Existing Annotations Review

GO Term	Evidence	Action	Reason
GO:0140570 extraction of mislocalized protein from mitochondrial outer membrane	IBA GO_REF:0000033	ACCEPT	Summary: This is the most specific existing biological-process annotation for the conserved ATAD1/Msp1 pathway. 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. Supporting Evidence: PMID:24843043 human ATAD1 limits the mitochondrial mislocalization of PEX26 and GOS28 PMID:24843043 conserved members of the mitochondrial protein quality control system that might promote the extraction and degradation of mislocalized TA proteins PMID:35550246 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
GO:0005741 mitochondrial outer membrane	IBA GO_REF:0000033	ACCEPT	Summary: ATAD1 is an outer-mitochondrial-membrane anchored AAA+ dislocase. Reason: The mitochondrial outer membrane is the active location for ATAD1-mediated removal of mistargeted tail-anchored proteins. Supporting Evidence: file:human/ATAD1/ATAD1-uniprot.txt SUBCELLULAR LOCATION: Mitochondrion outer membrane PMID:24843043 Msp1 limits the accumulation of mislocalized TA proteins on mitochondria
GO:0005524 ATP binding	IEA GO_REF:0000002	KEEP AS NON CORE	Summary: ATAD1 has a canonical AAA ATPase domain and predicted ATP-binding residues. Reason: ATP binding is accurate but less informative than ATP hydrolysis activity and membrane protein dislocase activity, which capture the functional mechanism. Supporting Evidence: file:human/ATAD1/ATAD1-uniprot.txt /ligand="ATP"
GO:0005741 mitochondrial outer membrane	IEA GO_REF:0000044	ACCEPT	Summary: UniProt subcellular-location mapping correctly places ATAD1 in the mitochondrial outer membrane. Reason: This is the core membrane location for the dislocase function. Supporting Evidence: file:human/ATAD1/ATAD1-uniprot.txt SUBCELLULAR LOCATION: Mitochondrion outer membrane
GO:0005778 peroxisomal membrane	IEA GO_REF:0000044	KEEP AS NON CORE	Summary: UniProt reports peroxisomal membrane localization, but the reviewed core function is mitochondrial outer-membrane protein extraction. Reason: Keep this localization as supported non-core context. Current evidence does not establish peroxisomal membrane extraction as ATAD1's main conserved function. Supporting Evidence: file:human/ATAD1/ATAD1-uniprot.txt Peroxisome membrane {ECO:0000269\|PubMed:24843043}
GO:0016020 membrane	IEA GO_REF:0000117	MODIFY	Summary: ATAD1 is a membrane protein, but the generic term loses the informative mitochondrial outer-membrane and peroxisomal-membrane localizations. Reason: Replace the generic membrane annotation with the specific experimentally supported membrane locations. Proposed replacements: mitochondrial outer membrane peroxisomal membrane Supporting Evidence: file:human/ATAD1/ATAD1-uniprot.txt Mitochondrion outer membrane file:human/ATAD1/ATAD1-uniprot.txt Peroxisome membrane
GO:0016887 ATP hydrolysis activity	IEA GO_REF:0000120	ACCEPT	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. Reason: Retain this molecular-function annotation as a core activity of the AAA+ ATPase. Supporting Evidence: file:human/ATAD1/ATAD1-uniprot.txt ATAD1-catalyzed ATP hydrolysis PMID:35550246 extract hydrophobic membrane proteins from the lipid bilayer...utilization of multiple aromatic amino acids to firmly grip the substrate in the central pore
GO:0045211 postsynaptic membrane	IEA GO_REF:0000120	KEEP AS NON CORE	Summary: Postsynaptic localization is transferred from mouse Thorase/Atad1 biology and is relevant to the AMPA receptor trafficking phenotype. Reason: Keep as non-core neuronal context. The conserved core activity is membrane protein extraction at the mitochondrial outer membrane. Supporting Evidence: file:human/ATAD1/ATAD1-uniprot.txt Postsynaptic cell membrane PMID:29659736 ATAD1 encephalopathy and stiff baby syndrome
GO:0140567 membrane protein dislocase activity	IEA GO_REF:0000116	ACCEPT	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. 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. Supporting Evidence: file:human/ATAD1/ATAD1-uniprot.txt acts as a dislocase that mediates the ATP-dependent extraction of mistargeted tail-anchored transmembrane proteins PMID:35550246 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
GO:0002092 positive regulation of receptor internalization	IEA GO_REF:0000107	KEEP AS NON CORE	Summary: This automated transfer reflects AMPA receptor internalization biology in the Thorase/Atad1 literature. 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. Supporting Evidence: file:human/ATAD1/ATAD1-uniprot.txt Required for NMDA-stimulated AMPAR internalization
GO:0007612 learning	IEA GO_REF:0000107	MARK AS OVER ANNOTATED	Summary: Learning is a high-level organismal phenotype transferred from mouse Thorase/Atad1 studies. 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. Supporting Evidence: file:human/ATAD1/ATAD1-uniprot.txt thereby regulating synaptic plasticity and learning
GO:0007613 memory	IEA GO_REF:0000107	MARK AS OVER ANNOTATED	Summary: Memory is a high-level behavioral consequence inferred from mouse Thorase/Atad1 studies. Reason: This phenotype-level term is too indirect for the core human annotation set. AMPAR receptor trafficking terms are more mechanistically useful. Supporting Evidence: file:human/ATAD1/ATAD1-uniprot.txt learning and memory (By similarity)
GO:0051967 negative regulation of synaptic transmission, glutamatergic	IEA GO_REF:0000107	KEEP AS NON CORE	Summary: This term summarizes the inferred synaptic consequence of ATAD1-dependent AMPAR trafficking. Reason: The annotation is plausible for neuronal ATAD1/Thorase biology but is secondary to the conserved mitochondrial dislocase/protein-quality-control function. Supporting Evidence: file:human/ATAD1/ATAD1-uniprot.txt regulating synaptic plasticity
GO:0098794 postsynapse	IEA GO_REF:0000107	KEEP AS NON CORE	Summary: Postsynapse is a transferred neuronal location consistent with the AMPAR-trafficking model. Reason: Keep as non-core neuronal context; it should not displace the mitochondrial outer membrane as the principal active location. Supporting Evidence: file:human/ATAD1/ATAD1-uniprot.txt Postsynaptic cell membrane
GO:0098978 glutamatergic synapse	IEA GO_REF:0000107	KEEP AS NON CORE	Summary: Glutamatergic synapse is a transferred neuronal location for the AMPAR-trafficking role. Reason: Keep as non-core context because the mechanistic evidence is by similarity and disease context rather than direct human localization. Supporting Evidence: file:human/ATAD1/ATAD1-uniprot.txt Required for NMDA-stimulated AMPAR internalization
GO:0099149 regulation of postsynaptic neurotransmitter receptor internalization	IEA GO_REF:0000107	KEEP AS NON CORE	Summary: This is the most specific of the transferred receptor-internalization annotations. 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. Supporting Evidence: file:human/ATAD1/ATAD1-uniprot.txt Required for NMDA-stimulated AMPAR internalization
GO:0045211 postsynaptic membrane	ISS GO_REF:0000024	KEEP AS NON CORE	Summary: The manual transfer from mouse supports a neuronal postsynaptic membrane context. Reason: Keep as non-core because ATAD1's best-supported conserved location is the mitochondrial outer membrane. Supporting Evidence: file:human/ATAD1/ATAD1-uniprot.txt Postsynaptic cell membrane
GO:0005739 mitochondrion	HTP PMID:34800366 Quantitative high-confidence human mitochondrial proteome an...	MODIFY	Summary: The MitoCoP proteomics study supports mitochondrial assignment, but the more precise location for ATAD1 is the mitochondrial outer membrane. Reason: Replace the broad mitochondrion term with mitochondrial outer membrane when representing ATAD1's active localization. Proposed replacements: mitochondrial outer membrane Supporting Evidence: PMID:34800366 mitochondrial high-confidence proteome of >1,100 proteins file:human/ATAD1/ATAD1-uniprot.txt Mitochondrion outer membrane
GO:0016887 ATP hydrolysis activity	ISS GO_REF:0000024	ACCEPT	Summary: ATP hydrolysis activity is conserved across ATAD1/Msp1 orthologs and powers dislocation/extraction. Reason: Retain as a core molecular function of the AAA+ ATPase. Supporting Evidence: file:human/ATAD1/ATAD1-uniprot.txt ATAD1-catalyzed ATP hydrolysis
GO:0005741 mitochondrial outer membrane	IDA PMID:24843043 Msp1/ATAD1 maintains mitochondrial function by facilitating ...	ACCEPT	Summary: Direct ATAD1 work supports mitochondrial localization for the protein quality-control function. Reason: The mitochondrial outer membrane is the site from which ATAD1 extracts mistargeted tail-anchored proteins. Supporting Evidence: PMID:24843043 Msp1 limits the accumulation of mislocalized TA proteins on mitochondria file:human/ATAD1/ATAD1-uniprot.txt Mitochondrion outer membrane
GO:0005778 peroxisomal membrane	IDA PMID:24843043 Msp1/ATAD1 maintains mitochondrial function by facilitating ...	KEEP AS NON CORE	Summary: Peroxisomal membrane localization is supported, but the direct functional evidence in this paper centers on mitochondrial mislocalization and mitochondrial quality control. Reason: Keep the location as supported non-core context. Do not infer an equivalent peroxisomal extraction function without direct evidence. Supporting Evidence: file:human/ATAD1/ATAD1-uniprot.txt Peroxisome membrane {ECO:0000269\|PubMed:24843043}
GO:0140570 extraction of mislocalized protein from mitochondrial outer membrane	IDA PMID:24843043 Msp1/ATAD1 maintains mitochondrial function by facilitating ...	ACCEPT	Summary: Direct ATAD1/Msp1 evidence supports extraction of mislocalized tail-anchored proteins from mitochondria. Reason: This term captures the direct, specific ATAD1 biological process and is the best annotation for the PN-relevant mitochondrial quality-control role. Supporting Evidence: PMID:24843043 human ATAD1 limits the mitochondrial mislocalization of PEX26 and GOS28 PMID:24843043 promote the extraction and degradation of mislocalized TA proteins
GO:0005778 peroxisomal membrane	TAS Reactome:R-HSA-9603775	KEEP AS NON CORE	Summary: Reactome treats ATAD1 as a class I peroxisomal membrane protein in the PEX19/PEX3 import pathway. Reason: Keep as non-core localization/pathway context. This does not change the core function from mitochondrial outer-membrane dislocation. Supporting Evidence: Reactome:R-HSA-9603804 Human class I peroxisomal membrane proteins that are bound by PEX19 include Reactome:R-HSA-9603804 ATAD1 (Liu et al. 2016)
GO:0005829 cytosol	TAS Reactome:R-HSA-9603775	REMOVE	Summary: The cytosol localization appears to come from the PEX19 cytosolic step in peroxisomal membrane protein import rather than ATAD1 itself. 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. Supporting Evidence: Reactome:R-HSA-9603804 In the cytosol, PEX19 binds newly synthesized class I peroxisomal membrane proteins file:human/ATAD1/ATAD1-uniprot.txt Single-pass membrane protein
GO:0005829 cytosol	TAS Reactome:R-HSA-9603784	REMOVE	Summary: This Reactome cytosol annotation reflects cytosolic PEX19-cargo handling, not a soluble ATAD1 pool. 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. Supporting Evidence: Reactome:R-HSA-9603784 Cytosolic PEX19 bound to a peroxisomal membrane protein file:human/ATAD1/ATAD1-uniprot.txt Single-pass membrane protein
GO:0005829 cytosol	TAS Reactome:R-HSA-9603804	REMOVE	Summary: Reactome explicitly places PEX19 in the cytosol; ATAD1 is one of the membrane protein cargos listed in the same pathway context. Reason: The cytosolic reaction context should not be propagated as ATAD1 cytosolic localization. Supporting Evidence: Reactome:R-HSA-9603804 In the cytosol, PEX19 binds newly synthesized class I peroxisomal membrane proteins Reactome:R-HSA-9603804 ATAD1 (Liu et al. 2016)
GO:0016020 membrane	HDA PMID:19946888 Defining the membrane proteome of NK cells.	MODIFY	Summary: The high-throughput NK-cell membrane proteome annotation supports ATAD1 as membrane-associated but is less specific than curated subcellular locations. Reason: Replace the broad membrane term with mitochondrial outer membrane and peroxisomal membrane where relevant. Proposed replacements: mitochondrial outer membrane peroxisomal membrane Supporting Evidence: PMID:19946888 approximately 40% of the identified proteins were predicted as plausible membrane proteins file:human/ATAD1/ATAD1-uniprot.txt Mitochondrion outer membrane
GO:0005778 peroxisomal membrane	HDA PMID:21525035 PEX14 is required for microtubule-based peroxisome motility ...	KEEP AS NON CORE	Summary: The peroxisomal proteomics/co-complex study is compatible with ATAD1 peroxisomal membrane localization, but it does not define the main ATAD1 function. Reason: Keep as non-core localization. The peroxisomal evidence is useful but weaker for functional inference than the direct mitochondrial quality-control evidence. Supporting Evidence: PMID:21525035 Using mass spectrometric analysis, almost all known human peroxins involved in protein import were identified file:human/ATAD1/ATAD1-uniprot.txt Peroxisome membrane
GO:0002092 positive regulation of receptor internalization	ISS GO_REF:0000024	KEEP AS NON CORE	Summary: Manual transfer from mouse captures ATAD1/Thorase-dependent AMPAR internalization. Reason: Keep as a secondary neuronal function. The more specific postsynaptic neurotransmitter receptor internalization term is preferable when representing this axis. Supporting Evidence: file:human/ATAD1/ATAD1-uniprot.txt Required for NMDA-stimulated AMPAR internalization
GO:0007612 learning	ISS GO_REF:0000024	MARK AS OVER ANNOTATED	Summary: Learning is a downstream phenotype from transferred mouse evidence. Reason: Do not retain behavioral phenotype terms as core human ATAD1 function. Receptor trafficking and synaptic transmission annotations better capture the mechanistic neuronal axis. Supporting Evidence: file:human/ATAD1/ATAD1-uniprot.txt thereby regulating synaptic plasticity and learning
GO:0007613 memory	ISS GO_REF:0000024	MARK AS OVER ANNOTATED	Summary: Memory is a downstream behavioral phenotype from transferred mouse evidence. Reason: The term is too high-level and indirect for ATAD1's gene-function core. Supporting Evidence: file:human/ATAD1/ATAD1-uniprot.txt learning and memory (By similarity)
GO:0045211 postsynaptic membrane	ISS GO_REF:0000024	KEEP AS NON CORE	Summary: Manual orthology transfer supports a postsynaptic membrane context. Reason: Retain as secondary neuronal localization; mitochondrial outer membrane remains the principal location for the core dislocase function. Supporting Evidence: file:human/ATAD1/ATAD1-uniprot.txt Postsynaptic cell membrane
GO:0051967 negative regulation of synaptic transmission, glutamatergic	ISS GO_REF:0000024	KEEP AS NON CORE	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. 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. Supporting Evidence: file:human/ATAD1/ATAD1-uniprot.txt regulating synaptic plasticity
GO:0035694 mitochondrial protein catabolic process	TAS PMID:24843043 Msp1/ATAD1 maintains mitochondrial function by facilitating ...	NEW	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. 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. Supporting Evidence: PMID:24843043 facilitating the degradation of mislocalized tail-anchored proteins PMID:24843043 GOS28 protein level is also increased in ATAD1(-/-) mouse tissues

Core Functions

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.

Molecular Function:

membrane protein dislocase activity

Directly Involved In:

extraction of mislocalized protein from mitochondrial outer membrane mitochondrial protein catabolic process

Cellular Locations:

mitochondrial outer membrane

Supporting Evidence:

PMID:24843043
human ATAD1 limits the mitochondrial mislocalization of PEX26 and GOS28
file:human/ATAD1/ATAD1-uniprot.txt
acts as a dislocase that mediates the ATP-dependent extraction of mistargeted tail-anchored transmembrane proteins

ATAD1 hydrolyzes ATP through its AAA+ ATPase domain to power extraction of membrane protein substrates and disassembly of selected protein complexes.

Molecular Function:

ATP hydrolysis activity

Directly Involved In:

extraction of mislocalized protein from mitochondrial outer membrane

Cellular Locations:

mitochondrial outer membrane

Supporting Evidence:

file:human/ATAD1/ATAD1-uniprot.txt
ATAD1-catalyzed ATP hydrolysis

References

GO_REF:0000002

Gene Ontology annotation through association of InterPro records with GO terms

InterPro AAA ATPase domains support the generic ATP-binding annotation, but more informative ATP hydrolysis and dislocase terms are available.

GO_REF:0000024

Manual transfer of experimentally-verified manual GO annotation data to orthologs by curator judgment of sequence similarity

Manual transfer from mouse supports the AMPAR/postsynaptic annotation block, which is retained as non-core neuronal context.

GO_REF:0000033

Annotation inferences using phylogenetic trees

The IBA mitochondrial outer-membrane extraction and localization annotations align with direct ATAD1/Msp1 evidence.

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

UniProt location mapping correctly captures mitochondrial outer membrane and peroxisomal membrane localizations.

GO_REF:0000107

Automatic transfer of experimentally verified manual GO annotation data to orthologs using Ensembl Compara

Ensembl Compara transfers mouse ATAD1/Thorase postsynaptic and receptor-trafficking annotations; these are not the conserved core proteostasis role.

GO_REF:0000116

Automatic Gene Ontology annotation based on Rhea mapping

Rhea mapping supports the translocase/dislocase reaction driven by ATP hydrolysis.

GO_REF:0000117

Electronic Gene Ontology annotations created by ARBA machine learning models

The generic membrane annotation should be replaced by specific membrane locations.

GO_REF:0000120

Combined Automated Annotation using Multiple IEA Methods

Combined automated ATPase and postsynaptic annotations are broadly compatible with UniProt but require core/non-core separation.

PMID:24843043

Msp1/ATAD1 maintains mitochondrial function by facilitating the degradation of mislocalized tail-anchored proteins.

Human ATAD1 limits mitochondrial mislocalization of PEX26 and GOS28 and is proposed as a conserved mitochondrial protein quality-control factor.

"human ATAD1 limits the mitochondrial mislocalization of PEX26 and GOS28"
ATAD1/Msp1 promotes extraction and degradation of mislocalized tail-anchored proteins.

"promote the extraction and degradation of mislocalized TA proteins"

PMID:19946888

Defining the membrane proteome of NK cells.

High-throughput membrane proteomics supports a broad membrane annotation but not a specific ATAD1 active compartment.

"approximately 40% of the identified proteins were predicted as plausible membrane proteins"

PMID:21525035

PEX14 is required for microtubule-based peroxisome motility in human cells.

Peroxisomal proteomics provides supporting context for peroxisomal membrane localization but not ATAD1 core function.

"Using mass spectrometric analysis, almost all known human peroxins involved in protein import were identified"

PMID:34800366

Quantitative high-confidence human mitochondrial proteome and its dynamics in cellular context.

MitoCoP supports ATAD1 as part of the high-confidence human mitochondrial proteome.

"mitochondrial high-confidence proteome of >1,100 proteins"

PMID:29659736

ATAD1 encephalopathy and stiff baby syndrome: a recognizable clinical presentation.

Human ATAD1 disease provides context for neuronal/post-synaptic relevance, although this short article is not the primary mechanistic AMPAR trafficking paper.

"ATAD1 encephalopathy and stiff baby syndrome"

PMID:36409067

Collateral deletion of the mitochondrial AAA+ ATPase ATAD1 sensitizes cancer cells to proteasome dysfunction.

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.
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.

PMID:35550246

Conserved structural elements specialize ATAD1 as a membrane protein extraction machine.

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.

PMID:31999255

Structure of the AAA protein Msp1 reveals mechanism of mislocalized membrane protein extraction.

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.

PMID:32541053

The AAA+ ATPase Msp1 is a processive protein translocase with robust unfoldase activity.

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.

Reactome:R-HSA-9603775

PEX3:PEX19:class I PMP dissociates

Reactome records a PEX19/PEX3 class I peroxisomal membrane protein import step.

"The PEX19:PEX3:peroxisomal membrane protein complex dissociates"

Reactome:R-HSA-9603784

PEX19:class I PMP binds PEX3

Reactome places cytosolic PEX19 in this pathway step, explaining why cytosol should not be propagated as ATAD1 localization.

"Cytosolic PEX19 bound to a peroxisomal membrane protein"

Reactome:R-HSA-9603804

PEX19 binds class I peroxisomal membrane proteins

Reactome lists ATAD1 among class I peroxisomal membrane proteins bound by PEX19.

"ATAD1 (Liu et al. 2016)"

file:human/ATAD1/ATAD1-uniprot.txt

UniProtKB ATAD1_HUMAN record

UniProt summarizes ATAD1 as an outer mitochondrial transmembrane helix translocase with ATP-dependent dislocase activity.

"acts as a dislocase that mediates the ATP-dependent extraction of mistargeted tail-anchored transmembrane proteins"
UniProt records mitochondrial outer membrane, peroxisome membrane, and postsynaptic cell membrane localizations.

"SUBCELLULAR LOCATION: Mitochondrion outer membrane"

file:projects/PROTEOSTASIS/reports/pn_projection/pn_projected_candidate_additions.tsv

PN projected candidate additions report

The PN projection flags ATAD1 as a new-to-GOA candidate for mitochondrial protein catabolic process from the organelle-specific protein degradation class.

file:projects/PROTEOSTASIS/reports/pn_mapping_audit/current_mapping_scrutiny.tsv

PN mapping scrutiny report

The mitochondrial protein catabolic process mapping is class-level and requires manual gene-level review before changing a gene review.

Suggested Experiments

Experiment: 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.

Experiment: 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.

Experiment: 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.

Deep Research

Falcon

(ATAD1-deep-research-falcon.md)

Comprehensive research report: **ATAD1 (UniProt Q8NBU5; human Thorase/MSP1 homolog)** Falcon Edison Scientific Literature 38 citations 2 artifacts 2026-06-07T04:54:36.962742

Edison artifact artifact-00 (text/markdown)

## Context ID: pqac-00000025 The requested information can be found in Figure 2, specifically panels H through K. These panels illustrate a reconstituted extrac (image/png)

The research report should be a detailed narrative explaining the function, biological processes, and localization of the gene product. Citations should be given for all claims.

You should prioritize authoritative reviews and primary scientific literature when conducting research. You can supplement
this with annotations you find in gene/protein databases, but these can be outdated or inaccurate.

We are specifically interested in the primary function of the gene - for enzymes, what reaction is catalyzed, and what is the substrate specificity? For transporters, what is the substrate? For structural proteins or adapters, what is the broader structural role? For signaling molecules, what is the role in the pathway.

We are interested in where in or outside the cell the gene product carries out its function.

We are also interested in the signaling or biochemical pathways in which the gene functions. We are less interested in broad pleiotropic effects, except where these elucidate the precise role.

Include evidence where possible. We are interested in both experimental evidence as well as inference from structure, evolution, or bioinformatic analysis. Precise studies should be prioritized over high-throughput, where available.

Comprehensive research report: ATAD1 (UniProt Q8NBU5; human Thorase/MSP1 homolog)

0) Gene/protein verification (mandatory identity check)

The literature retrieved and cited here consistently describes human ATAD1 (UniProt Q8NBU5) as a membrane-anchored AAA+ ATPase (MSP1 subfamily) localized primarily to the outer mitochondrial membrane (OMM), with well-established roles as a membrane-protein extractase/dislocase that removes mislocalized membrane proteins (notably tail-anchored proteins) and stalled import substrates. This matches the UniProt description (“Outer mitochondrial transmembrane helix translocase”; AAA ATPase family; Thorase synonym) and is not a different gene with an ambiguous symbol. (wang2020msp1atad1inprotein pages 1-2, wang2022conservedstructuralelements pages 1-2)

1) Key concepts and definitions (current understanding)

1.1 ATAD1 is an ATP-driven membrane protein extractase

ATAD1 belongs to the AAA+ ATPase family and functions by hydrolyzing ATP to extract membrane proteins from the OMM into the cytosol, where they can be degraded or re-routed. This “extractase/dislocase” concept is central: ATAD1/Msp1 recognizes substrates embedded in the lipid bilayer (often tail-anchored proteins) and mechanically pulls them through its central pore. (wang2020msp1atad1inprotein pages 1-2, winter2022collateraldeletionof pages 1-2, winter2022collateraldeletionof pages 8-9)

1.2 Tail-anchored (TA) protein targeting and “proofreading”

Tail-anchored proteins have a single C-terminal transmembrane helix and are post-translationally inserted into membranes. Targeting is not perfectly faithful, so ER-destined TA proteins can mislocalize to mitochondria. Msp1/ATAD1 provides a proofreading layer by extracting mislocalized TA proteins from the OMM; extracted proteins may be degraded or handed off for correct targeting (e.g., to ER insertion pathways). (wang2020msp1atad1inprotein pages 2-4, matsumoto2023msp1mediatedproofreadingmechanism pages 5-6, matsumoto2023msp1mediatedproofreadingmechanism pages 1-2)

1.3 “Outer mitochondrial transmembrane helix translocase” as a functional label

In functional-annotation terms, ATAD1 is best conceptualized as an OMM transmembrane-helix removal/translocation factor (an extractase) rather than a classic importer: it recognizes membrane-embedded helices and uses ATP to move them out of the membrane environment, protecting organelle proteostasis. (wang2020msp1atad1inprotein pages 1-2, wang2022conservedstructuralelements pages 1-2)

2) Molecular function, mechanism, and key substrates

2.1 Subcellular localization and architecture

ATAD1 is described as membrane-anchored (single N-terminal transmembrane anchor) with the AAA domain facing the cytosol; it is predominantly at the OMM and is also discussed in the context of peroxisomal quality control in the broader Msp1/ATAD1 family. (fresenius2023developmentofaa pages 19-23, fresenius2023developmentofab pages 19-23, wang2020msp1atad1inprotein pages 1-2)

Structurally, human ATAD1 forms a hexameric AAA+ assembly adopting a right-handed spiral/“lock-washer” during substrate engagement, consistent with pore-threading translocation mechanisms used by AAA+ unfoldases. (wang2022conservedstructuralelements pages 1-2, wang2022conservedstructuralelements pages 2-3)

2.2 Central-pore substrate grip: aromatic pore loops specialize ATAD1

Cryo-EM and mutational analyses indicate human ATAD1’s central pore has features adapted for gripping hydrophobic substrates: pore-loop residues W166 and Y167 (among others) intercalate with substrate side chains, and mutations at these sites strongly reduce binding/activity (including reports of >100-fold reduced peptide binding for several mutants in vitro). (wang2022conservedstructuralelements pages 11-13, wang2022conservedstructuralelements pages 2-3)

2.3 Foundational substrates: mislocalized TA proteins (Pex15/PEX26; Gos1/GOS28)

A foundational function is removing mislocalized TA proteins from mitochondria. In yeast, canonical substrates include Pex15 (peroxisomal TA) and Gos1 (Golgi v-SNARE), discovered using genetic and “substrate-trap” AAA mutants. Conservation to mammals is supported by increased mitochondrial localization/levels of substrates such as PEX26 and GOS28 when ATAD1 is depleted. (chen2014msp1atad1maintainsmitochondrial pages 6-7, chen2014msp1atad1maintainsmitochondrial pages 10-11, chen2014msp1atad1maintainsmitochondrial pages 9-10)

2.4 Rerouting vs degradation: coupling to GET/TRC and ubiquitin–proteasome systems

Mechanistically, extracted TA proteins may be rerouted to the ER via TA targeting machinery (GET/TRC pathway) rather than obligatorily destroyed, creating an intracellular proofreading system. Evidence includes time-lapse microscopy and biochemical interaction (e.g., Msp1-dependent association of extracted substrates with Get3). (matsumoto2023msp1mediatedproofreadingmechanism pages 5-6, matsumoto2023msp1mediatedproofreadingmechanism pages 1-2)

In other cases, extraction feeds into ubiquitination and proteasome-dependent degradation; a 2023 synthesis describes models where Msp1 binds non-ubiquitinated substrates, followed by ubiquitination (e.g., Doa10-dependent in yeast), engagement by Cdc48, and proteasomal degradation. (matsumoto2023msp1mediatedproofreadingmechanism pages 3-4)

2.5 Import stress and removal of stalled import substrates

ATAD1/Msp1 also extracts proteins that become stalled in the mitochondrial import channel/translocase, helping maintain mitochondrial protein import capacity and linking ATAD1 to mitochondrial import-stress quality control frameworks. (wang2020msp1atad1inprotein pages 1-2, wang2022conservedstructuralelements pages 1-2)

2.6 Human ATAD1 apoptotic substrate: direct extraction of BIM

A key human-specific mechanistic finding is that ATAD1 directly extracts the pro-apoptotic BH3-only protein BIM from membranes/mitochondria. In a reconstituted liposome assay, extraction was ATP-dependent, required membrane anchoring, and showed substrate selectivity (BIM extracted, while related proteins such as PUMA/BIK were not, under the tested conditions). (winter2022collateraldeletionof pages 8-9, winter2022collateraldeletionof media 8a98eb16)

3) Recent developments and latest research (prioritizing 2023–2024)

3.1 2024: hydrophobic mismatch as a substrate-recognition principle (reconstituted quantitative assays)

A 2024 bioRxiv preprint reports a quantitative reconstituted extraction assay and proposes that Msp1 recognizes substrates via hydrophobic mismatch between a substrate’s transmembrane domain (TMD) and the surrounding lipid bilayer; importantly, the authors conclude that TMD extraction from the bilayer is rate-limiting. While centered on yeast Msp1, the work explicitly frames relevance to the human homolog ATAD1 and provides a mechanistic model applicable to ATAD1-family substrate selectivity. (fresenius2024theaaa+protein pages 1-3, fresenius2024theaaa+protein pages 13-21)

3.2 2023: updated model of TA protein localization proofreading

A 2023 peer-reviewed review consolidates the “proofreading” model: Msp1/ATAD1 extracts mislocalized TA proteins from the OMM and supports their handoff to GET/TRC for ER targeting or channels them to degradation pathways, situating ATAD1 within a multilayer organelle targeting QC network. (matsumoto2023msp1mediatedproofreadingmechanism pages 3-4, matsumoto2023msp1mediatedproofreadingmechanism pages 1-2)

3.3 2023: expanded functional landscape—ATAD1-family involvement in mitochondrial fission control

A 2023 PLOS Biology study of the fission yeast ATAD1 homolog (Yta4) reports a role in preventing excessive mitochondrial fission, including interaction with mitochondrial divisome components and ATPase/translocase-dependent delocalization of factors such as Fis1/Mdv1; while not human ATAD1 directly, it broadens mechanistic hypotheses about how ATAD1-family extractases can tune organelle dynamics beyond proteostasis. (he2023theaaaatpaseyta4atad1 pages 1-2)

3.4 2024: energetic and mechanistic plasticity in Msp1-family extraction

A 2024 bioRxiv preprint using covalently linked dimers suggests a non-linear relationship between ATP hydrolysis rate and membrane extraction efficiency and proposes a minimum ATPase rate for effective TMH extraction; these results are mechanistically informative for ATAD1 by orthology, though not yet direct human ATAD1 measurements in the retrieved set. (fresenius2024theaaa+protein pages 1-3)

4) Current applications and real-world implementations

4.1 Cancer vulnerability (“collateral lethality”) in PTEN/10q23 deletions

ATAD1 is near PTEN (10q23) and is frequently co-deleted with PTEN. The 2022 eLife study proposes a clinically actionable vulnerability: ATAD1 loss sensitizes cells to proteasome dysfunction through BIM-dependent apoptosis, and ATAD1-null cells/xenografts are hypersensitive to proteasome inhibitors. (winter2022collateraldeletionof pages 1-2, winter2022collateraldeletionof pages 11-13)

Quantitative/implementation-relevant details from the study and supporting excerpts include:
- PTEN deletion rates cited as >33% of metastatic prostate tumors and ~10% of melanoma and glioblastoma multiforme, contextualizing the prevalence of adjacent-locus deletions. (winter2022collateraldeletionof pages 1-2)
- Mouse xenografts: bortezomib dosing of 1 mg/kg reduced growth of ATAD1-deleted PC3 tumors (but not controls in the excerpted comparison). (winter2022collateraldeletionof pages 11-13)
- Tumorigenicity shift in a glioma model: EV-transduced SW1088 cells formed 0/17 tumors, while ATAD1-transduced formed 20/21 tumors in NOD/SCID mice (suggesting ATAD1 can promote tumor growth/fitness in that context). (winter2022collateraldeletionof pages 11-13)

4.2 Clinical association: overall survival differences in mCRPC with ATAD1/PTEN co-deletion

Across the cited mCRPC context, median overall survival is reported as 77 months for tumors that are PTEN-null and ATAD1-null vs 37 months for PTEN-null or unaltered tumors. (winter2022collateraldeletionof pages 11-13, fresenius2023developmentofa pages 67-73)

4.3 Disease-modifier concept in Zellweger spectrum disorder (ZSD) models

In ZSD model systems, overexpression of ATAD1 (as a mitochondrial QC factor) was sufficient to rescue aspects of mitochondrial function, supporting an organelle-proteostasis “modifier” approach. (fresenius2023developmentofaa pages 19-23)

5) Expert opinions and authoritative synthesis

5.1 High-authority review perspective on core function and open questions

An authoritative 2020 Annual Review article synthesizes the field: ATAD1/Msp1 is a central mitochondrial proteostasis factor extracting mislocalized membrane proteins and import-stalled substrates; extracted clients are triaged to proteasomal degradation or rerouting, and the review highlights unresolved questions about substrate selection and how ATAD1’s specialization enables membrane extraction. (wang2020msp1atad1inprotein pages 1-2, wang2020msp1atad1inprotein pages 2-4)

5.2 Noncanonical neuronal role: AMPAR trafficking and synaptic plasticity

The same review compiles biochemical and neuronal data indicating ATAD1 (Thorase) can regulate synaptic receptor trafficking: ATAD1 forms complexes with GluR2 and GRIP1; ATAD1 can disassemble GluR2–GRIP1 in an ATP-dependent manner; perturbing ATAD1 changes surface AMPAR levels and affects activity-dependent synaptic downscaling (e.g., bicuculline-induced AMPAR internalization). (wang2020msp1atad1inprotein pages 18-20)

6) Relevant statistics and data highlights (recent and/or mechanistically informative)

6.1 Cancer prevalence and impact estimates (from 2023 mechanistic/translational synthesis)

A 2023 thesis-like source summarizes quantitative epidemiology and survival metrics related to ATAD1 loss in cancer:
- ATAD1 deletion frequency: 4.1% in gastric cancer; using global gastric cancer mortality (~800,000 deaths/year), the text estimates ~32,000 deaths/year associated with ATAD1-deficient gastric cancer. (fresenius2023developmentofac pages 67-73, fresenius2023developmentofa pages 67-73)
- Median overall survival in mCRPC: 77 vs 37 months (ATAD1/PTEN co-deleted vs PTEN-null/unaltered). (fresenius2023developmentofa pages 67-73, winter2022collateraldeletionof pages 11-13)

6.2 Mechanistic assay evidence (visual and biochemical)

Figure evidence from Winter et al. 2022 directly supports ATP-dependent and selective extraction of BIM by ATAD1 in a reconstituted system. (winter2022collateraldeletionof media 8a98eb16, winter2022collateraldeletionof media eae7fce6)

6.3 Disease association databases (hypothesis-generating)

Open Targets lists ATAD1 associations with terms including hereditary hyperekplexia / hyperekplexia 4 and broader neurodegenerative disease categories. These associations are useful for prioritizing follow-up but should be interpreted cautiously without direct primary-study confirmation in the same evidence bundle. (OpenTargets Search: -ATAD1)

7) Practical functional annotation summary (for gene/protein annotation)

7.1 Primary function (best-supported)

ATAD1 is an OMM AAA+ ATPase extractase/translocase that uses ATP hydrolysis to remove membrane-embedded proteins—especially mislocalized tail-anchored proteins and stalled import substrates—from the mitochondrial outer membrane, promoting rerouting and/or degradation to maintain organelle proteostasis. (wang2020msp1atad1inprotein pages 1-2, wang2022conservedstructuralelements pages 1-2, chen2014msp1atad1maintainsmitochondrial pages 10-11)

7.2 Substrates and specificity

Strong foundational substrate class: mislocalized TA proteins (Pex15/PEX26; Gos1/GOS28). (chen2014msp1atad1maintainsmitochondrial pages 10-11)
Human apoptosis substrate: BIM extracted directly and selectively in vitro. (winter2022collateraldeletionof pages 8-9, winter2022collateraldeletionof media 8a98eb16)
Selectivity determinants under active research: pore-loop aromatics for grip (human ATAD1) and hydrophobic mismatch models (Msp1; proposed generalizable principle). (wang2022conservedstructuralelements pages 11-13, fresenius2024theaaa+protein pages 1-3)

7.3 Localization

Primary: outer mitochondrial membrane (cytosolic AAA domain). (wang2020msp1atad1inprotein pages 1-2, winter2022collateraldeletionof pages 1-2)
Broader family context includes peroxisomal TA quality control and organelle cross-talk. (matsumoto2023msp1mediatedproofreadingmechanism pages 3-4)

Evidence summary table

The following table consolidates key findings, evidence types, and DOI URLs:

Functional aspect	Key findings	Evidence type	Key sources with year + DOI URL
Gene/protein identity	Human ATAD1 = Thorase, ortholog of yeast Msp1; UniProt Q8NBU5. Literature consistently matches a membrane-anchored AAA+ ATPase/extractase rather than an unrelated gene symbol. Belongs to the MSP1 subfamily and functions in outer mitochondrial membrane protein quality control (wang2020msp1atad1inprotein pages 1-2, fresenius2023developmentofa pages 19-23, wang2022conservedstructuralelements pages 1-2)	Review, structure, database-aligned annotation	Wang & Walter 2020, doi: https://doi.org/10.1146/annurev-cellbio-031220-015840; Wang et al. 2022, doi: https://doi.org/10.7554/elife.73941
Localization	ATAD1 is anchored by a single N-terminal transmembrane helix in the outer mitochondrial membrane (OMM) with the AAA domain exposed to the cytosol; several sources also note localization/function at peroxisomes for tail-anchored protein proofreading (wang2020msp1atad1inprotein pages 1-2, fresenius2023developmentofaa pages 19-23, fresenius2023developmentofab pages 19-23)	Review, cell biology, structural interpretation	Wang & Walter 2020, doi: https://doi.org/10.1146/annurev-cellbio-031220-015840; Chen et al. 2014, doi: https://doi.org/10.15252/embj.201487943
Domain/oligomeric architecture	Human ATAD1 is a hexameric AAA+ ATPase that forms a right-handed spiral/lock-washer assembly during substrate engagement. Conserved pore loops and a C-terminal helix adapt it for membrane protein extraction (wang2022conservedstructuralelements pages 1-2, wang2022conservedstructuralelements pages 11-13, wang2022conservedstructuralelements pages 2-3)	Cryo-EM structure, mutagenesis	Wang et al. 2022, doi: https://doi.org/10.7554/elife.73941; Wang et al. 2020, doi: https://doi.org/10.7554/elife.54031
Primary molecular activity	ATAD1 is an ATP-driven membrane protein extractase/translocase that removes mislocalized membrane proteins and proteins stalled in the mitochondrial import machinery; ATP hydrolysis is required for direct substrate removal from membranes (wang2020msp1atad1inprotein pages 1-2, winter2022collateraldeletionof pages 1-2, winter2022collateraldeletionof pages 8-9)	Review, biochemical reconstitution, cell biology	Wang & Walter 2020, doi: https://doi.org/10.1146/annurev-cellbio-031220-015840; Winter et al. 2022, doi: https://doi.org/10.7554/elife.82860
Foundational substrate class: mistargeted tail-anchored proteins	The founding quality-control role is extraction of mislocalized tail-anchored (TA) proteins from mitochondria. In yeast, Pex15 and Gos1 are canonical substrates; mammalian conservation is supported by increased mitochondrial localization of PEX26 and GOS28 after ATAD1 depletion/knockdown (chen2014msp1atad1maintainsmitochondrial pages 6-7, chen2014msp1atad1maintainsmitochondrial pages 10-11, chen2014msp1atad1maintainsmitochondrial pages 9-10)	Genetics, substrate-trap biochemistry, microscopy	Chen et al. 2014, doi: https://doi.org/10.15252/embj.201487943
Proofreading/rerouting pathway	Msp1/ATAD1-dependent extraction can reroute mislocalized TA proteins from mitochondria to the ER via the GET/TRC pathway, establishing an intracellular proofreading system rather than simple destruction in all cases (wang2020msp1atad1inprotein pages 2-4, matsumoto2023msp1mediatedproofreadingmechanism pages 5-6, matsumoto2023msp1mediatedproofreadingmechanism pages 1-2)	Time-lapse imaging, co-IP, review	Matsumoto et al. 2019, doi: https://doi.org/10.1016/j.molcel.2019.07.006; Matsumoto 2023, doi: https://doi.org/10.1093/jb/mvad025
Degradation pathway coupling	For some substrates, extraction precedes ubiquitination and proteasomal degradation; evidence places Msp1/ATAD1 upstream of ubiquitin-dependent Cdc48/proteasome clearance for mislocalized TA substrates (matsumoto2023msp1mediatedproofreadingmechanism pages 3-4)	Genetics, inhibitor studies, biochemistry	Matsumoto 2023, doi: https://doi.org/10.1093/jb/mvad025
Import-stress / translocase quality control	Beyond TA proteins, ATAD1/Msp1 extracts stuck import substrates from the mitochondrial outer membrane/translocase system, helping maintain mitochondrial protein import capacity and linking the protein to mitoCPR/import-stress pathways (wang2020msp1atad1inprotein pages 1-2, wang2022conservedstructuralelements pages 1-2, castanzo2020theaaa+atpase pages 1-2)	Review, genetics, mechanistic studies	Wang & Walter 2020, doi: https://doi.org/10.1146/annurev-cellbio-031220-015840; Castanzo et al. 2020, doi: https://doi.org/10.1073/pnas.1920109117
Mechanism of substrate engagement	Structural work shows substrate threading through a hydrophobic/aromatic central pore. Human ATAD1 uses pore-loop residues including W166/Y167 to grip substrate; mutations impair activity or peptide binding by >100-fold in some assays (wang2022conservedstructuralelements pages 11-13, wang2022conservedstructuralelements pages 2-3)	Cryo-EM, mutagenesis, peptide-binding assays	Wang et al. 2022, doi: https://doi.org/10.7554/elife.73941
Processive unfoldase/translocase behavior	Msp1/ATAD1-family enzymes act as processive protein translocases/unfoldases that thread substrates through the pore; ATPase activity depends on oligomeric state, supporting a mechanical extraction model for hydrophobic membrane proteins (castanzo2020theaaa+atpase pages 1-2)	Biochemical reconstitution, EM	Castanzo et al. 2020, doi: https://doi.org/10.1073/pnas.1920109117
Human apoptotic substrate: BIM	A key human ATAD1-specific finding is direct, specific extraction of BIM from membranes/mitochondria to inactivate this pro-apoptotic factor. In liposome assays, extraction is ATP-dependent, requires membrane anchoring, and is lost with the catalytic E193Q mutant (winter2022collateraldeletionof pages 1-2, winter2022collateraldeletionof pages 8-9, winter2022collateraldeletionof media 8a98eb16)	Reconstituted biochemistry, co-IP, genetics, figure-level assay evidence	Winter et al. 2022, doi: https://doi.org/10.7554/elife.82860
Substrate selectivity in apoptosis	ATAD1 extraction is selective, not universal for BH3-only proteins: in the reported reconstitution, ATAD1 extracted BIM but not BIK, PUMA, or yeast Fis1 under the same conditions (winter2022collateraldeletionof pages 8-9, winter2022collateraldeletionof media 8a98eb16)	Reconstituted biochemistry, figure quantification	Winter et al. 2022, doi: https://doi.org/10.7554/elife.82860
Cancer relevance / collateral lethality	ATAD1 is adjacent to PTEN on 10q23 and is often co-deleted with PTEN in tumors. ATAD1 loss sensitizes cells and xenografts to proteasome inhibitors by increasing BIM-dependent apoptotic priming, suggesting a therapeutic vulnerability in ATAD1-null cancers (winter2022collateraldeletionof pages 1-2, winter2022collateraldeletionof pages 8-9)	Cancer genetics, cell biology, xenografts	Winter et al. 2022, doi: https://doi.org/10.7554/elife.82860
Disease/application concept	Proposed application: exploit proteasome dysfunction/proteasome inhibitor sensitivity in cancers with ATAD1 loss; this is a preclinical therapeutic concept rather than an approved ATAD1-targeted therapy (winter2022collateraldeletionof pages 1-2)	Preclinical translational study	Winter et al. 2022, doi: https://doi.org/10.7554/elife.82860
Mitochondrial dynamics (newer role)	A 2023 study of the homolog Yta4/ATAD1 identified a role in inhibiting mitochondrial fission by acting on divisome components (Fis1, Mdv1, Dnm1), expanding the conceptual landscape of ATAD1-family biology beyond proteostasis alone (he2023theaaaatpaseyta4atad1 pages 1-2)	Genetics, interaction assays, in vitro assembly assays	He et al. 2023, doi: https://doi.org/10.1371/journal.pbio.3002247
2023 conceptual update on proofreading	2023 synthesis emphasized Msp1/ATAD1 as a proofreading system for TA protein localization, integrating extraction, GET-mediated rerouting, and selective degradation as a multilayer quality-control network (matsumoto2023msp1mediatedproofreadingmechanism pages 3-4, matsumoto2023msp1mediatedproofreadingmechanism pages 1-2)	Review	Matsumoto 2023, doi: https://doi.org/10.1093/jb/mvad025
2023-2024 reconstituted assay advance	New quantitative reconstituted assays using split-luciferase/defined proteoliposomes enabled controlled testing of substrate selectivity and membrane determinants of extraction, creating a more rigorous platform for ATAD1/Msp1 mechanism studies (fresenius2024theaaa+protein pages 1-3, fresenius2023developmentofac pages 110-116)	Method development, reconstitution	Fresenius et al. 2024, doi: https://doi.org/10.1101/2023.07.11.548587
2024 substrate-recognition model	2024 work proposed that substrate recognition depends strongly on hydrophobic mismatch between the substrate transmembrane segment and the surrounding bilayer; extraction of a substrate TMD from the membrane appears to be the rate-limiting step (fresenius2024theaaa+protein pages 1-3, fresenius2024theaaa+protein pages 13-21)	Reconstituted biochemistry, membrane engineering	Fresenius et al. 2024, doi: https://doi.org/10.1101/2023.07.11.548587
2024 energetic/mechanistic direction	Emerging 2024 linked-dimer/energetic studies indicate a minimum ATP hydrolysis rate is needed for efficient TMH extraction and suggest mechanistic plasticity in subunit coordination during extraction; relevant to ATAD1 by homology but not yet a direct human ATAD1 paper in the retrieved evidence set (fresenius2024theaaa+protein pages 1-3)	Preprint mechanistic biochemistry (family-level inference)	Smith et al. 2024, doi: https://doi.org/10.1101/2024.09.23.614443
Synaptic regulation	ATAD1/Thorase also has a noncanonical neuronal role in AMPA receptor trafficking. It forms complexes with GluR2 and GRIP1, can disassemble the GluR2–GRIP1 complex in an ATP-dependent manner, and is required for activity-dependent AMPAR internalization/downscaling (wang2020msp1atad1inprotein pages 1-2, wang2020msp1atad1inprotein pages 18-20)	Biochemistry, neuronal cell biology, mouse genetics	Wang & Walter 2020, doi: https://doi.org/10.1146/annurev-cellbio-031220-015840
Neurological phenotypes	ATAD1 loss/function compromise is associated with seizures, impaired fear conditioning, worsened post-stroke deficits in mice, and severe human encephalopathy/stiffness/arthrogryposis in homozygous mutation cases; AMPAR antagonists reportedly ameliorated some defects (fresenius2023developmentofac pages 19-23, wang2020msp1atad1inprotein pages 18-20)	Mouse genetics, clinical association, review	Wang & Walter 2020, doi: https://doi.org/10.1146/annurev-cellbio-031220-015840
Other disease associations / databases	Open Targets lists ATAD1 associations with hereditary hyperekplexia/hyperekplexia 4 and broader neurodegenerative phenotypes, but these database-level links should be interpreted as hypothesis-generating unless supported by primary studies (OpenTargets Search: -ATAD1)	Database	Open Targets platform query (context evidence)
Organelle-disease modifier role	In Zellweger-spectrum models, ATAD1 overexpression was reported to rescue aspects of mitochondrial dysfunction caused by mislocalized peroxisomal proteins, suggesting a disease-modifier role in organelle proteostasis (fresenius2023developmentofaa pages 19-23)	Cell biology, disease-model study	Nuebel et al. 2021, doi: https://doi.org/10.15252/embr.202051991
Overall functional annotation	Best-supported primary annotation for human ATAD1 is: outer mitochondrial membrane AAA+ extractase/translocase that removes mislocalized TA proteins and stalled import substrates, coupling ATP hydrolysis to membrane protein extraction; additional metazoan-specialized roles include apoptosis control via BIM extraction and neuronal AMPAR trafficking (wang2020msp1atad1inprotein pages 1-2, winter2022collateraldeletionof pages 1-2, wang2022conservedstructuralelements pages 1-2, wang2020msp1atad1inprotein pages 18-20)	Integrated review of structure, biochemistry, genetics, disease evidence	Chen et al. 2014, doi: https://doi.org/10.15252/embj.201487943; Wang & Walter 2020, doi: https://doi.org/10.1146/annurev-cellbio-031220-015840; Wang et al. 2022, doi: https://doi.org/10.7554/elife.73941; Winter et al. 2022, doi: https://doi.org/10.7554/elife.82860

Table: This table summarizes the main functional annotation evidence for human ATAD1/Thorase (UniProt Q8NBU5), spanning localization, molecular mechanism, substrates, pathways, disease relevance, and translational implications. It highlights both foundational studies and newer 2023-2024 developments in substrate recognition and membrane-extraction mechanism.

Key figure support (extracted image)

Panels from Winter et al. 2022 eLife Figure 2 show ATP-dependent, selective extraction of BIM by ATAD1 in a reconstituted liposome assay. (winter2022collateraldeletionof media 8a98eb16, winter2022collateraldeletionof media eae7fce6)

References (URLs + publication dates where available)

Chen et al. The EMBO Journal (Publication: Jul 2014). https://doi.org/10.15252/embj.201487943 (chen2014msp1atad1maintainsmitochondrial pages 6-7, chen2014msp1atad1maintainsmitochondrial pages 10-11)
Wang et al. eLife (Publication: Jan 2020). https://doi.org/10.7554/elife.54031 (wang2020structureofthe pages 1-2)
Castanzo et al. PNAS (Publication: Jun 2020). https://doi.org/10.1073/pnas.1920109117 (castanzo2020theaaa+atpase pages 1-2)
Wang & Walter Annual Review of Cell and Developmental Biology (Publication: Oct 2020). https://doi.org/10.1146/annurev-cellbio-031220-015840 (wang2020msp1atad1inprotein pages 1-2, wang2020msp1atad1inprotein pages 18-20)
Wang et al. eLife (Publication: May 2022). https://doi.org/10.7554/elife.73941 (wang2022conservedstructuralelements pages 1-2, wang2022conservedstructuralelements pages 11-13)
Winter et al. eLife (Publication: Nov 2022). https://doi.org/10.7554/elife.82860 (winter2022collateraldeletionof pages 1-2, winter2022collateraldeletionof pages 11-13)
Matsumoto Journal of Biochemistry (Publication: Mar 2023). https://doi.org/10.1093/jb/mvad025 (matsumoto2023msp1mediatedproofreadingmechanism pages 3-4)
He et al. PLOS Biology (Publication: Aug 2023). https://doi.org/10.1371/journal.pbio.3002247 (he2023theaaaatpaseyta4atad1 pages 1-2)
Fresenius et al. bioRxiv (Posted/Publication: Jul 2024). https://doi.org/10.1101/2023.07.11.548587 (fresenius2024theaaa+protein pages 1-3, fresenius2024theaaa+protein pages 13-21)

References

(wang2020msp1atad1inprotein pages 1-2): Lan Wang and Peter Walter. Msp1/atad1 in protein quality control and regulation of synaptic activities. Annual Review of Cell and Developmental Biology, 36:141-164, Oct 2020. URL: https://doi.org/10.1146/annurev-cellbio-031220-015840, doi:10.1146/annurev-cellbio-031220-015840. This article has 62 citations and is from a domain leading peer-reviewed journal.
(wang2022conservedstructuralelements pages 1-2): Lan Wang, Hannah Toutkoushian, Vladislav Belyy, Claire Y Kokontis, and Peter Walter. Conserved structural elements specialize atad1 as a membrane protein extraction machine. May 2022. URL: https://doi.org/10.7554/elife.73941, doi:10.7554/elife.73941. This article has 27 citations and is from a domain leading peer-reviewed journal.
(winter2022collateraldeletionof pages 1-2): Jacob M Winter, Heidi L Fresenius, Corey N Cunningham, Peng Wei, Heather R Keys, Jordan Berg, Alex Bott, Tarun Yadav, Jeremy Ryan, Deepika Sirohi, Sheryl R Tripp, Paige Barta, Neeraj Agarwal, Anthony Letai, David M Sabatini, Matthew L Wohlever, and Jared Rutter. Collateral deletion of the mitochondrial aaa+ atpase atad1 sensitizes cancer cells to proteasome dysfunction. eLife, Nov 2022. URL: https://doi.org/10.7554/elife.82860, doi:10.7554/elife.82860. This article has 22 citations and is from a domain leading peer-reviewed journal.
(winter2022collateraldeletionof pages 8-9): Jacob M Winter, Heidi L Fresenius, Corey N Cunningham, Peng Wei, Heather R Keys, Jordan Berg, Alex Bott, Tarun Yadav, Jeremy Ryan, Deepika Sirohi, Sheryl R Tripp, Paige Barta, Neeraj Agarwal, Anthony Letai, David M Sabatini, Matthew L Wohlever, and Jared Rutter. Collateral deletion of the mitochondrial aaa+ atpase atad1 sensitizes cancer cells to proteasome dysfunction. eLife, Nov 2022. URL: https://doi.org/10.7554/elife.82860, doi:10.7554/elife.82860. This article has 22 citations and is from a domain leading peer-reviewed journal.
(wang2020msp1atad1inprotein pages 2-4): Lan Wang and Peter Walter. Msp1/atad1 in protein quality control and regulation of synaptic activities. Annual Review of Cell and Developmental Biology, 36:141-164, Oct 2020. URL: https://doi.org/10.1146/annurev-cellbio-031220-015840, doi:10.1146/annurev-cellbio-031220-015840. This article has 62 citations and is from a domain leading peer-reviewed journal.
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(fresenius2023developmentofab pages 19-23): H Fresenius. Development of a quantitative reconstituted system to study msp1/atad1 substrate selectivity and apoptotic regulation. Unknown journal, 2023.
(wang2022conservedstructuralelements pages 2-3): Lan Wang, Hannah Toutkoushian, Vladislav Belyy, Claire Y Kokontis, and Peter Walter. Conserved structural elements specialize atad1 as a membrane protein extraction machine. May 2022. URL: https://doi.org/10.7554/elife.73941, doi:10.7554/elife.73941. This article has 27 citations and is from a domain leading peer-reviewed journal.
(wang2022conservedstructuralelements pages 11-13): Lan Wang, Hannah Toutkoushian, Vladislav Belyy, Claire Y Kokontis, and Peter Walter. Conserved structural elements specialize atad1 as a membrane protein extraction machine. May 2022. URL: https://doi.org/10.7554/elife.73941, doi:10.7554/elife.73941. This article has 27 citations and is from a domain leading peer-reviewed journal.
(chen2014msp1atad1maintainsmitochondrial pages 6-7): Yu‐Chan Chen, George K E Umanah, Noah Dephoure, Shaida A Andrabi, Steven P Gygi, Ted M Dawson, Valina L Dawson, and Jared Rutter. Msp1/atad1 maintains mitochondrial function by facilitating the degradation of mislocalized tail‐anchored proteins. The EMBO Journal, 33:1548-1564, Jul 2014. URL: https://doi.org/10.15252/embj.201487943, doi:10.15252/embj.201487943. This article has 267 citations.
(chen2014msp1atad1maintainsmitochondrial pages 10-11): Yu‐Chan Chen, George K E Umanah, Noah Dephoure, Shaida A Andrabi, Steven P Gygi, Ted M Dawson, Valina L Dawson, and Jared Rutter. Msp1/atad1 maintains mitochondrial function by facilitating the degradation of mislocalized tail‐anchored proteins. The EMBO Journal, 33:1548-1564, Jul 2014. URL: https://doi.org/10.15252/embj.201487943, doi:10.15252/embj.201487943. This article has 267 citations.
(chen2014msp1atad1maintainsmitochondrial pages 9-10): Yu‐Chan Chen, George K E Umanah, Noah Dephoure, Shaida A Andrabi, Steven P Gygi, Ted M Dawson, Valina L Dawson, and Jared Rutter. Msp1/atad1 maintains mitochondrial function by facilitating the degradation of mislocalized tail‐anchored proteins. The EMBO Journal, 33:1548-1564, Jul 2014. URL: https://doi.org/10.15252/embj.201487943, doi:10.15252/embj.201487943. This article has 267 citations.
(matsumoto2023msp1mediatedproofreadingmechanism pages 3-4): Shunsuke Matsumoto. Msp1-mediated proofreading mechanism for localization of tail-anchored membrane proteins. Journal of biochemistry, 174:13-20, Mar 2023. URL: https://doi.org/10.1093/jb/mvad025, doi:10.1093/jb/mvad025. This article has 4 citations and is from a peer-reviewed journal.
(winter2022collateraldeletionof media 8a98eb16): Jacob M Winter, Heidi L Fresenius, Corey N Cunningham, Peng Wei, Heather R Keys, Jordan Berg, Alex Bott, Tarun Yadav, Jeremy Ryan, Deepika Sirohi, Sheryl R Tripp, Paige Barta, Neeraj Agarwal, Anthony Letai, David M Sabatini, Matthew L Wohlever, and Jared Rutter. Collateral deletion of the mitochondrial aaa+ atpase atad1 sensitizes cancer cells to proteasome dysfunction. eLife, Nov 2022. URL: https://doi.org/10.7554/elife.82860, doi:10.7554/elife.82860. This article has 22 citations and is from a domain leading peer-reviewed journal.
(fresenius2024theaaa+protein pages 1-3): Heidi L. Fresenius, Deepika Gaur, Baylee Smith, Brian Acquaviva, and Matthew L. Wohlever. The aaa+ protein msp1 recognizes substrates by a hydrophobic mismatch. bioRxiv, Jul 2024. URL: https://doi.org/10.1101/2023.07.11.548587, doi:10.1101/2023.07.11.548587. This article has 5 citations.
(fresenius2024theaaa+protein pages 13-21): Heidi L. Fresenius, Deepika Gaur, Baylee Smith, Brian Acquaviva, and Matthew L. Wohlever. The aaa+ protein msp1 recognizes substrates by a hydrophobic mismatch. bioRxiv, Jul 2024. URL: https://doi.org/10.1101/2023.07.11.548587, doi:10.1101/2023.07.11.548587. This article has 5 citations.
(he2023theaaaatpaseyta4atad1 pages 1-2): Jiajia He, Ke Liu, Yifan Wu, Chenhui Zhao, Shuaijie Yan, Jia-Hui Chen, Lizhu Hu, Dongmei Wang, Fan Zheng, Wenfan Wei, Chao Xu, Chengdong Huang, Xing Liu, Xuebiao Yao, Lijun Ding, Zhiyou Fang, Ai-Hui Tang, and Chuanhai Fu. The aaa-atpase yta4/atad1 interacts with the mitochondrial divisome to inhibit mitochondrial fission. PLOS Biology, 21:e3002247, Aug 2023. URL: https://doi.org/10.1371/journal.pbio.3002247, doi:10.1371/journal.pbio.3002247. This article has 11 citations and is from a highest quality peer-reviewed journal.
(winter2022collateraldeletionof pages 11-13): Jacob M Winter, Heidi L Fresenius, Corey N Cunningham, Peng Wei, Heather R Keys, Jordan Berg, Alex Bott, Tarun Yadav, Jeremy Ryan, Deepika Sirohi, Sheryl R Tripp, Paige Barta, Neeraj Agarwal, Anthony Letai, David M Sabatini, Matthew L Wohlever, and Jared Rutter. Collateral deletion of the mitochondrial aaa+ atpase atad1 sensitizes cancer cells to proteasome dysfunction. eLife, Nov 2022. URL: https://doi.org/10.7554/elife.82860, doi:10.7554/elife.82860. This article has 22 citations and is from a domain leading peer-reviewed journal.
(fresenius2023developmentofa pages 67-73): H Fresenius. Development of a quantitative reconstituted system to study msp1/atad1 substrate selectivity and apoptotic regulation. Unknown journal, 2023.
(wang2020msp1atad1inprotein pages 18-20): Lan Wang and Peter Walter. Msp1/atad1 in protein quality control and regulation of synaptic activities. Annual Review of Cell and Developmental Biology, 36:141-164, Oct 2020. URL: https://doi.org/10.1146/annurev-cellbio-031220-015840, doi:10.1146/annurev-cellbio-031220-015840. This article has 62 citations and is from a domain leading peer-reviewed journal.
(fresenius2023developmentofac pages 67-73): H Fresenius. Development of a quantitative reconstituted system to study msp1/atad1 substrate selectivity and apoptotic regulation. Unknown journal, 2023.
(winter2022collateraldeletionof media eae7fce6): Jacob M Winter, Heidi L Fresenius, Corey N Cunningham, Peng Wei, Heather R Keys, Jordan Berg, Alex Bott, Tarun Yadav, Jeremy Ryan, Deepika Sirohi, Sheryl R Tripp, Paige Barta, Neeraj Agarwal, Anthony Letai, David M Sabatini, Matthew L Wohlever, and Jared Rutter. Collateral deletion of the mitochondrial aaa+ atpase atad1 sensitizes cancer cells to proteasome dysfunction. eLife, Nov 2022. URL: https://doi.org/10.7554/elife.82860, doi:10.7554/elife.82860. This article has 22 citations and is from a domain leading peer-reviewed journal.
(OpenTargets Search: -ATAD1): Open Targets Query (-ATAD1, 5 results). Buniello, A. et al. (2025). Open Targets Platform: facilitating therapeutic hypotheses building in drug discovery. Nucleic Acids Research.
(fresenius2023developmentofa pages 19-23): H Fresenius. Development of a quantitative reconstituted system to study msp1/atad1 substrate selectivity and apoptotic regulation. Unknown journal, 2023.
(castanzo2020theaaa+atpase pages 1-2): Dominic T. Castanzo, Benjamin LaFrance, and Andreas Martin. The aaa+ atpase msp1 is a processive protein translocase with robust unfoldase activity. Proceedings of the National Academy of Sciences, 117:14970-14977, Jun 2020. URL: https://doi.org/10.1073/pnas.1920109117, doi:10.1073/pnas.1920109117. This article has 41 citations and is from a highest quality peer-reviewed journal.
(fresenius2023developmentofac pages 110-116): H Fresenius. Development of a quantitative reconstituted system to study msp1/atad1 substrate selectivity and apoptotic regulation. Unknown journal, 2023.
(fresenius2023developmentofac pages 19-23): H Fresenius. Development of a quantitative reconstituted system to study msp1/atad1 substrate selectivity and apoptotic regulation. Unknown journal, 2023.
(wang2020structureofthe pages 1-2): Lan Wang, Alexander Myasnikov, Xingjie Pan, and Peter Walter. Structure of the aaa protein msp1 reveals mechanism of mislocalized membrane protein extraction. eLife, Jan 2020. URL: https://doi.org/10.7554/elife.54031, doi:10.7554/elife.54031. This article has 72 citations and is from a domain leading peer-reviewed journal.

Artifacts

Edison artifact artifact-00

Citations

winter2022collateraldeletionof pages 1-2
winter2022collateraldeletionof pages 11-13
fresenius2023developmentofaa pages 19-23
wang2020structureofthe pages 1-2
wang2022conservedstructuralelements pages 1-2
winter2022collateraldeletionof pages 8-9
fresenius2023developmentofab pages 19-23
wang2022conservedstructuralelements pages 2-3
wang2022conservedstructuralelements pages 11-13
fresenius2023developmentofa pages 67-73
fresenius2023developmentofac pages 67-73
fresenius2023developmentofa pages 19-23
fresenius2023developmentofac pages 110-116
fresenius2023developmentofac pages 19-23
https://doi.org/10.1146/annurev-cellbio-031220-015840;
https://doi.org/10.7554/elife.73941
https://doi.org/10.15252/embj.201487943
https://doi.org/10.7554/elife.73941;
https://doi.org/10.7554/elife.54031
https://doi.org/10.7554/elife.82860
https://doi.org/10.1016/j.molcel.2019.07.006;
https://doi.org/10.1093/jb/mvad025
https://doi.org/10.1073/pnas.1920109117
https://doi.org/10.1371/journal.pbio.3002247
https://doi.org/10.1101/2023.07.11.548587
https://doi.org/10.1101/2024.09.23.614443
https://doi.org/10.1146/annurev-cellbio-031220-015840
https://doi.org/10.15252/embr.202051991
https://doi.org/10.15252/embj.201487943;
https://doi.org/10.1146/annurev-cellbio-031220-015840,
https://doi.org/10.7554/elife.73941,
https://doi.org/10.7554/elife.82860,
https://doi.org/10.1093/jb/mvad025,
https://doi.org/10.15252/embj.201487943,
https://doi.org/10.1101/2023.07.11.548587,
https://doi.org/10.1371/journal.pbio.3002247,
https://doi.org/10.1073/pnas.1920109117,
https://doi.org/10.7554/elife.54031,

📚 Additional Documentation

Notes

(ATAD1-notes.md)

ATAD1 Notes

2026-06-03 Proteostasis PN review

Falcon deep research was attempted with the required perplexity-lite fallback.
Falcon timed out after 600 seconds and the fallback failed with a Perplexity API
quota error, so this review uses cached primary evidence, UniProt, Reactome, and
the local PN projection reports rather than a generated Falcon research artifact.

ATAD1 is a strong fit for the mitochondrial proteostasis batch, but the safest
core term remains the existing specific process GO:0140570 extraction of
mislocalized protein from mitochondrial outer membrane. The direct ATAD1/Msp1
paper says human ATAD1 limits mitochondrial mislocalization of PEX26 and GOS28
and proposes ATAD1/Msp1 as mitochondrial protein quality-control factors that
promote extraction and degradation of mislocalized tail-anchored proteins
[PMID:24843043 "human ATAD1 limits the mitochondrial mislocalization of PEX26
and GOS28"; PMID:24843043 "promote the extraction and degradation of
mislocalized TA proteins"].

The PN projection report proposes GO:0035694 mitochondrial protein catabolic
process for ATAD1 from
Mitochondrial proteostasis|Organelle-specific protein degradation|mitoCPR pathway. This is a class-level propagation, and the mapping audit flags this
source as requiring manual gene-level review before changing a review. I accepted
the projected term only as a broad NEW candidate because PMID:24843043 supports
degradation as the downstream outcome, not because the PN source alone is
sufficient. I used TAS rather than IMP for this candidate because the cached
paper text supports a traceable degradation claim, while the explicit
protein-level knockout evidence available in the cached abstract is from mouse
tissue. It should not replace GO:0140570, which is the sharper mechanism.

Peroxisomal membrane localization is retained as non-core. UniProt reports
peroxisome membrane localization and Reactome lists ATAD1 as a class I
peroxisomal membrane protein bound by PEX19, but the current evidence does not
establish peroxisomal substrate extraction as ATAD1's primary function
[file:human/ATAD1/ATAD1-uniprot.txt "Peroxisome membrane";
Reactome:R-HSA-9603804 "ATAD1 (Liu et al. 2016)"].

The synaptic/behavioral block is treated conservatively. UniProt summarizes
mouse-derived AMPAR trafficking, synaptic plasticity, learning, and memory
biology by similarity, and human ATAD1 encephalopathy provides disease context
[file:human/ATAD1/ATAD1-uniprot.txt "Required for NMDA-stimulated AMPAR
internalization"; PMID:29659736 "ATAD1 encephalopathy and stiff baby syndrome"].
I kept postsynaptic/receptor-internalization terms as non-core and marked the
high-level learning/memory annotations as over-annotations.

Falcon deep research findings (2026-06-07)

A Falcon (Edison Scientific) deep research report was generated successfully (the
earlier 2026-06-03 run had failed). It largely CONFIRMS the existing review but
adds several mechanistic/translational findings that were not previously cited.
Key synthesis (CONFIRMS / NEW / PROVISIONAL labels are relative to the prior
review):

CONFIRMS core function. ATAD1/Msp1 is a hexameric OMM AAA+ extractase that
uses ATP hydrolysis to thread membrane-embedded substrates (especially
mislocalized tail-anchored proteins, e.g. PEX26/GOS28, and stalled import
substrates) through its central pore for rerouting or degradation
PMID:24843043. This is already the accepted core (GO:0140567, GO:0140570).
NEW (human, direct, primary): ATAD1 directly and selectively extracts the
pro-apoptotic BH3-only protein BIM from mitochondrial membranes to inactivate
it; extraction is ATP-dependent, requires membrane anchoring, and is selective
(BIM extracted but not BIK/PUMA/Fis1 under the same reconstituted conditions;
lost in the catalytic E193Q mutant). This connects ATAD1 to apoptotic priming
and to a cancer "collateral lethality" with PTEN (10q23 co-deletion):
ATAD1-null cells/xenografts are hypersensitized to proteasome inhibitors via
BIM-dependent apoptosis [PMID:36409067 Winter et al. 2022 eLife, doi:10.7554/eLife.82860
"ATAD1 directly and specifically extracts the pro-apoptotic protein BIM from
mitochondria to inactivate it"]. This is a genuinely new molecular substrate
axis and a new disease/translational link not in the prior review.
NEW (human, structural/mechanistic, primary): Cryo-EM of human ATAD1 bound to
a peptide substrate shows phylogenetically conserved pore-loop aromatics
(pore-loop 1 W166/Y167) are required to grip hydrophobic substrate and cannot
be replaced by aliphatic residues; a C-terminal alpha-helix promotes
oligomerization, specializing ATAD1 among AAA proteins [PMID:35550246 Wang et
al. 2022 eLife, doi:10.7554/eLife.73941 "both aromatic amino acids in pore-loop 1
are required for ATAD1's function"]. Mechanistic support for the dislocase /
ATP-hydrolysis core via yeast Msp1 structure [PMID:31999255 Wang et al. 2020
eLife, doi:10.7554/eLife.54031] and processive bidirectional translocase /
unfoldase activity, dependent on hexamerization and inhibited by Pex3
[PMID:32541053 Castanzo et al. 2020 PNAS, doi:10.1073/pnas.1920109117].
NEW/CONFIRMS (pathway coupling): Extracted TA proteins are not obligatorily
degraded; they can be rerouted to the ER via the GET/TRC (Get3) pathway as an
intracellular "proofreading" system, or handed to ubiquitin-proteasome
(Cdc48) clearance [Matsumoto 2023 J Biochem doi:10.1093/jb/mvad025;
Matsumoto et al. 2019 Mol Cell doi:10.1016/j.molcel.2019.07.006 — yeast Msp1].
The 2019 Mol Cell DOI did not resolve to a confirmed PMID via PubMed and is
yeast-focused, so I am NOT adding it to references; kept in notes only.
PROVISIONAL (homolog, not human): A fission-yeast ATAD1 ortholog (Yta4) was
reported to inhibit excessive mitochondrial fission by acting on divisome
components Fis1/Mdv1/Dnm1 — a role beyond proteostasis [He et al. 2023 PLOS
Biology, PMID:37590302, doi:10.1371/journal.pbio.3002247]. Because this is the
Schizosaccharomyces homolog rather than human ATAD1, I treat it as
hypothesis-generating only and do NOT use it to add/modify human annotations.
PROVISIONAL (preprint / database): A 2024 bioRxiv preprint proposes Msp1
substrate recognition by hydrophobic mismatch with TMD extraction as the
rate-limiting step [Fresenius et al. 2024 bioRxiv doi:10.1101/2023.07.11.548587];
Open Targets lists ATAD1 with hyperekplexia 4 / neurodegenerative terms. These
are preprint/database-level and explicitly NOT used to change annotations.
CONFIRMS (neuronal axis): The Wang & Walter 2020 review compiles the
noncanonical neuronal role — ATAD1/Thorase forms complexes with GluR2 and
GRIP1 and disassembles GluR2-GRIP1 in an ATP-dependent manner, regulating
surface AMPAR levels and activity-dependent synaptic downscaling
[Wang & Walter 2020 Annu Rev Cell Dev Biol doi:10.1146/annurev-cellbio-031220-015840].
This supports keeping the existing AMPAR/postsynaptic annotations as non-core
(no change warranted).

Conservative actions taken in the YAML: added the four human-relevant primary
references (PMID:36409067, PMID:35550246, PMID:31999255, PMID:32541053) as
statement-only (full_text_unavailable, no supporting_text since none are cached
locally); added one suggested question (BIM/apoptosis axis) and one suggested
experiment (selective BIM extraction). No existing annotation actions were
changed — all new findings reinforce rather than contradict the current calls.

Pn Notes

(ATAD1-pn-notes.md)

ATAD1 PN Consistency Notes

Generated: 2026-06-18
Project: PROTEOSTASIS
Scope: PN consistency rereview against local AIGR review and available deep-research artifacts
UniProt: Q8NBU5
AIGR review status: COMPLETE
Review batch: proteostasis-batch-2026-06-03 (PR 1372)
Batch change status: added

Source Files Checked

AIGR review YAML: present - genes/human/ATAD1/ATAD1-ai-review.yaml
AIGR review HTML: present - genes/human/ATAD1/ATAD1-ai-review.html
Gene notes: present - genes/human/ATAD1/ATAD1-notes.md
GOA TSV: present - genes/human/ATAD1/ATAD1-goa.tsv
UniProt record: present - genes/human/ATAD1/ATAD1-uniprot.txt
PN dossier: projects/PROTEOSTASIS/reports/phase1_dossiers/ATAD1.md
PN consistency section: projects/PROTEOSTASIS/reports/phase1_dossiers/_sections/ATAD1.md
PN projection report: projects/PROTEOSTASIS/reports/pn_projection/pn_projected_gene_go_summary.tsv
PN mapping audit: projects/PROTEOSTASIS/reports/pn_mapping_audit/current_mapping_scrutiny.tsv

Deep Research Files

genes/human/ATAD1/ATAD1-deep-research-falcon.md

AIGR Review Snapshot

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.
Existing/core annotation action counts: ACCEPT: 8; KEEP_AS_NON_CORE: 15; MARK_AS_OVER_ANNOTATED: 4; MODIFY: 3; NEW: 1; REMOVE: 3

PN Consistency Summary

Consistency: Consistent. Deep research, notes, review YAML agree ATAD1/Msp1 is a hexameric OMM AAA+ extractase/dislocase that removes mislocalized tail-anchored proteins (PEX26/GOS28) and the BH3-only protein BIM, for rerouting or degradation. Review core = GO:0140567 (membrane protein dislocase) + GO:0140570 (extraction of mislocalized protein from mitochondrial OM). The PN class is degradation-centric; ATAD1's sharper mechanism is extraction, but degradation is a real downstream outcome.
PN story / NEW pressure: PN projects GO:0035694 (mitochondrial protein catabolic process), absent from ATAD1 GOA. The review accepted it as NEW (TAS) — notably GO:0140570 is NOT a subclass of GO:0035694 (verified via OLS: GO:0140570 sits under establishment-of-protein-localization, not catabolic process), so the two are orthogonal, not redundant. Adding GO:0035694 is defensible (degradation outcome supported by PMID:24843043) though broader/less mechanistic than GO:0140570. Conclude: ADD already done in-review (accepted NEW); both terms real and complementary.
Evidence alignment: PN row carries no reference titles. Review anchors on PMID:24843043 (extraction/degradation of TA proteins) plus new human primaries (PMID:36409067 BIM; PMID:35550246 cryo-EM) — all reinforce the dislocase core. No citation conflicts.
Verdict: Consistent; PN GO:0035694 is real, complementary to GO:0140570, and already added as NEW. No edits warranted.

Full Consistency Review

UniProt: Q8NBU5 · batch: proteostasis-batch-2026-06-03 · review status: COMPLETE (Falcon DR present)
PN placement: Mitochondrial proteostasis|Organelle-specific protein degradation|mitoCPR pathway ; PN-node mapping: group(mitoCPR)=no_mapping; class(Organelle-specific protein degradation)=mapped/ok GO:0035694 (mitochondrial protein catabolic process, new_to_goa); branch=no_mapping.
Consistency: Consistent. Deep research, notes, review YAML agree ATAD1/Msp1 is a hexameric OMM AAA+ extractase/dislocase that removes mislocalized tail-anchored proteins (PEX26/GOS28) and the BH3-only protein BIM, for rerouting or degradation. Review core = GO:0140567 (membrane protein dislocase) + GO:0140570 (extraction of mislocalized protein from mitochondrial OM). The PN class is degradation-centric; ATAD1's sharper mechanism is extraction, but degradation is a real downstream outcome.
PN story / NEW pressure: PN projects GO:0035694 (mitochondrial protein catabolic process), absent from ATAD1 GOA. The review accepted it as NEW (TAS) — notably GO:0140570 is NOT a subclass of GO:0035694 (verified via OLS: GO:0140570 sits under establishment-of-protein-localization, not catabolic process), so the two are orthogonal, not redundant. Adding GO:0035694 is defensible (degradation outcome supported by PMID:24843043) though broader/less mechanistic than GO:0140570. Conclude: ADD already done in-review (accepted NEW); both terms real and complementary.
Mapping strategy: ATAD1 mildly supports the class mapping. GO:0035694 is broader than the gene's specific GO:0140570 but, unlike TOMM20-type rejections, it is a distinct degradation axis the review judged worth a conservative NEW. mitoCPR leaf no_mapping is appropriate (human mitoCPR poorly defined). Node status/scope fine.
Evidence alignment: PN row carries no reference titles. Review anchors on PMID:24843043 (extraction/degradation of TA proteins) plus new human primaries (PMID:36409067 BIM; PMID:35550246 cryo-EM) — all reinforce the dislocase core. No citation conflicts.
Verdict: Consistent; PN GO:0035694 is real, complementary to GO:0140570, and already added as NEW. No edits warranted.

PN Dossier Context

review_batch: proteostasis-batch-2026-06-03
review_yaml: genes/human/ATAD1/ATAD1-ai-review.yaml
PN workbook rows: 1

PN row 1: Mitochondrial proteostasis | Organelle-specific protein degradation | mitoCPR pathway

UniProt: Q8NBU5
In branches: MI
PN-node mapping records (path + ancestors):
- [group] Mitochondrial proteostasis|Organelle-specific protein degradation|mitoCPR pathway
  status=no_mapping scope= GO=[]
  rationale: Reviewed as a narrower taxonomy bucket that is already covered by a curated parent mapping or by gene-level annotations. No additional direct GO mapping is appropriate from this node.
- [class] Mitochondrial proteostasis|Organelle-specific protein degradation
  status=mapped scope=ok_for_propagation_to_go GO=[GO:0035694 mitochondrial protein catabolic process]
  rationale: This PN class groups mitochondrial protein-degradation pathways. GO mitochondrial protein catabolic process is the conservative shared target.
- [branch] Mitochondrial proteostasis
  status=no_mapping scope= GO=[]
  rationale: Reviewed as a top-level PN branch. This is a systems/taxonomy umbrella, not a direct GO assertion; narrower child curations carry any propagating GO mappings.

Projected GO annotations (1)

GO:0035694 mitochondrial protein catabolic process | scope=ok_for_propagation_to_go | goa_status=new_to_goa | from=Mitochondrial proteostasis|Organelle-specific protein degradation

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: 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

ATAD1

Gene Description

Existing Annotations Review

Core Functions

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.

ATAD1 hydrolyzes ATP through its AAA+ ATPase domain to power extraction of membrane protein substrates and disassembly of selected protein complexes.

References

Suggested Questions for Experts

Suggested Experiments

Tags

Deep Research

Falcon

Comprehensive research report: ATAD1 (UniProt Q8NBU5; human Thorase/MSP1 homolog)

0) Gene/protein verification (mandatory identity check)

1) Key concepts and definitions (current understanding)

1.1 ATAD1 is an ATP-driven membrane protein extractase

1.2 Tail-anchored (TA) protein targeting and “proofreading”

1.3 “Outer mitochondrial transmembrane helix translocase” as a functional label

2) Molecular function, mechanism, and key substrates

2.1 Subcellular localization and architecture

2.2 Central-pore substrate grip: aromatic pore loops specialize ATAD1

2.3 Foundational substrates: mislocalized TA proteins (Pex15/PEX26; Gos1/GOS28)

2.4 Rerouting vs degradation: coupling to GET/TRC and ubiquitin–proteasome systems

2.5 Import stress and removal of stalled import substrates

2.6 Human ATAD1 apoptotic substrate: direct extraction of BIM

3) Recent developments and latest research (prioritizing 2023–2024)

3.1 2024: hydrophobic mismatch as a substrate-recognition principle (reconstituted quantitative assays)

3.2 2023: updated model of TA protein localization proofreading

3.3 2023: expanded functional landscape—ATAD1-family involvement in mitochondrial fission control

3.4 2024: energetic and mechanistic plasticity in Msp1-family extraction

4) Current applications and real-world implementations

4.1 Cancer vulnerability (“collateral lethality”) in PTEN/10q23 deletions

4.2 Clinical association: overall survival differences in mCRPC with ATAD1/PTEN co-deletion

4.3 Disease-modifier concept in Zellweger spectrum disorder (ZSD) models

5) Expert opinions and authoritative synthesis

5.1 High-authority review perspective on core function and open questions

5.2 Noncanonical neuronal role: AMPAR trafficking and synaptic plasticity

6) Relevant statistics and data highlights (recent and/or mechanistically informative)

6.1 Cancer prevalence and impact estimates (from 2023 mechanistic/translational synthesis)

6.2 Mechanistic assay evidence (visual and biochemical)

6.3 Disease association databases (hypothesis-generating)

7) Practical functional annotation summary (for gene/protein annotation)

7.1 Primary function (best-supported)

7.2 Substrates and specificity

7.3 Localization

Evidence summary table

Key figure support (extracted image)

References (URLs + publication dates where available)

Artifacts

Citations

📚 Additional Documentation

Notes

ATAD1 Notes

2026-06-03 Proteostasis PN review

Falcon deep research findings (2026-06-07)

Pn Notes

ATAD1 PN Consistency Notes

Source Files Checked

Deep Research Files

AIGR Review Snapshot

PN Consistency Summary

Full Consistency Review

PN Dossier Context

PN row 1: Mitochondrial proteostasis | Organelle-specific protein degradation | mitoCPR pathway

Projected GO annotations (1)

Note

📄 View Raw YAML