id: Q8NBU5 gene_symbol: ATAD1 product_type: PROTEIN status: COMPLETE taxon: id: NCBITaxon:9606 label: Homo sapiens description: >- ATAD1 is a conserved single-pass AAA+ ATPase anchored mainly in the mitochondrial outer membrane, with additional evidence for peroxisomal membrane localization. It functions as an ATP-dependent membrane protein dislocase that extracts mistargeted tail-anchored membrane proteins from the mitochondrial outer membrane so that they can be cleared, thereby protecting mitochondrial integrity. In neurons, ATAD1/Thorase has a separate disease-relevant role in AMPA receptor complex disassembly and postsynaptic receptor trafficking, but the conserved molecular activity remains ATP-driven membrane protein extraction. alternative_products: - name: '1' id: Q8NBU5-1 - name: '2' id: Q8NBU5-2 sequence_note: VSP_037304 existing_annotations: - term: id: GO:0140570 label: extraction of mislocalized protein from mitochondrial outer membrane evidence_type: IBA original_reference_id: GO_REF:0000033 qualifier: involved_in review: summary: >- This is the most specific existing biological-process annotation for the conserved ATAD1/Msp1 pathway. action: ACCEPT reason: >- The IBA call matches direct human/yeast evidence that ATAD1/Msp1 limits accumulation of mistargeted tail-anchored proteins on mitochondria and promotes their extraction and degradation. This should be retained as a core function and is more precise than the PN-projected parent process. supported_by: - reference_id: PMID:24843043 supporting_text: >- human ATAD1 limits the mitochondrial mislocalization of PEX26 and GOS28 - reference_id: PMID:24843043 supporting_text: >- conserved members of the mitochondrial protein quality control system that might promote the extraction and degradation of mislocalized TA proteins - reference_id: PMID:35550246 supporting_text: >- removes mislocalized membrane proteins, as well as stuck import substrates from the mitochondrial outer membrane, facilitating their re-insertion into their cognate organelles and maintaining mitochondria's protein import capacity. In doing so, it helps to maintain proteostasis in mitochondria - term: id: GO:0005741 label: mitochondrial outer membrane evidence_type: IBA original_reference_id: GO_REF:0000033 qualifier: is_active_in review: summary: >- ATAD1 is an outer-mitochondrial-membrane anchored AAA+ dislocase. action: ACCEPT reason: >- The mitochondrial outer membrane is the active location for ATAD1-mediated removal of mistargeted tail-anchored proteins. supported_by: - reference_id: file:human/ATAD1/ATAD1-uniprot.txt supporting_text: 'SUBCELLULAR LOCATION: Mitochondrion outer membrane' - reference_id: PMID:24843043 supporting_text: >- Msp1 limits the accumulation of mislocalized TA proteins on mitochondria - term: id: GO:0005524 label: ATP binding evidence_type: IEA original_reference_id: GO_REF:0000002 qualifier: enables review: summary: >- ATAD1 has a canonical AAA ATPase domain and predicted ATP-binding residues. action: KEEP_AS_NON_CORE reason: >- ATP binding is accurate but less informative than ATP hydrolysis activity and membrane protein dislocase activity, which capture the functional mechanism. supported_by: - reference_id: file:human/ATAD1/ATAD1-uniprot.txt supporting_text: /ligand="ATP" - term: id: GO:0005741 label: mitochondrial outer membrane evidence_type: IEA original_reference_id: GO_REF:0000044 qualifier: located_in review: summary: >- UniProt subcellular-location mapping correctly places ATAD1 in the mitochondrial outer membrane. action: ACCEPT reason: >- This is the core membrane location for the dislocase function. supported_by: - reference_id: file:human/ATAD1/ATAD1-uniprot.txt supporting_text: 'SUBCELLULAR LOCATION: Mitochondrion outer membrane' - term: id: GO:0005778 label: peroxisomal membrane evidence_type: IEA original_reference_id: GO_REF:0000044 qualifier: located_in review: summary: >- UniProt reports peroxisomal membrane localization, but the reviewed core function is mitochondrial outer-membrane protein extraction. action: KEEP_AS_NON_CORE reason: >- Keep this localization as supported non-core context. Current evidence does not establish peroxisomal membrane extraction as ATAD1's main conserved function. supported_by: - reference_id: file:human/ATAD1/ATAD1-uniprot.txt supporting_text: 'Peroxisome membrane {ECO:0000269|PubMed:24843043}' - term: id: GO:0016020 label: membrane evidence_type: IEA original_reference_id: GO_REF:0000117 qualifier: located_in review: summary: >- ATAD1 is a membrane protein, but the generic term loses the informative mitochondrial outer-membrane and peroxisomal-membrane localizations. action: MODIFY reason: >- Replace the generic membrane annotation with the specific experimentally supported membrane locations. proposed_replacement_terms: - id: GO:0005741 label: mitochondrial outer membrane - id: GO:0005778 label: peroxisomal membrane supported_by: - reference_id: file:human/ATAD1/ATAD1-uniprot.txt supporting_text: 'Mitochondrion outer membrane' - reference_id: file:human/ATAD1/ATAD1-uniprot.txt supporting_text: 'Peroxisome membrane' - term: id: GO:0016887 label: ATP hydrolysis activity evidence_type: IEA original_reference_id: GO_REF:0000120 qualifier: enables review: summary: >- ATP hydrolysis is the enzymatic activity that powers ATAD1 dislocase function. The cryo-EM structures of human ATAD1 (PDB 7UPR with ATP/Mg; 7UPT with ADP+ATP/Mg) capture the hexameric AAA+ assembly engaging a peptide substrate, consistent with ATP-hydrolysis-driven substrate translocation through the central pore. action: ACCEPT reason: >- Retain this molecular-function annotation as a core activity of the AAA+ ATPase. supported_by: - reference_id: file:human/ATAD1/ATAD1-uniprot.txt supporting_text: 'ATAD1-catalyzed ATP hydrolysis' - reference_id: PMID:35550246 supporting_text: >- extract hydrophobic membrane proteins from the lipid bilayer...utilization of multiple aromatic amino acids to firmly grip the substrate in the central pore - term: id: GO:0045211 label: postsynaptic membrane evidence_type: IEA original_reference_id: GO_REF:0000120 qualifier: located_in review: summary: >- Postsynaptic localization is transferred from mouse Thorase/Atad1 biology and is relevant to the AMPA receptor trafficking phenotype. action: KEEP_AS_NON_CORE reason: >- Keep as non-core neuronal context. The conserved core activity is membrane protein extraction at the mitochondrial outer membrane. supported_by: - reference_id: file:human/ATAD1/ATAD1-uniprot.txt supporting_text: 'Postsynaptic cell membrane' - reference_id: PMID:29659736 supporting_text: 'ATAD1 encephalopathy and stiff baby syndrome' - term: id: GO:0140567 label: membrane protein dislocase activity evidence_type: IEA original_reference_id: GO_REF:0000116 qualifier: enables review: summary: >- Membrane protein dislocase activity captures the core molecular function of ATAD1 more informatively than ATP binding alone. The cryo-EM structures of human ATAD1 (PDB 7UPR/7UPT) bound to a peptide substrate show a hexameric AAA+ spiral that grips the substrate in its central pore via conserved aromatic pore-loop 1 residues, directly visualizing the extraction/dislocase mechanism. action: ACCEPT reason: >- UniProt describes ATAD1 as a dislocase that mediates ATP-dependent extraction of mistargeted tail-anchored transmembrane proteins; the Rhea mapping is therefore biologically appropriate. supported_by: - reference_id: file:human/ATAD1/ATAD1-uniprot.txt supporting_text: >- acts as a dislocase that mediates the ATP-dependent extraction of mistargeted tail-anchored transmembrane proteins - reference_id: PMID:35550246 supporting_text: >- removes mislocalized membrane proteins, as well as stuck import substrates from the mitochondrial outer membrane...utilization of multiple aromatic amino acids to firmly grip the substrate in the central pore...both aromatic amino acids in pore-loop 1 are required for ATAD1's function and cannot be substituted by aliphatic amino acids - term: id: GO:0002092 label: positive regulation of receptor internalization evidence_type: IEA original_reference_id: GO_REF:0000107 qualifier: involved_in review: summary: >- This automated transfer reflects AMPA receptor internalization biology in the Thorase/Atad1 literature. action: KEEP_AS_NON_CORE reason: >- Retain as a non-core neuronal receptor-trafficking process. It is not the primary conserved proteostasis function emphasized by the direct ATAD1 mitochondrial evidence. supported_by: - reference_id: file:human/ATAD1/ATAD1-uniprot.txt supporting_text: 'Required for NMDA-stimulated AMPAR internalization' - term: id: GO:0007612 label: learning evidence_type: IEA original_reference_id: GO_REF:0000107 qualifier: involved_in review: summary: >- Learning is a high-level organismal phenotype transferred from mouse Thorase/Atad1 studies. action: MARK_AS_OVER_ANNOTATED reason: >- The term is too far downstream for a human ATAD1 gene-function review. The mechanistic neuronal annotations should be retained instead of treating learning as a core ATAD1 function. supported_by: - reference_id: file:human/ATAD1/ATAD1-uniprot.txt supporting_text: 'thereby regulating synaptic plasticity and learning' - term: id: GO:0007613 label: memory evidence_type: IEA original_reference_id: GO_REF:0000107 qualifier: involved_in review: summary: >- Memory is a high-level behavioral consequence inferred from mouse Thorase/Atad1 studies. action: MARK_AS_OVER_ANNOTATED reason: >- This phenotype-level term is too indirect for the core human annotation set. AMPAR receptor trafficking terms are more mechanistically useful. supported_by: - reference_id: file:human/ATAD1/ATAD1-uniprot.txt supporting_text: 'learning and memory (By similarity)' - term: id: GO:0051967 label: negative regulation of synaptic transmission, glutamatergic evidence_type: IEA original_reference_id: GO_REF:0000107 qualifier: involved_in review: summary: >- This term summarizes the inferred synaptic consequence of ATAD1-dependent AMPAR trafficking. action: KEEP_AS_NON_CORE reason: >- The annotation is plausible for neuronal ATAD1/Thorase biology but is secondary to the conserved mitochondrial dislocase/protein-quality-control function. supported_by: - reference_id: file:human/ATAD1/ATAD1-uniprot.txt supporting_text: 'regulating synaptic plasticity' - term: id: GO:0098794 label: postsynapse evidence_type: IEA original_reference_id: GO_REF:0000107 qualifier: is_active_in review: summary: >- Postsynapse is a transferred neuronal location consistent with the AMPAR-trafficking model. action: KEEP_AS_NON_CORE reason: >- Keep as non-core neuronal context; it should not displace the mitochondrial outer membrane as the principal active location. supported_by: - reference_id: file:human/ATAD1/ATAD1-uniprot.txt supporting_text: 'Postsynaptic cell membrane' - term: id: GO:0098978 label: glutamatergic synapse evidence_type: IEA original_reference_id: GO_REF:0000107 qualifier: is_active_in review: summary: >- Glutamatergic synapse is a transferred neuronal location for the AMPAR-trafficking role. action: KEEP_AS_NON_CORE reason: >- Keep as non-core context because the mechanistic evidence is by similarity and disease context rather than direct human localization. supported_by: - reference_id: file:human/ATAD1/ATAD1-uniprot.txt supporting_text: 'Required for NMDA-stimulated AMPAR internalization' - term: id: GO:0099149 label: regulation of postsynaptic neurotransmitter receptor internalization evidence_type: IEA original_reference_id: GO_REF:0000107 qualifier: involved_in review: summary: >- This is the most specific of the transferred receptor-internalization annotations. action: KEEP_AS_NON_CORE reason: >- Retain as non-core neuronal context. It is mechanistically more appropriate than learning or memory but remains secondary to ATAD1's conserved membrane protein dislocase role. supported_by: - reference_id: file:human/ATAD1/ATAD1-uniprot.txt supporting_text: 'Required for NMDA-stimulated AMPAR internalization' - term: id: GO:0045211 label: postsynaptic membrane evidence_type: ISS original_reference_id: GO_REF:0000024 qualifier: located_in review: summary: >- The manual transfer from mouse supports a neuronal postsynaptic membrane context. action: KEEP_AS_NON_CORE reason: >- Keep as non-core because ATAD1's best-supported conserved location is the mitochondrial outer membrane. supported_by: - reference_id: file:human/ATAD1/ATAD1-uniprot.txt supporting_text: 'Postsynaptic cell membrane' - term: id: GO:0005739 label: mitochondrion evidence_type: HTP original_reference_id: PMID:34800366 qualifier: located_in review: summary: >- The MitoCoP proteomics study supports mitochondrial assignment, but the more precise location for ATAD1 is the mitochondrial outer membrane. action: MODIFY reason: >- Replace the broad mitochondrion term with mitochondrial outer membrane when representing ATAD1's active localization. proposed_replacement_terms: - id: GO:0005741 label: mitochondrial outer membrane supported_by: - reference_id: PMID:34800366 supporting_text: >- mitochondrial high-confidence proteome of >1,100 proteins - reference_id: file:human/ATAD1/ATAD1-uniprot.txt supporting_text: 'Mitochondrion outer membrane' - term: id: GO:0016887 label: ATP hydrolysis activity evidence_type: ISS original_reference_id: GO_REF:0000024 qualifier: enables review: summary: >- ATP hydrolysis activity is conserved across ATAD1/Msp1 orthologs and powers dislocation/extraction. action: ACCEPT reason: >- Retain as a core molecular function of the AAA+ ATPase. supported_by: - reference_id: file:human/ATAD1/ATAD1-uniprot.txt supporting_text: 'ATAD1-catalyzed ATP hydrolysis' - term: id: GO:0005741 label: mitochondrial outer membrane evidence_type: IDA original_reference_id: PMID:24843043 qualifier: located_in review: summary: >- Direct ATAD1 work supports mitochondrial localization for the protein quality-control function. action: ACCEPT reason: >- The mitochondrial outer membrane is the site from which ATAD1 extracts mistargeted tail-anchored proteins. supported_by: - reference_id: PMID:24843043 supporting_text: >- Msp1 limits the accumulation of mislocalized TA proteins on mitochondria - reference_id: file:human/ATAD1/ATAD1-uniprot.txt supporting_text: 'Mitochondrion outer membrane' - term: id: GO:0005778 label: peroxisomal membrane evidence_type: IDA original_reference_id: PMID:24843043 qualifier: located_in review: summary: >- Peroxisomal membrane localization is supported, but the direct functional evidence in this paper centers on mitochondrial mislocalization and mitochondrial quality control. action: KEEP_AS_NON_CORE reason: >- Keep the location as supported non-core context. Do not infer an equivalent peroxisomal extraction function without direct evidence. supported_by: - reference_id: file:human/ATAD1/ATAD1-uniprot.txt supporting_text: 'Peroxisome membrane {ECO:0000269|PubMed:24843043}' - term: id: GO:0140570 label: extraction of mislocalized protein from mitochondrial outer membrane evidence_type: IDA original_reference_id: PMID:24843043 qualifier: involved_in review: summary: >- Direct ATAD1/Msp1 evidence supports extraction of mislocalized tail-anchored proteins from mitochondria. action: ACCEPT reason: >- This term captures the direct, specific ATAD1 biological process and is the best annotation for the PN-relevant mitochondrial quality-control role. supported_by: - reference_id: PMID:24843043 supporting_text: >- human ATAD1 limits the mitochondrial mislocalization of PEX26 and GOS28 - reference_id: PMID:24843043 supporting_text: >- promote the extraction and degradation of mislocalized TA proteins - term: id: GO:0005778 label: peroxisomal membrane evidence_type: TAS original_reference_id: Reactome:R-HSA-9603775 qualifier: located_in review: summary: >- Reactome treats ATAD1 as a class I peroxisomal membrane protein in the PEX19/PEX3 import pathway. action: KEEP_AS_NON_CORE reason: >- Keep as non-core localization/pathway context. This does not change the core function from mitochondrial outer-membrane dislocation. additional_reference_ids: - Reactome:R-HSA-9603804 supported_by: - reference_id: Reactome:R-HSA-9603804 supporting_text: >- Human class I peroxisomal membrane proteins that are bound by PEX19 include - reference_id: Reactome:R-HSA-9603804 supporting_text: 'ATAD1 (Liu et al. 2016)' - term: id: GO:0005829 label: cytosol evidence_type: TAS original_reference_id: Reactome:R-HSA-9603775 qualifier: located_in review: summary: >- The cytosol localization appears to come from the PEX19 cytosolic step in peroxisomal membrane protein import rather than ATAD1 itself. action: REMOVE reason: >- ATAD1 is a single-pass membrane protein with mitochondrial outer membrane, peroxisomal membrane, and postsynaptic membrane annotations; cytosol is not an appropriate cellular-component annotation for the gene product. additional_reference_ids: - Reactome:R-HSA-9603804 supported_by: - reference_id: Reactome:R-HSA-9603804 supporting_text: >- In the cytosol, PEX19 binds newly synthesized class I peroxisomal membrane proteins - reference_id: file:human/ATAD1/ATAD1-uniprot.txt supporting_text: 'Single-pass membrane protein' - term: id: GO:0005829 label: cytosol evidence_type: TAS original_reference_id: Reactome:R-HSA-9603784 qualifier: located_in review: summary: >- This Reactome cytosol annotation reflects cytosolic PEX19-cargo handling, not a soluble ATAD1 pool. action: REMOVE reason: >- Cytosol is inappropriate for ATAD1 because the protein is membrane anchored. The reaction can remain pathway context, but not as an ATAD1 cellular-component annotation. additional_reference_ids: - Reactome:R-HSA-9603804 supported_by: - reference_id: Reactome:R-HSA-9603784 supporting_text: 'Cytosolic PEX19 bound to a peroxisomal membrane protein' - reference_id: file:human/ATAD1/ATAD1-uniprot.txt supporting_text: 'Single-pass membrane protein' - term: id: GO:0005829 label: cytosol evidence_type: TAS original_reference_id: Reactome:R-HSA-9603804 qualifier: located_in review: summary: >- Reactome explicitly places PEX19 in the cytosol; ATAD1 is one of the membrane protein cargos listed in the same pathway context. action: REMOVE reason: >- The cytosolic reaction context should not be propagated as ATAD1 cytosolic localization. supported_by: - reference_id: Reactome:R-HSA-9603804 supporting_text: >- In the cytosol, PEX19 binds newly synthesized class I peroxisomal membrane proteins - reference_id: Reactome:R-HSA-9603804 supporting_text: 'ATAD1 (Liu et al. 2016)' - term: id: GO:0016020 label: membrane evidence_type: HDA original_reference_id: PMID:19946888 qualifier: located_in review: summary: >- The high-throughput NK-cell membrane proteome annotation supports ATAD1 as membrane-associated but is less specific than curated subcellular locations. action: MODIFY reason: >- Replace the broad membrane term with mitochondrial outer membrane and peroxisomal membrane where relevant. proposed_replacement_terms: - id: GO:0005741 label: mitochondrial outer membrane - id: GO:0005778 label: peroxisomal membrane supported_by: - reference_id: PMID:19946888 supporting_text: >- approximately 40% of the identified proteins were predicted as plausible membrane proteins - reference_id: file:human/ATAD1/ATAD1-uniprot.txt supporting_text: 'Mitochondrion outer membrane' - term: id: GO:0005778 label: peroxisomal membrane evidence_type: HDA original_reference_id: PMID:21525035 qualifier: located_in review: summary: >- The peroxisomal proteomics/co-complex study is compatible with ATAD1 peroxisomal membrane localization, but it does not define the main ATAD1 function. action: KEEP_AS_NON_CORE reason: >- Keep as non-core localization. The peroxisomal evidence is useful but weaker for functional inference than the direct mitochondrial quality-control evidence. supported_by: - reference_id: PMID:21525035 supporting_text: >- Using mass spectrometric analysis, almost all known human peroxins involved in protein import were identified - reference_id: file:human/ATAD1/ATAD1-uniprot.txt supporting_text: 'Peroxisome membrane' - term: id: GO:0002092 label: positive regulation of receptor internalization evidence_type: ISS original_reference_id: GO_REF:0000024 qualifier: involved_in review: summary: >- Manual transfer from mouse captures ATAD1/Thorase-dependent AMPAR internalization. action: KEEP_AS_NON_CORE reason: >- Keep as a secondary neuronal function. The more specific postsynaptic neurotransmitter receptor internalization term is preferable when representing this axis. supported_by: - reference_id: file:human/ATAD1/ATAD1-uniprot.txt supporting_text: 'Required for NMDA-stimulated AMPAR internalization' - term: id: GO:0007612 label: learning evidence_type: ISS original_reference_id: GO_REF:0000024 qualifier: involved_in review: summary: >- Learning is a downstream phenotype from transferred mouse evidence. action: MARK_AS_OVER_ANNOTATED reason: >- Do not retain behavioral phenotype terms as core human ATAD1 function. Receptor trafficking and synaptic transmission annotations better capture the mechanistic neuronal axis. supported_by: - reference_id: file:human/ATAD1/ATAD1-uniprot.txt supporting_text: 'thereby regulating synaptic plasticity and learning' - term: id: GO:0007613 label: memory evidence_type: ISS original_reference_id: GO_REF:0000024 qualifier: involved_in review: summary: >- Memory is a downstream behavioral phenotype from transferred mouse evidence. action: MARK_AS_OVER_ANNOTATED reason: >- The term is too high-level and indirect for ATAD1's gene-function core. supported_by: - reference_id: file:human/ATAD1/ATAD1-uniprot.txt supporting_text: 'learning and memory (By similarity)' - term: id: GO:0045211 label: postsynaptic membrane evidence_type: ISS original_reference_id: GO_REF:0000024 qualifier: located_in review: summary: >- Manual orthology transfer supports a postsynaptic membrane context. action: KEEP_AS_NON_CORE reason: >- Retain as secondary neuronal localization; mitochondrial outer membrane remains the principal location for the core dislocase function. supported_by: - reference_id: file:human/ATAD1/ATAD1-uniprot.txt supporting_text: 'Postsynaptic cell membrane' - term: id: GO:0051967 label: negative regulation of synaptic transmission, glutamatergic evidence_type: ISS original_reference_id: GO_REF:0000024 qualifier: involved_in review: summary: >- This GOA row was missing from the initial seeded review YAML and was added manually from ATAD1-goa.tsv to complete review coverage. The term is a transferred synaptic consequence of ATAD1/Thorase AMPAR trafficking. action: KEEP_AS_NON_CORE reason: >- Retain as non-core neuronal context rather than as a defining ATAD1 function. It is more mechanistic than learning/memory but still secondary to the conserved mitochondrial protein-quality-control role. supported_by: - reference_id: file:human/ATAD1/ATAD1-uniprot.txt supporting_text: 'regulating synaptic plasticity' - term: id: GO:0035694 label: mitochondrial protein catabolic process evidence_type: TAS original_reference_id: PMID:24843043 qualifier: involved_in review: summary: >- The PN projection proposed mitochondrial protein catabolic process for ATAD1 from the class-level organelle-specific protein degradation bucket. Direct ATAD1 evidence supports this as a broad downstream process because ATAD1 facilitates clearance of mislocalized mitochondrial outer-membrane tail-anchored proteins. action: NEW reason: >- Add conservatively as a broad PN-relevant candidate, supported by the traceable author statement and abstract-level evidence in the direct ATAD1 degradation paper. TAS is used rather than IMP because the cached evidence supports the process as a reported downstream outcome, while the stricter perturbation evidence for protein-level accumulation is from ATAD1(-/-) mouse tissue. This should not replace the more specific existing GO:0140570 extraction annotation, which remains the preferred core mechanistic process. additional_reference_ids: - file:projects/PROTEOSTASIS/reports/pn_projection/pn_projected_candidate_additions.tsv - file:projects/PROTEOSTASIS/reports/pn_mapping_audit/current_mapping_scrutiny.tsv supported_by: - reference_id: PMID:24843043 supporting_text: >- facilitating the degradation of mislocalized tail-anchored proteins - reference_id: PMID:24843043 supporting_text: >- GOS28 protein level is also increased in ATAD1(-/-) mouse tissues references: - id: GO_REF:0000002 title: Gene Ontology annotation through association of InterPro records with GO terms findings: - statement: >- InterPro AAA ATPase domains support the generic ATP-binding annotation, but more informative ATP hydrolysis and dislocase terms are available. - id: GO_REF:0000024 title: Manual transfer of experimentally-verified manual GO annotation data to orthologs by curator judgment of sequence similarity findings: - statement: >- Manual transfer from mouse supports the AMPAR/postsynaptic annotation block, which is retained as non-core neuronal context. - id: GO_REF:0000033 title: Annotation inferences using phylogenetic trees findings: - statement: >- The IBA mitochondrial outer-membrane extraction and localization annotations align with direct ATAD1/Msp1 evidence. - 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: - statement: >- UniProt location mapping correctly captures mitochondrial outer membrane and peroxisomal membrane localizations. - id: GO_REF:0000107 title: Automatic transfer of experimentally verified manual GO annotation data to orthologs using Ensembl Compara findings: - statement: >- Ensembl Compara transfers mouse ATAD1/Thorase postsynaptic and receptor-trafficking annotations; these are not the conserved core proteostasis role. - id: GO_REF:0000116 title: Automatic Gene Ontology annotation based on Rhea mapping findings: - statement: >- Rhea mapping supports the translocase/dislocase reaction driven by ATP hydrolysis. - id: GO_REF:0000117 title: Electronic Gene Ontology annotations created by ARBA machine learning models findings: - statement: >- The generic membrane annotation should be replaced by specific membrane locations. - id: GO_REF:0000120 title: Combined Automated Annotation using Multiple IEA Methods findings: - statement: >- Combined automated ATPase and postsynaptic annotations are broadly compatible with UniProt but require core/non-core separation. - id: PMID:24843043 title: Msp1/ATAD1 maintains mitochondrial function by facilitating the degradation of mislocalized tail-anchored proteins. full_text_unavailable: true findings: - statement: >- Human ATAD1 limits mitochondrial mislocalization of PEX26 and GOS28 and is proposed as a conserved mitochondrial protein quality-control factor. supporting_text: >- human ATAD1 limits the mitochondrial mislocalization of PEX26 and GOS28 - statement: >- ATAD1/Msp1 promotes extraction and degradation of mislocalized tail-anchored proteins. supporting_text: >- promote the extraction and degradation of mislocalized TA proteins - id: PMID:19946888 title: Defining the membrane proteome of NK cells. full_text_unavailable: true findings: - statement: >- High-throughput membrane proteomics supports a broad membrane annotation but not a specific ATAD1 active compartment. supporting_text: >- approximately 40% of the identified proteins were predicted as plausible membrane proteins - id: PMID:21525035 title: PEX14 is required for microtubule-based peroxisome motility in human cells. full_text_unavailable: true findings: - statement: >- Peroxisomal proteomics provides supporting context for peroxisomal membrane localization but not ATAD1 core function. supporting_text: >- Using mass spectrometric analysis, almost all known human peroxins involved in protein import were identified - id: PMID:34800366 title: Quantitative high-confidence human mitochondrial proteome and its dynamics in cellular context. findings: - statement: >- MitoCoP supports ATAD1 as part of the high-confidence human mitochondrial proteome. supporting_text: >- mitochondrial high-confidence proteome of >1,100 proteins - id: PMID:29659736 title: 'ATAD1 encephalopathy and stiff baby syndrome: a recognizable clinical presentation.' full_text_unavailable: true findings: - statement: >- Human ATAD1 disease provides context for neuronal/post-synaptic relevance, although this short article is not the primary mechanistic AMPAR trafficking paper. supporting_text: 'ATAD1 encephalopathy and stiff baby syndrome' - id: PMID:36409067 title: >- Collateral deletion of the mitochondrial AAA+ ATPase ATAD1 sensitizes cancer cells to proteasome dysfunction. full_text_unavailable: true findings: - statement: >- Human ATAD1 directly and selectively extracts the pro-apoptotic BH3-only protein BIM from mitochondria to inactivate it; extraction is ATP-dependent, requires membrane anchoring, and is lost in the catalytic E193Q mutant, supporting the dislocase/extractase activity. - statement: >- ATAD1 lies adjacent to PTEN on chromosome 10q23 and is frequently co-deleted; ATAD1 loss sensitizes cells and xenografts to proteasome inhibitors via BIM-dependent apoptosis, a candidate therapeutic vulnerability rather than a core annotation. - id: PMID:35550246 title: >- Conserved structural elements specialize ATAD1 as a membrane protein extraction machine. full_text_unavailable: true reference_review: relevance: HIGH correctness: VERIFIED review_notes: >- PubMed-verified cryo-EM structure of the human ATAD1 hexamer bound to a peptide substrate (PDB 7UPR/7UPT) supporting ATAD1's AAA+ membrane-protein-extraction function via conserved aromatic pore-loop residues. findings: - statement: >- Cryo-EM of human ATAD1 bound to a peptide substrate shows it forms a hexameric AAA+ spiral that threads substrate through a central pore; pore-loop 1 aromatic residues are required to grip hydrophobic substrate and a C-terminal helix promotes oligomerization, specializing ATAD1 for membrane protein extraction. - id: PMID:31999255 title: >- Structure of the AAA protein Msp1 reveals mechanism of mislocalized membrane protein extraction. full_text_unavailable: true findings: - statement: >- Cryo-EM structures of the ATAD1 ortholog Msp1 in complex with substrate establish that it forms hexameric spirals translocating substrate through a central aromatic pore, coupling ATP hydrolysis to membrane protein extraction. - id: PMID:32541053 title: >- The AAA+ ATPase Msp1 is a processive protein translocase with robust unfoldase activity. full_text_unavailable: true findings: - statement: >- The ATAD1 ortholog Msp1 is a processive, bidirectional protein translocase with unfoldase activity that threads substrates through its central pore; activity depends on the hexameric state and is inhibited by Pex3. - id: Reactome:R-HSA-9603775 title: PEX3:PEX19:class I PMP dissociates findings: - statement: >- Reactome records a PEX19/PEX3 class I peroxisomal membrane protein import step. supporting_text: >- The PEX19:PEX3:peroxisomal membrane protein complex dissociates - id: Reactome:R-HSA-9603784 title: PEX19:class I PMP binds PEX3 findings: - statement: >- Reactome places cytosolic PEX19 in this pathway step, explaining why cytosol should not be propagated as ATAD1 localization. supporting_text: 'Cytosolic PEX19 bound to a peroxisomal membrane protein' - id: Reactome:R-HSA-9603804 title: PEX19 binds class I peroxisomal membrane proteins findings: - statement: >- Reactome lists ATAD1 among class I peroxisomal membrane proteins bound by PEX19. supporting_text: 'ATAD1 (Liu et al. 2016)' - id: file:human/ATAD1/ATAD1-uniprot.txt title: UniProtKB ATAD1_HUMAN record findings: - statement: >- UniProt summarizes ATAD1 as an outer mitochondrial transmembrane helix translocase with ATP-dependent dislocase activity. supporting_text: >- acts as a dislocase that mediates the ATP-dependent extraction of mistargeted tail-anchored transmembrane proteins - statement: >- UniProt records mitochondrial outer membrane, peroxisome membrane, and postsynaptic cell membrane localizations. supporting_text: 'SUBCELLULAR LOCATION: Mitochondrion outer membrane' - id: file:projects/PROTEOSTASIS/reports/pn_projection/pn_projected_candidate_additions.tsv title: PN projected candidate additions report findings: - statement: >- The PN projection flags ATAD1 as a new-to-GOA candidate for mitochondrial protein catabolic process from the organelle-specific protein degradation class. - id: file:projects/PROTEOSTASIS/reports/pn_mapping_audit/current_mapping_scrutiny.tsv title: PN mapping scrutiny report findings: - statement: >- The mitochondrial protein catabolic process mapping is class-level and requires manual gene-level review before changing a gene review. core_functions: - molecular_function: id: GO:0140567 label: membrane protein dislocase activity description: >- ATAD1 is an ATP-dependent membrane protein dislocase that extracts mistargeted tail-anchored proteins from the mitochondrial outer membrane. This is the main conserved molecular role of the protein. directly_involved_in: - id: GO:0140570 label: extraction of mislocalized protein from mitochondrial outer membrane - id: GO:0035694 label: mitochondrial protein catabolic process locations: - id: GO:0005741 label: mitochondrial outer membrane supported_by: - reference_id: PMID:24843043 supporting_text: >- human ATAD1 limits the mitochondrial mislocalization of PEX26 and GOS28 - reference_id: file:human/ATAD1/ATAD1-uniprot.txt supporting_text: >- acts as a dislocase that mediates the ATP-dependent extraction of mistargeted tail-anchored transmembrane proteins - molecular_function: id: GO:0016887 label: ATP hydrolysis activity description: >- ATAD1 hydrolyzes ATP through its AAA+ ATPase domain to power extraction of membrane protein substrates and disassembly of selected protein complexes. directly_involved_in: - id: GO:0140570 label: extraction of mislocalized protein from mitochondrial outer membrane locations: - id: GO:0005741 label: mitochondrial outer membrane supported_by: - reference_id: file:human/ATAD1/ATAD1-uniprot.txt supporting_text: 'ATAD1-catalyzed ATP hydrolysis' proposed_new_terms: [] suggested_questions: - question: >- What is the direct molecular function of ATAD1 at the peroxisomal membrane, and does it extract or remodel peroxisomal membrane protein substrates in vivo? - question: >- For human ATAD1 disease, how much of the neurologic phenotype is caused by AMPAR trafficking defects versus mitochondrial protein quality-control defects? - question: >- Does ATAD1-mediated extraction of the pro-apoptotic protein BIM constitute a distinct, dedicated apoptotic-regulation function warranting its own GO annotation, or is it best represented as one substrate of the general membrane protein dislocase activity (GO:0140567)? suggested_experiments: - description: >- Reconstitute human ATAD1 with candidate mitochondrial and peroxisomal tail-anchored substrates and assay ATP-dependent extraction, substrate turnover, and downstream proteasomal dependence. hypothesis: >- ATAD1 directly extracts mistargeted mitochondrial outer-membrane substrates and may have a narrower or substrate-specific peroxisomal dislocase role. - description: >- In human neurons carrying ATAD1 loss-of-function or ATPase-defective variants, jointly assay AMPAR internalization, mitochondrial tail-anchored-protein accumulation, and mitochondrial health. hypothesis: >- ATAD1 neurologic disease reflects both postsynaptic receptor trafficking defects and mitochondrial outer-membrane protein quality-control failure. - description: >- Use a reconstituted proteoliposome extraction assay to test whether human ATAD1 selectively extracts BIM but not other BH3-only proteins (e.g., BIK, PUMA), comparing wild-type ATAD1 against a Walker-B/catalytic mutant. hypothesis: >- ATAD1 exerts substrate-selective, ATP-dependent extraction of the pro-apoptotic protein BIM from the mitochondrial outer membrane, linking its dislocase activity to regulation of apoptotic priming. tags: - proteostasis-pn - mitochondrial-proteostasis