ABTB3

UniProt ID: A6QL63
Organism: Homo sapiens
Review Status: COMPLETE
📝 Provide Detailed Feedback

Gene 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.

Existing Annotations Review

GO Term Evidence Action Reason
GO:0016020 membrane
IEA
GO_REF:0000044 		KEEP AS NON CORE
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.
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.
Supporting Evidence:
UniProt:A6QL63
SUBCELLULAR LOCATION: Membrane
PMID:37261953
These data indicate that Btbd11 is localized at glutamatergic synapses.
GO:0046982 protein heterodimerization activity
IEA
GO_REF:0000002 		MARK AS OVER ANNOTATED
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.
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.
Supporting Evidence:
UniProt:A6QL63
InterPro; IPR009072; Histone-fold.
PMID:37261953
Btbd11 contains a PDZ binding motif that interacts with PDZ1,2 of Psd-95
file:human/ABTB3/ABTB3-deep-research-manual.md
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.
GO:0030165 PDZ domain binding
IEA
GO_REF:0000107 		ACCEPT
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.
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.
Supporting Evidence:
PMID:37261953
The C-terminal region of Btbd11 is highly conserved between species
PMID:37261953
Btbd11 could pull down Psd-95-mCherry but only when the PBM was present
file:human/ABTB3/ABTB3-deep-research-manual.md
`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.
GO:0098978 glutamatergic synapse
IEA
GO_REF:0000107 		ACCEPT
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.
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.
Supporting Evidence:
PMID:37261953
identifying Btbd11 as an inhibitory interneuron-specific, synapse-enriched protein
PMID:37261953
These data indicate that Btbd11 is localized at glutamatergic synapses.
file:human/ABTB3/ABTB3-deep-research-manual.md
`GO:0098978 glutamatergic synapse`, because Btbd11 colocalizes with Psd-95, not gephyrin, and is enriched in PSD fractions.
GO:0005654 nucleoplasm
IDA
GO_REF:0000052 		KEEP AS NON CORE
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.
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.
Supporting Evidence:
GO_REF:0000052
Gene Ontology annotation based on curation of immunofluorescence data
GO:0050821 protein stabilization
ISO
PMID:37261953
Btbd11 supports cell-type-specific synaptic function 		NEW
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.
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.
Supporting Evidence:
PMID:37261953
Exogenous expression of Btbd11 stabilizes Psd-95 at glutamatergic synapses
PMID:37261953
Psd-95-mCherry FRAP was slower in the presence of overexpressed Btbd11
file:human/ABTB3/ABTB3-deep-research-manual.md
`GO:0050821 protein stabilization`, for Btbd11-mediated stabilization of Psd-95 at glutamatergic synapses.
GO:0035249 synaptic transmission, glutamatergic
ISO
PMID:37261953
Btbd11 supports cell-type-specific synaptic function 		NEW
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.
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.
Supporting Evidence:
PMID:37261953
Knockout of Btbd11 decreased glutamatergic signaling onto parvalbumin-positive interneurons.
PMID:37261953
we observed a dramatic decrease in the frequency of mEPSCs
file:human/ABTB3/ABTB3-deep-research-manual.md
`GO:0035249 synaptic transmission, glutamatergic`, for the decreased glutamatergic signaling in PV interneurons after mouse Btbd11 knockout.

Core Functions

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:
PDZ domain binding
Directly Involved In:
protein stabilization synaptic transmission, glutamatergic
Cellular Locations:
glutamatergic synapse
Substrates:
DLG4/PSD-95
Supporting Evidence:
  • PMID:37261953
    Btbd11 is highly conserved across species and binds to core postsynaptic proteins, including Psd-95.
  • PMID:37261953
    Knockout of Btbd11 decreased glutamatergic signaling onto parvalbumin-positive interneurons.

References

GO_REF:0000002
Gene Ontology annotation through association of InterPro records with GO terms
GO_REF:0000044
Gene Ontology annotation based on UniProtKB/Swiss-Prot Subcellular Location vocabulary mapping, accompanied by conservative changes to GO terms applied by UniProt
GO_REF:0000052
Gene Ontology annotation based on curation of immunofluorescence data
GO_REF:0000107
Automatic transfer of experimentally verified manual GO annotation data to orthologs using Ensembl Compara
UniProt:A6QL63
UniProt record for human ABTB3 (A6QL63)
  • UniProt describes human ABTB3 as an ankyrin repeat- and BTB/POZ domain-containing protein with inferred synaptic function and single-pass membrane association.
PMID:37261953
Btbd11 supports cell-type-specific synaptic function
  • 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.
file:human/ABTB3/ABTB3-deep-research-manual.md
Manual fallback research summary for ABTB3
  • 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.
file:projects/PROTEOSTASIS/reports/pn_projection/pn_projected_new_to_goa.tsv
Proteostasis PN projected new-to-GOA annotations
  • 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.

Suggested Questions for Experts

Q: Does human ABTB3 physically bind DLG4/PSD-95 through the same conserved C-terminal PDZ-binding motif demonstrated for mouse Btbd11?

Q: Does ABTB3 bind CUL3 or any CRL3 substrate in human neurons, or is the PN Cul3 substrate-receptor projection only a domain-architecture hypothesis?

Q: Are the UniProt isoforms functionally different with respect to the C-terminal PDZ-binding motif, synaptic localization, or predicted membrane association?

Q: Do the BTB-domain yeast two-hybrid hits Ataxin1 and Ataxin-1-like represent physiologic ABTB3/Btbd11 interactors in neurons?

Suggested Experiments

Experiment: 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.

Experiment: 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.

Experiment: 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.

Deep Research

Manual

(ABTB3-deep-research-manual.md)
Manual Deep Research: ABTB3 Manual

Manual Deep Research: ABTB3

Provider status: just deep-research-falcon human ABTB3 --fallback perplexity-lite was run on 2026-06-03. Falcon timed out after 600 seconds, and
the configured perplexity-lite fallback failed with a Perplexity API quota
401. Per project instructions, this file is a manual fallback research summary
and is not named as provider-generated deep research.

Identity

ABTB3 (UniProt A6QL63; synonym BTBD11) encodes ankyrin repeat- and BTB/POZ
domain-containing protein 3. UniProt lists the protein as reviewed, 1104 amino
acids, with ankyrin repeats, a BTB/POZ domain, a BACK domain, a histone-fold
signature, and five annotated isoforms [UniProt:A6QL63 "RecName: Full=Ankyrin
repeat- and BTB/POZ domain-containing protein 3;"].

The PANTHER family fetched during just fetch-gene human ABTB3 is PTHR46071,
Ankyrin repeat and BTB/POZ domain-containing protein. The reviewed entries in
the local family cache include human ABTB3 and ABTB2, mouse Abtb3 and Abtb2, rat
Abtb2, and zebrafish abtb3a/abtb3b, supporting conserved ABTB2/3 family context.

Main Experimental Evidence

The key functional study is the mouse Btbd11 Cell Reports paper by Bygrave et
al. 2023 PMID:37261953. It identifies Btbd11 as an inhibitory
interneuron-specific postsynaptic protein: PMID:37261953. The abstract
states that Btbd11 is conserved and binds Psd-95: PMID:37261953.

The paper directly supports PDZ-domain binding. The results section states that
Btbd11 has a PDZ-binding motif and that the conserved C-terminal region is
important: PMID:37261953 and PMID:37261953. The binding assays show dependence on the
PDZ-binding motif: PMID:37261953.

The same paper supports glutamatergic synapse localization. Endogenous and
tagged Btbd11 puncta colocalized with Psd-95 rather than gephyrin, and the paper
summarizes the result as PMID:37261953.

Btbd11 also stabilizes Psd-95 at glutamatergic synapses. The relevant heading
and FRAP result are PMID:37261953 and PMID:37261953. Knockout data support a
functional role in glutamatergic signaling onto PV interneurons:
PMID:37261953.

GO Review Implications

Accepted core annotations:

  • 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.
  • GO:0098978 glutamatergic synapse, because Btbd11 colocalizes with Psd-95,
    not gephyrin, and is enriched in PSD fractions.

Kept as non-core:

  • GO:0016020 membrane, because UniProt predicts membrane association but the
    functional localization is more specifically captured by glutamatergic synapse.
  • GO:0005654 nucleoplasm, because HPA immunofluorescence supports the source
    observation, but no mechanistic nucleoplasmic function is currently established.

Marked as over-annotated:

  • GO:0046982 protein heterodimerization activity, because it is an
    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.

Added as new orthology-supported BP annotations:

  • GO:0050821 protein stabilization, for Btbd11-mediated stabilization of
    Psd-95 at glutamatergic synapses.
  • GO:0035249 synaptic transmission, glutamatergic, for the decreased
    glutamatergic signaling in PV interneurons after mouse Btbd11 knockout.

Not added:

  • GO:0035640 exploration behavior, because it is a downstream organismal
    phenotype and should not be treated as the core gene-product function.
  • GO:1990756 ubiquitin-like ligase-substrate adaptor activity, because the PN
    projection is based on Cul3 substrate-receptor/domain context and the
    available ABTB3/Btbd11 evidence does not show CUL3 binding, CRL3 complex
    membership, a ubiquitinated substrate, or substrate-adaptor activity.

Proteostasis PN Context

The PN projection report lists ABTB3 as a candidate for GO:1990756 ubiquitin-like ligase-substrate adaptor activity from
Ubiquitin Proteasome System|E3 ubiquitin and UBL ligases|Cul3 substrate receptor|BTB-BACK, variant|ankyrin, transmembrane
[file:projects/PROTEOSTASIS/reports/pn_projection/pn_projected_new_to_goa.tsv].
The current mapping audit classifies Cul3 substrate-receptor propagation as
requiring manual gene-level review before gene review changes
[file:projects/PROTEOSTASIS/reports/pn_mapping_audit/current_mapping_scrutiny.tsv].

For ABTB3, the gene-level review does not support propagating the Cul3 adaptor
term. The evidence supports a synaptic PDZ-binding/stabilizer role. It does not
support adding a ubiquitin-like ligase-substrate adaptor activity annotation.

📚 Additional Documentation

Notes

(ABTB3-notes.md)

ABTB3 Gene Review Notes

2026-06-03 - Proteostasis PN batch review

ABTB3 was newly fetched for the human Proteostasis PN batch. The local GOA set
contains five annotations: membrane, protein heterodimerization activity, PDZ
domain binding, glutamatergic synapse, and nucleoplasm. UniProt also lists
Ensembl-transferred biological-process annotations for exploration behavior,
protein stabilization, and synaptic transmission, glutamatergic, but these were
not present in the fetched GOA TSV.

Deep research status: just deep-research-falcon human ABTB3 --fallback perplexity-lite was run. Falcon timed out after 600 seconds, then
perplexity-lite failed with a Perplexity API quota 401. Per project guidance,
I recorded the evidence synthesis in ABTB3-deep-research-manual.md rather than
creating a fake provider-named deep-research file.

The strongest gene-specific biology comes from mouse Btbd11. Bygrave et al.
identify Btbd11 as an inhibitory interneuron-specific synapse-enriched protein
that is highly conserved and binds Psd-95: PMID:37261953 and
PMID:37261953. The paper directly supports the
orthology-derived human GOA terms for PDZ domain binding and glutamatergic
synapse: PMID:37261953 and PMID:37261953.

The same mouse study supports adding two missing, conservative BP terms by
orthology. For protein stabilization, the relevant evidence is Psd-95 FRAP and
puncta-size data: PMID:37261953 and PMID:37261953. For glutamatergic synaptic
transmission, the direct phenotype is reduced excitatory signaling onto PV
interneurons: PMID:37261953.

Conservative calls:

  • Keep GO:0016020 membrane as non-core. UniProt has predicted membrane
    association, but the functional localization is better captured by
    GO:0098978 glutamatergic synapse.
  • Mark GO:0046982 protein heterodimerization activity as over-annotated. It is
    inferred from a histone-fold InterPro signature [UniProt:A6QL63 "InterPro;
    IPR009072; Histone-fold."], whereas the direct interaction evidence maps the
    PSD-95 interaction to the C-terminal PDZ-binding motif.
  • Keep GO:0005654 nucleoplasm as non-core. It is HPA immunofluorescence-derived
    and does not explain the currently supported synaptic role.
  • Do not add GO:0035640 exploration behavior; that is a downstream organismal
    phenotype from mouse knockout behavior, not the core gene-product function.

PN projected context

The Proteostasis PN projection proposes GO:1990756 ubiquitin-like ligase-substrate adaptor activity for ABTB3 from
Ubiquitin Proteasome System|E3 ubiquitin and UBL ligases|Cul3 substrate receptor|BTB-BACK, variant|ankyrin, transmembrane
[file:projects/PROTEOSTASIS/reports/pn_projection/pn_projected_new_to_goa.tsv].
The curated parent mapping says the Cul3 substrate receptor group maps to
GO:1990756, but the audit marks it as requiring manual gene-level review before
gene review changes
[file:projects/PROTEOSTASIS/reports/pn_mapping_audit/current_mapping_scrutiny.tsv].

I did not add GO:1990756 for ABTB3. The evidence found here supports PDZ-domain
binding and synaptic PSD stabilization; it does not show ABTB3-CUL3 binding, CRL3
complex membership, a ubiquitinated substrate, or substrate-adaptor activity.
This is analogous to the KCTD18 exclusion note in the same PN mapping: domain
architecture alone is not enough for a gene-level GO:1990756 assertion.

Pn Notes

(ABTB3-pn-notes.md)

ABTB3 PN Consistency Notes

  • Generated: 2026-06-18
  • Project: PROTEOSTASIS
  • Scope: PN consistency rereview against local AIGR review and available deep-research artifacts
  • UniProt: A6QL63
  • AIGR review status: COMPLETE
  • Review batch: proteostasis-batch-2026-06-03 (PR 1332)
  • Batch change status: added

Source Files Checked

Deep Research Files

AIGR Review Snapshot

  • 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.
  • Existing/core annotation action counts: ACCEPT: 2; KEEP_AS_NON_CORE: 2; MARK_AS_OVER_ANNOTATED: 1; NEW: 2

PN Consistency Summary

  • Consistency: CONTRADICTION (PN projection rejected by review). The PN node projects the same Cul3-adaptor term (GO:1990756) as for paralog ABTB2, purely on BTB-BACK/ankyrin domain architecture. Deep research, notes, and review YAML all converge instead on a synaptic scaffold/stabilizer role: mouse ortholog Btbd11 binds PSD-95 via a C-terminal PDZ-binding motif, stabilizes PSD-95, and supports glutamatergic input onto PV interneurons (PMID:37261953). The review explicitly declines GO:1990756: "the available ABTB3/Btbd11 evidence does not show CUL3 binding, CRL3 complex membership, a ubiquitinated substrate, or substrate-adaptor activity."
  • PN story / NEW pressure: PN asserts ubiquitin-ligase adaptor activity with no gene-level support for this gene — a domain-architecture inference. The actual GO captures the real biology (GO:0030165 PDZ domain binding ACCEPT; GO:0098978 glutamatergic synapse ACCEPT) and the review adds orthology-supported NEW terms GO:0050821 protein stabilization and GO:0035249 synaptic transmission, glutamatergic. The Cul3-adaptor story over-reaches and is correctly not added.
  • Evidence alignment: PN row references (PMID:15071497, 23912815 — generic Cul3/BTB reviews) do not overlap the review's primary evidence (PMID:37261953, the Btbd11 synaptic study). Complete divergence in evidence base, reflecting the domain-only vs functional-evidence split.
  • Verdict: PN Cul3-adaptor projection over-reaches (domain-only, contradicted by synaptic-function evidence); review correctly rejects GO:1990756. Recommended edits: [MAP] Suppress GO:1990756 projection for ABTB3 (no CUL3/CRL3/substrate evidence); retain the group mapping for genes with direct support (e.g. ABTB2).

Full Consistency Review

  • UniProt: A6QL63 (=BTBD11) · batch: proteostasis-batch-2026-06-03 · review status: COMPLETE
  • PN placement: Ubiquitin Proteasome System|E3 ubiquitin and UBL ligases|Cul3 substrate receptor|BTB-BACK, variant|ankyrin, transmembrane ; PN-node mapping: group Cul3 substrate receptor=mapped→GO:1990756 ubiquitin-like ligase-substrate adaptor activity (new_to_goa); class=context_only (too_broad→GO:0061630); subtype/type/branch=no_mapping.
  • Consistency: CONTRADICTION (PN projection rejected by review). The PN node projects the same Cul3-adaptor term (GO:1990756) as for paralog ABTB2, purely on BTB-BACK/ankyrin domain architecture. Deep research, notes, and review YAML all converge instead on a synaptic scaffold/stabilizer role: mouse ortholog Btbd11 binds PSD-95 via a C-terminal PDZ-binding motif, stabilizes PSD-95, and supports glutamatergic input onto PV interneurons (PMID:37261953). The review explicitly declines GO:1990756: "the available ABTB3/Btbd11 evidence does not show CUL3 binding, CRL3 complex membership, a ubiquitinated substrate, or substrate-adaptor activity."
  • PN story / NEW pressure: PN asserts ubiquitin-ligase adaptor activity with no gene-level support for this gene — a domain-architecture inference. The actual GO captures the real biology (GO:0030165 PDZ domain binding ACCEPT; GO:0098978 glutamatergic synapse ACCEPT) and the review adds orthology-supported NEW terms GO:0050821 protein stabilization and GO:0035249 synaptic transmission, glutamatergic. The Cul3-adaptor story over-reaches and is correctly not added.
  • Mapping strategy: This gene shows the Cul3-substrate-receptor group mapping does not safely propagate to all BTB-BACK-ankyrin members. GO:1990756 should be suppressed for ABTB3 pending direct CUL3/CRL3 evidence — a per-gene exception within an otherwise valid group mapping (contrast ABTB2, where it is supported). Precedent: reject a projected term lacking gene-level support.
  • Evidence alignment: PN row references (PMID:15071497, 23912815 — generic Cul3/BTB reviews) do not overlap the review's primary evidence (PMID:37261953, the Btbd11 synaptic study). Complete divergence in evidence base, reflecting the domain-only vs functional-evidence split.
  • Verdict: PN Cul3-adaptor projection over-reaches (domain-only, contradicted by synaptic-function evidence); review correctly rejects GO:1990756. Recommended edits: [MAP] Suppress GO:1990756 projection for ABTB3 (no CUL3/CRL3/substrate evidence); retain the group mapping for genes with direct support (e.g. ABTB2).

PN Dossier Context

  • review_batch: proteostasis-batch-2026-06-03
  • review_yaml: genes/human/ABTB3/ABTB3-ai-review.yaml
  • PN workbook rows: 1

PN row 1: Ubiquitin Proteasome System | E3 ubiquitin and UBL ligases | Cul3 substrate receptor | BTB-BACK, variant | ankyrin, transmembrane

  • UniProt: A6QL63
  • In branches: UPS
  • Signature domains: IPR000210, IPR047824
  • Auxiliary domains: IPR002110
  • PN references (titles):
    • 15071497 / rev
    • 23912815 / rev
  • PN-node mapping records (path + ancestors):
    • [subtype] Ubiquitin Proteasome System|E3 ubiquitin and UBL ligases|Cul3 substrate receptor|BTB-BACK, variant|ankyrin, transmembrane
      status=no_mapping scope= GO=[]
      rationale: Reviewed as a narrower substrate-receptor, adaptor, domain, or family subdivision already covered by the curated parent adaptor/receptor mapping. No additional direct GO mapping is needed at this node.
    • [type] Ubiquitin Proteasome System|E3 ubiquitin and UBL ligases|Cul3 substrate receptor|BTB-BACK, variant
      status=no_mapping scope= GO=[]
      rationale: Reviewed as a narrower substrate-receptor, adaptor, domain, or family subdivision already covered by the curated parent adaptor/receptor mapping. No additional direct GO mapping is needed at this node.
    • [group] Ubiquitin Proteasome System|E3 ubiquitin and UBL ligases|Cul3 substrate receptor
      status=mapped scope=ok_for_propagation_to_go GO=[GO:1990756 ubiquitin-like ligase-substrate adaptor activity]
      rationale: This PN group captures substrate receptors/adaptors for cullin/UBL ligase systems. The shared GO molecular-function target is ubiquitin-like ligase-substrate adaptor activity.
    • [class] Ubiquitin Proteasome System|E3 ubiquitin and UBL ligases
      status=context_only scope=too_broad_to_propagate GO=[GO:0061630 ubiquitin protein ligase activity]
      rationale: This class is a genuine E3-ligase context, but its descendants include catalytic ligases, cullin scaffolds, substrate receptors, adaptors, cofactors, regulators, and UBL modifier systems. A class-level propagation would over-annotate.
    • [branch] Ubiquitin Proteasome System
      status=no_mapping scope= GO=[]
      rationale: Reviewed as the top-level UPS branch. It is a project taxonomy umbrella rather than a direct GO assertion; UPS propagation must come from manually curated child nodes.

Projected GO annotations (1)

  • GO:1990756 ubiquitin-like ligase-substrate adaptor activity | scope=ok_for_propagation_to_go | goa_status=new_to_goa | from=Ubiquitin Proteasome System|E3 ubiquitin and UBL ligases|Cul3 substrate receptor

Note

This file is generated from the current PROTEOSTASIS phase-1 dossier and local gene-review artifacts. Edit the source review, PN mapping, or dossier rather than this generated note when correcting the underlying curation.

📄 View Raw YAML

 
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.