id: O43681
gene_symbol: GET3
product_type: PROTEIN
status: COMPLETE
taxon:
  id: NCBITaxon:9606
  label: Homo sapiens
description: GET3 (ASNA1; also known as TRC40 and arsenite-stimulated ATPase) is the central cytosolic ATPase of the GET/TRC pathway for post-translational targeting of tail-anchored (TA) membrane proteins to the endoplasmic reticulum (ER). It is a homodimeric P-loop NTPase of the ArsA/ArsA-like ATPase family. GET3 selectively recognizes and binds the single C-terminal transmembrane domain (TMD) of newly synthesized TA proteins in the cytosol, receiving them via the BAG6/UBL4A/GET4 pre-targeting and bridging machinery (and from the cochaperone SGTA), and shields the hydrophobic TMD as a soluble carrier/chaperone. ATP binding drives the homodimer into a closed state that captures the substrate; the GET3-TA complex then docks at the ER-membrane receptor-insertase formed by GET1/WRB and CAMLG/GET2, and ATP hydrolysis triggers TA release for insertion into the lipid bilayer, after which GET3 returns to the cytosol for another round. GET3 is thus the targeting factor and TMD chaperone of the pathway, not the membrane insertase itself. It was originally isolated as the human homolog of bacterial ArsA, an arsenite/antimonite-stimulated ATPase, but its physiological role is TA-protein biogenesis. Loss-of-function variants cause an autosomal recessive, rapidly progressive infantile dilated cardiomyopathy. GET3 acts predominantly in the cytoplasm and transiently at the ER membrane.
existing_annotations:
- term:
    id: GO:0016887
    label: ATP hydrolysis activity
  evidence_type: IBA
  original_reference_id: GO_REF:0000033
  qualifier: enables
  review:
    summary: Phylogenetic annotation of GET3's ATP hydrolysis activity, the catalytic core of its targeting cycle. Conserved across the ArsA/Get3 family.
    action: ACCEPT
    reason: Core molecular function; GET3 is an ATPase whose ATP hydrolysis drives TA-protein release/insertion, supported by IDA and EC 3.6.4.-.
    supported_by:
    - reference_id: file:human/GET3/GET3-uniprot.txt
      supporting_text: ATP hydrolysis is required for insertion.
- term:
    id: GO:0071816
    label: tail-anchored membrane protein insertion into ER membrane
  evidence_type: IBA
  original_reference_id: GO_REF:0000033
  qualifier: involved_in
  review:
    summary: Phylogenetic annotation of GET3's defining biological process. This is the standard GO term used for the GET-pathway role; GET3 is the cytosolic targeting factor whose action commits TA proteins to ER insertion.
    action: ACCEPT
    reason: Core biological process; conserved and supported by experimental evidence (IMP/IDA).
    supported_by:
    - reference_id: file:human/GET3/GET3-uniprot.txt
      supporting_text: ATPase required for the post-translational delivery of tail-
- term:
    id: GO:0005524
    label: ATP binding
  evidence_type: IEA
  original_reference_id: GO_REF:0000120
  qualifier: enables
  review:
    summary: ATP binding drives the GET3 homodimer to the closed state that captures the TA substrate. A structural/mechanistic attribute subsidiary to the catalytic ATP hydrolysis activity.
    action: KEEP_AS_NON_CORE
    reason: Accurate (GET3 binds ATP) but subsidiary to the more informative ATP hydrolysis activity that represents the core MF.
    supported_by:
    - reference_id: file:human/GET3/GET3-uniprot.txt
      supporting_text: ATP binding drives the
- term:
    id: GO:0005730
    label: nucleolus
  evidence_type: IEA
  original_reference_id: GO_REF:0000044
  qualifier: located_in
  review:
    summary: Electronic transfer of a legacy nucleolar localization reported in early arsenite-ATPase studies. Not tied to the core cytosolic TA-targeting function.
    action: KEEP_AS_NON_CORE
    reason: Legacy/secondary localization derived from early arsA-homolog studies; not part of the core GET-pathway function.
    supported_by:
    - reference_id: file:human/GET3/GET3-uniprot.txt
      supporting_text: 'Nucleus, nucleolus'
- term:
    id: GO:0005737
    label: cytoplasm
  evidence_type: IEA
  original_reference_id: GO_REF:0000044
  qualifier: located_in
  review:
    summary: Electronic transfer of the cytoplasmic localization, the primary site where GET3 captures TA substrates. Consistent with experimental evidence.
    action: ACCEPT
    reason: Correct primary compartment; GET3 is a cytosolic targeting factor.
    supported_by:
    - reference_id: file:human/GET3/GET3-uniprot.txt
      supporting_text: 'SUBCELLULAR LOCATION: Cytoplasm'
- term:
    id: GO:0005783
    label: endoplasmic reticulum
  evidence_type: IEA
  original_reference_id: GO_REF:0000120
  qualifier: located_in
  review:
    summary: Electronic annotation of ER localization, where GET3 transiently docks on the WRB/CAML receptor to deliver TA substrates. Consistent with experimental evidence.
    action: ACCEPT
    reason: Correct; GET3 visits the ER membrane to hand off its TA cargo.
    supported_by:
    - reference_id: file:human/GET3/GET3-uniprot.txt
      supporting_text: 'Endoplasmic'
- term:
    id: GO:0016887
    label: ATP hydrolysis activity
  evidence_type: IEA
  original_reference_id: GO_REF:0000120
  qualifier: enables
  review:
    summary: Electronic assignment of the core ATP hydrolysis activity, consistent with experimental IDA and the catalytic activity record.
    action: ACCEPT
    reason: Correct core molecular function; redundant with IDA/IBA.
    supported_by:
    - reference_id: file:human/GET3/GET3-uniprot.txt
      supporting_text: ATP hydrolysis is required for insertion.
- term:
    id: GO:0045048
    label: protein insertion into ER membrane
  evidence_type: IEA
  original_reference_id: GO_REF:0000104
  qualifier: involved_in
  review:
    summary: Electronic (Swiss-Prot keyword/feature transfer) annotation of the parent ER protein-insertion process. Correct but less specific than the TA-insertion term.
    action: KEEP_AS_NON_CORE
    reason: Correct but generic parent of GO:0071816, which better captures GET3's role.
    supported_by:
    - reference_id: file:human/GET3/GET3-uniprot.txt
      supporting_text: ATPase required for the post-translational delivery of tail-
- term:
    id: GO:0005515
    label: protein binding
  evidence_type: IPI
  original_reference_id: PMID:21516116
  qualifier: enables
  review:
    summary: High-throughput interactome screen capturing GET3 protein interactions. The bare protein binding term is uninformative.
    action: KEEP_AS_NON_CORE
    reason: Bare protein binding from a high-throughput screen; uninformative for the core MF.
    supported_by:
    - reference_id: PMID:21516116
      supporting_text: Next-generation sequencing to generate interactome datasets
- term:
    id: GO:0005515
    label: protein binding
  evidence_type: IPI
  original_reference_id: PMID:21911467
  qualifier: enables
  review:
    summary: Yersinia pestis-human protein-protein interaction screen; the captured partner is a bacterial xenobiotic protein (yscD), an incidental cross-species interaction unrelated to GET3's function.
    action: KEEP_AS_NON_CORE
    reason: Incidental xenobiotic (bacterial) interaction from a host-pathogen screen; bare protein binding, not relevant to core function.
    supported_by:
    - reference_id: file:human/GET3/GET3-uniprot.txt
      supporting_text: 'O43681; Q56975: yscD'
- term:
    id: GO:0005515
    label: protein binding
  evidence_type: IPI
  original_reference_id: PMID:25416956
  qualifier: enables
  review:
    summary: Proteome-scale human interactome map; source of IntAct partners including ER/secretory and TA-like proteins. Bare protein binding is uninformative.
    action: KEEP_AS_NON_CORE
    reason: High-throughput interactome; bare protein binding term is uninformative.
    supported_by:
    - reference_id: PMID:25416956
      supporting_text: A proteome-scale map of the human interactome network
- term:
    id: GO:0005515
    label: protein binding
  evidence_type: IPI
  original_reference_id: PMID:28514442
  qualifier: enables
  review:
    summary: Human interactome architecture study; captures GET3 interactions including the functionally relevant CAMLG partner, but uses the uninformative bare protein binding term.
    action: KEEP_AS_NON_CORE
    reason: Records real interactions (including CAMLG) but bare protein binding is uninformative; functional partners are captured via GET complex membership.
    supported_by:
    - reference_id: file:human/GET3/GET3-uniprot.txt
      supporting_text: 'O43681; P49069: CAMLG'
- term:
    id: GO:0005515
    label: protein binding
  evidence_type: IPI
  original_reference_id: PMID:32296183
  qualifier: enables
  review:
    summary: HuRI binary interactome (Y2H); source of many IntAct partners of GET3, including ER/secretory and TA-like proteins consistent with TA-client capture. Bare protein binding is uninformative.
    action: KEEP_AS_NON_CORE
    reason: High-throughput Y2H interactome; bare protein binding is uninformative.
    supported_by:
    - reference_id: PMID:32296183
      supporting_text: A reference map of the human binary protein interactome
- term:
    id: GO:0005515
    label: protein binding
  evidence_type: IPI
  original_reference_id: PMID:33961781
  qualifier: enables
  review:
    summary: Proteome-scale cell-specific interactome network; captures GET3 interactions including CAMLG. Bare protein binding is uninformative.
    action: KEEP_AS_NON_CORE
    reason: High-throughput interactome; bare protein binding is uninformative.
    supported_by:
    - reference_id: file:human/GET3/GET3-uniprot.txt
      supporting_text: 'O43681; P49069: CAMLG'
- term:
    id: GO:0005515
    label: protein binding
  evidence_type: IPI
  original_reference_id: PMID:40205054
  qualifier: enables
  review:
    summary: Multimodal cell map study; captures GET3 protein interactions including CAMLG. Bare protein binding is uninformative.
    action: KEEP_AS_NON_CORE
    reason: High-throughput interactome; bare protein binding is uninformative.
    supported_by:
    - reference_id: file:human/GET3/GET3-uniprot.txt
      supporting_text: 'O43681; P49069: CAMLG'
- term:
    id: GO:0043529
    label: GET complex
  evidence_type: IEA
  original_reference_id: GO_REF:0000120
  qualifier: part_of
  review:
    summary: Electronic assignment of GET complex membership. GET3/TRC40 is a defining subunit of the GET complex (GET1/WRB + CAMLG/GET2 + GET3/TRC40).
    action: ACCEPT
    reason: Core cellular component; consistent with experimental IDA/IPI evidence.
    supported_by:
    - reference_id: file:human/GET3/GET3-uniprot.txt
      supporting_text: Component of the Golgi to ER
- term:
    id: GO:0071816
    label: tail-anchored membrane protein insertion into ER membrane
  evidence_type: IEA
  original_reference_id: GO_REF:0000120
  qualifier: involved_in
  review:
    summary: Electronic assignment of the core TA-insertion process, consistent with experimental evidence.
    action: ACCEPT
    reason: Correct core process; redundant with IMP/IDA/IBA.
    supported_by:
    - reference_id: file:human/GET3/GET3-uniprot.txt
      supporting_text: ATPase required for the post-translational delivery of tail-
- term:
    id: GO:0005654
    label: nucleoplasm
  evidence_type: IDA
  original_reference_id: GO_REF:0000052
  qualifier: located_in
  review:
    summary: HPA immunofluorescence nucleoplasm localization. A secondary localization not connected to the core cytosolic TA-targeting function.
    action: KEEP_AS_NON_CORE
    reason: HPA-derived secondary localization; not part of the core GET-pathway function.
    supported_by:
    - reference_id: file:human/GET3/GET3-uniprot.txt
      supporting_text: 'Nucleus, nucleolus'
- term:
    id: GO:0005730
    label: nucleolus
  evidence_type: IDA
  original_reference_id: GO_REF:0000052
  qualifier: located_in
  review:
    summary: HPA immunofluorescence nucleolar localization, consistent with the legacy nucleolar distribution reported for the arsenite-ATPase. Secondary to the core function.
    action: KEEP_AS_NON_CORE
    reason: Secondary/legacy localization; not part of the core cytosolic targeting function.
    supported_by:
    - reference_id: file:human/GET3/GET3-uniprot.txt
      supporting_text: 'Nucleus, nucleolus'
- term:
    id: GO:0005737
    label: cytoplasm
  evidence_type: EXP
  original_reference_id: PMID:17382883
  qualifier: located_in
  review:
    summary: Direct experimental cytoplasmic localization from the study that identified TRC40/Asna-1 as the cytosolic TA-targeting ATPase.
    action: ACCEPT
    reason: Core compartment; GET3 acts as a cytosolic targeting factor.
    supported_by:
    - reference_id: PMID:17382883
      supporting_text: cytosolic TMD recognition complex (TRC) that targets TA proteins for insertion into the ER membrane
- term:
    id: GO:0005737
    label: cytoplasm
  evidence_type: EXP
  original_reference_id: PMID:21444755
  qualifier: located_in
  review:
    summary: Direct experimental cytoplasmic localization, consistent with GET3/TRC40 being a conserved cytosolic ATPase.
    action: ACCEPT
    reason: Core compartment; corroborated by multiple experimental sources.
    supported_by:
    - reference_id: PMID:21444755
      supporting_text: TRC40/Asna1 (Get3 in yeast)
- term:
    id: GO:0005783
    label: endoplasmic reticulum
  evidence_type: EXP
  original_reference_id: PMID:17382883
  qualifier: located_in
  review:
    summary: Direct experimental ER localization; GET3 docks on the ER membrane to deliver its TA cargo to the WRB/CAML receptor.
    action: ACCEPT
    reason: Correct; GET3 transiently associates with the ER during TA delivery.
    supported_by:
    - reference_id: PMID:17382883
      supporting_text: targets TA proteins for insertion into the ER membrane
- term:
    id: GO:0005783
    label: endoplasmic reticulum
  evidence_type: EXP
  original_reference_id: PMID:21444755
  qualifier: located_in
  review:
    summary: Direct experimental ER localization, consistent with GET3 delivering TA proteins to the ER membrane receptor.
    action: ACCEPT
    reason: Correct; GET3 visits the ER to hand off TA cargo.
    supported_by:
    - reference_id: PMID:21444755
      supporting_text: delivers them to the ER membrane for insertion
- term:
    id: GO:0005783
    label: endoplasmic reticulum
  evidence_type: EXP
  original_reference_id: PMID:31461301
  qualifier: located_in
  review:
    summary: Experimental ER localization from the ASNA1 cardiomyopathy study, in which ASNA1 mediates TA-protein insertion into the ER membrane.
    action: ACCEPT
    reason: Correct; GET3 associates with the ER membrane during TA delivery.
    supported_by:
    - reference_id: PMID:31461301
      supporting_text: mediates insertion of TA (tail-anchored) proteins into the endoplasmic reticulum (ER) membrane
- term:
    id: GO:0016887
    label: ATP hydrolysis activity
  evidence_type: IDA
  original_reference_id: PMID:8884272
  qualifier: enables
  review:
    summary: Direct biochemical demonstration that the human ArsA homolog (hARSA-I/ASNA1) is an ATPase. This is the experimental basis for GET3's core ATPase MF.
    action: ACCEPT
    reason: Core molecular function with direct biochemical (IDA) support.
    supported_by:
    - reference_id: PMID:8884272
      supporting_text: hARSA-I is an ATPase
- term:
    id: GO:0016887
    label: ATP hydrolysis activity
  evidence_type: IDA
  original_reference_id: PMID:9712828
  qualifier: enables
  review:
    summary: Direct biochemical characterization of the recombinant human protein measuring basal ATPase activity and ATP kinetics. Core ATPase MF.
    action: ACCEPT
    reason: Core molecular function with direct biochemical (IDA) support; KM/Vmax for ATP determined.
    supported_by:
    - reference_id: PMID:9712828
      supporting_text: ATPase activity
- term:
    id: GO:0005789
    label: endoplasmic reticulum membrane
  evidence_type: NAS
  original_reference_id: PMID:32910895
  qualifier: located_in
  review:
    summary: ComplexPortal NAS assertion of ER membrane localization, reflecting the GET complex (within which GET3 docks) residing at the ER membrane.
    action: ACCEPT
    reason: Correct; GET3 associates with the ER membrane GET complex during TA handoff.
    supported_by:
    - reference_id: PMID:32910895
      supporting_text: an insertase (yeast Get1/Get2 or mammalian WRB/CAML) that captures the TA from a cytoplasmic chaperone
- term:
    id: GO:0043529
    label: GET complex
  evidence_type: IPI
  original_reference_id: PMID:32910895
  qualifier: part_of
  review:
    summary: ComplexPortal IPI assignment of GET complex membership from the cryo-EM structure of the human GET insertase complex with bound GET3/TRC40.
    action: ACCEPT
    reason: Core cellular component; structurally demonstrated.
    supported_by:
    - reference_id: PMID:32910895
      supporting_text: captures the TA from a cytoplasmic chaperone (Get3 or TRC40, respectively)
- term:
    id: GO:0045048
    label: protein insertion into ER membrane
  evidence_type: NAS
  original_reference_id: PMID:23041287
  qualifier: involved_in
  review:
    summary: ComplexPortal NAS assertion of the (parent) ER protein-insertion process; GET3/TRC40 targets TA proteins to the WRB/CAML receptor for insertion.
    action: KEEP_AS_NON_CORE
    reason: Correct parent of GO:0071816; redundant general term.
    supported_by:
    - reference_id: PMID:23041287
      supporting_text: an ATPase targeting newly synthesized TA proteins
- term:
    id: GO:0071816
    label: tail-anchored membrane protein insertion into ER membrane
  evidence_type: IMP
  original_reference_id: PMID:31461301
  qualifier: involved_in
  review:
    summary: Mutant-phenotype evidence that the disease-associated Val163Ala ASNA1 mutant, while still able to capture a TA substrate, is inefficient in facilitating TA insertion into the ER membrane; asna1-null zebrafish show cardiac failure. Establishes GET3's role in the TA-insertion pathway.
    action: ACCEPT
    reason: Core biological process with mutant-phenotype (IMP) support directly linking ASNA1 function to TA insertion.
    supported_by:
    - reference_id: PMID:31461301
      supporting_text: inefficient in facilitating TA protein insertion into the ER membrane
- term:
    id: GO:0140597
    label: protein carrier activity
  evidence_type: IDA
  original_reference_id: PMID:23610396
  qualifier: enables
  review:
    summary: GET3/TRC40 is the TMD chaperone/carrier that shields the hydrophobic TA transmembrane domain and delivers it to the ER, harnessing ATP to drive TA membrane localization. This protein-carrier (chaperone) activity is a core molecular function complementary to its ATPase activity.
    action: ACCEPT
    reason: Core molecular function; GET3 carries the TA-protein cargo as a soluble TMD chaperone, demonstrated by IDA.
    supported_by:
    - reference_id: PMID:23610396
      supporting_text: Get3 harnesses the energy from ATP to drive
    - reference_id: PMID:37963916
      supporting_text: the Get3 chaperone captures the TA protein substrate and delivers it to the Get1/Get2 membrane protein complex (GET insertase)
- term:
    id: GO:0043529
    label: GET complex
  evidence_type: IDA
  original_reference_id: PMID:32910895
  qualifier: part_of
  review:
    summary: Direct structural evidence (cryo-EM) placing GET3/TRC40 within the GET insertase complex.
    action: ACCEPT
    reason: Core cellular component; structurally demonstrated.
    supported_by:
    - reference_id: PMID:32910895
      supporting_text: captures the TA from a cytoplasmic chaperone (Get3 or TRC40, respectively)
- term:
    id: GO:0071816
    label: tail-anchored membrane protein insertion into ER membrane
  evidence_type: IMP
  original_reference_id: PMID:23041287
  qualifier: involved_in
  review:
    summary: Mutant-phenotype evidence supporting GET3/TRC40's role as the ATPase targeting TA proteins for insertion, delivered to the CAML/WRB receptor complex.
    action: ACCEPT
    reason: Core biological process with IMP support.
    supported_by:
    - reference_id: PMID:23041287
      supporting_text: an ATPase targeting newly synthesized TA proteins
- term:
    id: GO:0043529
    label: GET complex
  evidence_type: IPI
  original_reference_id: PMID:23041287
  qualifier: part_of
  review:
    summary: IPI identification of GET3/TRC40 in the receptor (GET) complex with WRB and CAML.
    action: ACCEPT
    reason: Core cellular component; demonstrated by complex identification.
    supported_by:
    - reference_id: PMID:23041287
      supporting_text: CAML and WRB as components of the TRC40 receptor complex
- term:
    id: GO:0071816
    label: tail-anchored membrane protein insertion into ER membrane
  evidence_type: IDA
  original_reference_id: PMID:25535373
  qualifier: involved_in
  review:
    summary: Direct evidence that the minimal Bag6 complex facilitates TA substrate transfer from SGTA to TRC40/GET3, the loading step that commits TA proteins to the GET targeting pathway.
    action: ACCEPT
    reason: Core biological process; IDA demonstrating the TA-loading step onto GET3.
    supported_by:
    - reference_id: PMID:25535373
      supporting_text: substrate transfer from small glutamine-rich tetratricopeptide repeat-containing
- term:
    id: GO:0070062
    label: extracellular exosome
  evidence_type: HDA
  original_reference_id: PMID:19056867
  qualifier: located_in
  review:
    summary: High-throughput urinary exosome proteomics catalog hit. Not indicative of a core localization or function for GET3.
    action: KEEP_AS_NON_CORE
    reason: Proteomic catalog localization; not part of GET3's core cytosolic targeting function.
    supported_by:
    - reference_id: PMID:19056867
      supporting_text: Large-scale proteomics and phosphoproteomics of urinary exosomes
- term:
    id: GO:0005730
    label: nucleolus
  evidence_type: TAS
  original_reference_id: PMID:9736449
  qualifier: located_in
  review:
    summary: Legacy nucleolar localization reported in the early arsenite-ATPase characterization (cytoplasmic, perinuclear, and nucleolar distribution). Secondary to the core cytosolic targeting function.
    action: KEEP_AS_NON_CORE
    reason: Legacy localization from early arsA-homolog work; not part of the core GET-pathway function.
    supported_by:
    - reference_id: PMID:9736449
      supporting_text: Dual cytoplasmic and nuclear distribution of the novel arsenite-stimulated human ATPase
- term:
    id: GO:0005737
    label: cytoplasm
  evidence_type: TAS
  original_reference_id: PMID:9736449
  qualifier: located_in
  review:
    summary: Cytoplasmic localization from the early arsenite-ATPase study, consistent with GET3's primary cytosolic site of action.
    action: ACCEPT
    reason: Correct primary compartment; corroborated by experimental EXP evidence.
    supported_by:
    - reference_id: PMID:9736449
      supporting_text: Dual cytoplasmic and nuclear distribution
references:
- 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
  findings: []
- id: GO_REF:0000052
  title: Gene Ontology annotation based on curation of immunofluorescence data
  findings: []
- id: GO_REF:0000104
  title: Electronic Gene Ontology annotations created by transferring manual GO annotations between related proteins based on shared sequence features
  findings: []
- id: GO_REF:0000120
  title: Combined Automated Annotation using Multiple IEA Methods
  findings: []
- id: PMID:17382883
  title: Identification of a targeting factor for posttranslational membrane protein insertion into the ER.
  findings:
  - statement: Identified the cytosolic TMD recognition complex (TRC); the 40 kDa ATPase subunit TRC40 is Asna-1, which targets TA proteins for ER insertion with release dependent on ATP hydrolysis.
    reference_section_type: ABSTRACT
  reference_review:
    relevance: HIGH
    correctness: VERIFIED
    review_notes: Founding study identifying TRC40/Asna1 (GET3) as the cytosolic TA-targeting ATPase.
- id: PMID:19056867
  title: Large-scale proteomics and phosphoproteomics of urinary exosomes.
  findings: []
  reference_review:
    relevance: LOW
    correctness: VERIFIED
    review_notes: High-throughput exosome proteomics; source of the extracellular exosome catalog annotation.
- id: PMID:21444755
  title: WRB is the receptor for TRC40/Asna1-mediated insertion of tail-anchored proteins into the ER membrane.
  findings:
  - statement: TRC40/Asna1 (Get3 in yeast) is a conserved cytosolic ATPase that recognizes the TMD of TA proteins and delivers them to the ER membrane receptor WRB.
    reference_section_type: ABSTRACT
  reference_review:
    relevance: HIGH
    correctness: VERIFIED
    review_notes: Establishes GET3/TRC40 as the cytosolic ATPase delivering TA proteins to the ER WRB receptor.
- id: PMID:21516116
  title: Next-generation sequencing to generate interactome datasets.
  findings: []
  reference_review:
    relevance: LOW
    correctness: VERIFIED
    review_notes: High-throughput interactome; bare protein binding source.
- id: PMID:21911467
  title: Insight into bacterial virulence mechanisms against host immune response via the Yersinia pestis-human protein-protein interaction network.
  findings: []
  reference_review:
    relevance: NONE
    correctness: VERIFIED
    review_notes: Host-pathogen PPI screen; the GET3 partner is a bacterial protein (yscD), incidental and not relevant to GET3 function.
- id: PMID:23041287
  title: Molecular machinery for insertion of tail-anchored membrane proteins into the endoplasmic reticulum membrane in mammalian cells.
  findings:
  - statement: CAML and WRB are components of the TRC40 receptor complex; TRC40 is an ATPase targeting newly synthesized TA proteins to the ER for insertion.
    reference_section_type: ABSTRACT
  reference_review:
    relevance: HIGH
    correctness: VERIFIED
    review_notes: Defines the mammalian TRC40 receptor complex and GET3's targeting role.
- id: PMID:23610396
  title: Precise timing of ATPase activation drives targeting of tail-anchored proteins.
  findings:
  - statement: Get3 coordinates delivery of TA proteins to the ER; the Get4/5 loading complex locks Get3 in the ATP-bound state while the TA substrate activates Get3's ATPase ~100-fold, and Get3 harnesses ATP energy to drive TA membrane localization.
    reference_section_type: ABSTRACT
  reference_review:
    relevance: HIGH
    correctness: VERIFIED
    review_notes: Mechanistic study of the Get3 ATPase/carrier cycle; supports protein carrier (chaperone) activity.
- id: PMID:25416956
  title: A proteome-scale map of the human interactome network.
  findings: []
  reference_review:
    relevance: LOW
    correctness: VERIFIED
    review_notes: High-throughput interactome; bare protein binding source.
- id: PMID:25535373
  title: Bag6 complex contains a minimal tail-anchor-targeting module and a mock BAG domain.
  findings:
  - statement: The minimal Bag6 complex facilitates TA substrate transfer from SGTA to TRC40, the loading step of the GET pathway.
    reference_section_type: ABSTRACT
  reference_review:
    relevance: HIGH
    correctness: VERIFIED
    review_notes: Establishes the SGTA-to-TRC40/GET3 TA handoff.
- id: PMID:28514442
  title: Architecture of the human interactome defines protein communities and disease networks.
  findings: []
  reference_review:
    relevance: LOW
    correctness: VERIFIED
    review_notes: High-throughput interactome; bare protein binding, includes CAMLG.
- id: PMID:31461301
  title: Biallelic Variants in ASNA1, Encoding a Cytosolic Targeting Factor of Tail-Anchored Proteins, Cause Rapidly Progressive Pediatric Cardiomyopathy.
  findings:
  - statement: ASNA1 (TRC40/GET3) is a ubiquitously expressed cytosolic chaperone mediating TA-protein insertion into the ER; the disease Val163Ala mutant captures TA but is inefficient in facilitating insertion, and asna1-null zebrafish develop cardiac failure.
    reference_section_type: RESULTS
  reference_review:
    relevance: HIGH
    correctness: VERIFIED
    review_notes: Disease study; provides IMP evidence linking ASNA1/GET3 to TA insertion and human cardiomyopathy.
- id: PMID:32296183
  title: A reference map of the human binary protein interactome.
  findings: []
  reference_review:
    relevance: LOW
    correctness: VERIFIED
    review_notes: HuRI Y2H interactome; bare protein binding source.
- id: PMID:32910895
  title: Structural Basis of Tail-Anchored Membrane Protein Biogenesis by the GET Insertase Complex.
  findings:
  - statement: Cryo-EM of the GET insertase complex; the WRB/CAML (Get1/Get2) insertase captures the TA from the cytoplasmic chaperone GET3/TRC40 that GET3 binds as a homodimer.
    reference_section_type: ABSTRACT
  reference_review:
    relevance: HIGH
    correctness: VERIFIED
    review_notes: Definitive structure showing GET3 docking on the WRB/CAML insertase.
- id: PMID:33961781
  title: Dual proteome-scale networks reveal cell-specific remodeling of the human interactome.
  findings: []
  reference_review:
    relevance: LOW
    correctness: VERIFIED
    review_notes: High-throughput interactome; bare protein binding, includes CAMLG.
- id: PMID:40205054
  title: Multimodal cell maps as a foundation for structural and functional genomics.
  findings: []
  reference_review:
    relevance: LOW
    correctness: VERIFIED
    review_notes: High-throughput cell map; bare protein binding, includes CAMLG.
- id: PMID:8884272
  title: Isolation of the ATP-binding human homolog of the arsA component of the bacterial arsenite transporter.
  findings:
  - statement: Isolated the human homolog of bacterial arsA (hARSA-I/ASNA1) and showed it is an ATPase analogous to bacterial ArsA.
    reference_section_type: ABSTRACT
  reference_review:
    relevance: MEDIUM
    correctness: VERIFIED
    review_notes: Original cloning of ASNA1 as an arsA homolog; basis of the ATPase MF, legacy arsenite framing.
- id: PMID:9712828
  title: Biochemical characterization of the human arsenite-stimulated ATPase (hASNA-I).
  findings:
  - statement: Recombinant hASNA-I exhibits basal ATPase activity (modestly arsenite-stimulated; antimonite does not stimulate), with measured ATP kinetics.
    reference_section_type: ABSTRACT
  reference_review:
    relevance: MEDIUM
    correctness: VERIFIED
    review_notes: Biochemical ATPase characterization; legacy arsenite-stimulation is secondary to the TA-targeting role.
- id: PMID:9736449
  title: Dual cytoplasmic and nuclear distribution of the novel arsenite-stimulated human ATPase (hASNA-I).
  findings:
  - statement: Early study reporting a cytoplasmic, perinuclear, and nucleolar distribution of the arsenite-stimulated ATPase.
    reference_section_type: ABSTRACT
  reference_review:
    relevance: LOW
    correctness: VERIFIED
    review_notes: Source of legacy nucleolar/cytoplasmic localization annotations.
- id: PMID:34264263
  title: Capture and delivery of tail-anchored proteins to the endoplasmic reticulum.
  findings:
  - statement: Comprehensive review of the GET/TRC pathway; GET3/TRC40 is the central cytosolic homodimeric ATPase that captures TA substrates, shields the hydrophobic TMD, and delivers them to the ER WRB/CAML receptor-insertase for insertion.
    reference_section_type: ABSTRACT
  reference_review:
    relevance: HIGH
    correctness: VERIFIED
    review_notes: PubMed-verified (J Cell Biol 2021, 220:8). Authoritative pathway review of GET3/TRC40 as the cytosolic targeting ATPase/TMD chaperone.
- id: PMID:36640319
  title: The Get1/2 insertase forms a channel to mediate the insertion of tail-anchored proteins into the ER.
  findings:
  - statement: Get3 (TRC40) delivers TA proteins to the Get1/2 channel; Get3 binding seals the dynamically opening Get1/2 channel, and channel activity is required to release TA proteins from Get3 for insertion, defining the GET3-to-insertase handoff step.
    reference_section_type: ABSTRACT
  reference_review:
    relevance: MEDIUM
    correctness: VERIFIED
    review_notes: PubMed-verified (Cell Rep 2022, 42:111921). Mechanistic context for GET3/TRC40 handing off TA cargo to the Get1/2 (WRB/CAML) insertase channel; Get3 gates the channel.
- id: PMID:37963916
  title: The GET insertase exhibits conformational plasticity and induces membrane thinning.
  findings:
  - statement: Structures and simulations of human and C. thermophilum Get1/Get2/Get3 show that the gating interaction between Get2 helix alpha3' and Get3 drives conformational changes in both Get3 and the Get1/Get2 heterotetramer, promoting Get3 opening, nucleotide release, and TA substrate transfer to the membrane.
    reference_section_type: ABSTRACT
  reference_review:
    relevance: HIGH
    correctness: VERIFIED
    review_notes: PubMed-verified (Nat Commun 2023, 14:7355). Structural mechanism of the Get3/Get1/Get2 cycle including GET3/TRC40 conformational opening on receptor engagement; includes human GET3.
- id: file:human/GET3/GET3-uniprot.txt
  title: UniProt entry O43681 (GET3_HUMAN), ATPase ASNA1/TRC40
  findings:
  - statement: ATPase required for post-translational delivery of TA proteins to the ER; recognizes the TA TMD in the cytosol, targets to the GET1/WRB-CAMLG/GET2 receptor where ATP hydrolysis drives release/insertion; component of the GET complex; cytoplasmic/ER/nucleolar.
    reference_section_type: OTHER
core_functions:
- description: Cytosolic ATPase and TMD chaperone of the GET/TRC pathway that recognizes and binds the C-terminal transmembrane domain of newly synthesized tail-anchored proteins and, in an ATP-driven cycle, carries and delivers them to the ER membrane receptor for insertion.
  molecular_function:
    id: GO:0016887
    label: ATP hydrolysis activity
  locations:
  - id: GO:0005737
    label: cytoplasm
  supported_by:
  - reference_id: PMID:17382883
    supporting_text: cytosolic TMD recognition complex (TRC) that targets TA proteins for insertion into the ER membrane
  - reference_id: file:human/GET3/GET3-uniprot.txt
    supporting_text: ATP hydrolysis is required for insertion.
  directly_involved_in:
  - id: GO:0071816
    label: tail-anchored membrane protein insertion into ER membrane
- description: Soluble protein carrier (TMD chaperone) that shields the hydrophobic tail anchor of TA substrates and, as part of the GET complex docking on the WRB/CAML insertase, delivers them for ER membrane insertion.
  molecular_function:
    id: GO:0140597
    label: protein carrier activity
  in_complex:
    id: GO:0043529
    label: GET complex
  supported_by:
  - reference_id: PMID:23610396
    supporting_text: Get3 harnesses the energy from ATP to drive
  - reference_id: file:human/GET3/GET3-uniprot.txt
    supporting_text: Recognizes and selectively binds the transmembrane domain of TA
  directly_involved_in:
  - id: GO:0071816
    label: tail-anchored membrane protein insertion into ER membrane
proposed_new_terms: []
suggested_questions:
- question: To what extent is the legacy arsenite/antimonite-stimulated ATPase activity physiologically relevant in humans, versus being a vestige of the ancestral ArsA fold now repurposed for TA targeting?
- question: Which specific cardiac tail-anchored proteins are mislocalized when ASNA1 is impaired, and do they account for the dilated cardiomyopathy phenotype?
suggested_experiments:
- description: Reconstitute the full handoff cascade (SGTA -> BAG6/UBL4A/GET4 -> GET3 -> WRB/CAML) with purified components to quantify how GET4 priming and substrate-induced ATPase activation set the timing of TA capture and release.
- description: Define the endogenous GET3/ASNA1 TA-substrate repertoire in cardiomyocytes by proximity labeling and compare wild-type versus the Val163Ala disease variant to identify the TA clients whose mislocalization drives cardiomyopathy.