-HSA-9609507 Protein localization 2 R-HSA-4839726 Chromatin organization 1
Partners
APPCASKCOILCREBBPDLG4GRIN2BKIF17SYNGAP1
Complex memberships
postsynaptic density

Evidence

Reading pass · 14 per-paper findings extracted from the source corpus
Year Finding Method Journal Conf PMIDs
2007 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. Co-immunoprecipitation, subcellular fractionation, immunofluorescence, neuronal stimulation assays Nature neuroscience High 17334360
2009 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. NMR structure determination, thermal stability assays Journal of molecular biology High 19666031
2004 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. Co-immunoprecipitation, in vitro binding assay, transfection/overexpression with subcellular localization imaging Journal of Alzheimer's disease : JAD Medium 15004329
2005 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. Co-immunoprecipitation, competition binding assays, siRNA knockdown, immunofluorescence BMC cell biology Medium 15862129
2015 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. Conditional knockout mouse, electrophysiology, biochemical fractionation, Co-immunoprecipitation, lentiviral shRNA knockdown, immunocytochemistry The Journal of neuroscience High 26085624
2015 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. Immunogold electron microscopy with two antibodies recognizing different epitopes, pharmacological stimulation PloS one Medium 26356309
2016 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. Phosphorylation assay with PSD fractions, immuno-electron microscopy, pharmacological inhibition of CaMKII FEBS letters Medium 27477489
2015 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. Yeast two-hybrid screen, siRNA knockdown, overexpression, permeability assays, pharmacological inhibition PloS one Medium 26698571
2019 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. Quantitative proteomics (interactome), patient-derived iPSC neurons, transgenic haploinsufficiency mouse model, behavioral assays Nature communications Medium 31388001
2023 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. Cell type-specific conditional knockout (oligodendrocyte lineage vs. neuronal), myelination assays, Rac1 activity assay, behavioral assays, 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 revealed the molecular basis of this specific interaction. Affinity purification, biochemical binding assays, crystal structure determination Journal of molecular biology High 38759928
2012 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). Lentiviral shRNA knockdown, immunofluorescence, pharmacological treatments (ethanol, AP-V, NMDA, palmitoylation inhibitor) Alcohol (Fayetteville, N.Y.) Low 22703994
2026 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. Proteomics, OGD/R cell model, site-directed mutagenesis (K1222R), ubiquitin-proteasome pathway assays, Ca2+ imaging, cell death assays Biochemical and biophysical research communications Medium 41564684
2026 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. Co-immunoprecipitation, ChIP assay (H3K27ac), viral vector-mediated ANKS1B manipulation, cocaine self-administration rat model Advanced science Medium 42228033

Source papers

Stage 0 corpus · 26 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 97 17334360
2014 ANKS1B is a smoking-related molecular alteration in clear cell renal cell carcinoma. BMC urology 51 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 36 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 29 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
2023 ANKS1B encoded AIDA-1 regulates social behaviors by controlling oligodendrocyte function. Nature communications 15 38129387
2019 The ANKS1B gene and its associated phenotypes: focus on CNS drug response. Pharmacogenomics 15 31250731
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 12 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
2026 ANKS1B in the Nucleus Accumbens Controls Escalated Cocaine Self-Administration via Regulating CBP-FoxO3 Complex. Advanced science (Weinheim, Baden-Wurttemberg, Germany) 0 42228033

Missed literature

Know a paper Affinage missed for ANKS1B? Flag it for the maintainers and the community.

No submissions yet.