id: A6QL63 gene_symbol: ABTB3 product_type: PROTEIN status: COMPLETE taxon: id: NCBITaxon:9606 label: Homo sapiens description: >- ABTB3 encodes a conserved ankyrin repeat- and BTB/POZ domain-containing protein, also known as BTBD11. The best characterized functional evidence comes from the mouse ortholog Btbd11, which is enriched at glutamatergic postsynaptic densities in cortical and hippocampal inhibitory interneurons. Btbd11 contains a conserved C-terminal PDZ-binding motif that binds PSD-95 (DLG4), promotes PSD-95 stabilization at glutamatergic synapses, and supports excitatory synaptic input onto parvalbumin-positive interneurons. Human ABTB3 is predicted to share this synaptic scaffold/stabilizer role by orthology, but direct human functional assays and CUL3 substrate-adaptor activity have not been established. alternative_products: - name: '1' id: A6QL63-1 - name: '2' id: A6QL63-2 sequence_note: VSP_032802 - name: '3' id: A6QL63-3 sequence_note: VSP_032803 - name: '4' id: A6QL63-4 sequence_note: VSP_032801 - name: '5' id: A6QL63-5 sequence_note: VSP_045802, VSP_045803 references: - id: GO_REF:0000002 title: Gene Ontology annotation through association of InterPro records with GO terms findings: [] - id: GO_REF:0000044 title: Gene Ontology annotation based on UniProtKB/Swiss-Prot Subcellular Location vocabulary mapping, accompanied by conservative changes to GO terms applied by UniProt findings: [] - id: GO_REF:0000052 title: Gene Ontology annotation based on curation of immunofluorescence data findings: [] - id: GO_REF:0000107 title: Automatic transfer of experimentally verified manual GO annotation data to orthologs using Ensembl Compara findings: [] - id: UniProt:A6QL63 title: UniProt record for human ABTB3 (A6QL63) findings: - statement: >- UniProt describes human ABTB3 as an ankyrin repeat- and BTB/POZ domain-containing protein with inferred synaptic function and single-pass membrane association. - id: PMID:37261953 title: Btbd11 supports cell-type-specific synaptic function findings: - statement: >- Mouse Btbd11 is a conserved inhibitory-interneuron synaptic protein that binds PSD-95, localizes to glutamatergic synapses, stabilizes PSD-95, and supports glutamatergic synaptic signaling. - id: file:human/ABTB3/ABTB3-deep-research-manual.md title: Manual fallback research summary for ABTB3 findings: - statement: >- Falcon deep research timed out and the configured perplexity-lite fallback failed for quota reasons; this manual file records the evidence synthesis used for the review. - id: file:projects/PROTEOSTASIS/reports/pn_projection/pn_projected_new_to_goa.tsv title: Proteostasis PN projected new-to-GOA annotations findings: - statement: >- PN projects ABTB3 to GO:1990756 from the Cul3 substrate receptor group, but the projection report marks these cases for manual gene-level review before changing gene annotations. existing_annotations: - term: id: GO:0016020 label: membrane evidence_type: IEA original_reference_id: GO_REF:0000044 qualifier: located_in review: summary: >- UniProt maps ABTB3 to membrane based on its subcellular-location record and predicted single-pass membrane association. This broad location is compatible with synaptic localization but is less informative than the orthology-supported glutamatergic synapse term. action: KEEP_AS_NON_CORE reason: >- Retain as a broad, source-supported cellular-component annotation, but do not treat it as the defining localization. The more functionally informative location is glutamatergic synapse, supported by the mouse Btbd11 paper and transferred to human by orthology. supported_by: - reference_id: UniProt:A6QL63 supporting_text: "SUBCELLULAR LOCATION: Membrane" - reference_id: PMID:37261953 supporting_text: "These data indicate that Btbd11 is localized at glutamatergic synapses." - term: id: GO:0046982 label: protein heterodimerization activity evidence_type: IEA original_reference_id: GO_REF:0000002 qualifier: enables review: summary: >- This is an InterPro2GO inference from the histone-fold superfamily signature. ABTB3/Btbd11 has experimentally supported protein interactions, most clearly PDZ-mediated binding to PSD-95, but the available gene-specific evidence does not establish a physiologic heterodimerization activity as the molecular function. action: MARK_AS_OVER_ANNOTATED reason: >- The histone-fold architecture may support protein-protein interaction potential, but this broad InterPro transfer is less informative than the directly supported PDZ domain binding annotation. The 2023 Btbd11 study maps the PSD-95 interaction to a C-terminal PDZ-binding motif, not to a demonstrated histone-fold heterodimerization mechanism. additional_reference_ids: - file:human/ABTB3/ABTB3-deep-research-manual.md supported_by: - reference_id: UniProt:A6QL63 supporting_text: "InterPro; IPR009072; Histone-fold." - reference_id: PMID:37261953 supporting_text: "Btbd11 contains a PDZ binding motif that interacts with PDZ1,2 of Psd-95" - reference_id: file:human/ABTB3/ABTB3-deep-research-manual.md supporting_text: >- InterPro2GO inference from the histone-fold signature rather than a demonstrated physiologic heterodimerization function. The experimentally supported interaction mechanism is PDZ-motif-mediated binding to Psd-95. - term: id: GO:0030165 label: PDZ domain binding evidence_type: IEA original_reference_id: GO_REF:0000107 qualifier: enables review: summary: >- Orthology-transferred annotation from mouse Btbd11. The source study directly supports PDZ-domain binding: the conserved C-terminal PDZ-binding motif is required for interaction with Psd-95/DLG4 PDZ1,2. action: ACCEPT reason: >- This is the best-supported molecular function for ABTB3/Btbd11. The cited mouse paper demonstrates PDZ-motif-dependent interaction with Psd-95 by yeast two-hybrid and GST pulldown assays, and notes conservation of the C-terminal region between species, making orthology transfer to human ABTB3 appropriate. additional_reference_ids: - PMID:37261953 - file:human/ABTB3/ABTB3-deep-research-manual.md supported_by: - reference_id: PMID:37261953 supporting_text: "The C-terminal region of Btbd11 is highly conserved between species" - reference_id: PMID:37261953 supporting_text: "Btbd11 could pull down Psd-95-mCherry but only when the PBM was present" - reference_id: file:human/ABTB3/ABTB3-deep-research-manual.md supporting_text: >- `GO:0030165 PDZ domain binding`, because the source mouse study directly maps Psd-95 binding to the Btbd11 C-terminal PDZ-binding motif and the region is conserved. - term: id: GO:0098978 label: glutamatergic synapse evidence_type: IEA original_reference_id: GO_REF:0000107 qualifier: located_in review: summary: >- Orthology-transferred annotation from mouse Btbd11. The mouse paper identifies Btbd11 as an inhibitory interneuron postsynaptic-density protein that colocalizes with Psd-95 and is enriched at glutamatergic synapses. action: ACCEPT reason: >- The source evidence directly demonstrates localization at glutamatergic synapses by endogenous labeling, immunofluorescence, and PSD fraction enrichment. This is the most informative cellular-component annotation for ABTB3/Btbd11. additional_reference_ids: - PMID:37261953 - file:human/ABTB3/ABTB3-deep-research-manual.md supported_by: - reference_id: PMID:37261953 supporting_text: "identifying Btbd11 as an inhibitory interneuron-specific, synapse-enriched protein" - reference_id: PMID:37261953 supporting_text: "These data indicate that Btbd11 is localized at glutamatergic synapses." - reference_id: file:human/ABTB3/ABTB3-deep-research-manual.md supporting_text: >- `GO:0098978 glutamatergic synapse`, because Btbd11 colocalizes with Psd-95, not gephyrin, and is enriched in PSD fractions. - term: id: GO:0005654 label: nucleoplasm evidence_type: IDA original_reference_id: GO_REF:0000052 qualifier: located_in review: summary: >- HPA immunofluorescence supports a nucleoplasm localization signal in surveyed human cells. This does not match the main synaptic biology supported by the mouse ortholog, but it can be retained as a non-core high-throughput localization observation. action: KEEP_AS_NON_CORE reason: >- Keep as source-specific experimental localization, but do not use it to define the core function of ABTB3. The primary functional evidence points to a glutamatergic synapse role; there is no current mechanistic evidence that a nucleoplasmic ABTB3 pool mediates the core synaptic function. supported_by: - reference_id: GO_REF:0000052 supporting_text: "Gene Ontology annotation based on curation of immunofluorescence data" - term: id: GO:0050821 label: protein stabilization evidence_type: ISO original_reference_id: PMID:37261953 qualifier: involved_in review: summary: >- Proposed NEW human annotation by orthology to mouse Btbd11. The source paper shows that Btbd11 promotes Psd-95 stabilization at glutamatergic synapses and that Btbd11 knockout reduces Psd-95 puncta size in parvalbumin-positive interneurons. action: NEW reason: >- This process term captures the experimentally supported synaptic stabilizer role. It is already listed in the human UniProt record as an Ensembl-transferred process annotation, but it was not present in the fetched GOA set; adding it keeps the review aligned with the strongest orthology-supported biology. additional_reference_ids: - file:human/ABTB3/ABTB3-deep-research-manual.md supported_by: - reference_id: PMID:37261953 supporting_text: "Exogenous expression of Btbd11 stabilizes Psd-95 at glutamatergic synapses" - reference_id: PMID:37261953 supporting_text: "Psd-95-mCherry FRAP was slower in the presence of overexpressed Btbd11" - reference_id: file:human/ABTB3/ABTB3-deep-research-manual.md supporting_text: >- `GO:0050821 protein stabilization`, for Btbd11-mediated stabilization of Psd-95 at glutamatergic synapses. - term: id: GO:0035249 label: synaptic transmission, glutamatergic evidence_type: ISO original_reference_id: PMID:37261953 qualifier: involved_in review: summary: >- Proposed NEW human annotation by orthology to mouse Btbd11. Mouse interneuron-specific Btbd11 knockout decreases glutamatergic signaling onto parvalbumin-positive interneurons and alters circuit activity. action: NEW reason: >- This BP term is appropriate as a non-catalytic synaptic-process annotation supported by direct mouse ortholog experiments. It should be kept distinct from the higher-level exploration behavior phenotype, which is downstream and not recommended as a core annotation. additional_reference_ids: - file:human/ABTB3/ABTB3-deep-research-manual.md supported_by: - reference_id: PMID:37261953 supporting_text: "Knockout of Btbd11 decreased glutamatergic signaling onto parvalbumin-positive interneurons." - reference_id: PMID:37261953 supporting_text: "we observed a dramatic decrease in the frequency of mEPSCs" - reference_id: file:human/ABTB3/ABTB3-deep-research-manual.md supporting_text: >- `GO:0035249 synaptic transmission, glutamatergic`, for the decreased glutamatergic signaling in PV interneurons after mouse Btbd11 knockout. core_functions: - description: >- ABTB3/Btbd11 acts as a PDZ-domain-binding synaptic scaffold/stabilizer at glutamatergic postsynaptic densities in inhibitory interneurons, binding PSD-95/DLG4, forming PSD-95-associated liquid-like condensates in overexpression assays, and supporting excitatory synaptic input onto PV interneurons. molecular_function: id: GO:0030165 label: PDZ domain binding directly_involved_in: - id: GO:0050821 label: protein stabilization - id: GO:0035249 label: synaptic transmission, glutamatergic locations: - id: GO:0098978 label: glutamatergic synapse substrates: - id: UniProtKB:P78352 label: DLG4/PSD-95 supported_by: - reference_id: PMID:37261953 supporting_text: "Btbd11 is highly conserved across species and binds to core postsynaptic proteins, including Psd-95." - reference_id: PMID:37261953 supporting_text: "Knockout of Btbd11 decreased glutamatergic signaling onto parvalbumin-positive interneurons." suggested_questions: - question: >- Does human ABTB3 physically bind DLG4/PSD-95 through the same conserved C-terminal PDZ-binding motif demonstrated for mouse Btbd11? - question: >- Does ABTB3 bind CUL3 or any CRL3 substrate in human neurons, or is the PN Cul3 substrate-receptor projection only a domain-architecture hypothesis? - question: >- Are the UniProt isoforms functionally different with respect to the C-terminal PDZ-binding motif, synaptic localization, or predicted membrane association? - question: >- Do the BTB-domain yeast two-hybrid hits Ataxin1 and Ataxin-1-like represent physiologic ABTB3/Btbd11 interactors in neurons? suggested_experiments: - description: >- Test human ABTB3 interaction with DLG4/PSD-95 PDZ domains using yeast two-hybrid or pulldown assays with full-length and PBM-deleted isoforms. hypothesis: >- Human ABTB3 uses a conserved C-terminal PDZ-binding motif to bind DLG4/PSD-95. - description: >- Express tagged human ABTB3 in human iPSC-derived inhibitory interneurons and quantify localization with PSD-95, gephyrin, and glutamatergic synapse markers. hypothesis: >- Human ABTB3 localizes preferentially to glutamatergic postsynaptic densities rather than inhibitory synapses or nucleoplasm. - description: >- Perform ABTB3-CUL3 co-immunoprecipitation and ubiquitination/substrate discovery assays in neuronal cells. hypothesis: >- If ABTB3 is a true CRL3 substrate receptor, it should form a CUL3 complex and show substrate-linked ubiquitination activity; absence of these results would argue against propagating the PN Cul3-adaptor term.