{"gene":"ATAD1","run_date":"2026-06-09T22:02:44","timeline":{"discoveries":[{"year":1993,"finding":"Yeast MSP1 (mitochondrial sorting of proteins 1) is an intrinsic mitochondrial outer membrane protein with a large cytosolic domain, belonging to a novel family of putative ATPases sharing a conserved ~185-aa domain including a nucleotide-binding motif. Overexpression causes mislocalization of a fusion protein from the outer to the inner membrane, suggesting a role in intramitochondrial protein sorting.","method":"Gene isolation, sequence analysis, overexpression phenotype, subcellular fractionation","journal":"The Journal of biological chemistry","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — fractionation plus functional overexpression phenotype, single lab, foundational identification paper","pmids":["8226973"],"is_preprint":false},{"year":1999,"finding":"Fission yeast Msp1p (a dynamin-related protein, distinct from budding yeast/human ATAD1 Msp1) localizes to mitochondria and anchors to the matrix side of the inner membrane; this paper describes a different Msp1 and is a symbol collision — excluded from ATAD1 discoveries.","method":"N/A — excluded","journal":"Journal of cell science","confidence":"Low","confidence_rationale":"Excluded — symbol collision (fission yeast dynamin-related protein, not the AAA-ATPase ATAD1/budding yeast Msp1)","pmids":["10547374"],"is_preprint":false},{"year":2014,"finding":"Yeast Msp1 (ATAD1 ortholog) localizes to mitochondria and peroxisomes and limits accumulation of mislocalized tail-anchored (TA) proteins (Pex15, Gos1) on the outer mitochondrial membrane (OMM). Loss of Msp1 combined with loss of the GET pathway causes synergistic growth defects and severe mitochondrial damage (loss of mtDNA, aberrant morphology). Human ATAD1 similarly limits mitochondrial mislocalization of PEX26 and GOS28.","method":"Deletion genetics, epistasis (msp1Δ × GET pathway mutants), fluorescence microscopy, mitochondrial fractionation, mammalian ATAD1 knockout mouse tissue analysis","journal":"The EMBO journal","confidence":"High","confidence_rationale":"Tier 2 / Strong — reciprocal genetic epistasis, subcellular fractionation, KO phenotype, replicated in yeast and mammalian model","pmids":["24843043"],"is_preprint":false},{"year":2014,"finding":"Msp1, a membrane-anchored AAA-ATPase on the OMM and peroxisomes, functions in a quality control pathway that senses and degrades TA proteins mistargeted to the OMM. Msp1 binds and promotes turnover of a Pex15 mutant misdirected to the OMM; loss of both Msp1 and the GET pathway causes accumulation of Pex15 on the OMM and severe mitochondrial morphology defects.","method":"Co-immunoprecipitation (Msp1–Pex15 interaction), fluorescence microscopy, genetic epistasis, protein turnover assays","journal":"Proceedings of the National Academy of Sciences of the United States of America","confidence":"High","confidence_rationale":"Tier 2 / Strong — Co-IP, epistasis, turnover assay, orthogonal methods in single rigorous study","pmids":["24821790"],"is_preprint":false},{"year":2017,"finding":"Msp1 is both necessary and sufficient to drive ATP-dependent extraction of TA proteins from the lipid bilayer (membrane dislocase activity). Crystal structure of the Msp1 cytosolic region modeled as a ring hexamer reveals a conserved membrane-facing surface adjacent to a central pore; structure-guided mutagenesis of pore residues abolishes TA protein extraction in vitro and fails to complement msp1Δ in yeast.","method":"Reconstitution into proteoliposomes with purified components, crystal structure, structure-guided mutagenesis, in vitro ATP-dependent extraction assay, yeast complementation","journal":"Molecular cell","confidence":"High","confidence_rationale":"Tier 1 / Strong — in vitro reconstitution, crystal structure, mutagenesis, and yeast complementation in single study","pmids":["28712723"],"is_preprint":false},{"year":2017,"finding":"Msp1 clears excess or overexpressed peroxisomal TA proteins (Pex15) from peroxisomal membranes as well as from mitochondria. Pex15 at peroxisomes is rapidly converted from an Msp1-sensitive to an Msp1-resistant state by interaction with the peroxisomal membrane protein Pex3, which shields Pex15 from Msp1-dependent turnover. Thus Msp1 selects substrates on the basis of their solitary membrane existence.","method":"Live-cell quantitative fluorescence microscopy, drug-inducible gene expression, kinetic modeling, Co-IP (Pex15–Pex3 interaction)","journal":"eLife","confidence":"High","confidence_rationale":"Tier 2 / Strong — live imaging, kinetic measurements, Co-IP, orthogonal methods, mechanistically defines substrate selectivity","pmids":["28906250"],"is_preprint":false},{"year":2018,"finding":"ATAD1 (Thorase) controls internalization of AMPA receptors by disassembling complexes between the AMPA receptor subunit GluA2 and the receptor-binding protein GRIP1 at postsynapses. A homozygous frameshift ATAD1 mutation (c.1070_1071delAT) impairs GluA2/Thorase complex disassembly, alters Thorase oligomeric state, reduces GluA2 at the cell surface, and causes lethal encephalopathy with arthrogryposis.","method":"Whole-exome sequencing, biochemical complex disassembly assay, oligomeric state analysis (gel filtration/biochemistry), cell-surface GluA2 quantification in Atad1−/− neurons expressing mutant Thorase","journal":"Brain : a journal of neurology","confidence":"High","confidence_rationale":"Tier 2 / Strong — human genetics combined with biochemical disassembly assay and neuronal cell surface receptor quantification, multiple orthogonal methods","pmids":["29390050"],"is_preprint":false},{"year":2019,"finding":"Msp1 facilitates transfer of mistargeted TA proteins from the OMM to the ER membrane, where Doa10 ubiquitinates them with Ubc6/Ubc7, and Cdc48 (with Ufd1/Npl4) extracts them for proteasomal degradation. Msp1 acts as an extractase that hands off substrates to the ER quality control machinery rather than degrading them directly.","method":"Genetic epistasis (msp1Δ, doa10Δ, cdc48 mutants), subcellular fractionation, ubiquitination assay, co-immunoprecipitation","journal":"Molecular cell","confidence":"High","confidence_rationale":"Tier 2 / Strong — multiple genetic mutants with epistasis, biochemical ubiquitination assay, Co-IP, orthogonal methods in single study","pmids":["31445887"],"is_preprint":false},{"year":2019,"finding":"Msp1 detects mislocalized TA proteins through a dual-recognition mechanism: (1) conserved hydrophobic residues on Msp1 recognize hydrophobic surfaces exposed on cytoplasmic faces of mislocalized substrates; (2) Msp1's IMS domain (acidic D12 residue) recognizes basic IMS-facing residues on substrates. Introducing a hydrophobic patch into native mitochondrial TA proteins converts them into Msp1 substrates.","method":"Systematic mutagenesis of Msp1 and substrates, complementation assays, fluorescence microscopy, new substrate identification (Frt1, Ysy6)","journal":"EMBO reports","confidence":"High","confidence_rationale":"Tier 2 / Strong — extensive mutagenesis of both enzyme and substrates with functional readouts, dual-recognition mechanism established by multiple orthogonal experiments","pmids":["30858337"],"is_preprint":false},{"year":2019,"finding":"ATAD1 (Thorase) mediates removal of the pro-apoptotic protein BIM from mitochondria to inactivate it. Loss of ATAD1 hypersensitizes cancer cells and mouse xenografts to proteasome inhibitor-induced apoptosis via BIM activation, demonstrating a direct functional interaction between ATAD1 and BIM at mitochondria.","method":"ATAD1 KO cell lines, mouse xenografts, proteasome inhibitor treatment, BIM protein interaction/localization assays, apoptosis assays","journal":"eLife","confidence":"High","confidence_rationale":"Tier 2 / Strong — KO cells and mouse xenografts with specific apoptotic phenotype, direct BIM extraction assay, multiple orthogonal methods","pmids":["36409067"],"is_preprint":false},{"year":2020,"finding":"Cryo-EM structures of Msp1-substrate complexes at near-atomic resolution show that Msp1 forms hexameric spirals that translocate substrates through a central pore. A singular hydrophobic substrate recruitment site at the spiral's seam positions substrate for pore entry. Aromatic amino acids in the pore grip substrate in a sequence-promiscuous hydrophobic milieu; intersubunit interfaces coordinate ATP hydrolysis with subunit position in the spiral.","method":"Cryo-EM structure determination, structure-guided mutagenesis, biochemical validation","journal":"eLife","confidence":"High","confidence_rationale":"Tier 1 / Strong — near-atomic cryo-EM structure with mutagenesis validation, comprehensive mechanistic model","pmids":["31999255"],"is_preprint":false},{"year":2020,"finding":"The soluble hexameric Msp1 AAA+ motor is a processive bidirectional protein translocase that unfolds diverse substrates by threading through its central pore. Unfoldase activity is inhibited by Pex3, the peroxisomal membrane protein that protects native Pex15 from Msp1-dependent turnover.","method":"Hexamerization scaffold to stabilize soluble Msp1 hexamer, negative-stain EM confirmation of hexameric state, in vitro translocation/unfolding assays with diverse substrates, Pex3 inhibition assay","journal":"Proceedings of the National Academy of Sciences of the United States of America","confidence":"High","confidence_rationale":"Tier 1 / Strong — in vitro reconstitution with EM verification, mechanistic translocation and unfoldase assays, inhibition by Pex3","pmids":["32541053"],"is_preprint":false},{"year":2020,"finding":"ATAD1 (Thorase) controls AMPA receptor recycling by disassembling GluA2–GRIP1 complexes at postsynapses, mediating release of neurotransmitter receptors from postsynaptic scaffolds. Loss of ATAD1 in knockout mice causes behavioral defects, brain MRI abnormalities, seizures, and shortened survival; AMPA receptor antagonist (perampanel) treatment rescues these phenotypes, confirming excessive AMPA receptor activity as pathomechanism.","method":"ATAD1 knockout mice, behavioral assays, brain MRI, seizure monitoring, perampanel pharmacological rescue, human patient treatment","journal":"Annual review of cell and developmental biology","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — KO mouse with defined cellular phenotype and pharmacological rescue, primarily review citing original data; original data from PMID:28180185","pmids":["32886535","28180185"],"is_preprint":false},{"year":2017,"finding":"ATAD1 (Thorase) loss-of-function in mice causes excessive AMPA receptor activity due to impaired GluA2–GRIP1 complex disassembly; perampanel (AMPA receptor antagonist) reverses behavioral defects, normalizes brain MRI, prevents seizures, and prolongs survival in Atad1 KO mice. Human patients with ATAD1 mutation treated with perampanel showed improvement in hypertonicity and resolution of seizures.","method":"Atad1 KO mouse model, behavioral and MRI phenotyping, perampanel pharmacological rescue, human patient case report with targeted therapy","journal":"Neurology. Genetics","confidence":"High","confidence_rationale":"Tier 2 / Strong — KO mouse with specific molecular mechanism (AMPA receptor recycling defect) confirmed by pharmacological rescue in both mouse model and human patients","pmids":["28180185"],"is_preprint":false},{"year":2022,"finding":"Cryo-EM structures of human ATAD1 in complex with a peptide substrate at near-atomic resolution show that phylogenetically conserved structural elements specialize ATAD1 for membrane protein extraction while following the general AAA protein mechanism. Both aromatic amino acids in pore-loop 1 are required for ATAD1 function and cannot be substituted by aliphatic residues. A C-terminal α-helix strongly facilitates ATAD1 oligomerization, distinguishing it from closely related proteins. A live-cell microscopy assay directly confirmed ATAD1 activity in vivo.","method":"Cryo-EM structure determination, structure-guided mutagenesis (aromatic-to-aliphatic substitutions), live-cell microscopy-based mislocalization assay","journal":"eLife","confidence":"High","confidence_rationale":"Tier 1 / Strong — near-atomic cryo-EM structure, mutagenesis, live-cell functional assay, multiple orthogonal methods","pmids":["35550246"],"is_preprint":false},{"year":2024,"finding":"Human ATAD1 prevents clogging of the mitochondrial translocase of the outer membrane (TOM) by un-imported mitochondrial precursor proteins. ATAD1 interacts with both TOM components and stalled (un-imported) proteins; ATAD1 knockout leads to extensive accumulation of mitochondrial precursors outside the organelle and decreased protein import efficiency. Increased ATAD1 expression improves fitness of cells with inefficient mitochondrial protein import.","method":"ATAD1 KO human cells, co-immunoprecipitation (ATAD1–TOM interaction), protein import assays, quantitative proteomics of un-imported precursors, ATAD1 overexpression rescue","journal":"Cell reports","confidence":"High","confidence_rationale":"Tier 2 / Strong — KO cells with defined import phenotype, Co-IP of ATAD1 with TOM complex, overexpression rescue, multiple orthogonal methods","pmids":["39024102"],"is_preprint":false}],"current_model":"ATAD1 (yeast ortholog Msp1) is a membrane-anchored AAA-ATPase on the mitochondrial outer membrane (and peroxisomes) that forms ATP-hydrolysis-driven hexameric spirals to extract mislocalized tail-anchored membrane proteins and stalled import substrates from the OMM—recognizing substrates via exposed hydrophobic surfaces and basic IMS-facing residues—transferring them to the ER for ubiquitin/proteasome-dependent degradation, while also directly extracting the pro-apoptotic protein BIM to inactivate it; in the mammalian nervous system ATAD1 (Thorase) additionally disassembles postsynaptic GluA2–GRIP1 complexes to regulate AMPA receptor surface trafficking and synaptic plasticity."},"narrative":{"mechanistic_narrative":"ATAD1 (yeast ortholog Msp1) is a membrane-anchored AAA+ ATPase of the mitochondrial outer membrane and peroxisomes that operates as a quality-control dislocase, extracting mislocalized and stalled membrane proteins from the bilayer in an ATP-dependent manner [PMID:24843043, PMID:28712723]. It is both necessary and sufficient to dislodge tail-anchored (TA) proteins such as Pex15, Gos1, PEX26 and GOS28 that become mistargeted to the OMM, acting in parallel with the GET targeting pathway; loss of both causes synergistic mitochondrial damage [PMID:24843043, PMID:24821790, PMID:28712723]. Substrate selection is governed by a dual-recognition mechanism: conserved hydrophobic residues engage exposed hydrophobic surfaces on cytosolic faces while an acidic IMS residue (D12) reads out basic IMS-facing residues, so that solitary, unshielded membrane proteins are recognized whereas substrates protected by partners (Pex15 bound to Pex3) escape turnover [PMID:28906250, PMID:30858337, PMID:32541053]. Mechanistically, ATAD1/Msp1 assembles into hexameric spirals that thread substrate through a central pore lined by aromatic pore-loop residues, gripping it in a sequence-promiscuous hydrophobic milieu and coordinating ATP hydrolysis with subunit position to processively translocate and unfold polypeptides [PMID:28712723, PMID:31999255, PMID:32541053, PMID:35550246]. Extracted TA proteins are handed off to ER quality control, where Doa10/Ubc6/Ubc7 ubiquitinate them and Cdc48 directs them to the proteasome [PMID:31445887]. Beyond TA-protein clearance, ATAD1 prevents clogging of the TOM translocase by un-imported precursors, interacting with TOM components and stalled substrates to maintain import efficiency [PMID:39024102], and directly extracts the pro-apoptotic protein BIM from mitochondria to restrain apoptosis [PMID:36409067]. In the mammalian nervous system ATAD1 (Thorase) disassembles postsynaptic GluA2–GRIP1 complexes to control AMPA receptor surface trafficking [PMID:29390050, PMID:28180185]; loss-of-function mutations cause a lethal encephalopathy with seizures driven by excessive AMPA receptor activity that is reversible by the AMPA antagonist perampanel in both Atad1 knockout mice and patients [PMID:29390050, PMID:28180185].","teleology":[{"year":1993,"claim":"Established the founding identity of Msp1 as an outer-membrane protein of a novel ATPase family with a role in intramitochondrial protein sorting, framing the gene as a putative motor acting on membrane proteins.","evidence":"Gene isolation, sequence analysis, overexpression mislocalization phenotype, and subcellular fractionation in yeast","pmids":["8226973"],"confidence":"Medium","gaps":["No biochemical demonstration of ATPase or extraction activity","Physiological substrates unidentified","Mechanism of sorting unresolved"]},{"year":2014,"claim":"Defined Msp1/ATAD1 as a quality-control factor that limits accumulation of mislocalized tail-anchored proteins on the OMM, acting in parallel to the GET targeting pathway, and showed conservation to mammalian ATAD1.","evidence":"Deletion genetics, msp1Δ × GET epistasis, Co-IP with Pex15, turnover assays, fluorescence microscopy, and mammalian KO mouse tissue","pmids":["24843043","24821790"],"confidence":"High","gaps":["Did not show direct membrane extraction in vitro","Fate of extracted substrates undefined","Mechanism of substrate discrimination unknown"]},{"year":2017,"claim":"Demonstrated that Msp1 is itself the ATP-dependent membrane dislocase — necessary and sufficient to extract TA proteins from the bilayer — and that a central pore is essential for activity.","evidence":"Proteoliposome reconstitution with purified components, crystal structure of the cytosolic hexamer, pore-residue mutagenesis, and yeast complementation","pmids":["28712723"],"confidence":"High","gaps":["Atomic view of substrate engagement not captured by crystal model","Downstream degradation route not addressed","Selectivity rules not defined"]},{"year":2017,"claim":"Explained substrate selectivity: Msp1 targets proteins in a solitary membrane state, while partner binding (Pex3 shielding Pex15) renders substrates resistant.","evidence":"Live-cell quantitative fluorescence microscopy, drug-inducible expression, kinetic modeling, and Pex15–Pex3 Co-IP","pmids":["28906250"],"confidence":"High","gaps":["Molecular basis of shielding not structurally defined","Generality across substrates beyond Pex15 untested"]},{"year":2019,"claim":"Resolved the molecular recognition code, showing Msp1 reads both exposed hydrophobic surfaces and basic IMS-facing residues, and that introducing a hydrophobic patch converts native proteins into substrates.","evidence":"Systematic mutagenesis of enzyme and substrates, complementation, microscopy, and identification of new substrates Frt1/Ysy6","pmids":["30858337"],"confidence":"High","gaps":["Quantitative contribution of each recognition arm unresolved","How recognition couples to ATP cycle not addressed"]},{"year":2019,"claim":"Placed Msp1 in a degradation pathway, showing it functions as an extractase that hands TA substrates to ER machinery (Doa10/Ubc6/Ubc7, Cdc48) for proteasomal degradation rather than degrading them itself.","evidence":"Genetic epistasis across msp1Δ/doa10Δ/cdc48 mutants, fractionation, ubiquitination assays, and Co-IP","pmids":["31445887"],"confidence":"High","gaps":["Physical handoff intermediate not isolated","Whether mammalian ATAD1 uses an equivalent ER route untested here"]},{"year":2019,"claim":"Extended ATAD1 function to apoptosis regulation, demonstrating it removes pro-apoptotic BIM from mitochondria, with loss sensitizing cancer cells to proteasome-inhibitor-induced death.","evidence":"ATAD1 KO cell lines, mouse xenografts, proteasome inhibitor challenge, BIM interaction/localization and apoptosis assays","pmids":["36409067"],"confidence":"High","gaps":["Structural basis of BIM recognition undefined","Relationship between BIM extraction and TA-protein dislocase activity unclear"]},{"year":2020,"claim":"Provided near-atomic mechanistic models showing hexameric spirals translocate substrate through an aromatic-lined pore, with a seam recruitment site and hand-over-hand ATP coupling, and that the soluble motor is a processive bidirectional unfoldase.","evidence":"Cryo-EM of Msp1-substrate complexes, negative-stain EM of stabilized hexamers, in vitro translocation/unfolding assays, and Pex3 inhibition","pmids":["31999255","32541053"],"confidence":"High","gaps":["How spiral engages substrate within an intact bilayer not captured","Step size and directionality regulation in vivo unresolved"]},{"year":2020,"claim":"Consolidated the neuronal role of ATAD1/Thorase in disassembling GluA2–GRIP1 complexes and showed AMPA-receptor antagonism rescues knockout phenotypes, establishing excessive AMPA activity as the pathomechanism.","evidence":"Atad1 KO mice, behavioral and MRI phenotyping, seizure monitoring, and perampanel pharmacological rescue","pmids":["32886535","28180185"],"confidence":"Medium","gaps":["Structural basis of GluA2–GRIP1 disassembly not defined","Link between synaptic and mitochondrial functions unclear"]},{"year":2018,"claim":"Linked ATAD1 to human disease, showing a homozygous frameshift mutation impairs GluA2/Thorase complex disassembly and reduces surface GluA2, causing lethal encephalopathy with arthrogryposis.","evidence":"Whole-exome sequencing, biochemical complex-disassembly assay, oligomeric state analysis, and surface GluA2 quantification in mutant-expressing neurons","pmids":["29390050"],"confidence":"High","gaps":["Genotype–phenotype range across patients undefined","Whether mitochondrial functions contribute to disease unaddressed"]},{"year":2022,"claim":"Defined human ATAD1 structurally, showing conserved elements specialize it for membrane extraction, that both pore-loop-1 aromatics are essential, and that a C-terminal helix drives oligomerization distinguishing it from relatives.","evidence":"Cryo-EM of human ATAD1–peptide complex, aromatic-to-aliphatic mutagenesis, and live-cell mislocalization assay","pmids":["35550246"],"confidence":"High","gaps":["Full substrate range of human enzyme not mapped","Regulation of oligomerization in vivo unresolved"]},{"year":2024,"claim":"Revealed a new role in import-stress relief, showing ATAD1 prevents TOM translocase clogging by un-imported precursors and that its expression buffers cells with inefficient import.","evidence":"ATAD1 KO human cells, ATAD1–TOM Co-IP, import assays, quantitative proteomics of un-imported precursors, and overexpression rescue","pmids":["39024102"],"confidence":"High","gaps":["Whether ATAD1 directly extracts stalled chains from the TOM channel not structurally shown","Coordination with TA-protein and BIM substrates unresolved"]},{"year":null,"claim":"How a single dislocase mechanistically partitions among its diverse substrate classes — mislocalized TA proteins, BIM, TOM-clogging precursors, and synaptic GluA2–GRIP1 complexes — and whether these activities are differentially regulated across tissues remains unresolved.","evidence":"","pmids":[],"confidence":"High","gaps":["No unified model reconciling mitochondrial and synaptic substrates","Tissue-specific regulation of substrate choice unknown","In-membrane structural intermediate of extraction not captured"]}],"mechanism_profile":{"molecular_activity":[{"term_id":"GO:0140657","term_label":"ATP-dependent activity","supporting_discovery_ids":[4,10,11,14]},{"term_id":"GO:0140096","term_label":"catalytic activity, acting on a protein","supporting_discovery_ids":[4,6,9,11]}],"localization":[{"term_id":"GO:0005739","term_label":"mitochondrion","supporting_discovery_ids":[0,2,3,9,15]},{"term_id":"GO:0005777","term_label":"peroxisome","supporting_discovery_ids":[2,3,5]}],"pathway":[{"term_id":"R-HSA-392499","term_label":"Metabolism of proteins","supporting_discovery_ids":[2,4,7,15]},{"term_id":"R-HSA-9609507","term_label":"Protein localization","supporting_discovery_ids":[2,7,15]},{"term_id":"R-HSA-5357801","term_label":"Programmed Cell Death","supporting_discovery_ids":[9]},{"term_id":"R-HSA-112316","term_label":"Neuronal System","supporting_discovery_ids":[6,12,13]}],"complexes":[],"partners":["PEX15","PEX3","GRIP1","GLUA2","BIM","TOM COMPLEX","DOA10","CDC48"],"other_free_text":[]}},"prefetch_data":{"uniprot":{"accession":"Q8NBU5","full_name":"Outer mitochondrial transmembrane helix translocase","aliases":["ATPase family AAA domain-containing protein 1","hATAD1","Thorase"],"length_aa":361,"mass_kda":40.7,"function":"Outer mitochondrial translocase required to remove mislocalized tail-anchored transmembrane proteins on mitochondria (PubMed:24843043). Specifically recognizes and binds tail-anchored transmembrane proteins: acts as a dislocase that mediates the ATP-dependent extraction of mistargeted tail-anchored transmembrane proteins from the mitochondrion outer membrane (By similarity). Also plays a critical role in regulating the surface expression of AMPA receptors (AMPAR), thereby regulating synaptic plasticity and learning and memory (By similarity). Required for NMDA-stimulated AMPAR internalization and inhibition of GRIA1 and GRIA2 recycling back to the plasma membrane; these activities are ATPase-dependent (By similarity)","subcellular_location":"Mitochondrion outer membrane; Peroxisome membrane; Postsynaptic cell membrane","url":"https://www.uniprot.org/uniprotkb/Q8NBU5/entry"},"depmap":{"release":"DepMap","has_data":true,"is_common_essential":false,"resolved_as":"","url":"https://depmap.org/portal/gene/ATAD1","classification":"Not Classified","n_dependent_lines":0,"n_total_lines":1208,"dependency_fraction":0.0},"opencell":{"profiled":false,"resolved_as":"","ensg_id":"","cell_line_id":"","localizations":[],"interactors":[{"gene":"METAP2","stoichiometry":0.2},{"gene":"NFKB1","stoichiometry":0.2},{"gene":"RELA","stoichiometry":0.2},{"gene":"SYAP1","stoichiometry":0.2},{"gene":"TPT1","stoichiometry":0.2},{"gene":"VDAC1","stoichiometry":0.2}],"url":"https://opencell.sf.czbiohub.org/search/ATAD1","total_profiled":1310},"omim":[{"mim_id":"618011","title":"HYPEREKPLEXIA 4; HKPX4","url":"https://www.omim.org/entry/618011"},{"mim_id":"614452","title":"ATPase FAMILY, AAA DOMAIN-CONTAINING, MEMBER 1; ATAD1","url":"https://www.omim.org/entry/614452"},{"mim_id":"149400","title":"HYPEREKPLEXIA 1; HKPX1","url":"https://www.omim.org/entry/149400"}],"hpa":{"profiled":true,"resolved_as":"","reliability":"Approved","locations":[{"location":"Nucleoli rim","reliability":"Approved"},{"location":"Mitochondria","reliability":"Additional"}],"tissue_specificity":"Low tissue specificity","tissue_distribution":"Detected in all","driving_tissues":[],"url":"https://www.proteinatlas.org/search/ATAD1"},"hgnc":{"alias_symbol":["FLJ14600","Msp1"],"prev_symbol":[]},"alphafold":{"accession":"Q8NBU5","domains":[{"cath_id":"3.40.50.300","chopping":"68-255","consensus_level":"high","plddt":86.4085,"start":68,"end":255},{"cath_id":"1.10.8.60","chopping":"261-318_328-353","consensus_level":"high","plddt":92.9644,"start":261,"end":353}],"viewer_url":"https://alphafold.ebi.ac.uk/entry/Q8NBU5","model_url":"https://alphafold.ebi.ac.uk/files/AF-Q8NBU5-F1-model_v6.cif","pae_url":"https://alphafold.ebi.ac.uk/files/AF-Q8NBU5-F1-predicted_aligned_error_v6.png","plddt_mean":84.12},"mouse_models":{"mgi_url":"https://www.informatics.jax.org/marker/summary?nomen=ATAD1","jax_strain_url":"https://www.jax.org/strain/search?query=ATAD1"},"sequence":{"accession":"Q8NBU5","fasta_url":"https://rest.uniprot.org/uniprotkb/Q8NBU5.fasta","uniprot_url":"https://www.uniprot.org/uniprotkb/Q8NBU5/entry","alphafold_viewer_url":"https://alphafold.ebi.ac.uk/entry/Q8NBU5"}},"corpus_meta":[{"pmid":"8515771","id":"PMC_8515771","title":"Analysis of sequence diversity in the Plasmodium falciparum merozoite surface protein-1 (MSP-1).","date":"1993","source":"Molecular and biochemical parasitology","url":"https://pubmed.ncbi.nlm.nih.gov/8515771","citation_count":337,"is_preprint":false},{"pmid":"12897248","id":"PMC_12897248","title":"The MSP1 gene is necessary to restrict the number of cells entering into male and female sporogenesis and to initiate anther wall formation in rice.","date":"2003","source":"The Plant cell","url":"https://pubmed.ncbi.nlm.nih.gov/12897248","citation_count":226,"is_preprint":false},{"pmid":"24843043","id":"PMC_24843043","title":"Msp1/ATAD1 maintains mitochondrial function by facilitating the degradation of mislocalized tail-anchored proteins.","date":"2014","source":"The EMBO journal","url":"https://pubmed.ncbi.nlm.nih.gov/24843043","citation_count":192,"is_preprint":false},{"pmid":"24821790","id":"PMC_24821790","title":"The conserved AAA-ATPase Msp1 confers organelle specificity to tail-anchored proteins.","date":"2014","source":"Proceedings of the National Academy of Sciences of the United States of America","url":"https://pubmed.ncbi.nlm.nih.gov/24821790","citation_count":185,"is_preprint":false},{"pmid":"1741018","id":"PMC_1741018","title":"Secondary processing of the Plasmodium falciparum merozoite surface protein-1 (MSP1) by a calcium-dependent membrane-bound serine protease: shedding of MSP133 as a noncovalently associated complex with other fragments of the MSP1.","date":"1992","source":"Molecular and biochemical parasitology","url":"https://pubmed.ncbi.nlm.nih.gov/1741018","citation_count":177,"is_preprint":false},{"pmid":"23089736","id":"PMC_23089736","title":"ChAd63-MVA-vectored blood-stage malaria vaccines targeting MSP1 and AMA1: assessment of efficacy against mosquito bite challenge in humans.","date":"2012","source":"Molecular therapy : the journal of the American Society of Gene 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proteasome dysfunction.","date":"2022","source":"eLife","url":"https://pubmed.ncbi.nlm.nih.gov/36409067","citation_count":20,"is_preprint":false},{"pmid":"27708348","id":"PMC_27708348","title":"A chimeric protein-based malaria vaccine candidate induces robust T cell responses against Plasmodium vivax MSP119.","date":"2016","source":"Scientific reports","url":"https://pubmed.ncbi.nlm.nih.gov/27708348","citation_count":20,"is_preprint":false},{"pmid":"11922426","id":"PMC_11922426","title":"Immunogenic properties of the Plasmodium vivax vaccine candidate MSP1(19) expressed as a secreted non-glycosylated polypeptide from Pichia pastoris.","date":"2002","source":"Parasitology","url":"https://pubmed.ncbi.nlm.nih.gov/11922426","citation_count":20,"is_preprint":false},{"pmid":"31394253","id":"PMC_31394253","title":"Sorting out how Msp1 maintains mitochondrial membrane 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MSP119.","date":"2017","source":"Vaccine","url":"https://pubmed.ncbi.nlm.nih.gov/28341111","citation_count":15,"is_preprint":false},{"pmid":"37558673","id":"PMC_37558673","title":"Multifunctional IgG/IgM antibodies and cellular cytotoxicity are elicited by the full-length MSP1 SumayaVac-1 malaria vaccine.","date":"2023","source":"NPJ vaccines","url":"https://pubmed.ncbi.nlm.nih.gov/37558673","citation_count":15,"is_preprint":false},{"pmid":"35914717","id":"PMC_35914717","title":"TMT-based quantitative membrane proteomics identified PRRs potentially involved in the perception of MSP1 in rice leaves.","date":"2022","source":"Journal of proteomics","url":"https://pubmed.ncbi.nlm.nih.gov/35914717","citation_count":15,"is_preprint":false},{"pmid":"8613353","id":"PMC_8613353","title":"Dominance of conserved B-cell epitopes of the Plasmodium falciparum merozoite surface protein, MSP1, in blood-stage infections of naive Aotus monkeys.","date":"1996","source":"Infection and immunity","url":"https://pubmed.ncbi.nlm.nih.gov/8613353","citation_count":15,"is_preprint":false},{"pmid":"19454325","id":"PMC_19454325","title":"Temporal and spatial variation in MSP1 clonal composition of Plasmodium falciparum in districts of Assam, Northeast India.","date":"2009","source":"Infection, genetics and evolution : journal of molecular epidemiology and evolutionary genetics in infectious diseases","url":"https://pubmed.ncbi.nlm.nih.gov/19454325","citation_count":15,"is_preprint":false},{"pmid":"18287863","id":"PMC_18287863","title":"Association of CYP1A1 Msp1 polymorphism with tobacco-related risk of gallbladder cancer in a north Indian population.","date":"2008","source":"European journal of cancer prevention : the official journal of the European Cancer Prevention Organisation (ECP)","url":"https://pubmed.ncbi.nlm.nih.gov/18287863","citation_count":15,"is_preprint":false}],"cost":{"stage1":{"model":"claude-sonnet-4-6","input_tokens":52782,"output_tokens":4368,"usd":0.111933,"stage1_stop_reason":"end_turn"},"stage2":{"model":"claude-opus-4-8","input_tokens":12461,"output_tokens":4483,"usd":0.08719,"stage2_stop_reason":"end_turn"},"total_usd":0.199123,"stage1_batch_id":"msgbatch_0179Z2pxRYBsXi2xADneafRw","stage2_batch_id":"msgbatch_01LaY9ZaVdgjWArcZo9eqQE5","note":"batch pricing = 50% of standard"},"stage1_raw":"```json\n{\n  \"discoveries\": [\n    {\n      \"year\": 1993,\n      \"finding\": \"Yeast MSP1 (mitochondrial sorting of proteins 1) is an intrinsic mitochondrial outer membrane protein with a large cytosolic domain, belonging to a novel family of putative ATPases sharing a conserved ~185-aa domain including a nucleotide-binding motif. Overexpression causes mislocalization of a fusion protein from the outer to the inner membrane, suggesting a role in intramitochondrial protein sorting.\",\n      \"method\": \"Gene isolation, sequence analysis, overexpression phenotype, subcellular fractionation\",\n      \"journal\": \"The Journal of biological chemistry\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — fractionation plus functional overexpression phenotype, single lab, foundational identification paper\",\n      \"pmids\": [\"8226973\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 1999,\n      \"finding\": \"Fission yeast Msp1p (a dynamin-related protein, distinct from budding yeast/human ATAD1 Msp1) localizes to mitochondria and anchors to the matrix side of the inner membrane; this paper describes a different Msp1 and is a symbol collision — excluded from ATAD1 discoveries.\",\n      \"method\": \"N/A — excluded\",\n      \"journal\": \"Journal of cell science\",\n      \"confidence\": \"Low\",\n      \"confidence_rationale\": \"Excluded — symbol collision (fission yeast dynamin-related protein, not the AAA-ATPase ATAD1/budding yeast Msp1)\",\n      \"pmids\": [\"10547374\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2014,\n      \"finding\": \"Yeast Msp1 (ATAD1 ortholog) localizes to mitochondria and peroxisomes and limits accumulation of mislocalized tail-anchored (TA) proteins (Pex15, Gos1) on the outer mitochondrial membrane (OMM). Loss of Msp1 combined with loss of the GET pathway causes synergistic growth defects and severe mitochondrial damage (loss of mtDNA, aberrant morphology). Human ATAD1 similarly limits mitochondrial mislocalization of PEX26 and GOS28.\",\n      \"method\": \"Deletion genetics, epistasis (msp1Δ × GET pathway mutants), fluorescence microscopy, mitochondrial fractionation, mammalian ATAD1 knockout mouse tissue analysis\",\n      \"journal\": \"The EMBO journal\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — reciprocal genetic epistasis, subcellular fractionation, KO phenotype, replicated in yeast and mammalian model\",\n      \"pmids\": [\"24843043\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2014,\n      \"finding\": \"Msp1, a membrane-anchored AAA-ATPase on the OMM and peroxisomes, functions in a quality control pathway that senses and degrades TA proteins mistargeted to the OMM. Msp1 binds and promotes turnover of a Pex15 mutant misdirected to the OMM; loss of both Msp1 and the GET pathway causes accumulation of Pex15 on the OMM and severe mitochondrial morphology defects.\",\n      \"method\": \"Co-immunoprecipitation (Msp1–Pex15 interaction), fluorescence microscopy, genetic epistasis, protein turnover assays\",\n      \"journal\": \"Proceedings of the National Academy of Sciences of the United States of America\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — Co-IP, epistasis, turnover assay, orthogonal methods in single rigorous study\",\n      \"pmids\": [\"24821790\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2017,\n      \"finding\": \"Msp1 is both necessary and sufficient to drive ATP-dependent extraction of TA proteins from the lipid bilayer (membrane dislocase activity). Crystal structure of the Msp1 cytosolic region modeled as a ring hexamer reveals a conserved membrane-facing surface adjacent to a central pore; structure-guided mutagenesis of pore residues abolishes TA protein extraction in vitro and fails to complement msp1Δ in yeast.\",\n      \"method\": \"Reconstitution into proteoliposomes with purified components, crystal structure, structure-guided mutagenesis, in vitro ATP-dependent extraction assay, yeast complementation\",\n      \"journal\": \"Molecular cell\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 / Strong — in vitro reconstitution, crystal structure, mutagenesis, and yeast complementation in single study\",\n      \"pmids\": [\"28712723\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2017,\n      \"finding\": \"Msp1 clears excess or overexpressed peroxisomal TA proteins (Pex15) from peroxisomal membranes as well as from mitochondria. Pex15 at peroxisomes is rapidly converted from an Msp1-sensitive to an Msp1-resistant state by interaction with the peroxisomal membrane protein Pex3, which shields Pex15 from Msp1-dependent turnover. Thus Msp1 selects substrates on the basis of their solitary membrane existence.\",\n      \"method\": \"Live-cell quantitative fluorescence microscopy, drug-inducible gene expression, kinetic modeling, Co-IP (Pex15–Pex3 interaction)\",\n      \"journal\": \"eLife\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — live imaging, kinetic measurements, Co-IP, orthogonal methods, mechanistically defines substrate selectivity\",\n      \"pmids\": [\"28906250\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2018,\n      \"finding\": \"ATAD1 (Thorase) controls internalization of AMPA receptors by disassembling complexes between the AMPA receptor subunit GluA2 and the receptor-binding protein GRIP1 at postsynapses. A homozygous frameshift ATAD1 mutation (c.1070_1071delAT) impairs GluA2/Thorase complex disassembly, alters Thorase oligomeric state, reduces GluA2 at the cell surface, and causes lethal encephalopathy with arthrogryposis.\",\n      \"method\": \"Whole-exome sequencing, biochemical complex disassembly assay, oligomeric state analysis (gel filtration/biochemistry), cell-surface GluA2 quantification in Atad1−/− neurons expressing mutant Thorase\",\n      \"journal\": \"Brain : a journal of neurology\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — human genetics combined with biochemical disassembly assay and neuronal cell surface receptor quantification, multiple orthogonal methods\",\n      \"pmids\": [\"29390050\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2019,\n      \"finding\": \"Msp1 facilitates transfer of mistargeted TA proteins from the OMM to the ER membrane, where Doa10 ubiquitinates them with Ubc6/Ubc7, and Cdc48 (with Ufd1/Npl4) extracts them for proteasomal degradation. Msp1 acts as an extractase that hands off substrates to the ER quality control machinery rather than degrading them directly.\",\n      \"method\": \"Genetic epistasis (msp1Δ, doa10Δ, cdc48 mutants), subcellular fractionation, ubiquitination assay, co-immunoprecipitation\",\n      \"journal\": \"Molecular cell\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — multiple genetic mutants with epistasis, biochemical ubiquitination assay, Co-IP, orthogonal methods in single study\",\n      \"pmids\": [\"31445887\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2019,\n      \"finding\": \"Msp1 detects mislocalized TA proteins through a dual-recognition mechanism: (1) conserved hydrophobic residues on Msp1 recognize hydrophobic surfaces exposed on cytoplasmic faces of mislocalized substrates; (2) Msp1's IMS domain (acidic D12 residue) recognizes basic IMS-facing residues on substrates. Introducing a hydrophobic patch into native mitochondrial TA proteins converts them into Msp1 substrates.\",\n      \"method\": \"Systematic mutagenesis of Msp1 and substrates, complementation assays, fluorescence microscopy, new substrate identification (Frt1, Ysy6)\",\n      \"journal\": \"EMBO reports\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — extensive mutagenesis of both enzyme and substrates with functional readouts, dual-recognition mechanism established by multiple orthogonal experiments\",\n      \"pmids\": [\"30858337\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2019,\n      \"finding\": \"ATAD1 (Thorase) mediates removal of the pro-apoptotic protein BIM from mitochondria to inactivate it. Loss of ATAD1 hypersensitizes cancer cells and mouse xenografts to proteasome inhibitor-induced apoptosis via BIM activation, demonstrating a direct functional interaction between ATAD1 and BIM at mitochondria.\",\n      \"method\": \"ATAD1 KO cell lines, mouse xenografts, proteasome inhibitor treatment, BIM protein interaction/localization assays, apoptosis assays\",\n      \"journal\": \"eLife\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — KO cells and mouse xenografts with specific apoptotic phenotype, direct BIM extraction assay, multiple orthogonal methods\",\n      \"pmids\": [\"36409067\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2020,\n      \"finding\": \"Cryo-EM structures of Msp1-substrate complexes at near-atomic resolution show that Msp1 forms hexameric spirals that translocate substrates through a central pore. A singular hydrophobic substrate recruitment site at the spiral's seam positions substrate for pore entry. Aromatic amino acids in the pore grip substrate in a sequence-promiscuous hydrophobic milieu; intersubunit interfaces coordinate ATP hydrolysis with subunit position in the spiral.\",\n      \"method\": \"Cryo-EM structure determination, structure-guided mutagenesis, biochemical validation\",\n      \"journal\": \"eLife\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 / Strong — near-atomic cryo-EM structure with mutagenesis validation, comprehensive mechanistic model\",\n      \"pmids\": [\"31999255\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2020,\n      \"finding\": \"The soluble hexameric Msp1 AAA+ motor is a processive bidirectional protein translocase that unfolds diverse substrates by threading through its central pore. Unfoldase activity is inhibited by Pex3, the peroxisomal membrane protein that protects native Pex15 from Msp1-dependent turnover.\",\n      \"method\": \"Hexamerization scaffold to stabilize soluble Msp1 hexamer, negative-stain EM confirmation of hexameric state, in vitro translocation/unfolding assays with diverse substrates, Pex3 inhibition assay\",\n      \"journal\": \"Proceedings of the National Academy of Sciences of the United States of America\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 / Strong — in vitro reconstitution with EM verification, mechanistic translocation and unfoldase assays, inhibition by Pex3\",\n      \"pmids\": [\"32541053\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2020,\n      \"finding\": \"ATAD1 (Thorase) controls AMPA receptor recycling by disassembling GluA2–GRIP1 complexes at postsynapses, mediating release of neurotransmitter receptors from postsynaptic scaffolds. Loss of ATAD1 in knockout mice causes behavioral defects, brain MRI abnormalities, seizures, and shortened survival; AMPA receptor antagonist (perampanel) treatment rescues these phenotypes, confirming excessive AMPA receptor activity as pathomechanism.\",\n      \"method\": \"ATAD1 knockout mice, behavioral assays, brain MRI, seizure monitoring, perampanel pharmacological rescue, human patient treatment\",\n      \"journal\": \"Annual review of cell and developmental biology\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — KO mouse with defined cellular phenotype and pharmacological rescue, primarily review citing original data; original data from PMID:28180185\",\n      \"pmids\": [\"32886535\", \"28180185\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2017,\n      \"finding\": \"ATAD1 (Thorase) loss-of-function in mice causes excessive AMPA receptor activity due to impaired GluA2–GRIP1 complex disassembly; perampanel (AMPA receptor antagonist) reverses behavioral defects, normalizes brain MRI, prevents seizures, and prolongs survival in Atad1 KO mice. Human patients with ATAD1 mutation treated with perampanel showed improvement in hypertonicity and resolution of seizures.\",\n      \"method\": \"Atad1 KO mouse model, behavioral and MRI phenotyping, perampanel pharmacological rescue, human patient case report with targeted therapy\",\n      \"journal\": \"Neurology. Genetics\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — KO mouse with specific molecular mechanism (AMPA receptor recycling defect) confirmed by pharmacological rescue in both mouse model and human patients\",\n      \"pmids\": [\"28180185\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2022,\n      \"finding\": \"Cryo-EM structures of human ATAD1 in complex with a peptide substrate at near-atomic resolution show that phylogenetically conserved structural elements specialize ATAD1 for membrane protein extraction while following the general AAA protein mechanism. Both aromatic amino acids in pore-loop 1 are required for ATAD1 function and cannot be substituted by aliphatic residues. A C-terminal α-helix strongly facilitates ATAD1 oligomerization, distinguishing it from closely related proteins. A live-cell microscopy assay directly confirmed ATAD1 activity in vivo.\",\n      \"method\": \"Cryo-EM structure determination, structure-guided mutagenesis (aromatic-to-aliphatic substitutions), live-cell microscopy-based mislocalization assay\",\n      \"journal\": \"eLife\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 / Strong — near-atomic cryo-EM structure, mutagenesis, live-cell functional assay, multiple orthogonal methods\",\n      \"pmids\": [\"35550246\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2024,\n      \"finding\": \"Human ATAD1 prevents clogging of the mitochondrial translocase of the outer membrane (TOM) by un-imported mitochondrial precursor proteins. ATAD1 interacts with both TOM components and stalled (un-imported) proteins; ATAD1 knockout leads to extensive accumulation of mitochondrial precursors outside the organelle and decreased protein import efficiency. Increased ATAD1 expression improves fitness of cells with inefficient mitochondrial protein import.\",\n      \"method\": \"ATAD1 KO human cells, co-immunoprecipitation (ATAD1–TOM interaction), protein import assays, quantitative proteomics of un-imported precursors, ATAD1 overexpression rescue\",\n      \"journal\": \"Cell reports\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — KO cells with defined import phenotype, Co-IP of ATAD1 with TOM complex, overexpression rescue, multiple orthogonal methods\",\n      \"pmids\": [\"39024102\"],\n      \"is_preprint\": false\n    }\n  ],\n  \"current_model\": \"ATAD1 (yeast ortholog Msp1) is a membrane-anchored AAA-ATPase on the mitochondrial outer membrane (and peroxisomes) that forms ATP-hydrolysis-driven hexameric spirals to extract mislocalized tail-anchored membrane proteins and stalled import substrates from the OMM—recognizing substrates via exposed hydrophobic surfaces and basic IMS-facing residues—transferring them to the ER for ubiquitin/proteasome-dependent degradation, while also directly extracting the pro-apoptotic protein BIM to inactivate it; in the mammalian nervous system ATAD1 (Thorase) additionally disassembles postsynaptic GluA2–GRIP1 complexes to regulate AMPA receptor surface trafficking and synaptic plasticity.\"\n}\n```","stage2_raw":"{\n  \"mechanistic_narrative\": \"ATAD1 (yeast ortholog Msp1) is a membrane-anchored AAA+ ATPase of the mitochondrial outer membrane and peroxisomes that operates as a quality-control dislocase, extracting mislocalized and stalled membrane proteins from the bilayer in an ATP-dependent manner [#2, #4]. It is both necessary and sufficient to dislodge tail-anchored (TA) proteins such as Pex15, Gos1, PEX26 and GOS28 that become mistargeted to the OMM, acting in parallel with the GET targeting pathway; loss of both causes synergistic mitochondrial damage [#2, #3, #4]. Substrate selection is governed by a dual-recognition mechanism: conserved hydrophobic residues engage exposed hydrophobic surfaces on cytosolic faces while an acidic IMS residue (D12) reads out basic IMS-facing residues, so that solitary, unshielded membrane proteins are recognized whereas substrates protected by partners (Pex15 bound to Pex3) escape turnover [#5, #8, #11]. Mechanistically, ATAD1/Msp1 assembles into hexameric spirals that thread substrate through a central pore lined by aromatic pore-loop residues, gripping it in a sequence-promiscuous hydrophobic milieu and coordinating ATP hydrolysis with subunit position to processively translocate and unfold polypeptides [#4, #10, #11, #14]. Extracted TA proteins are handed off to ER quality control, where Doa10/Ubc6/Ubc7 ubiquitinate them and Cdc48 directs them to the proteasome [#7]. Beyond TA-protein clearance, ATAD1 prevents clogging of the TOM translocase by un-imported precursors, interacting with TOM components and stalled substrates to maintain import efficiency [#15], and directly extracts the pro-apoptotic protein BIM from mitochondria to restrain apoptosis [#9]. In the mammalian nervous system ATAD1 (Thorase) disassembles postsynaptic GluA2\\u2013GRIP1 complexes to control AMPA receptor surface trafficking [#6, #13]; loss-of-function mutations cause a lethal encephalopathy with seizures driven by excessive AMPA receptor activity that is reversible by the AMPA antagonist perampanel in both Atad1 knockout mice and patients [#6, #13].\",\n  \"teleology\": [\n    {\n      \"year\": 1993,\n      \"claim\": \"Established the founding identity of Msp1 as an outer-membrane protein of a novel ATPase family with a role in intramitochondrial protein sorting, framing the gene as a putative motor acting on membrane proteins.\",\n      \"evidence\": \"Gene isolation, sequence analysis, overexpression mislocalization phenotype, and subcellular fractionation in yeast\",\n      \"pmids\": [\"8226973\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"No biochemical demonstration of ATPase or extraction activity\", \"Physiological substrates unidentified\", \"Mechanism of sorting unresolved\"]\n    },\n    {\n      \"year\": 2014,\n      \"claim\": \"Defined Msp1/ATAD1 as a quality-control factor that limits accumulation of mislocalized tail-anchored proteins on the OMM, acting in parallel to the GET targeting pathway, and showed conservation to mammalian ATAD1.\",\n      \"evidence\": \"Deletion genetics, msp1\\u0394 \\u00d7 GET epistasis, Co-IP with Pex15, turnover assays, fluorescence microscopy, and mammalian KO mouse tissue\",\n      \"pmids\": [\"24843043\", \"24821790\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Did not show direct membrane extraction in vitro\", \"Fate of extracted substrates undefined\", \"Mechanism of substrate discrimination unknown\"]\n    },\n    {\n      \"year\": 2017,\n      \"claim\": \"Demonstrated that Msp1 is itself the ATP-dependent membrane dislocase \\u2014 necessary and sufficient to extract TA proteins from the bilayer \\u2014 and that a central pore is essential for activity.\",\n      \"evidence\": \"Proteoliposome reconstitution with purified components, crystal structure of the cytosolic hexamer, pore-residue mutagenesis, and yeast complementation\",\n      \"pmids\": [\"28712723\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Atomic view of substrate engagement not captured by crystal model\", \"Downstream degradation route not addressed\", \"Selectivity rules not defined\"]\n    },\n    {\n      \"year\": 2017,\n      \"claim\": \"Explained substrate selectivity: Msp1 targets proteins in a solitary membrane state, while partner binding (Pex3 shielding Pex15) renders substrates resistant.\",\n      \"evidence\": \"Live-cell quantitative fluorescence microscopy, drug-inducible expression, kinetic modeling, and Pex15\\u2013Pex3 Co-IP\",\n      \"pmids\": [\"28906250\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Molecular basis of shielding not structurally defined\", \"Generality across substrates beyond Pex15 untested\"]\n    },\n    {\n      \"year\": 2019,\n      \"claim\": \"Resolved the molecular recognition code, showing Msp1 reads both exposed hydrophobic surfaces and basic IMS-facing residues, and that introducing a hydrophobic patch converts native proteins into substrates.\",\n      \"evidence\": \"Systematic mutagenesis of enzyme and substrates, complementation, microscopy, and identification of new substrates Frt1/Ysy6\",\n      \"pmids\": [\"30858337\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Quantitative contribution of each recognition arm unresolved\", \"How recognition couples to ATP cycle not addressed\"]\n    },\n    {\n      \"year\": 2019,\n      \"claim\": \"Placed Msp1 in a degradation pathway, showing it functions as an extractase that hands TA substrates to ER machinery (Doa10/Ubc6/Ubc7, Cdc48) for proteasomal degradation rather than degrading them itself.\",\n      \"evidence\": \"Genetic epistasis across msp1\\u0394/doa10\\u0394/cdc48 mutants, fractionation, ubiquitination assays, and Co-IP\",\n      \"pmids\": [\"31445887\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Physical handoff intermediate not isolated\", \"Whether mammalian ATAD1 uses an equivalent ER route untested here\"]\n    },\n    {\n      \"year\": 2019,\n      \"claim\": \"Extended ATAD1 function to apoptosis regulation, demonstrating it removes pro-apoptotic BIM from mitochondria, with loss sensitizing cancer cells to proteasome-inhibitor-induced death.\",\n      \"evidence\": \"ATAD1 KO cell lines, mouse xenografts, proteasome inhibitor challenge, BIM interaction/localization and apoptosis assays\",\n      \"pmids\": [\"36409067\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Structural basis of BIM recognition undefined\", \"Relationship between BIM extraction and TA-protein dislocase activity unclear\"]\n    },\n    {\n      \"year\": 2020,\n      \"claim\": \"Provided near-atomic mechanistic models showing hexameric spirals translocate substrate through an aromatic-lined pore, with a seam recruitment site and hand-over-hand ATP coupling, and that the soluble motor is a processive bidirectional unfoldase.\",\n      \"evidence\": \"Cryo-EM of Msp1-substrate complexes, negative-stain EM of stabilized hexamers, in vitro translocation/unfolding assays, and Pex3 inhibition\",\n      \"pmids\": [\"31999255\", \"32541053\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"How spiral engages substrate within an intact bilayer not captured\", \"Step size and directionality regulation in vivo unresolved\"]\n    },\n    {\n      \"year\": 2020,\n      \"claim\": \"Consolidated the neuronal role of ATAD1/Thorase in disassembling GluA2\\u2013GRIP1 complexes and showed AMPA-receptor antagonism rescues knockout phenotypes, establishing excessive AMPA activity as the pathomechanism.\",\n      \"evidence\": \"Atad1 KO mice, behavioral and MRI phenotyping, seizure monitoring, and perampanel pharmacological rescue\",\n      \"pmids\": [\"32886535\", \"28180185\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Structural basis of GluA2\\u2013GRIP1 disassembly not defined\", \"Link between synaptic and mitochondrial functions unclear\"]\n    },\n    {\n      \"year\": 2018,\n      \"claim\": \"Linked ATAD1 to human disease, showing a homozygous frameshift mutation impairs GluA2/Thorase complex disassembly and reduces surface GluA2, causing lethal encephalopathy with arthrogryposis.\",\n      \"evidence\": \"Whole-exome sequencing, biochemical complex-disassembly assay, oligomeric state analysis, and surface GluA2 quantification in mutant-expressing neurons\",\n      \"pmids\": [\"29390050\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Genotype\\u2013phenotype range across patients undefined\", \"Whether mitochondrial functions contribute to disease unaddressed\"]\n    },\n    {\n      \"year\": 2022,\n      \"claim\": \"Defined human ATAD1 structurally, showing conserved elements specialize it for membrane extraction, that both pore-loop-1 aromatics are essential, and that a C-terminal helix drives oligomerization distinguishing it from relatives.\",\n      \"evidence\": \"Cryo-EM of human ATAD1\\u2013peptide complex, aromatic-to-aliphatic mutagenesis, and live-cell mislocalization assay\",\n      \"pmids\": [\"35550246\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Full substrate range of human enzyme not mapped\", \"Regulation of oligomerization in vivo unresolved\"]\n    },\n    {\n      \"year\": 2024,\n      \"claim\": \"Revealed a new role in import-stress relief, showing ATAD1 prevents TOM translocase clogging by un-imported precursors and that its expression buffers cells with inefficient import.\",\n      \"evidence\": \"ATAD1 KO human cells, ATAD1\\u2013TOM Co-IP, import assays, quantitative proteomics of un-imported precursors, and overexpression rescue\",\n      \"pmids\": [\"39024102\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Whether ATAD1 directly extracts stalled chains from the TOM channel not structurally shown\", \"Coordination with TA-protein and BIM substrates unresolved\"]\n    },\n    {\n      \"year\": null,\n      \"claim\": \"How a single dislocase mechanistically partitions among its diverse substrate classes \\u2014 mislocalized TA proteins, BIM, TOM-clogging precursors, and synaptic GluA2\\u2013GRIP1 complexes \\u2014 and whether these activities are differentially regulated across tissues remains unresolved.\",\n      \"evidence\": \"\",\n      \"pmids\": [],\n      \"confidence\": \"High\",\n      \"gaps\": [\"No unified model reconciling mitochondrial and synaptic substrates\", \"Tissue-specific regulation of substrate choice unknown\", \"In-membrane structural intermediate of extraction not captured\"]\n    }\n  ],\n  \"mechanism_profile\": {\n    \"molecular_activity\": [\n      {\"term_id\": \"GO:0140657\", \"supporting_discovery_ids\": [4, 10, 11, 14]},\n      {\"term_id\": \"GO:0140096\", \"supporting_discovery_ids\": [4, 6, 9, 11]},\n      {\"term_id\": \"GO:0016887\", \"supporting_discovery_ids\": [4]}\n    ],\n    \"localization\": [\n      {\"term_id\": \"GO:0005739\", \"supporting_discovery_ids\": [0, 2, 3, 9, 15]},\n      {\"term_id\": \"GO:0005777\", \"supporting_discovery_ids\": [2, 3, 5]}\n    ],\n    \"pathway\": [\n      {\"term_id\": \"R-HSA-392499\", \"supporting_discovery_ids\": [2, 4, 7, 15]},\n      {\"term_id\": \"R-HSA-9609507\", \"supporting_discovery_ids\": [2, 7, 15]},\n      {\"term_id\": \"R-HSA-5357801\", \"supporting_discovery_ids\": [9]},\n      {\"term_id\": \"R-HSA-112316\", \"supporting_discovery_ids\": [6, 12, 13]}\n    ],\n    \"complexes\": [],\n    \"partners\": [\"PEX15\", \"PEX3\", \"GRIP1\", \"GluA2\", \"BIM\", \"TOM complex\", \"DOA10\", \"CDC48\"],\n    \"other_free_text\": []\n  }\n}","audit_flag":null,"evaluation":{"pairwise":"win","faith_supported":7,"faith_total":7,"faith_pct":100.0}}