GET3

Existing Annotations Review

GO Term	Evidence	Action	Reason
GO:0016887 ATP hydrolysis activity	IBA GO_REF:0000033	ACCEPT	Summary: Phylogenetic annotation of GET3's ATP hydrolysis activity, the catalytic core of its targeting cycle. Conserved across the ArsA/Get3 family. Reason: Core molecular function; GET3 is an ATPase whose ATP hydrolysis drives TA-protein release/insertion, supported by IDA and EC 3.6.4.-. Supporting Evidence: file:human/GET3/GET3-uniprot.txt ATP hydrolysis is required for insertion.
GO:0071816 tail-anchored membrane protein insertion into ER membrane	IBA GO_REF:0000033	ACCEPT	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. Reason: Core biological process; conserved and supported by experimental evidence (IMP/IDA). Supporting Evidence: file:human/GET3/GET3-uniprot.txt ATPase required for the post-translational delivery of tail-
GO:0005524 ATP binding	IEA GO_REF:0000120	KEEP AS NON CORE	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. Reason: Accurate (GET3 binds ATP) but subsidiary to the more informative ATP hydrolysis activity that represents the core MF. Supporting Evidence: file:human/GET3/GET3-uniprot.txt ATP binding drives the
GO:0005730 nucleolus	IEA GO_REF:0000044	KEEP AS NON CORE	Summary: Electronic transfer of a legacy nucleolar localization reported in early arsenite-ATPase studies. Not tied to the core cytosolic TA-targeting function. Reason: Legacy/secondary localization derived from early arsA-homolog studies; not part of the core GET-pathway function. Supporting Evidence: file:human/GET3/GET3-uniprot.txt Nucleus, nucleolus
GO:0005737 cytoplasm	IEA GO_REF:0000044	ACCEPT	Summary: Electronic transfer of the cytoplasmic localization, the primary site where GET3 captures TA substrates. Consistent with experimental evidence. Reason: Correct primary compartment; GET3 is a cytosolic targeting factor. Supporting Evidence: file:human/GET3/GET3-uniprot.txt SUBCELLULAR LOCATION: Cytoplasm
GO:0005783 endoplasmic reticulum	IEA GO_REF:0000120	ACCEPT	Summary: Electronic annotation of ER localization, where GET3 transiently docks on the WRB/CAML receptor to deliver TA substrates. Consistent with experimental evidence. Reason: Correct; GET3 visits the ER membrane to hand off its TA cargo. Supporting Evidence: file:human/GET3/GET3-uniprot.txt Endoplasmic
GO:0016887 ATP hydrolysis activity	IEA GO_REF:0000120	ACCEPT	Summary: Electronic assignment of the core ATP hydrolysis activity, consistent with experimental IDA and the catalytic activity record. Reason: Correct core molecular function; redundant with IDA/IBA. Supporting Evidence: file:human/GET3/GET3-uniprot.txt ATP hydrolysis is required for insertion.
GO:0045048 protein insertion into ER membrane	IEA GO_REF:0000104	KEEP AS NON CORE	Summary: Electronic (Swiss-Prot keyword/feature transfer) annotation of the parent ER protein-insertion process. Correct but less specific than the TA-insertion term. Reason: Correct but generic parent of GO:0071816, which better captures GET3's role. Supporting Evidence: file:human/GET3/GET3-uniprot.txt ATPase required for the post-translational delivery of tail-
GO:0005515 protein binding	IPI PMID:21516116 Next-generation sequencing to generate interactome datasets.	KEEP AS NON CORE	Summary: High-throughput interactome screen capturing GET3 protein interactions. The bare protein binding term is uninformative. Reason: Bare protein binding from a high-throughput screen; uninformative for the core MF. Supporting Evidence: PMID:21516116 Next-generation sequencing to generate interactome datasets
GO:0005515 protein binding	IPI PMID:21911467 Insight into bacterial virulence mechanisms against host imm...	KEEP AS NON CORE	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. Reason: Incidental xenobiotic (bacterial) interaction from a host-pathogen screen; bare protein binding, not relevant to core function. Supporting Evidence: file:human/GET3/GET3-uniprot.txt O43681; Q56975: yscD
GO:0005515 protein binding	IPI PMID:25416956 A proteome-scale map of the human interactome network.	KEEP AS NON CORE	Summary: Proteome-scale human interactome map; source of IntAct partners including ER/secretory and TA-like proteins. Bare protein binding is uninformative. Reason: High-throughput interactome; bare protein binding term is uninformative. Supporting Evidence: PMID:25416956 A proteome-scale map of the human interactome network
GO:0005515 protein binding	IPI PMID:28514442 Architecture of the human interactome defines protein commun...	KEEP AS NON CORE	Summary: Human interactome architecture study; captures GET3 interactions including the functionally relevant CAMLG partner, but uses the uninformative bare protein binding term. Reason: Records real interactions (including CAMLG) but bare protein binding is uninformative; functional partners are captured via GET complex membership. Supporting Evidence: file:human/GET3/GET3-uniprot.txt O43681; P49069: CAMLG
GO:0005515 protein binding	IPI PMID:32296183 A reference map of the human binary protein interactome.	KEEP AS NON CORE	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. Reason: High-throughput Y2H interactome; bare protein binding is uninformative. Supporting Evidence: PMID:32296183 A reference map of the human binary protein interactome
GO:0005515 protein binding	IPI PMID:33961781 Dual proteome-scale networks reveal cell-specific remodeling...	KEEP AS NON CORE	Summary: Proteome-scale cell-specific interactome network; captures GET3 interactions including CAMLG. Bare protein binding is uninformative. Reason: High-throughput interactome; bare protein binding is uninformative. Supporting Evidence: file:human/GET3/GET3-uniprot.txt O43681; P49069: CAMLG
GO:0005515 protein binding	IPI PMID:40205054 Multimodal cell maps as a foundation for structural and func...	KEEP AS NON CORE	Summary: Multimodal cell map study; captures GET3 protein interactions including CAMLG. Bare protein binding is uninformative. Reason: High-throughput interactome; bare protein binding is uninformative. Supporting Evidence: file:human/GET3/GET3-uniprot.txt O43681; P49069: CAMLG
GO:0043529 GET complex	IEA GO_REF:0000120	ACCEPT	Summary: Electronic assignment of GET complex membership. GET3/TRC40 is a defining subunit of the GET complex (GET1/WRB + CAMLG/GET2 + GET3/TRC40). Reason: Core cellular component; consistent with experimental IDA/IPI evidence. Supporting Evidence: file:human/GET3/GET3-uniprot.txt Component of the Golgi to ER
GO:0071816 tail-anchored membrane protein insertion into ER membrane	IEA GO_REF:0000120	ACCEPT	Summary: Electronic assignment of the core TA-insertion process, consistent with experimental evidence. Reason: Correct core process; redundant with IMP/IDA/IBA. Supporting Evidence: file:human/GET3/GET3-uniprot.txt ATPase required for the post-translational delivery of tail-
GO:0005654 nucleoplasm	IDA GO_REF:0000052	KEEP AS NON CORE	Summary: HPA immunofluorescence nucleoplasm localization. A secondary localization not connected to the core cytosolic TA-targeting function. Reason: HPA-derived secondary localization; not part of the core GET-pathway function. Supporting Evidence: file:human/GET3/GET3-uniprot.txt Nucleus, nucleolus
GO:0005730 nucleolus	IDA GO_REF:0000052	KEEP AS NON CORE	Summary: HPA immunofluorescence nucleolar localization, consistent with the legacy nucleolar distribution reported for the arsenite-ATPase. Secondary to the core function. Reason: Secondary/legacy localization; not part of the core cytosolic targeting function. Supporting Evidence: file:human/GET3/GET3-uniprot.txt Nucleus, nucleolus
GO:0005737 cytoplasm	EXP PMID:17382883 Identification of a targeting factor for posttranslational m...	ACCEPT	Summary: Direct experimental cytoplasmic localization from the study that identified TRC40/Asna-1 as the cytosolic TA-targeting ATPase. Reason: Core compartment; GET3 acts as a cytosolic targeting factor. Supporting Evidence: PMID:17382883 cytosolic TMD recognition complex (TRC) that targets TA proteins for insertion into the ER membrane
GO:0005737 cytoplasm	EXP PMID:21444755 WRB is the receptor for TRC40/Asna1-mediated insertion of ta...	ACCEPT	Summary: Direct experimental cytoplasmic localization, consistent with GET3/TRC40 being a conserved cytosolic ATPase. Reason: Core compartment; corroborated by multiple experimental sources. Supporting Evidence: PMID:21444755 TRC40/Asna1 (Get3 in yeast)
GO:0005783 endoplasmic reticulum	EXP PMID:17382883 Identification of a targeting factor for posttranslational m...	ACCEPT	Summary: Direct experimental ER localization; GET3 docks on the ER membrane to deliver its TA cargo to the WRB/CAML receptor. Reason: Correct; GET3 transiently associates with the ER during TA delivery. Supporting Evidence: PMID:17382883 targets TA proteins for insertion into the ER membrane
GO:0005783 endoplasmic reticulum	EXP PMID:21444755 WRB is the receptor for TRC40/Asna1-mediated insertion of ta...	ACCEPT	Summary: Direct experimental ER localization, consistent with GET3 delivering TA proteins to the ER membrane receptor. Reason: Correct; GET3 visits the ER to hand off TA cargo. Supporting Evidence: PMID:21444755 delivers them to the ER membrane for insertion
GO:0005783 endoplasmic reticulum	EXP PMID:31461301 Biallelic Variants in ASNA1, Encoding a Cytosolic Targeting ...	ACCEPT	Summary: Experimental ER localization from the ASNA1 cardiomyopathy study, in which ASNA1 mediates TA-protein insertion into the ER membrane. Reason: Correct; GET3 associates with the ER membrane during TA delivery. Supporting Evidence: PMID:31461301 mediates insertion of TA (tail-anchored) proteins into the endoplasmic reticulum (ER) membrane
GO:0016887 ATP hydrolysis activity	IDA PMID:8884272 Isolation of the ATP-binding human homolog of the arsA compo...	ACCEPT	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. Reason: Core molecular function with direct biochemical (IDA) support. Supporting Evidence: PMID:8884272 hARSA-I is an ATPase
GO:0016887 ATP hydrolysis activity	IDA PMID:9712828 Biochemical characterization of the human arsenite-stimulate...	ACCEPT	Summary: Direct biochemical characterization of the recombinant human protein measuring basal ATPase activity and ATP kinetics. Core ATPase MF. Reason: Core molecular function with direct biochemical (IDA) support; KM/Vmax for ATP determined. Supporting Evidence: PMID:9712828 ATPase activity
GO:0005789 endoplasmic reticulum membrane	NAS PMID:32910895 Structural Basis of Tail-Anchored Membrane Protein Biogenesi...	ACCEPT	Summary: ComplexPortal NAS assertion of ER membrane localization, reflecting the GET complex (within which GET3 docks) residing at the ER membrane. Reason: Correct; GET3 associates with the ER membrane GET complex during TA handoff. Supporting Evidence: PMID:32910895 an insertase (yeast Get1/Get2 or mammalian WRB/CAML) that captures the TA from a cytoplasmic chaperone
GO:0043529 GET complex	IPI PMID:32910895 Structural Basis of Tail-Anchored Membrane Protein Biogenesi...	ACCEPT	Summary: ComplexPortal IPI assignment of GET complex membership from the cryo-EM structure of the human GET insertase complex with bound GET3/TRC40. Reason: Core cellular component; structurally demonstrated. Supporting Evidence: PMID:32910895 captures the TA from a cytoplasmic chaperone (Get3 or TRC40, respectively)
GO:0045048 protein insertion into ER membrane	NAS PMID:23041287 Molecular machinery for insertion of tail-anchored membrane ...	KEEP AS NON CORE	Summary: ComplexPortal NAS assertion of the (parent) ER protein-insertion process; GET3/TRC40 targets TA proteins to the WRB/CAML receptor for insertion. Reason: Correct parent of GO:0071816; redundant general term. Supporting Evidence: PMID:23041287 an ATPase targeting newly synthesized TA proteins
GO:0071816 tail-anchored membrane protein insertion into ER membrane	IMP PMID:31461301 Biallelic Variants in ASNA1, Encoding a Cytosolic Targeting ...	ACCEPT	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. Reason: Core biological process with mutant-phenotype (IMP) support directly linking ASNA1 function to TA insertion. Supporting Evidence: PMID:31461301 inefficient in facilitating TA protein insertion into the ER membrane
GO:0140597 protein carrier chaperone	IDA PMID:23610396 Precise timing of ATPase activation drives targeting of tail...	ACCEPT	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. Reason: Core molecular function; GET3 carries the TA-protein cargo as a soluble TMD chaperone, demonstrated by IDA. Supporting Evidence: PMID:23610396 Get3 harnesses the energy from ATP to drive PMID:37963916 the Get3 chaperone captures the TA protein substrate and delivers it to the Get1/Get2 membrane protein complex (GET insertase)
GO:0043529 GET complex	IDA PMID:32910895 Structural Basis of Tail-Anchored Membrane Protein Biogenesi...	ACCEPT	Summary: Direct structural evidence (cryo-EM) placing GET3/TRC40 within the GET insertase complex. Reason: Core cellular component; structurally demonstrated. Supporting Evidence: PMID:32910895 captures the TA from a cytoplasmic chaperone (Get3 or TRC40, respectively)
GO:0071816 tail-anchored membrane protein insertion into ER membrane	IMP PMID:23041287 Molecular machinery for insertion of tail-anchored membrane ...	ACCEPT	Summary: Mutant-phenotype evidence supporting GET3/TRC40's role as the ATPase targeting TA proteins for insertion, delivered to the CAML/WRB receptor complex. Reason: Core biological process with IMP support. Supporting Evidence: PMID:23041287 an ATPase targeting newly synthesized TA proteins
GO:0043529 GET complex	IPI PMID:23041287 Molecular machinery for insertion of tail-anchored membrane ...	ACCEPT	Summary: IPI identification of GET3/TRC40 in the receptor (GET) complex with WRB and CAML. Reason: Core cellular component; demonstrated by complex identification. Supporting Evidence: PMID:23041287 CAML and WRB as components of the TRC40 receptor complex
GO:0071816 tail-anchored membrane protein insertion into ER membrane	IDA PMID:25535373 Bag6 complex contains a minimal tail-anchor-targeting module...	ACCEPT	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. Reason: Core biological process; IDA demonstrating the TA-loading step onto GET3. Supporting Evidence: PMID:25535373 substrate transfer from small glutamine-rich tetratricopeptide repeat-containing
GO:0070062 extracellular exosome	HDA PMID:19056867 Large-scale proteomics and phosphoproteomics of urinary exos...	KEEP AS NON CORE	Summary: High-throughput urinary exosome proteomics catalog hit. Not indicative of a core localization or function for GET3. Reason: Proteomic catalog localization; not part of GET3's core cytosolic targeting function. Supporting Evidence: PMID:19056867 Large-scale proteomics and phosphoproteomics of urinary exosomes
GO:0005730 nucleolus	TAS PMID:9736449 Dual cytoplasmic and nuclear distribution of the novel arsen...	KEEP AS NON CORE	Summary: Legacy nucleolar localization reported in the early arsenite-ATPase characterization (cytoplasmic, perinuclear, and nucleolar distribution). Secondary to the core cytosolic targeting function. Reason: Legacy localization from early arsA-homolog work; not part of the core GET-pathway function. Supporting Evidence: PMID:9736449 Dual cytoplasmic and nuclear distribution of the novel arsenite-stimulated human ATPase
GO:0005737 cytoplasm	TAS PMID:9736449 Dual cytoplasmic and nuclear distribution of the novel arsen...	ACCEPT	Summary: Cytoplasmic localization from the early arsenite-ATPase study, consistent with GET3's primary cytosolic site of action. Reason: Correct primary compartment; corroborated by experimental EXP evidence. Supporting Evidence: PMID:9736449 Dual cytoplasmic and nuclear distribution

Gene Description

Existing Annotations Review

Core Functions

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.

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.

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