id: Q6DD88 gene_symbol: ATL3 product_type: PROTEIN status: COMPLETE taxon: id: NCBITaxon:9606 label: Homo sapiens description: >- ATL3 encodes atlastin-3, a multi-pass endoplasmic reticulum membrane dynamin-like GTPase. The protein acts on ER tubules and three-way junctions, where GTP binding, hydrolysis, and transient atlastin dimerization drive homotypic ER membrane fusion and maintain the branched tubular ER network. Pathogenic ATL3 variants disrupt ER network organization and are associated with hereditary sensory neuropathy. references: - id: GO_REF:0000002 title: Gene Ontology annotation through association of InterPro records with GO terms findings: [] - id: GO_REF:0000033 title: Annotation inferences using phylogenetic trees findings: [] - id: GO_REF:0000044 title: Gene Ontology annotation based on UniProtKB/Swiss-Prot Subcellular Location vocabulary mapping, accompanied by conservative changes to GO terms applied by UniProt findings: [] - id: GO_REF:0000052 title: Gene Ontology annotation based on curation of immunofluorescence data findings: [] - id: GO_REF:0000117 title: Electronic Gene Ontology annotations created by ARBA machine learning models findings: [] - id: GO_REF:0000120 title: Combined Automated Annotation using Multiple IEA Methods findings: [] - id: PMID:18270207 title: Atlastin GTPases are required for Golgi apparatus and ER morphogenesis. findings: - statement: ATL2 and ATL3 localize to the ER and atlastin GTPase-defective mutants disrupt ER reticularization, while general ER-to-Golgi trafficking remains essentially normal. supporting_text: "atlastin-2 and -3 are localized to the endoplasmic reticulum (ER)" reference_section_type: ABSTRACT - id: PMID:19665976 title: A class of dynamin-like GTPases involved in the generation of the tubular ER network. findings: - statement: Mammalian atlastins are dynamin-like integral membrane GTPases that localize to tubular ER and support formation of the tubular ER network. supporting_text: "mammalian atlastins, which are dynamin-like, integral membrane GTPases, interact with the tubule-shaping proteins" reference_section_type: ABSTRACT - id: PMID:19946888 title: Defining the membrane proteome of NK cells. findings: - statement: A broad high-throughput membrane proteomics study identified membrane-associated proteins; this supports only a generic membrane annotation for ATL3. supporting_text: "The present study was initiated to define the composition of the membrane proteome of the Natural Killer (NK) like cell line YTS." reference_section_type: ABSTRACT - id: PMID:23969831 title: Protrudin binds atlastins and endoplasmic reticulum-shaping proteins and regulates network formation. findings: - statement: Protrudin/ZFYVE27 binds atlastins and other tubular ER network proteins, supporting an interaction annotation but not a specific molecular activity for ATL3. supporting_text: "Protrudin binds atlastins and endoplasmic reticulum-shaping proteins and regulates network formation." reference_section_type: TITLE - id: PMID:24459106 title: Sensory neuropathy with bone destruction due to a mutation in the membrane-shaping atlastin GTPase 3. findings: - statement: ATL3 is an ER-shaping GTPase enriched at three-way junctions, and the HSN1F variant disrupts tubular ER structure. supporting_text: "ATL3 proteins are enriched in three-way junctions, branch points of the endoplasmic reticulum that connect membranous tubules to a continuous network." reference_section_type: ABSTRACT - id: PMID:25548161 title: Lunapark stabilizes nascent three-way junctions in the endoplasmic reticulum. findings: - statement: Lunapark work supports the three-way-junction context of the ER tubular network, but the accessible cached abstract is not ATL3-specific. supporting_text: "The endoplasmic reticulum (ER) consists of a polygonal network of sheets and tubules interconnected by three-way junctions." reference_section_type: ABSTRACT - id: PMID:27619977 title: Cooperation of the ER-shaping proteins atlastin, lunapark, and reticulons to generate a tubular membrane network. findings: - statement: ATL proteins, including ATL3 in mammalian cells, are needed for formation and maintenance of the tubular ER network. supporting_text: "ATL is needed to not only form, but also maintain, the ER network." reference_section_type: ABSTRACT - id: PMID:28602821 title: Timing and Reset Mechanism of GTP Hydrolysis-Driven Conformational Changes of Atlastin. findings: - statement: Structural and kinetic work on ATL1 and ATL3 supports ATL3 GTPase activity and nucleotide-dependent dimerization during the atlastin catalytic cycle. supporting_text: "we identify discrete temporal steps in the catalytic cycle for the two most dissimilar isoforms, ATL1 and ATL3" reference_section_type: ABSTRACT - id: PMID:32075961 title: REEP5 depletion causes sarco-endoplasmic reticulum vacuolization and cardiac functional defects. findings: - statement: REEP5 work places atlastin-mediated membrane fusion in the SR/ER network organization context and supports an ATL3-REEP5 interaction annotation only as a generic protein interaction. supporting_text: "ER tubules are also stabilized by forming a characteristic polygonal network through membrane fusion mediated by the atlastin family of dynamin-related GTPases" reference_section_type: ABSTRACT - id: PMID:34546351 title: The hypervariable region of atlastin-1 is a site for intrinsic and extrinsic regulation. findings: - statement: Atlastin proteins catalyze homotypic peripheral ER tubule fusion, and the study includes ATL3 structural/biochemical comparisons. supporting_text: "Atlastin (ATL) GTPases catalyze homotypic membrane fusion of the peripheral endoplasmic reticulum (ER)." reference_section_type: ABSTRACT - id: PMID:37102997 title: Human atlastin-3 is a constitutive ER membrane fusion catalyst. findings: - statement: Purified human ATL3 directly catalyzes GTP-dependent membrane fusion and can sustain ER network structure in ATL knockout cells. supporting_text: "purified human ATL3 catalyzes efficient membrane fusion in vitro and is sufficient to sustain the ER network in triple knockout cells." reference_section_type: ABSTRACT - id: file:human/ATL3/ATL3-notes.md title: ATL3 review notes for Proteostasis PN batch findings: - statement: The PN reticulophagy projection for ATL3 was reviewed conservatively and was not promoted to a proposed GO annotation. - id: file:human/ATL3/ATL3-deep-research-falcon.md title: Falcon deep research report on ATL3 findings: - statement: The Falcon report supports ATL3 as an ER-resident atlastin GTPase and distinguishes its core ER fusion role from more tentative ER-phagy receptor claims. - id: file:projects/PROTEOSTASIS/reports/pn_projection/pn_projected_annotations.tsv title: Proteostasis Network projected annotations report findings: - statement: The PN projection report lists ATL3 as a candidate for GO:0061709 reticulophagy from an ERphagy receptor category, requiring gene-level review before any GO change. existing_annotations: - term: id: GO:0007029 label: endoplasmic reticulum organization evidence_type: IBA original_reference_id: GO_REF:0000033 qualifier: involved_in review: summary: ATL3 is a conserved atlastin-family ER-shaping GTPase whose experimentally supported role is maintaining tubular ER network organization. action: ACCEPT reason: The IBA term is broad but consistent with the direct ATL3 literature showing ER network maintenance and with the more specific reviewed ER tubular network membrane organization annotations. additional_reference_ids: - PMID:27619977 - PMID:37102997 supported_by: - reference_id: PMID:27619977 supporting_text: "ATL is needed to not only form, but also maintain, the ER network." reference_section_type: ABSTRACT - term: id: GO:0051260 label: protein homooligomerization evidence_type: IBA original_reference_id: GO_REF:0000033 qualifier: involved_in review: summary: ATL3 forms transient atlastin dimers as part of the GTPase-dependent membrane fusion cycle. action: KEEP_AS_NON_CORE reason: Homooligomerization is an important mechanistic step in ATL3 fusion catalysis, but the core biological role is ER membrane fusion and ER network maintenance rather than oligomerization as an independent outcome. additional_reference_ids: - PMID:28602821 - PMID:37102997 supported_by: - reference_id: PMID:28602821 supporting_text: "from nucleotide binding and hydrolysis to ATL dimerization and phosphate release." reference_section_type: ABSTRACT - term: id: GO:0005525 label: GTP binding evidence_type: IBA original_reference_id: GO_REF:0000033 qualifier: enables review: summary: ATL3 contains the conserved atlastin GTPase domain and binds nucleotide during its catalytic cycle. action: ACCEPT reason: GTP binding is an intrinsic molecular function required for ATL3 GTPase activity and fusogenic activity. additional_reference_ids: - PMID:28602821 - PMID:37102997 supported_by: - reference_id: PMID:28602821 supporting_text: "from nucleotide binding and hydrolysis to ATL dimerization and phosphate release." reference_section_type: ABSTRACT - term: id: GO:0003924 label: GTPase activity evidence_type: IEA original_reference_id: GO_REF:0000120 qualifier: enables review: summary: Automated GTPase annotation is supported by experimental ATL3 kinetic and structural studies. action: ACCEPT reason: ATL3 hydrolyzes GTP as part of the atlastin catalytic cycle that drives ER membrane fusion. additional_reference_ids: - PMID:28602821 - PMID:37102997 supported_by: - reference_id: PMID:28602821 supporting_text: "A crystal structure of ATL3 suggests a mechanism for the displacement of the catalytic Mg2+ ion following guanosine triphosphate (GTP) hydrolysis." reference_section_type: ABSTRACT - term: id: GO:0005525 label: GTP binding evidence_type: IEA original_reference_id: GO_REF:0000002 qualifier: enables review: summary: InterPro-derived GTP binding is consistent with the ATL3 GB1/RHD3-type GTPase domain and experimental catalytic-cycle data. action: ACCEPT reason: ATL3 nucleotide binding is directly coupled to GTP hydrolysis, dimerization, and fusion. additional_reference_ids: - PMID:28602821 supported_by: - reference_id: PMID:28602821 supporting_text: "from nucleotide binding and hydrolysis to ATL dimerization and phosphate release." reference_section_type: ABSTRACT - term: id: GO:0005789 label: endoplasmic reticulum membrane evidence_type: IEA original_reference_id: GO_REF:0000044 qualifier: located_in review: summary: UniProt subcellular-location mapping to ER membrane is consistent with multiple experimental localization studies. action: ACCEPT reason: ATL3 is a multi-pass ER membrane protein localized to ER tubules and junctions. additional_reference_ids: - PMID:18270207 - PMID:37102997 supported_by: - reference_id: PMID:18270207 supporting_text: "atlastin-2 and -3 are localized to the endoplasmic reticulum (ER)" reference_section_type: ABSTRACT - term: id: GO:0016320 label: endoplasmic reticulum membrane fusion evidence_type: IEA original_reference_id: GO_REF:0000117 qualifier: involved_in review: summary: ARBA propagation to ER membrane fusion is strongly supported by direct ATL3 fusion experiments. action: ACCEPT reason: Purified human ATL3 catalyzes GTP-dependent lipid bilayer fusion in vitro and rescues ER network morphology in ATL knockout cells. additional_reference_ids: - PMID:37102997 supported_by: - reference_id: PMID:37102997 supporting_text: "purified human ATL3 catalyzes efficient membrane fusion in vitro and is sufficient to sustain the ER network in triple knockout cells." reference_section_type: ABSTRACT - term: id: GO:0098826 label: endoplasmic reticulum tubular network membrane evidence_type: IEA original_reference_id: GO_REF:0000117 qualifier: located_in review: summary: Automated localization to the ER tubular network membrane matches ATL3 localization at ER tubules and three-way junctions. action: ACCEPT reason: ATL3 is an ER membrane atlastin whose fusion function is active on ER tubules and junctions. additional_reference_ids: - PMID:24459106 - PMID:27619977 supported_by: - reference_id: PMID:24459106 supporting_text: "ATL3 proteins are enriched in three-way junctions, branch points of the endoplasmic reticulum that connect membranous tubules to a continuous network." reference_section_type: ABSTRACT - term: id: GO:0140523 label: GTPase-dependent fusogenic activity evidence_type: IEA original_reference_id: GO_REF:0000117 qualifier: enables review: summary: Automated fusogenic-activity annotation is directly supported by purified ATL3 fusion assays. action: ACCEPT reason: The most specific molecular function for ATL3 is GTPase-dependent fusogenic activity, integrating GTPase activity with membrane fusion. additional_reference_ids: - PMID:37102997 supported_by: - reference_id: PMID:37102997 supporting_text: "ATL3 incorporated at a 1:1,000 M protein/lipid ratio catalyzed robust lipid mixing." reference_section_type: RESULTS - term: id: GO:1990809 label: endoplasmic reticulum tubular network membrane organization evidence_type: IEA original_reference_id: GO_REF:0000117 qualifier: involved_in review: summary: Automated ER tubular network membrane organization annotation is supported by ATL3 rescue and ER morphology studies. action: ACCEPT reason: ATL3-mediated ER membrane fusion maintains the branched tubular ER network. additional_reference_ids: - PMID:27619977 - PMID:37102997 supported_by: - reference_id: PMID:37102997 supporting_text: "ATL3 can restore and maintain a normal ER network." reference_section_type: RESULTS - term: id: GO:0005515 label: protein binding evidence_type: IPI original_reference_id: PMID:23969831 qualifier: enables review: summary: ATL3 interacts with ZFYVE27/protrudin in ER network biology, but GO:0005515 is uninformative as a molecular-function annotation. action: MARK_AS_OVER_ANNOTATED reason: The evidence supports a physical interaction in an ER-shaping protein network, not a specific ATL3 molecular activity beyond its GTPase-dependent fusogenic function. supported_by: - reference_id: PMID:23969831 supporting_text: "Protrudin binds atlastins and endoplasmic reticulum-shaping proteins and regulates network formation." reference_section_type: TITLE - term: id: GO:0005783 label: endoplasmic reticulum evidence_type: IDA original_reference_id: GO_REF:0000052 qualifier: located_in review: summary: HPA ER localization is consistent with the broader experimental literature. action: ACCEPT reason: ATL3 is an ER-localized multi-pass membrane protein, although more specific ER membrane and ER tubular network membrane terms capture the main localization. additional_reference_ids: - PMID:18270207 - PMID:19665976 supported_by: - reference_id: PMID:18270207 supporting_text: "atlastin-2 and -3 are localized to the endoplasmic reticulum (ER)" reference_section_type: ABSTRACT - term: id: GO:0003924 label: GTPase activity evidence_type: EXP original_reference_id: PMID:28602821 qualifier: enables review: summary: ATL3 GTPase activity is directly examined in structural and kinetic studies of the atlastin catalytic cycle. action: ACCEPT reason: GTP hydrolysis is the enzymatic activity that powers ATL3 dimerization-cycle progression and membrane remodeling. supported_by: - reference_id: PMID:28602821 supporting_text: "the data extend the mechanistic framework for how GTP hydrolysis drives conformational changes in ATL" reference_section_type: ABSTRACT - term: id: GO:0003924 label: GTPase activity evidence_type: EXP original_reference_id: PMID:34546351 qualifier: enables review: summary: ATL3 was included in comparative atlastin biochemical analyses supporting conserved GTPase activity. action: ACCEPT reason: The study treats ATL3 as a catalytically active atlastin and reports ATL3 GTPase/tethering comparisons with ATL1. supported_by: - reference_id: PMID:34546351 supporting_text: "The N-terminal, cytosol-facing portion of ATL, composed of the G and middle domains, constitutes the protein's catalytic core." reference_section_type: INTRODUCTION - term: id: GO:0003924 label: GTPase activity evidence_type: EXP original_reference_id: PMID:37102997 qualifier: enables review: summary: Direct ATL3 fusion work includes GTPase assays and GTP-dependent fusion requirements. action: ACCEPT reason: ATL3 fusion is GTP dependent, and GTPase activity is part of the catalytic fusion mechanism. supported_by: - reference_id: PMID:37102997 supporting_text: "ATL3 incorporated at a 1:1,000 M protein/lipid ratio catalyzed robust lipid mixing." reference_section_type: RESULTS - term: id: GO:0005789 label: endoplasmic reticulum membrane evidence_type: EXP original_reference_id: PMID:19665976 qualifier: located_in review: summary: Mammalian atlastins, including ATL3, localize predominantly to tubular ER membranes. action: ACCEPT reason: The publication shows atlastins localize to tubular ER and interact with ER tubule-shaping proteins. supported_by: - reference_id: PMID:19665976 supporting_text: "Similar results were obtained with Myc-ATL2 and Myc-ATL3" reference_section_type: RESULTS - term: id: GO:0005789 label: endoplasmic reticulum membrane evidence_type: EXP original_reference_id: PMID:23969831 qualifier: located_in review: summary: Protrudin-network work places ATL proteins in the tubular ER network. action: ACCEPT reason: Although the cached abstract is not detailed for ATL3 sublocalization, it supports an atlastin/tubular-ER context and the annotation is independently supported by ATL3 localization literature. additional_reference_ids: - PMID:18270207 - PMID:24459106 supported_by: - reference_id: PMID:23969831 supporting_text: "Protrudin binds atlastins and endoplasmic reticulum-shaping proteins and regulates network formation." reference_section_type: TITLE - term: id: GO:0005789 label: endoplasmic reticulum membrane evidence_type: EXP original_reference_id: PMID:24459106 qualifier: located_in review: summary: Disease-variant work supports ATL3 as an ER-shaping protein at ER branch points. action: ACCEPT reason: The wild-type ATL3 localization and mutant mislocalization/disruption support ER membrane localization. supported_by: - reference_id: PMID:24459106 supporting_text: "ATL3 proteins are enriched in three-way junctions, branch points of the endoplasmic reticulum that connect membranous tubules to a continuous network." reference_section_type: ABSTRACT - term: id: GO:0005789 label: endoplasmic reticulum membrane evidence_type: EXP original_reference_id: PMID:25548161 qualifier: located_in review: summary: The accessible cached Lunapark abstract supports the ER three-way-junction context but not ATL3-specific localization; other ATL3-specific sources support retaining the term. action: ACCEPT reason: The term is well supported for ATL3 by multiple other accessible references, but this specific abstract is not the strongest source for ATL3. additional_reference_ids: - PMID:18270207 - PMID:24459106 supported_by: - reference_id: PMID:25548161 supporting_text: "The endoplasmic reticulum (ER) consists of a polygonal network of sheets and tubules interconnected by three-way junctions." reference_section_type: ABSTRACT - term: id: GO:0005789 label: endoplasmic reticulum membrane evidence_type: EXP original_reference_id: PMID:27619977 qualifier: located_in review: summary: ATL3 localization to ER tubule junctions supports ER membrane annotation. action: ACCEPT reason: Tagged ATL3 localizes to ER three-way junctions and ATL function maintains the ER network. supported_by: - reference_id: PMID:27619977 supporting_text: "wild type ATL-3 and ATL-2 localized in punctae at three-way junctions" reference_section_type: RESULTS - term: id: GO:0005789 label: endoplasmic reticulum membrane evidence_type: EXP original_reference_id: PMID:37102997 qualifier: located_in review: summary: Direct ATL3 fusion/rescue study supports ATL3 as an ER membrane fusion catalyst. action: ACCEPT reason: ATL3 is assayed as a membrane protein reconstituted into liposomes and as an ER network-maintenance factor in cells. supported_by: - reference_id: PMID:37102997 supporting_text: "Purified protein (Fig. S1 A) was incorporated into synthetic liposomes" reference_section_type: RESULTS - term: id: GO:0005789 label: endoplasmic reticulum membrane evidence_type: IDA original_reference_id: PMID:18270207 qualifier: located_in review: summary: ATL2 and ATL3 were reported as ER-localized proteins. action: ACCEPT reason: This is direct localization evidence for ATL3 at the ER membrane. supported_by: - reference_id: PMID:18270207 supporting_text: "atlastin-2 and -3 are localized to the endoplasmic reticulum (ER)" reference_section_type: ABSTRACT - term: id: GO:0016320 label: endoplasmic reticulum membrane fusion evidence_type: IMP original_reference_id: PMID:27619977 qualifier: involved_in review: summary: ATL function is required for ER network formation and maintenance, consistent with ER membrane fusion. action: ACCEPT reason: Although the study is pan-atlastin and network-level, it supports the process that later ATL3-specific reconstitution confirms directly. additional_reference_ids: - PMID:37102997 supported_by: - reference_id: PMID:27619977 supporting_text: "Connecting tubules into a network requires membrane fusion, which is mediated by membrane-anchored GTPases, the atlastins" reference_section_type: INTRODUCTION - term: id: GO:0016320 label: endoplasmic reticulum membrane fusion evidence_type: IDA original_reference_id: PMID:37102997 qualifier: involved_in review: summary: Purified human ATL3 directly catalyzes membrane fusion. action: ACCEPT reason: This is the strongest ATL3-specific evidence for ER membrane fusion. supported_by: - reference_id: PMID:37102997 supporting_text: "purified human ATL3 catalyzes efficient membrane fusion in vitro and is sufficient to sustain the ER network in triple knockout cells." reference_section_type: ABSTRACT - term: id: GO:0098826 label: endoplasmic reticulum tubular network membrane evidence_type: IDA original_reference_id: PMID:37102997 qualifier: is_active_in review: summary: ATL3 fusogenic activity occurs on ER tubular network membranes. action: ACCEPT reason: ATL3 restores and maintains ER network morphology as the sole atlastin source in triple-knockout cells. supported_by: - reference_id: PMID:37102997 supporting_text: "ATL3 can restore and maintain a normal ER network." reference_section_type: RESULTS - term: id: GO:0140523 label: GTPase-dependent fusogenic activity evidence_type: IDA original_reference_id: PMID:37102997 qualifier: enables review: summary: ATL3 has directly demonstrated GTP-dependent membrane fusogenic activity. action: ACCEPT reason: This term is the best molecular-function description for ATL3 because it captures both GTPase dependence and membrane fusion activity. supported_by: - reference_id: PMID:37102997 supporting_text: "purified human ATL3 catalyzes efficient membrane fusion in vitro" reference_section_type: ABSTRACT - term: id: GO:1990809 label: endoplasmic reticulum tubular network membrane organization evidence_type: IMP original_reference_id: PMID:27619977 qualifier: involved_in review: summary: ATL activity is required for ER tubular network organization and maintenance. action: ACCEPT reason: The term accurately reflects the cellular consequence of ATL3-family ER fusion activity. supported_by: - reference_id: PMID:27619977 supporting_text: "ATL is needed to not only form, but also maintain, the ER network." reference_section_type: ABSTRACT - term: id: GO:1990809 label: endoplasmic reticulum tubular network membrane organization evidence_type: IMP original_reference_id: PMID:37102997 qualifier: involved_in review: summary: ATL3-specific rescue of ATL knockout cells supports ER tubular network membrane organization. action: ACCEPT reason: ATL3 is sufficient to restore a branched ER network, linking the molecular fusion activity to ER network organization. supported_by: - reference_id: PMID:37102997 supporting_text: "ATL3 can restore and maintain a normal ER network." reference_section_type: RESULTS - term: id: GO:0098826 label: endoplasmic reticulum tubular network membrane evidence_type: IDA original_reference_id: PMID:27619977 qualifier: is_active_in review: summary: ATL3 localizes at ER three-way junctions in the tubular network. action: ACCEPT reason: The active site of ATL3 function is the ER tubular network membrane, especially tubule junctions. supported_by: - reference_id: PMID:27619977 supporting_text: "wild type ATL-3 and ATL-2 localized in punctae at three-way junctions" reference_section_type: RESULTS - term: id: GO:1990809 label: endoplasmic reticulum tubular network membrane organization evidence_type: IMP original_reference_id: PMID:18270207 qualifier: involved_in review: summary: Dominant-negative atlastin perturbation affects ER reticularization, supporting ATL3-family roles in ER network organization. action: ACCEPT reason: The annotation is supported by the publication's ATL2/ATL3 localization and ER morphogenesis data, and is reinforced by later ATL3-specific work. additional_reference_ids: - PMID:37102997 supported_by: - reference_id: PMID:18270207 supporting_text: "expression of SPG3A mutant or dominant-negative atlastin proteins lacking GTPase activity causes prominent inhibition of ER reticularization" reference_section_type: ABSTRACT - term: id: GO:1990809 label: endoplasmic reticulum tubular network membrane organization evidence_type: IMP original_reference_id: PMID:19665976 qualifier: involved_in review: summary: Atlastins are required for tubular ER network formation and interconnection. action: ACCEPT reason: ATL3 belongs to the mammalian atlastin group tested for ER tubular network formation; later direct ATL3 experiments confirm the assignment. additional_reference_ids: - PMID:37102997 supported_by: - reference_id: PMID:19665976 supporting_text: "The atlastins localize to the tubular ER and are required for proper network formation in vivo and in vitro." reference_section_type: ABSTRACT - term: id: GO:0005515 label: protein binding evidence_type: IPI original_reference_id: PMID:32075961 qualifier: enables review: summary: ATL3 is reported as an interactor in REEP5/SR-ER network biology, but protein binding is too generic for ATL3 molecular function. action: MARK_AS_OVER_ANNOTATED reason: The physical interaction supports ER-shaping network context. It should not obscure the more specific ATL3 molecular function, GTPase-dependent fusogenic activity. supported_by: - reference_id: PMID:32075961 supporting_text: "ER tubules are also stabilized by forming a characteristic polygonal network through membrane fusion mediated by the atlastin family of dynamin-related GTPases" reference_section_type: INTRODUCTION - term: id: GO:0098826 label: endoplasmic reticulum tubular network membrane evidence_type: IDA original_reference_id: PMID:25548161 qualifier: located_in review: summary: The term is correct for ATL3, though the accessible cached abstract for this reference is not ATL3-specific. action: ACCEPT reason: ATL3 localization to ER tubule junctions and ER tubular network membrane is supported by other accessible ATL3-specific references. additional_reference_ids: - PMID:24459106 - PMID:27619977 supported_by: - reference_id: PMID:24459106 supporting_text: "ATL3 proteins are enriched in three-way junctions, branch points of the endoplasmic reticulum that connect membranous tubules to a continuous network." reference_section_type: ABSTRACT - term: id: GO:0005515 label: protein binding evidence_type: IPI original_reference_id: PMID:23969831 qualifier: enables review: summary: The duplicated GOA ZFYVE27/protrudin interaction row supports an interaction but not a useful molecular-function annotation. action: MARK_AS_OVER_ANNOTATED reason: Protein binding is a non-informative term for ATL3; the actionable molecular function is GTPase-dependent ER membrane fusion. This entry is retained separately because it reflects a duplicate seeded GOA row rather than a distinct ATL3 function. supported_by: - reference_id: PMID:23969831 supporting_text: "Protrudin binds atlastins and endoplasmic reticulum-shaping proteins and regulates network formation." reference_section_type: TITLE - term: id: GO:0071782 label: endoplasmic reticulum tubular network evidence_type: IDA original_reference_id: PMID:23969831 qualifier: located_in review: summary: ATL3 is located in the ER tubular network. action: ACCEPT reason: The term is consistent with protrudin/atlastin ER network biology and with ATL3-specific junction localization in independent studies. additional_reference_ids: - PMID:24459106 - PMID:27619977 supported_by: - reference_id: PMID:24459106 supporting_text: "ATL3 proteins are enriched in three-way junctions, branch points of the endoplasmic reticulum that connect membranous tubules to a continuous network." reference_section_type: ABSTRACT - term: id: GO:0016020 label: membrane evidence_type: HDA original_reference_id: PMID:19946888 qualifier: located_in review: summary: High-throughput membrane proteomics is compatible with ATL3 being a membrane protein, but the term is very broad. action: MARK_AS_OVER_ANNOTATED reason: ATL3 is specifically an ER membrane and ER tubular network membrane protein; the generic membrane term adds little beyond more precise accepted annotations. additional_reference_ids: - PMID:18270207 supported_by: - reference_id: PMID:19946888 supporting_text: "The present study was initiated to define the composition of the membrane proteome of the Natural Killer (NK) like cell line YTS." reference_section_type: ABSTRACT - term: id: GO:0006888 label: endoplasmic reticulum to Golgi vesicle-mediated transport evidence_type: IMP original_reference_id: PMID:18270207 qualifier: involved_in negated: true review: summary: >- The NOT annotation is supported: ATL perturbation did not generally block anterograde ER-to-Golgi trafficking in the VSVG-GFP assay. action: ACCEPT reason: The negated annotation is important because ATL3's core role is ER morphology/fusion rather than general ER-to-Golgi vesicle-mediated transport. supported_by: - reference_id: PMID:18270207 supporting_text: "secretory pathway trafficking as assessed using vesicular stomatitis virus G protein fused to green fluorescent protein (VSVG-GFP) as a reporter was essentially normal" reference_section_type: ABSTRACT - term: id: GO:0042802 label: identical protein binding evidence_type: IDA original_reference_id: PMID:18270207 qualifier: enables review: summary: ATL3 homotypic interactions are part of the atlastin fusion mechanism. action: ACCEPT reason: Identical protein binding is more informative than generic protein binding for ATL3 because trans homodimerization of atlastin molecules is mechanistically required for fusion. additional_reference_ids: - PMID:28602821 - PMID:37102997 supported_by: - reference_id: PMID:37102997 supporting_text: "GTP-binding induced GTPase (G) domain dimerization in trans" reference_section_type: INTRODUCTION core_functions: - description: >- ATL3 is a constitutive ER membrane fusion catalyst. GTP binding and hydrolysis by cytosolic ATL3 domains promote transient atlastin homodimerization across apposed ER membranes, driving homotypic ER membrane fusion and maintaining the branched tubular ER network. molecular_function: id: GO:0140523 label: GTPase-dependent fusogenic activity directly_involved_in: - id: GO:0016320 label: endoplasmic reticulum membrane fusion - id: GO:1990809 label: endoplasmic reticulum tubular network membrane organization locations: - id: GO:0098826 label: endoplasmic reticulum tubular network membrane - id: GO:0005789 label: endoplasmic reticulum membrane supported_by: - reference_id: PMID:37102997 supporting_text: "purified human ATL3 catalyzes efficient membrane fusion in vitro and is sufficient to sustain the ER network in triple knockout cells." reference_section_type: ABSTRACT - reference_id: PMID:27619977 supporting_text: "ATL is needed to not only form, but also maintain, the ER network." reference_section_type: ABSTRACT - reference_id: file:human/ATL3/ATL3-deep-research-falcon.md supporting_text: "Atlastins are **large dynamin-like membrane GTPases** localized to the ER that catalyze **homotypic fusion of ER tubules**" reference_section_type: OTHER proposed_new_terms: [] suggested_questions: - question: >- Does endogenous ATL3 have a direct receptor-like role in ER-phagy/reticulophagy under defined stress conditions, or are reported autophagy phenotypes secondary to changes in ER network architecture? - question: >- Which cellular contexts depend specifically on constitutive ATL3 fusion activity rather than partially redundant ATL1 or ATL2 activity? suggested_experiments: - description: >- Compare reticulophagy reporter flux in ATL3 knockout cells rescued with wild-type ATL3, fusion-defective ATL3, and candidate GABARAP/LIR-interaction mutants, while separately quantifying ER network morphology. experiment_type: cell-based reticulophagy reporter rescue hypothesis: >- If ATL3 is a direct reticulophagy receptor, autophagy-receptor mutants should impair ER turnover independently of their effect on GTPase-dependent ER fusion. - description: >- Reconstitute purified ATL3 with ER-phagy receptor candidates and ATG8-family proteins on ER-like membranes to test whether ATL3 directly recruits autophagy machinery or only changes membrane fusion/topology. experiment_type: biochemical membrane reconstitution hypothesis: >- ATL3's core activity is membrane fusion; a direct receptor role would require separable ATG8-family recruitment activity.