Existing Annotations Review

GO Term	Evidence	Action	Reason
GO:0007029 endoplasmic reticulum organization	IBA GO_REF:0000033	ACCEPT	Summary: ATL3 is a conserved atlastin-family ER-shaping GTPase whose experimentally supported role is maintaining tubular ER network organization. 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. Supporting Evidence: PMID:27619977 ATL is needed to not only form, but also maintain, the ER network.
GO:0051260 protein homooligomerization	IBA GO_REF:0000033	KEEP AS NON CORE	Summary: ATL3 forms transient atlastin dimers as part of the GTPase-dependent membrane fusion cycle. 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. Supporting Evidence: PMID:28602821 from nucleotide binding and hydrolysis to ATL dimerization and phosphate release.
GO:0005525 GTP binding	IBA GO_REF:0000033	ACCEPT	Summary: ATL3 contains the conserved atlastin GTPase domain and binds nucleotide during its catalytic cycle. Reason: GTP binding is an intrinsic molecular function required for ATL3 GTPase activity and fusogenic activity. Supporting Evidence: PMID:28602821 from nucleotide binding and hydrolysis to ATL dimerization and phosphate release.
GO:0003924 GTPase activity	IEA GO_REF:0000120	ACCEPT	Summary: Automated GTPase annotation is supported by experimental ATL3 kinetic and structural studies. Reason: ATL3 hydrolyzes GTP as part of the atlastin catalytic cycle that drives ER membrane fusion. Supporting Evidence: PMID:28602821 A crystal structure of ATL3 suggests a mechanism for the displacement of the catalytic Mg2+ ion following guanosine triphosphate (GTP) hydrolysis.
GO:0005525 GTP binding	IEA GO_REF:0000002	ACCEPT	Summary: InterPro-derived GTP binding is consistent with the ATL3 GB1/RHD3-type GTPase domain and experimental catalytic-cycle data. Reason: ATL3 nucleotide binding is directly coupled to GTP hydrolysis, dimerization, and fusion. Supporting Evidence: PMID:28602821 from nucleotide binding and hydrolysis to ATL dimerization and phosphate release.
GO:0005789 endoplasmic reticulum membrane	IEA GO_REF:0000044	ACCEPT	Summary: UniProt subcellular-location mapping to ER membrane is consistent with multiple experimental localization studies. Reason: ATL3 is a multi-pass ER membrane protein localized to ER tubules and junctions. Supporting Evidence: PMID:18270207 atlastin-2 and -3 are localized to the endoplasmic reticulum (ER)
GO:0016320 endoplasmic reticulum membrane fusion	IEA GO_REF:0000117	ACCEPT	Summary: ARBA propagation to ER membrane fusion is strongly supported by direct ATL3 fusion experiments. Reason: Purified human ATL3 catalyzes GTP-dependent lipid bilayer fusion in vitro and rescues ER network morphology in ATL knockout cells. Supporting Evidence: PMID:37102997 purified human ATL3 catalyzes efficient membrane fusion in vitro and is sufficient to sustain the ER network in triple knockout cells.
GO:0098826 endoplasmic reticulum tubular network membrane	IEA GO_REF:0000117	ACCEPT	Summary: Automated localization to the ER tubular network membrane matches ATL3 localization at ER tubules and three-way junctions. Reason: ATL3 is an ER membrane atlastin whose fusion function is active on ER tubules and junctions. Supporting Evidence: PMID:24459106 ATL3 proteins are enriched in three-way junctions, branch points of the endoplasmic reticulum that connect membranous tubules to a continuous network.
GO:0140523 GTPase-dependent fusogenic activity	IEA GO_REF:0000117	ACCEPT	Summary: Automated fusogenic-activity annotation is directly supported by purified ATL3 fusion assays. Reason: The most specific molecular function for ATL3 is GTPase-dependent fusogenic activity, integrating GTPase activity with membrane fusion. Supporting Evidence: PMID:37102997 ATL3 incorporated at a 1:1,000 M protein/lipid ratio catalyzed robust lipid mixing.
GO:1990809 endoplasmic reticulum tubular network membrane organization	IEA GO_REF:0000117	ACCEPT	Summary: Automated ER tubular network membrane organization annotation is supported by ATL3 rescue and ER morphology studies. Reason: ATL3-mediated ER membrane fusion maintains the branched tubular ER network. Supporting Evidence: PMID:37102997 ATL3 can restore and maintain a normal ER network.
GO:0005515 protein binding	IPI PMID:23969831 Protrudin binds atlastins and endoplasmic reticulum-shaping ...	MARK AS OVER ANNOTATED	Summary: ATL3 interacts with ZFYVE27/protrudin in ER network biology, but GO:0005515 is uninformative as a molecular-function annotation. 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. Supporting Evidence: PMID:23969831 Protrudin binds atlastins and endoplasmic reticulum-shaping proteins and regulates network formation.
GO:0005783 endoplasmic reticulum	IDA GO_REF:0000052	ACCEPT	Summary: HPA ER localization is consistent with the broader experimental literature. 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. Supporting Evidence: PMID:18270207 atlastin-2 and -3 are localized to the endoplasmic reticulum (ER)
GO:0003924 GTPase activity	EXP PMID:28602821 Timing and Reset Mechanism of GTP Hydrolysis-Driven Conforma...	ACCEPT	Summary: ATL3 GTPase activity is directly examined in structural and kinetic studies of the atlastin catalytic cycle. Reason: GTP hydrolysis is the enzymatic activity that powers ATL3 dimerization-cycle progression and membrane remodeling. Supporting Evidence: PMID:28602821 the data extend the mechanistic framework for how GTP hydrolysis drives conformational changes in ATL
GO:0003924 GTPase activity	EXP PMID:34546351 The hypervariable region of atlastin-1 is a site for intrins...	ACCEPT	Summary: ATL3 was included in comparative atlastin biochemical analyses supporting conserved GTPase activity. Reason: The study treats ATL3 as a catalytically active atlastin and reports ATL3 GTPase/tethering comparisons with ATL1. Supporting Evidence: PMID:34546351 The N-terminal, cytosol-facing portion of ATL, composed of the G and middle domains, constitutes the protein's catalytic core.
GO:0003924 GTPase activity	EXP PMID:37102997 Human atlastin-3 is a constitutive ER membrane fusion cataly...	ACCEPT	Summary: Direct ATL3 fusion work includes GTPase assays and GTP-dependent fusion requirements. Reason: ATL3 fusion is GTP dependent, and GTPase activity is part of the catalytic fusion mechanism. Supporting Evidence: PMID:37102997 ATL3 incorporated at a 1:1,000 M protein/lipid ratio catalyzed robust lipid mixing.
GO:0005789 endoplasmic reticulum membrane	EXP PMID:19665976 A class of dynamin-like GTPases involved in the generation o...	ACCEPT	Summary: Mammalian atlastins, including ATL3, localize predominantly to tubular ER membranes. Reason: The publication shows atlastins localize to tubular ER and interact with ER tubule-shaping proteins. Supporting Evidence: PMID:19665976 Similar results were obtained with Myc-ATL2 and Myc-ATL3
GO:0005789 endoplasmic reticulum membrane	EXP PMID:23969831 Protrudin binds atlastins and endoplasmic reticulum-shaping ...	ACCEPT	Summary: Protrudin-network work places ATL proteins in the tubular ER network. 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. Supporting Evidence: PMID:23969831 Protrudin binds atlastins and endoplasmic reticulum-shaping proteins and regulates network formation.
GO:0005789 endoplasmic reticulum membrane	EXP PMID:24459106 Sensory neuropathy with bone destruction due to a mutation i...	ACCEPT	Summary: Disease-variant work supports ATL3 as an ER-shaping protein at ER branch points. Reason: The wild-type ATL3 localization and mutant mislocalization/disruption support ER membrane localization. Supporting Evidence: PMID:24459106 ATL3 proteins are enriched in three-way junctions, branch points of the endoplasmic reticulum that connect membranous tubules to a continuous network.
GO:0005789 endoplasmic reticulum membrane	EXP PMID:25548161 Lunapark stabilizes nascent three-way junctions in the endop...	ACCEPT	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. Reason: The term is well supported for ATL3 by multiple other accessible references, but this specific abstract is not the strongest source for ATL3. Supporting Evidence: PMID:25548161 The endoplasmic reticulum (ER) consists of a polygonal network of sheets and tubules interconnected by three-way junctions.
GO:0005789 endoplasmic reticulum membrane	EXP PMID:27619977 Cooperation of the ER-shaping proteins atlastin, lunapark, a...	ACCEPT	Summary: ATL3 localization to ER tubule junctions supports ER membrane annotation. Reason: Tagged ATL3 localizes to ER three-way junctions and ATL function maintains the ER network. Supporting Evidence: PMID:27619977 wild type ATL-3 and ATL-2 localized in punctae at three-way junctions
GO:0005789 endoplasmic reticulum membrane	EXP PMID:37102997 Human atlastin-3 is a constitutive ER membrane fusion cataly...	ACCEPT	Summary: Direct ATL3 fusion/rescue study supports ATL3 as an ER membrane fusion catalyst. Reason: ATL3 is assayed as a membrane protein reconstituted into liposomes and as an ER network-maintenance factor in cells. Supporting Evidence: PMID:37102997 Purified protein (Fig. S1 A) was incorporated into synthetic liposomes
GO:0005789 endoplasmic reticulum membrane	IDA PMID:18270207 Atlastin GTPases are required for Golgi apparatus and ER mor...	ACCEPT	Summary: ATL2 and ATL3 were reported as ER-localized proteins. Reason: This is direct localization evidence for ATL3 at the ER membrane. Supporting Evidence: PMID:18270207 atlastin-2 and -3 are localized to the endoplasmic reticulum (ER)
GO:0016320 endoplasmic reticulum membrane fusion	IMP PMID:27619977 Cooperation of the ER-shaping proteins atlastin, lunapark, a...	ACCEPT	Summary: ATL function is required for ER network formation and maintenance, consistent with ER membrane fusion. Reason: Although the study is pan-atlastin and network-level, it supports the process that later ATL3-specific reconstitution confirms directly. Supporting Evidence: PMID:27619977 Connecting tubules into a network requires membrane fusion, which is mediated by membrane-anchored GTPases, the atlastins
GO:0016320 endoplasmic reticulum membrane fusion	IDA PMID:37102997 Human atlastin-3 is a constitutive ER membrane fusion cataly...	ACCEPT	Summary: Purified human ATL3 directly catalyzes membrane fusion. Reason: This is the strongest ATL3-specific evidence for ER membrane fusion. Supporting Evidence: PMID:37102997 purified human ATL3 catalyzes efficient membrane fusion in vitro and is sufficient to sustain the ER network in triple knockout cells.
GO:0098826 endoplasmic reticulum tubular network membrane	IDA PMID:37102997 Human atlastin-3 is a constitutive ER membrane fusion cataly...	ACCEPT	Summary: ATL3 fusogenic activity occurs on ER tubular network membranes. Reason: ATL3 restores and maintains ER network morphology as the sole atlastin source in triple-knockout cells. Supporting Evidence: PMID:37102997 ATL3 can restore and maintain a normal ER network.
GO:0140523 GTPase-dependent fusogenic activity	IDA PMID:37102997 Human atlastin-3 is a constitutive ER membrane fusion cataly...	ACCEPT	Summary: ATL3 has directly demonstrated GTP-dependent membrane fusogenic activity. Reason: This term is the best molecular-function description for ATL3 because it captures both GTPase dependence and membrane fusion activity. Supporting Evidence: PMID:37102997 purified human ATL3 catalyzes efficient membrane fusion in vitro
GO:1990809 endoplasmic reticulum tubular network membrane organization	IMP PMID:27619977 Cooperation of the ER-shaping proteins atlastin, lunapark, a...	ACCEPT	Summary: ATL activity is required for ER tubular network organization and maintenance. Reason: The term accurately reflects the cellular consequence of ATL3-family ER fusion activity. Supporting Evidence: PMID:27619977 ATL is needed to not only form, but also maintain, the ER network.
GO:1990809 endoplasmic reticulum tubular network membrane organization	IMP PMID:37102997 Human atlastin-3 is a constitutive ER membrane fusion cataly...	ACCEPT	Summary: ATL3-specific rescue of ATL knockout cells supports ER tubular network membrane organization. Reason: ATL3 is sufficient to restore a branched ER network, linking the molecular fusion activity to ER network organization. Supporting Evidence: PMID:37102997 ATL3 can restore and maintain a normal ER network.
GO:0098826 endoplasmic reticulum tubular network membrane	IDA PMID:27619977 Cooperation of the ER-shaping proteins atlastin, lunapark, a...	ACCEPT	Summary: ATL3 localizes at ER three-way junctions in the tubular network. Reason: The active site of ATL3 function is the ER tubular network membrane, especially tubule junctions. Supporting Evidence: PMID:27619977 wild type ATL-3 and ATL-2 localized in punctae at three-way junctions
GO:1990809 endoplasmic reticulum tubular network membrane organization	IMP PMID:18270207 Atlastin GTPases are required for Golgi apparatus and ER mor...	ACCEPT	Summary: Dominant-negative atlastin perturbation affects ER reticularization, supporting ATL3-family roles in ER network organization. Reason: The annotation is supported by the publication's ATL2/ATL3 localization and ER morphogenesis data, and is reinforced by later ATL3-specific work. Supporting Evidence: PMID:18270207 expression of SPG3A mutant or dominant-negative atlastin proteins lacking GTPase activity causes prominent inhibition of ER reticularization
GO:1990809 endoplasmic reticulum tubular network membrane organization	IMP PMID:19665976 A class of dynamin-like GTPases involved in the generation o...	ACCEPT	Summary: Atlastins are required for tubular ER network formation and interconnection. Reason: ATL3 belongs to the mammalian atlastin group tested for ER tubular network formation; later direct ATL3 experiments confirm the assignment. Supporting Evidence: PMID:19665976 The atlastins localize to the tubular ER and are required for proper network formation in vivo and in vitro.
GO:0005515 protein binding	IPI PMID:32075961 REEP5 depletion causes sarco-endoplasmic reticulum vacuoliza...	MARK AS OVER ANNOTATED	Summary: ATL3 is reported as an interactor in REEP5/SR-ER network biology, but protein binding is too generic for ATL3 molecular function. Reason: The physical interaction supports ER-shaping network context. It should not obscure the more specific ATL3 molecular function, GTPase-dependent fusogenic activity. Supporting Evidence: PMID:32075961 ER tubules are also stabilized by forming a characteristic polygonal network through membrane fusion mediated by the atlastin family of dynamin-related GTPases
GO:0098826 endoplasmic reticulum tubular network membrane	IDA PMID:25548161 Lunapark stabilizes nascent three-way junctions in the endop...	ACCEPT	Summary: The term is correct for ATL3, though the accessible cached abstract for this reference is not ATL3-specific. Reason: ATL3 localization to ER tubule junctions and ER tubular network membrane is supported by other accessible ATL3-specific references. Supporting Evidence: PMID:24459106 ATL3 proteins are enriched in three-way junctions, branch points of the endoplasmic reticulum that connect membranous tubules to a continuous network.
GO:0005515 protein binding	IPI PMID:23969831 Protrudin binds atlastins and endoplasmic reticulum-shaping ...	MARK AS OVER ANNOTATED	Summary: The duplicated GOA ZFYVE27/protrudin interaction row supports an interaction but not a useful molecular-function annotation. 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. Supporting Evidence: PMID:23969831 Protrudin binds atlastins and endoplasmic reticulum-shaping proteins and regulates network formation.
GO:0071782 endoplasmic reticulum tubular network	IDA PMID:23969831 Protrudin binds atlastins and endoplasmic reticulum-shaping ...	ACCEPT	Summary: ATL3 is located in the ER tubular network. Reason: The term is consistent with protrudin/atlastin ER network biology and with ATL3-specific junction localization in independent studies. Supporting Evidence: PMID:24459106 ATL3 proteins are enriched in three-way junctions, branch points of the endoplasmic reticulum that connect membranous tubules to a continuous network.
GO:0016020 membrane	HDA PMID:19946888 Defining the membrane proteome of NK cells.	MARK AS OVER ANNOTATED	Summary: High-throughput membrane proteomics is compatible with ATL3 being a membrane protein, but the term is very broad. Reason: ATL3 is specifically an ER membrane and ER tubular network membrane protein; the generic membrane term adds little beyond more precise accepted annotations. Supporting Evidence: PMID:19946888 The present study was initiated to define the composition of the membrane proteome of the Natural Killer (NK) like cell line YTS.
GO:0006888 endoplasmic reticulum to Golgi vesicle-mediated transport	IMP NOT PMID:18270207 Atlastin GTPases are required for Golgi apparatus and ER mor...	ACCEPT	Summary: The NOT annotation is supported: ATL perturbation did not generally block anterograde ER-to-Golgi trafficking in the VSVG-GFP assay. Reason: The negated annotation is important because ATL3's core role is ER morphology/fusion rather than general ER-to-Golgi vesicle-mediated transport. Supporting Evidence: PMID:18270207 secretory pathway trafficking as assessed using vesicular stomatitis virus G protein fused to green fluorescent protein (VSVG-GFP) as a reporter was essentially normal
GO:0042802 identical protein binding	IDA PMID:18270207 Atlastin GTPases are required for Golgi apparatus and ER mor...	ACCEPT	Summary: ATL3 homotypic interactions are part of the atlastin fusion mechanism. Reason: Identical protein binding is more informative than generic protein binding for ATL3 because trans homodimerization of atlastin molecules is mechanistically required for fusion. Supporting Evidence: PMID:37102997 GTP-binding induced GTPase (G) domain dimerization in trans

Core Functions

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:

GTPase-dependent fusogenic activity

Directly Involved In:

endoplasmic reticulum membrane fusion endoplasmic reticulum tubular network membrane organization

Cellular Locations:

endoplasmic reticulum tubular network membrane endoplasmic reticulum membrane

Supporting Evidence:

PMID:37102997
purified human ATL3 catalyzes efficient membrane fusion in vitro and is sufficient to sustain the ER network in triple knockout cells.
PMID:27619977
ATL is needed to not only form, but also maintain, the ER network.
file:human/ATL3/ATL3-deep-research-falcon.md
Atlastins are **large dynamin-like membrane GTPases** localized to the ER that catalyze **homotypic fusion of ER tubules**

References

GO_REF:0000002

Gene Ontology annotation through association of InterPro records with GO terms

GO_REF:0000033

Annotation inferences using phylogenetic trees

GO_REF:0000044

Gene Ontology annotation based on UniProtKB/Swiss-Prot Subcellular Location vocabulary mapping, accompanied by conservative changes to GO terms applied by UniProt

GO_REF:0000052

Gene Ontology annotation based on curation of immunofluorescence data

GO_REF:0000117

Electronic Gene Ontology annotations created by ARBA machine learning models

GO_REF:0000120

Combined Automated Annotation using Multiple IEA Methods

PMID:18270207

Atlastin GTPases are required for Golgi apparatus and ER morphogenesis.

ATL2 and ATL3 localize to the ER and atlastin GTPase-defective mutants disrupt ER reticularization, while general ER-to-Golgi trafficking remains essentially normal.

"atlastin-2 and -3 are localized to the endoplasmic reticulum (ER)"

PMID:19665976

A class of dynamin-like GTPases involved in the generation of the tubular ER network.

Mammalian atlastins are dynamin-like integral membrane GTPases that localize to tubular ER and support formation of the tubular ER network.

"mammalian atlastins, which are dynamin-like, integral membrane GTPases, interact with the tubule-shaping proteins"

PMID:19946888

Defining the membrane proteome of NK cells.

A broad high-throughput membrane proteomics study identified membrane-associated proteins; this supports only a generic membrane annotation for ATL3.

"The present study was initiated to define the composition of the membrane proteome of the Natural Killer (NK) like cell line YTS."

PMID:23969831

Protrudin binds atlastins and endoplasmic reticulum-shaping proteins and regulates network formation.

Protrudin/ZFYVE27 binds atlastins and other tubular ER network proteins, supporting an interaction annotation but not a specific molecular activity for ATL3.

"Protrudin binds atlastins and endoplasmic reticulum-shaping proteins and regulates network formation."

PMID:24459106

Sensory neuropathy with bone destruction due to a mutation in the membrane-shaping atlastin GTPase 3.

ATL3 is an ER-shaping GTPase enriched at three-way junctions, and the HSN1F variant disrupts tubular ER structure.

"ATL3 proteins are enriched in three-way junctions, branch points of the endoplasmic reticulum that connect membranous tubules to a continuous network."

PMID:25548161

Lunapark stabilizes nascent three-way junctions in the endoplasmic reticulum.

Lunapark work supports the three-way-junction context of the ER tubular network, but the accessible cached abstract is not ATL3-specific.

"The endoplasmic reticulum (ER) consists of a polygonal network of sheets and tubules interconnected by three-way junctions."

PMID:27619977

Cooperation of the ER-shaping proteins atlastin, lunapark, and reticulons to generate a tubular membrane network.

ATL proteins, including ATL3 in mammalian cells, are needed for formation and maintenance of the tubular ER network.

"ATL is needed to not only form, but also maintain, the ER network."

PMID:28602821

Timing and Reset Mechanism of GTP Hydrolysis-Driven Conformational Changes of Atlastin.

Structural and kinetic work on ATL1 and ATL3 supports ATL3 GTPase activity and nucleotide-dependent dimerization during the atlastin catalytic cycle.

"we identify discrete temporal steps in the catalytic cycle for the two most dissimilar isoforms, ATL1 and ATL3"

PMID:32075961

REEP5 depletion causes sarco-endoplasmic reticulum vacuolization and cardiac functional defects.

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.

"ER tubules are also stabilized by forming a characteristic polygonal network through membrane fusion mediated by the atlastin family of dynamin-related GTPases"

PMID:34546351

The hypervariable region of atlastin-1 is a site for intrinsic and extrinsic regulation.

Atlastin proteins catalyze homotypic peripheral ER tubule fusion, and the study includes ATL3 structural/biochemical comparisons.

"Atlastin (ATL) GTPases catalyze homotypic membrane fusion of the peripheral endoplasmic reticulum (ER)."

PMID:37102997

Human atlastin-3 is a constitutive ER membrane fusion catalyst.

Purified human ATL3 directly catalyzes GTP-dependent membrane fusion and can sustain ER network structure in ATL knockout cells.

"purified human ATL3 catalyzes efficient membrane fusion in vitro and is sufficient to sustain the ER network in triple knockout cells."

file:human/ATL3/ATL3-notes.md

ATL3 review notes for Proteostasis PN batch

The PN reticulophagy projection for ATL3 was reviewed conservatively and was not promoted to a proposed GO annotation.

file:human/ATL3/ATL3-deep-research-falcon.md

Falcon deep research report on ATL3

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.

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

Proteostasis Network projected annotations report

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.

Suggested Experiments

Experiment: 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.

Hypothesis: If ATL3 is a direct reticulophagy receptor, autophagy-receptor mutants should impair ER turnover independently of their effect on GTPase-dependent ER fusion.

Type: cell-based reticulophagy reporter rescue

Experiment: 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.

Hypothesis: ATL3's core activity is membrane fusion; a direct receptor role would require separable ATG8-family recruitment activity.

Type: biochemical membrane reconstitution

Deep Research

Falcon

(ATL3-deep-research-falcon.md)

this with annotations you find in gene/protein databases, but these can be outdated or inaccurate. Falcon Edison Scientific Literature 36 citations 1 artifacts 2026-06-03T12:46:22.465212

Edison artifact artifact-00 (text/markdown)

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

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

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

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

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

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

Research Report: Human ATL3 / Atlastin-3 (UniProt: Q6DD88) — Functional Annotation

0) Target verification (gene/protein disambiguation)

The symbol ATL3 in the retrieved scientific literature refers to human atlastin GTPase 3 (atlastin-3), a member of the atlastin family of ER-resident dynamin-like GTPases that shape the tubular endoplasmic reticulum (ER) network via homotypic ER membrane fusion. Humans encode three paralogs (ATL1–ATL3) with differences in expression patterns and disease associations. (greco2024decipheringtherole pages 22-26, arias2025precisionmedicinefor pages 99-103, zlamalova2024atlastin1regulatesendosomal pages 1-2)

1) Key concepts and definitions (current understanding)

1.1 Atlastins and ER network formation

Atlastins are large dynamin-like membrane GTPases localized to the ER that catalyze homotypic fusion of ER tubules and thereby generate/maintain the polygonal ER network and three-way junctions. (zlamalova2024atlastin1regulatesendosomal pages 1-2, pletan2023theatlastiner pages 2-6)

ATL3 specifically is discussed as an ER reshaping factor enriched in tubular ER/three-way junction regions, consistent with a role in network branching and dynamics. (arias2025precisionmedicinefor pages 99-103)

1.2 Biochemical activity (enzyme reaction and substrate specificity)

ATL3 is a GTPase: it binds and hydrolyzes GTP (substrate), and atlastin-family GTPase activity is required for their ER membrane fusion function. In a direct ATL3 functional context, GTPase-defective ATL3 mutants fail to rescue ATL3-dependent phenotypes, supporting that ATL3’s enzymatic cycle is required in cells. (pletan2023theatlastiner pages 2-6, pletan2023theatlastiner pages 6-9)

1.3 ER-phagy (reticulophagy) and receptor logic

ER-phagy is selective autophagy of ER subdomains. Multiple reviews classify ATL3 as an ER-phagy receptor (or receptor-like factor) that preferentially targets tubular ER for degradation and connects ER membranes to ATG8-family proteins via interaction motifs. (hubner2020erphagyandhuman pages 1-2, hubner2020erphagyandhuman pages 2-4, hill2023er‐phagyinneurodegeneration pages 2-2)

A key ATL3-specific concept is its selective binding to the ATG8-family subfamily GABARAP through GABARAP-interaction motifs (GIMs), reported as two GIMs in the N-terminal cytosolic region, with selectivity for GABARAP rather than LC3 in cited work. (hill2023er‐phagyinneurodegeneration pages 5-5)

2) Recent developments and latest research (prioritize 2023–2024)

2.1 2024: Single-molecule mechanism of atlastin-mediated ER fusion (family-mechanistic framework)

A major 2024 advance used single-molecule FRET (smFRET) and molecular dynamics to dissect nucleotide-dependent conformational transitions in human atlastin cytosolic domains (performed on ATL1 as an atlastin-family model). The study supports a refined mechanism:

GTP binding promotes formation of a “loose crossover dimer” (Form 2-like). (shi2024dissectingthemechanism pages 1-2, shi2024dissectingthemechanism pages 3-4, shi2024dissectingthemechanism pages 4-5)
The GTP hydrolysis transition state drives tightening into a “tight crossover dimer” (Form 3-like), consistent with force generation for membrane fusion. (shi2024dissectingthemechanism pages 4-5, shi2024dissectingthemechanism pages 8-9)
Pi release favors dimer disassembly and increased flexibility; GDP dissociation resets the monomeric conformational preferences for a new cycle. (shi2024dissectingthemechanism pages 1-2, shi2024dissectingthemechanism pages 8-9, shi2024dissectingthemechanism pages 9-10)
A membrane-embedded α-helical element between the cytosolic helical bundle and transmembrane region self-associates and is required for atlastin function, providing a coupling element between cytosolic rearrangements and the bilayer. (shi2024dissectingthemechanism pages 1-2, shi2024dissectingthemechanism pages 8-9)

Quantitatively, crossover dimer smFRET populations were reported around ~0.28 (loose) and ~0.66 (tight) under specific nucleotide conditions, and monomeric state centers were also mapped (e.g., ~0.18, ~0.41, ~0.63, ~0.83). (shi2024dissectingthemechanism pages 4-5, shi2024dissectingthemechanism pages 8-9)

Although these experiments are on ATL1, they represent the current high-resolution mechanistic model for atlastin-family fusion, which is widely used to interpret paralogs including ATL3. (shi2024dissectingthemechanism pages 1-2, shi2024dissectingthemechanism pages 9-10)

Source details: Shi et al., Nature Communications (published Mar 2024). DOI/URL: https://doi.org/10.1038/s41467-024-46919-z (shi2024dissectingthemechanism pages 1-2)

2.2 2023: ATL3 as a host factor in non-enveloped virus entry (SV40)

A 2023 primary study demonstrated that ATL3 and ATL2 are required for formation of SV40-induced ER “escape” foci (ER-foci), but with distinct roles: ATL3 relocalizes to ER-foci and uses its GTPase-dependent fusion activity to promote multi-tubular ER junctions within these sites. (pletan2023theatlastiner pages 1-2)

ATL3 showed strong spatial association with ER-foci markers: approximately 75% of Bap31+ foci colocalized with ATL3 foci. (pletan2023theatlastiner pages 6-9)

Mechanistically, ATL3 was found to engage components of an ER membrane penetration complex, including interactions with ER morphogenic proteins Lunapark (LNP) and reticulon RTN4B, and in infected extracts was detected in complexes containing viral structural protein VP1. (pletan2023theatlastiner pages 1-2, pletan2023theatlastiner pages 6-9)

Functionally, siRNA knockdown of ATL3 reduced infection and could be rescued by siRNA-resistant ATL3, but not by a GTPase-defective ATL3 (K47A), demonstrating the requirement for ATL3’s enzymatic activity in this ER remodeling pathway. (pletan2023theatlastiner pages 2-6, pletan2023theatlastiner pages 6-9)

Source details: Pletan et al., Journal of Virology (published Aug 2023). DOI/URL: https://doi.org/10.1128/jvi.00756-23 (pletan2023theatlastiner pages 2-6)

2.3 2023: Coronavirus subversion of ER-phagy via ATL3

A 2023 Cell Reports study reported that a SARS-CoV-2 protein (ORF8) forms condensates with p62 and can hijack ATL3 (and FAM134B) into ORF8/p62 liquid droplets. This sequestration is reported to inhibit ER-phagy, promote ER stress, and facilitate viral replication/replication-organelle (DMV) formation. (tan2023coronavirussubvertserphagy pages 1-4)

Source details: Tan et al., Cell Reports (published Apr 2023). DOI/URL: https://doi.org/10.1016/j.celrep.2023.112286 (tan2023coronavirussubvertserphagy pages 1-4)

3) Current applications and real-world implementations

3.1 Cell biology: manipulating ER morphology and junction architecture

ATL3 is operationally used in cell biology as an ER-shaping GTPase whose perturbation (knockdown, mutant expression) informs how ER three-way junction formation and tubular ER remodeling are controlled by the GTPase cycle and membrane-coupling helices. The SV40 ER-foci work provides an example where ATL3-dependent remodeling creates multi-tubular junctions functioning as a membrane penetration platform. (pletan2023theatlastiner pages 1-2, pletan2023theatlastiner pages 6-9)

3.2 Autophagy research: tubular ER quality control (ER-phagy)

ATL3 is widely cited as a tubular ER-phagy receptor (or ER-phagy factor) and is used to study how ER tubules are selected for autophagic turnover under nutrient stress and other conditions, including selective engagement of GABARAP via GIMs. (hill2023er‐phagyinneurodegeneration pages 5-5, hubner2020erphagyandhuman pages 1-2, hubner2020erphagyandhuman pages 2-4)

3.3 Infection biology: host factor dependencies

Both SV40 and SARS-CoV-2 studies position ATL3 as a host factor impacting infection: (i) constructing ER penetration sites (SV40) via GTPase-dependent remodeling, and (ii) being targeted by viral proteins to suppress ER-phagy (SARS-CoV-2 ORF8). (pletan2023theatlastiner pages 1-2, tan2023coronavirussubvertserphagy pages 1-4)

3.4 Clinical genetics: rare neuropathy diagnostics

ATL3 is implemented as a candidate gene in genetic testing and mechanistic follow-up for inherited neuropathies. Open Targets lists ATL3 associations with hereditary sensory neuropathy type 1F (HSAN1F) and axonal Charcot–Marie–Tooth disease type 2N, supporting its clinical relevance in rare disease genetics. (OpenTargets Search: -ATL3)

4) Expert opinions and analysis (authoritative synthesis)

4.1 ATL3 functional partitioning: fusion vs turnover

A 2023 review focused on ER-phagy in neurodegeneration summarizes the view that while atlastins are ER fusogens, ATL3 may be relatively more involved in ER turnover, citing evidence that ATL3 promotes tubular ER degradation upon starvation and binds GABARAP via two GIMs (selective vs LC3). (hill2023er‐phagyinneurodegeneration pages 5-5)

This “functional partitioning” model provides a coherent reconciliation of ATL3’s dual roles: a constitutive ER-shaping GTPase that can also act as an adaptor/receptor in ER-phagy pathways, potentially tuned by motif composition and paralog-specific activities. (hill2023er‐phagyinneurodegeneration pages 5-5, hubner2020erphagyandhuman pages 2-4)

4.2 Paralog complexity

Evidence comparing paralogs indicates isoform-specific expression and phenotypic associations (e.g., ATL1 primarily CNS-enriched; ATL2/ATL3 more peripheral), with distinct disease spectra and potentially distinct mechanistic vulnerabilities within the shared atlastin fusion cycle. (greco2024decipheringtherole pages 22-26, arias2025precisionmedicinefor pages 99-103)

5) Relevant statistics and data (recent studies)

5.1 Quantitative cell biology (SV40 ER-foci)

During SV40 infection, ~75% of Bap31+ ER foci colocalize with ATL3, supporting strong ATL3 recruitment to penetration sites; rescue experiments and other quantifications were reported as mean ± SD across three independent experiments with standard significance thresholds (e.g., P ≤ 0.01; *P ≤ 0.001). (pletan2023theatlastiner pages 6-9)

5.2 Quantitative ER–mitochondria contacts in an ATL3-variant study

In patient fibroblasts carrying a heterozygous ATL3 p.Gln170Glu variant (GTPase/globular domain), ER–mitochondria contacts measured by proximity ligation assay (IP3R–VDAC) were markedly reduced: 21.5 ± 2.5 and 24.8 ± 3.1 dots/cell in two variant carriers versus 118.2 ± 7.7 (father) and 103.5 ± 6.0 (control). (arias2025precisionmedicinefor pages 107-112)

5.3 Quantitative mechanistic biophysics (atlastin fusion cycle)

smFRET analysis of atlastin-family conformational states provides quantitative markers for mechanistic modeling: loose vs tight crossover dimer populations at approximately ~0.28 and ~0.66 FRET under defined nucleotide conditions, and multiple monomeric conformational states with nucleotide-dependent occupancy. (shi2024dissectingthemechanism pages 4-5, shi2024dissectingthemechanism pages 8-9)

6) Summary table (evidence map)

The following table consolidates ATL3’s functional annotation, mechanisms, disease links, and key recent sources.

Category	Key points	Key recent sources (with year, journal, DOI URL)
Identity/domains	ATL3 in this report corresponds to human atlastin GTPase 3, an ER-resident dynamin-like large GTPase/atlastin-family protein. Reported architecture includes an N-terminal GTPase domain, a stalk/3-helix bundle, and a C-terminal transmembrane region with membrane-associated helical elements; ATL3 is preferentially associated with ER three-way junctions/tubular ER and differs from ATL1/ATL2 by broader non-CNS expression and distinct disease associations (greco2024decipheringtherole pages 22-26, arias2025precisionmedicinefor pages 99-103, zlamalova2024atlastin1regulatesendosomal pages 1-2).	Arias 2025, unknown journal, n/a; Greco 2024, unknown journal, n/a; Zlamalova et al. 2024, Neurobiology of Disease, https://doi.org/10.1016/j.nbd.2024.106556
Biochemical activity	ATL3 is a membrane-fusion GTPase that uses GTP as substrate; atlastin-family GTPase activity is required for homotypic ER membrane fusion and generation of ER three-way junctions. In ATL3-specific experiments, GTPase-defective ATL3 mutants fail to rescue functional phenotypes, supporting that ATL3’s enzymatic GTPase activity is required for its ER-remodeling function (pletan2023theatlastiner pages 2-6, pletan2023theatlastiner pages 1-2).	Pletan et al. 2023, Journal of Virology, https://doi.org/10.1128/jvi.00756-23
Mechanism of ER fusion	Recent single-molecule work on human atlastin mechanism (performed on ATL1 cytosolic domain, used here as family-mechanistic context) supports a cycle in which GTP binding promotes a loose crossover dimer, GTP hydrolysis tightens the 3HB interface to drive fusion, and Pi/GDP release resets the protein. A membrane-embedded helix between the 3HB and transmembrane region self-associates and is required for fusion; small sequence differences between paralogs can tune this cycle and are relevant to ATL3 interpretation (shi2024dissectingthemechanism pages 1-2, shi2024dissectingthemechanism pages 3-4, shi2024dissectingthemechanism pages 4-5, shi2024dissectingthemechanism pages 8-9, shi2024dissectingthemechanism pages 9-10).	Shi et al. 2024, Nature Communications, https://doi.org/10.1038/s41467-024-46919-z
ER-phagy role	ATL3 is described as a tubular-ER ER-phagy/reticulophagy receptor or receptor-like factor. Reviews and cited primary work indicate ATL3 promotes degradation of tubular ER during starvation, preferentially targets ER tubules, and contains two GIM motifs in its N-terminal cytosolic region that mediate selective binding to GABARAP rather than LC3, linking tubular ER to the autophagy machinery (hill2023er‐phagyinneurodegeneration pages 5-5, hubner2020erphagyandhuman pages 1-2, hubner2020erphagyandhuman pages 2-4, hill2023er‐phagyinneurodegeneration pages 2-2, yang2026erphagyreceptorsstructural pages 2-4).	Hill et al. 2023, Journal of Neuroscience Research, https://doi.org/10.1002/jnr.25225; Hübner & Dikic 2020, Cell Death & Differentiation, https://doi.org/10.1038/s41418-019-0444-0; Yang & Sheng 2026, Acta Pharmacologica Sinica, https://doi.org/10.1038/s41401-025-01724-2
Viral infection role	ATL3 has emerging infection-related functions in ER remodeling. During SV40 entry, ATL3 relocalizes to ER foci, forms complexes with LNP/RTN4B and virus-containing penetration machinery, and uses GTPase-dependent fusion activity to help build multi-tubular ER junctions needed for membrane penetration. In coronavirus studies, ATL3 is also reported as an ER-phagy receptor hijacked into ORF8/p62 condensates, suppressing ER-phagy and favoring viral replication/DMV formation (pletan2023theatlastiner pages 2-6, pletan2023theatlastiner pages 1-2, tan2023coronavirussubvertserphagy pages 1-4, pletan2023theatlastiner pages 6-9).	Pletan et al. 2023, Journal of Virology, https://doi.org/10.1128/jvi.00756-23; Tan et al. 2023, Cell Reports, https://doi.org/10.1016/j.celrep.2023.112286
Disease associations	ATL3 is linked to inherited neuropathies, especially hereditary sensory and autonomic neuropathy type 1F and Charcot-Marie-Tooth disease axonal type 2N in target-disease databases. Human genetic/functional studies also support ATL3 variants causing sensory neuropathy and expanding phenotypes to motor axonopathy; disease-associated variants affect the GTPase/globular domain or later steps of the fusion cycle, with downstream effects on ER architecture, ER-mitochondria contacts, Golgi morphology, and autophagic flux (OpenTargets Search: -ATL3, arias2025precisionmedicinefor pages 93-99, arias2025precisionmedicinefor pages 112-116, arias2025precisionmedicinefor pages 116-120, arias2025precisionmedicinefor pages 107-112).	Open Targets, ATL3 associations, context pqac-00000000; Arias 2025, unknown journal, n/a
Quantitative data	Recent quantitative findings include: in ATL1 family-mechanistic smFRET experiments, crossover dimer states were centered around ~0.28 and ~0.66 FRET, with monomeric states around ~0.18, ~0.41, ~0.63, and ~0.83 depending on nucleotide state; in SV40 studies, ~75% of Bap31+ ER foci colocalized with ATL3 foci, and ATL3 rescue experiments were analyzed over 3 independent experiments with P ≤ 0.01 or *P ≤ 0.001; in ATL3 p.Gln170Glu patient fibroblasts, ER-mitochondria contact sites were reduced to 21.5 ± 2.5 and 24.8 ± 3.1 dots/cell versus 118.2 ± 7.7 and 103.5 ± 6.0 in controls/father (shi2024dissectingthemechanism pages 4-5, shi2024dissectingthemechanism pages 8-9, pletan2023theatlastiner pages 6-9, arias2025precisionmedicinefor pages 107-112).	Shi et al. 2024, Nature Communications, https://doi.org/10.1038/s41467-024-46919-z; Pletan et al. 2023, Journal of Virology, https://doi.org/10.1128/jvi.00756-23; Arias 2025, unknown journal, n/a

Table: This table summarizes the current functional annotation of human ATL3, including identity, biochemical activity, ER fusion mechanism, ER-phagy, infection-related roles, disease links, and selected quantitative findings. It is useful as a compact evidence map with direct source and context-ID support.

7) Limitations of this report (evidence boundaries)

Several mechanistic details of the GTPase cycle are derived from 2024 single-molecule experiments performed on ATL1 (family model), and are used here as the best available high-resolution mechanistic framework for atlastins, rather than as direct ATL3-only measurements. (shi2024dissectingthemechanism pages 1-2, shi2024dissectingthemechanism pages 9-10)
Some newer ER-phagy receptor mechanistic reviews were retrieved (including 2026), but the most direct primary quantitative data extracted here are from 2023–2024 infection studies and a quantitative patient-fibroblast phenotype study. (tan2023coronavirussubvertserphagy pages 1-4, pletan2023theatlastiner pages 6-9, arias2025precisionmedicinefor pages 107-112)

References (URLs and publication months/years)

Shi L. et al. Mar 2024. Nature Communications. “Dissecting the mechanism of atlastin-mediated homotypic membrane fusion at the single-molecule level.” https://doi.org/10.1038/s41467-024-46919-z (shi2024dissectingthemechanism pages 1-2)
Pletan M. et al. Aug 2023. Journal of Virology. “The atlastin ER morphogenic proteins promote formation of a membrane penetration site during non-enveloped virus entry.” https://doi.org/10.1128/jvi.00756-23 (pletan2023theatlastiner pages 2-6)
Tan X. et al. Apr 2023. Cell Reports. “Coronavirus subverts ER-phagy by hijacking FAM134B and ATL3 into p62 condensates to facilitate viral replication.” https://doi.org/10.1016/j.celrep.2023.112286 (tan2023coronavirussubvertserphagy pages 1-4)
Hill M.A. et al. Jun 2023. Journal of Neuroscience Research. “ER-phagy in neurodegeneration.” https://doi.org/10.1002/jnr.25225 (hill2023er‐phagyinneurodegeneration pages 5-5)
Hübner C.A., Dikic I. Oct 2020. Cell Death & Differentiation. “ER-phagy and human diseases.” https://doi.org/10.1038/s41418-019-0444-0 (hubner2020erphagyandhuman pages 1-2)
Open Targets Platform (disease-target associations for ATL3; accessed via tool context). (OpenTargets Search: -ATL3)

References

(greco2024decipheringtherole pages 22-26): F Greco. Deciphering the role of bmp signalling pathway in hereditary spastic paraplegia: identification of a novel therapeutic approach in zebrafish knockout models for …. Unknown journal, 2024.
(arias2025precisionmedicinefor pages 99-103): B Estévez Arias. Precision medicine for rare neuromuscular diseases: clinical, genetic and pathophysiological studies. Unknown journal, 2025.
(zlamalova2024atlastin1regulatesendosomal pages 1-2): Eliska Zlamalova, Catherine Rodger, Francesca Greco, Julia Kleniuk, Aishwarya G. Nadadhur, Zuzana Kadlecova, and Evan Reid. Atlastin-1 regulates endosomal tubulation and lysosomal proteolysis in human cortical neurons. Neurobiology of Disease, Feb 2024. URL: https://doi.org/10.1016/j.nbd.2024.106556, doi:10.1016/j.nbd.2024.106556. This article has 3 citations and is from a domain leading peer-reviewed journal.
(pletan2023theatlastiner pages 2-6): Madison Pletan, Xiaofang Liu, Grace Cha, Yu-Jie Chen, Jeffrey Knupp, and Billy Tsai. The atlastin er morphogenic proteins promote formation of a membrane penetration site during non-enveloped virus entry. Journal of Virology, Aug 2023. URL: https://doi.org/10.1128/jvi.00756-23, doi:10.1128/jvi.00756-23. This article has 5 citations and is from a domain leading peer-reviewed journal.
(pletan2023theatlastiner pages 6-9): Madison Pletan, Xiaofang Liu, Grace Cha, Yu-Jie Chen, Jeffrey Knupp, and Billy Tsai. The atlastin er morphogenic proteins promote formation of a membrane penetration site during non-enveloped virus entry. Journal of Virology, Aug 2023. URL: https://doi.org/10.1128/jvi.00756-23, doi:10.1128/jvi.00756-23. This article has 5 citations and is from a domain leading peer-reviewed journal.
(hubner2020erphagyandhuman pages 1-2): Christian A. Hübner and Ivan Dikic. Er-phagy and human diseases. Cell Death & Differentiation, 27:833-842, Oct 2020. URL: https://doi.org/10.1038/s41418-019-0444-0, doi:10.1038/s41418-019-0444-0. This article has 152 citations and is from a domain leading peer-reviewed journal.
(hubner2020erphagyandhuman pages 2-4): Christian A. Hübner and Ivan Dikic. Er-phagy and human diseases. Cell Death & Differentiation, 27:833-842, Oct 2020. URL: https://doi.org/10.1038/s41418-019-0444-0, doi:10.1038/s41418-019-0444-0. This article has 152 citations and is from a domain leading peer-reviewed journal.
(hill2023er‐phagyinneurodegeneration pages 2-2): Melissa A. Hill, Alex M. Sykes, and George D. Mellick. Er‐phagy in neurodegeneration. Journal of Neuroscience Research, 101:1611-1623, Jun 2023. URL: https://doi.org/10.1002/jnr.25225, doi:10.1002/jnr.25225. This article has 23 citations and is from a peer-reviewed journal.
(hill2023er‐phagyinneurodegeneration pages 5-5): Melissa A. Hill, Alex M. Sykes, and George D. Mellick. Er‐phagy in neurodegeneration. Journal of Neuroscience Research, 101:1611-1623, Jun 2023. URL: https://doi.org/10.1002/jnr.25225, doi:10.1002/jnr.25225. This article has 23 citations and is from a peer-reviewed journal.
(shi2024dissectingthemechanism pages 1-2): Lijun Shi, Chenguang Yang, Mingyuan Zhang, Kangning Li, Keying Wang, Li Jiao, Ruming Liu, Yunyun Wang, Ming Li, Yong Wang, Lu Ma, Shuxin Hu, and Xin Bian. Dissecting the mechanism of atlastin-mediated homotypic membrane fusion at the single-molecule level. Nature Communications, Mar 2024. URL: https://doi.org/10.1038/s41467-024-46919-z, doi:10.1038/s41467-024-46919-z. This article has 12 citations and is from a highest quality peer-reviewed journal.
(shi2024dissectingthemechanism pages 3-4): Lijun Shi, Chenguang Yang, Mingyuan Zhang, Kangning Li, Keying Wang, Li Jiao, Ruming Liu, Yunyun Wang, Ming Li, Yong Wang, Lu Ma, Shuxin Hu, and Xin Bian. Dissecting the mechanism of atlastin-mediated homotypic membrane fusion at the single-molecule level. Nature Communications, Mar 2024. URL: https://doi.org/10.1038/s41467-024-46919-z, doi:10.1038/s41467-024-46919-z. This article has 12 citations and is from a highest quality peer-reviewed journal.
(shi2024dissectingthemechanism pages 4-5): Lijun Shi, Chenguang Yang, Mingyuan Zhang, Kangning Li, Keying Wang, Li Jiao, Ruming Liu, Yunyun Wang, Ming Li, Yong Wang, Lu Ma, Shuxin Hu, and Xin Bian. Dissecting the mechanism of atlastin-mediated homotypic membrane fusion at the single-molecule level. Nature Communications, Mar 2024. URL: https://doi.org/10.1038/s41467-024-46919-z, doi:10.1038/s41467-024-46919-z. This article has 12 citations and is from a highest quality peer-reviewed journal.
(shi2024dissectingthemechanism pages 8-9): Lijun Shi, Chenguang Yang, Mingyuan Zhang, Kangning Li, Keying Wang, Li Jiao, Ruming Liu, Yunyun Wang, Ming Li, Yong Wang, Lu Ma, Shuxin Hu, and Xin Bian. Dissecting the mechanism of atlastin-mediated homotypic membrane fusion at the single-molecule level. Nature Communications, Mar 2024. URL: https://doi.org/10.1038/s41467-024-46919-z, doi:10.1038/s41467-024-46919-z. This article has 12 citations and is from a highest quality peer-reviewed journal.
(shi2024dissectingthemechanism pages 9-10): Lijun Shi, Chenguang Yang, Mingyuan Zhang, Kangning Li, Keying Wang, Li Jiao, Ruming Liu, Yunyun Wang, Ming Li, Yong Wang, Lu Ma, Shuxin Hu, and Xin Bian. Dissecting the mechanism of atlastin-mediated homotypic membrane fusion at the single-molecule level. Nature Communications, Mar 2024. URL: https://doi.org/10.1038/s41467-024-46919-z, doi:10.1038/s41467-024-46919-z. This article has 12 citations and is from a highest quality peer-reviewed journal.
(pletan2023theatlastiner pages 1-2): Madison Pletan, Xiaofang Liu, Grace Cha, Yu-Jie Chen, Jeffrey Knupp, and Billy Tsai. The atlastin er morphogenic proteins promote formation of a membrane penetration site during non-enveloped virus entry. Journal of Virology, Aug 2023. URL: https://doi.org/10.1128/jvi.00756-23, doi:10.1128/jvi.00756-23. This article has 5 citations and is from a domain leading peer-reviewed journal.
(tan2023coronavirussubvertserphagy pages 1-4): Xuan Tan, Kun Cai, Jiajia Li, Zhen Yuan, Ruifeng Chen, Hurong Xiao, Chuanrui Xu, Bing Hu, Yali Qin, and Binbin Ding. Coronavirus subverts er-phagy by hijacking fam134b and atl3 into p62 condensates to facilitate viral replication. Cell Reports, 42:112286, Apr 2023. URL: https://doi.org/10.1016/j.celrep.2023.112286, doi:10.1016/j.celrep.2023.112286. This article has 60 citations and is from a highest quality peer-reviewed journal.
(OpenTargets Search: -ATL3): Open Targets Query (-ATL3, 8 results). Buniello, A. et al. (2025). Open Targets Platform: facilitating therapeutic hypotheses building in drug discovery. Nucleic Acids Research.
(arias2025precisionmedicinefor pages 107-112): B Estévez Arias. Precision medicine for rare neuromuscular diseases: clinical, genetic and pathophysiological studies. Unknown journal, 2025.
(yang2026erphagyreceptorsstructural pages 2-4): Wen-Jing Yang and Rui Sheng. Er-phagy receptors: structural mechanisms in selective er degradation and disease implications. Acta Pharmacologica Sinica, 47(6):1385-1400, Jan 2026. URL: https://doi.org/10.1038/s41401-025-01724-2, doi:10.1038/s41401-025-01724-2. This article has 0 citations and is from a peer-reviewed journal.
(arias2025precisionmedicinefor pages 93-99): B Estévez Arias. Precision medicine for rare neuromuscular diseases: clinical, genetic and pathophysiological studies. Unknown journal, 2025.
(arias2025precisionmedicinefor pages 112-116): B Estévez Arias. Precision medicine for rare neuromuscular diseases: clinical, genetic and pathophysiological studies. Unknown journal, 2025.
(arias2025precisionmedicinefor pages 116-120): B Estévez Arias. Precision medicine for rare neuromuscular diseases: clinical, genetic and pathophysiological studies. Unknown journal, 2025.

Artifacts

Edison artifact artifact-00

Citations

arias2025precisionmedicinefor pages 99-103
shi2024dissectingthemechanism pages 1-2
pletan2023theatlastiner pages 1-2
pletan2023theatlastiner pages 6-9
pletan2023theatlastiner pages 2-6
tan2023coronavirussubvertserphagy pages 1-4
arias2025precisionmedicinefor pages 107-112
hubner2020erphagyandhuman pages 1-2
greco2024decipheringtherole pages 22-26
hubner2020erphagyandhuman pages 2-4
shi2024dissectingthemechanism pages 3-4
shi2024dissectingthemechanism pages 4-5
shi2024dissectingthemechanism pages 8-9
shi2024dissectingthemechanism pages 9-10
yang2026erphagyreceptorsstructural pages 2-4
arias2025precisionmedicinefor pages 93-99
arias2025precisionmedicinefor pages 112-116
arias2025precisionmedicinefor pages 116-120
https://doi.org/10.1038/s41467-024-46919-z
https://doi.org/10.1128/jvi.00756-23
https://doi.org/10.1016/j.celrep.2023.112286
https://doi.org/10.1016/j.nbd.2024.106556
https://doi.org/10.1002/jnr.25225;
https://doi.org/10.1038/s41418-019-0444-0;
https://doi.org/10.1038/s41401-025-01724-2
https://doi.org/10.1128/jvi.00756-23;
https://doi.org/10.1038/s41467-024-46919-z;
https://doi.org/10.1002/jnr.25225
https://doi.org/10.1038/s41418-019-0444-0
https://doi.org/10.1016/j.nbd.2024.106556,
https://doi.org/10.1128/jvi.00756-23,
https://doi.org/10.1038/s41418-019-0444-0,
https://doi.org/10.1002/jnr.25225,
https://doi.org/10.1038/s41467-024-46919-z,
https://doi.org/10.1016/j.celrep.2023.112286,
https://doi.org/10.1038/s41401-025-01724-2,

📚 Additional Documentation

Notes

(ATL3-notes.md)

ATL3 notes

Review summary

ATL3 is best supported as an ER membrane atlastin GTPase whose core role is
GTP-dependent homotypic ER membrane fusion and maintenance of the branched tubular
ER network. The strongest ATL3-specific source is Bryce et al. 2023, which reports
that "purified human ATL3 catalyzes efficient membrane fusion in vitro and is
sufficient to sustain the ER network in triple knockout cells" PMID:37102997.
Earlier ER-shaping work supports the shared atlastin role: "ATL is needed to not
only form, but also maintain, the ER network" PMID:27619977. Disease genetics
also points to ER morphology, with ATL3 enriched at ER branch points and the
p.Tyr192Cys variant disrupting tubular ER structure PMID:24459106.

PN proteostasis projection

The local Proteostasis Network projection reports an ATL3 candidate addition to
GO:0061709 reticulophagy from the PN path
Autophagy-Lysosome Pathway|Autophagy substrate selection|Selective autophagy receptor|ERphagy
[file:projects/PROTEOSTASIS/reports/pn_projection/pn_projected_annotations.tsv
"ATL3 ... GO:0061709 reticulophagy ... new_to_goa"]. I reviewed this conservatively.
The seeded GOA and accessible primary sources support ER membrane fusion and ER
tubular network organization, not a direct GO reticulophagy annotation.

Bryce et al. 2023 explicitly frames the autophagy literature as unsettled context
rather than the main demonstrated activity: ATL3 "has been identified as a possible
ER-autophagy receptor that interacts with GABARAP proteins" and the authors add
that "Some of these diverse roles could stem from a primary role for ATL3 in ER
structural maintenance, but they could also indicate one or more ATL3 functions
outside of membrane fusion" PMID:37102997. Therefore I did not add reticulophagy
as a proposed GO annotation. I recorded the issue as a suggested expert question
and experiment to separate a possible direct receptor role from indirect effects
of altered ER morphology.

Annotation decisions

Accepted the ER membrane, ER tubular network membrane, ER membrane fusion,
ER network organization, GTP binding, GTPase activity, and
GTPase-dependent fusogenic activity annotations.
Kept protein homooligomerization as non-core because dimerization is a
mechanistic step in fusion, not ATL3's standalone biological role.
Marked generic protein binding annotations as over-annotated. The ZFYVE27 and
REEP5 interactions support ER-shaping network context, but they do not define
ATL3's molecular function.
Marked generic high-throughput membrane as over-annotated because more
informative ER membrane annotations exist.
Accepted the NOT annotation to ER-to-Golgi vesicle-mediated transport because
Rismanchi et al. report that VSVG-GFP trafficking was essentially normal after
atlastin perturbation PMID:18270207.

Pn Notes

(ATL3-pn-notes.md)

ATL3 PN Consistency Notes

Generated: 2026-06-18
Project: PROTEOSTASIS
Scope: PN consistency rereview against local AIGR review and available deep-research artifacts
UniProt: Q6DD88
AIGR review status: COMPLETE
Review batch: proteostasis-batch-2026-06-03 (PR 1376)
Batch change status: added

Source Files Checked

AIGR review YAML: present - genes/human/ATL3/ATL3-ai-review.yaml
AIGR review HTML: present - genes/human/ATL3/ATL3-ai-review.html
Gene notes: present - genes/human/ATL3/ATL3-notes.md
GOA TSV: present - genes/human/ATL3/ATL3-goa.tsv
UniProt record: present - genes/human/ATL3/ATL3-uniprot.txt
PN dossier: projects/PROTEOSTASIS/reports/phase1_dossiers/ATL3.md
PN consistency section: projects/PROTEOSTASIS/reports/phase1_dossiers/_sections/ATL3.md
PN projection report: projects/PROTEOSTASIS/reports/pn_projection/pn_projected_gene_go_summary.tsv
PN mapping audit: projects/PROTEOSTASIS/reports/pn_mapping_audit/current_mapping_scrutiny.tsv

Deep Research Files

genes/human/ATL3/ATL3-deep-research-falcon.md

AIGR Review Snapshot

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.
Existing/core annotation action counts: ACCEPT: 33; KEEP_AS_NON_CORE: 1; MARK_AS_OVER_ANNOTATED: 4

PN Consistency Summary

Consistency: Internally consistent. Deep research (Falcon) and review YAML both center ATL3 on GTP-dependent homotypic ER membrane fusion / tubular-ER maintenance; both treat the ER-phagy receptor role as unsettled. The notes explicitly document the PN reticulophagy projection and the reasoned decision NOT to add it, quoting Bryce 2023 framing ER-phagy as "possible" context. No contradictions.
PN story / NEW pressure: PN asserts ATL3 as an ERphagy receptor → GO:0061709 reticulophagy, which is NOT in existing GOA and is a real term. The review correctly declined to ADD it: the ATL3-specific evidence supports ER fusion/morphology, and the GABARAP-interaction/ER-phagy receptor claim (Chen 2019, not cited in YAML) is not anchored to a cached supporting quote. Verdict: PN story over-reaches as a confident GO assertion; appropriately held as suggested question/experiment rather than a NEW annotation.
Evidence alignment: Divergent. PN cites review-style titles (Chen 2019 ATL3 ER-phagy receptor; Liu/atlastin-ULK1 JCB) not present in the review's PMID set. Review is built on fusion/structure papers (PMID:37102997, 27619977, 28602821, 24459106). No PMID overlap on the ER-phagy claim → the projection is unsupported within the dossier's own citations.
Verdict: Consistent; PN reticulophagy claim correctly NOT added (over-reaches gene-level evidence). No edits required.

Full Consistency Review

UniProt: Q6DD88 · batch: proteostasis-batch-2026-06-03 · review status: COMPLETE
PN placement: ALP|Autophagy substrate selection|Selective autophagy receptor|ERphagy (also ...|Autophagophore initiation and elongation|ULK1 pathway, direct|Modulator of ULK1 activity) ; PN-node mapping: type-leaf mapped, ok_for_propagation_to_go → GO:0061709 reticulophagy (verified real, OLS); ULK1 leaf no_mapping.
Consistency: Internally consistent. Deep research (Falcon) and review YAML both center ATL3 on GTP-dependent homotypic ER membrane fusion / tubular-ER maintenance; both treat the ER-phagy receptor role as unsettled. The notes explicitly document the PN reticulophagy projection and the reasoned decision NOT to add it, quoting Bryce 2023 framing ER-phagy as "possible" context. No contradictions.
PN story / NEW pressure: PN asserts ATL3 as an ERphagy receptor → GO:0061709 reticulophagy, which is NOT in existing GOA and is a real term. The review correctly declined to ADD it: the ATL3-specific evidence supports ER fusion/morphology, and the GABARAP-interaction/ER-phagy receptor claim (Chen 2019, not cited in YAML) is not anchored to a cached supporting quote. Verdict: PN story over-reaches as a confident GO assertion; appropriately held as suggested question/experiment rather than a NEW annotation.
Mapping strategy: Gene does not change the node mapping; the type-leaf mapped/ok_for_propagation stands as a class-level statement, but this individual gene is a defensible decline (like TOMM20/HSPA8 precedent where projection out-reaches gene evidence). Projected term is narrower than review scope only in that review omits it entirely.
Evidence alignment: Divergent. PN cites review-style titles (Chen 2019 ATL3 ER-phagy receptor; Liu/atlastin-ULK1 JCB) not present in the review's PMID set. Review is built on fusion/structure papers (PMID:37102997, 27619977, 28602821, 24459106). No PMID overlap on the ER-phagy claim → the projection is unsupported within the dossier's own citations.
Verdict: Consistent; PN reticulophagy claim correctly NOT added (over-reaches gene-level evidence). No edits required.

PN Dossier Context

review_batch: proteostasis-batch-2026-06-03
review_yaml: genes/human/ATL3/ATL3-ai-review.yaml
PN workbook rows: 2

PN row 1: Autophagy-Lysosome Pathway | Autophagophore initiation and elongation | ULK1 pathway, direct | Modulator of ULK1 activity

UniProt: Q6DD88
In branches: ALP
Notes: Receptor for selective autophagy. ATL3 specifically binds to GABARAP via 2 GABARAP interaction motifs (GIMs). An ER-phagy receptor that promotes tubular ER degradation. Also ATL2/3 directly interact with ULK1 and ATG13 and facilitate the ATG13-mediated recruitment/stabilization of ULK1 and ATG101.
PN references (titles):
- Selective Autophagy: ATG8 Family Proteins, LIR Motifs and Cargo Receptors - ScienceDirect
- Atlastin 2/3 regulate ER targeting of the ULK1 complex to initiate autophagy | Journal of Cell Biology | Rockefeller University Press (rupress.org)
- ATL3 Is a Tubular ER-Phagy Receptor for GABARAP-Mediated Selective Autophagy
PN-node mapping records (path + ancestors):
- [type] Autophagy-Lysosome Pathway|Autophagophore initiation and elongation|ULK1 pathway, direct|Modulator of ULK1 activity
  status=no_mapping scope= GO=[]
  rationale: This PN leaf groups diverse regulators placed around ULK1 activity, but the current members span phosphatase regulation, stress signaling, vesicle/lysosome biology, and proteostasis context rather than a single reusable GO term for ULK1 modulation.
- [group] Autophagy-Lysosome Pathway|Autophagophore initiation and elongation|ULK1 pathway, direct
  status=no_mapping scope= GO=[]
  rationale: Reviewed as a broad PN taxonomy container. The descendants mix components, regulators, context labels, and mechanistic leaves, so propagation should come only from narrower curated nodes.
- [class] Autophagy-Lysosome Pathway|Autophagophore initiation and elongation
  status=context_only scope=too_broad_to_propagate GO=[GO:0016236 macroautophagy]
  rationale: This class is a real macroautophagy context, but its descendants include core factors, component buckets, upstream modulators, localization roles, and residual categories. Projecting generic macroautophagy from this ancestor creates TRAPP-like overpropagation, so candidate GO annotations must come from narrower curated nodes.
- [branch] Autophagy-Lysosome Pathway
  status=no_mapping scope= GO=[]
  rationale: Reviewed as the top-level PN branch. It is a project taxonomy umbrella rather than a direct GO assertion; all propagation must come from manually curated child nodes.

PN row 2: Autophagy-Lysosome Pathway | Autophagy substrate selection | Selective autophagy receptor | ERphagy

UniProt: Q6DD88
In branches: ALP
Notes: Receptor for selective autophagy. ATL3 specifically binds to GABARAP via 2 GABARAP interaction motifs (GIMs). An ER-phagy receptor that promotes tubular ER degradation. Also ATL2/3 directly interact with ULK1 and ATG13 and facilitate the ATG13-mediated recruitment/stabilization of ULK1 and ATG101.
PN references (titles):
- Selective Autophagy: ATG8 Family Proteins, LIR Motifs and Cargo Receptors - ScienceDirect
- Atlastin 2/3 regulate ER targeting of the ULK1 complex to initiate autophagy | Journal of Cell Biology | Rockefeller University Press (rupress.org)
- ATL3 Is a Tubular ER-Phagy Receptor for GABARAP-Mediated Selective Autophagy
PN-node mapping records (path + ancestors):
- [type] Autophagy-Lysosome Pathway|Autophagy substrate selection|Selective autophagy receptor|ERphagy
  status=mapped scope=ok_for_propagation_to_go GO=[GO:0061709 reticulophagy]
  rationale: The PN uses the community label ERphagy for selective autophagy of the endoplasmic reticulum, while GO uses the synonym reticulophagy. Receptor members of this PN category are suitable for propagation to the GO reticulophagy process.
- [group] Autophagy-Lysosome Pathway|Autophagy substrate selection|Selective autophagy receptor
  status=no_mapping scope= GO=[]
  rationale: Reviewed as a broad PN taxonomy container. The descendants mix components, regulators, context labels, and mechanistic leaves, so propagation should come only from narrower curated nodes.
- [class] Autophagy-Lysosome Pathway|Autophagy substrate selection
  status=no_mapping scope= GO=[]
  rationale: Reviewed as a broad substrate-selection container. GO has useful targets for specific receptor, cargo-adaptor, and selective-autophagy leaves, but this class mixes marking, recognition, receptor regulation, and unknown roles and should not propagate as one term.
- [branch] Autophagy-Lysosome Pathway
  status=no_mapping scope= GO=[]
  rationale: Reviewed as the top-level PN branch. It is a project taxonomy umbrella rather than a direct GO assertion; all propagation must come from manually curated child nodes.

Projected GO annotations (1)

GO:0061709 reticulophagy | scope=ok_for_propagation_to_go | goa_status=new_to_goa | from=Autophagy-Lysosome Pathway|Autophagy substrate selection|Selective autophagy receptor|ERphagy

Note

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

📄 View Raw YAML

id: 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.

ATL3

Gene Description

Existing Annotations Review

Core Functions

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.

References

Suggested Questions for Experts

Suggested Experiments

Deep Research

Falcon

Research Report: Human ATL3 / Atlastin-3 (UniProt: Q6DD88) — Functional Annotation

0) Target verification (gene/protein disambiguation)

1) Key concepts and definitions (current understanding)

1.1 Atlastins and ER network formation

1.2 Biochemical activity (enzyme reaction and substrate specificity)

1.3 ER-phagy (reticulophagy) and receptor logic

2) Recent developments and latest research (prioritize 2023–2024)

2.1 2024: Single-molecule mechanism of atlastin-mediated ER fusion (family-mechanistic framework)

2.2 2023: ATL3 as a host factor in non-enveloped virus entry (SV40)

2.3 2023: Coronavirus subversion of ER-phagy via ATL3

3) Current applications and real-world implementations

3.1 Cell biology: manipulating ER morphology and junction architecture

3.2 Autophagy research: tubular ER quality control (ER-phagy)

3.3 Infection biology: host factor dependencies

3.4 Clinical genetics: rare neuropathy diagnostics

4) Expert opinions and analysis (authoritative synthesis)

4.1 ATL3 functional partitioning: fusion vs turnover

4.2 Paralog complexity

5) Relevant statistics and data (recent studies)

5.1 Quantitative cell biology (SV40 ER-foci)

5.2 Quantitative ER–mitochondria contacts in an ATL3-variant study

5.3 Quantitative mechanistic biophysics (atlastin fusion cycle)

6) Summary table (evidence map)

7) Limitations of this report (evidence boundaries)

References (URLs and publication months/years)

Artifacts

Citations

📚 Additional Documentation

Notes

ATL3 notes

Review summary

PN proteostasis projection

Annotation decisions

Pn Notes

ATL3 PN Consistency Notes

Source Files Checked

Deep Research Files

AIGR Review Snapshot

PN Consistency Summary

Full Consistency Review

PN Dossier Context

PN row 1: Autophagy-Lysosome Pathway | Autophagophore initiation and elongation | ULK1 pathway, direct | Modulator of ULK1 activity

PN row 2: Autophagy-Lysosome Pathway | Autophagy substrate selection | Selective autophagy receptor | ERphagy

Projected GO annotations (1)

Note

📄 View Raw YAML