id: P55039 gene_symbol: DRG2 product_type: PROTEIN status: COMPLETE taxon: id: NCBITaxon:9606 label: Homo sapiens description: DRG2 (Developmentally-regulated GTP-binding protein 2) is a translational GTPase of the TRAFAC class, OBG-HflX-like superfamily (DRG/OBG GTPase family). It catalyzes hydrolysis of GTP to GDP, using Mg2+ as cofactor, and belongs to the conserved DRG family of ribosome-associated GTPases. DRG2 is stabilized by and functions together with its DFRP (DRG family regulatory protein) cofactor DFRP2/RWDD1, whose binding protects DRG2 from polyubiquitination and proteolytic degradation. DRG2 is a substrate of the JmjC oxygenase JMJD7, which catalyzes (3S)-lysyl hydroxylation at Lys-21; this modification is associated with RNA binding and a role in translation. DRG2 is found in both the cytoplasm and the nucleus and is most highly expressed in skeletal muscle, heart and kidney. Through its GTPase activity and ribosome/translation association it is implicated in regulation of protein synthesis, and at the cellular level it has been linked to cell proliferation and growth control. existing_annotations: - term: id: GO:0002181 label: cytoplasmic translation evidence_type: IBA original_reference_id: GO_REF:0000033 qualifier: involved_in review: summary: DRG2 is a ribosome-associated translational GTPase, so a broad "cytoplasmic translation" process annotation is plausible by phylogenetic inference. Recent work frames DRG2 (with its paralog DRG1) as a translation factor that associates with stalled/paused ribosomes through its DFRP2 partner, but the detailed mechanism (e.g. stimulation of peptidyl transfer) is largely extrapolated from DRG1, bacterial Obg, and yeast Rbg2 orthologs rather than directly demonstrated for human DRG2. The specific regulatory role of human DRG2 in translation therefore remains imprecisely defined, so this broad term is retained as non-core. action: KEEP_AS_NON_CORE reason: DRG/OBG-family GTPases associate with translating ribosomes, but the broad cytoplasmic translation term does not capture a specific mechanism; the informative core is the GTPase activity. The falcon deep-research synthesis supports a ribosome/translation association for DRG2 but the stalled-ribosome rescue mechanism is inferred from paralogs and ortholog structures, so the term is kept non-core in line with handling of broad translation terms for ribosome-associated factors. supported_by: - reference_id: file:human/DRG2/DRG2-uniprot.txt supporting_text: may bind to RNA and play a role in translation - reference_id: file:human/DRG2/DRG2-deep-research-falcon.md supporting_text: DRG2, in complex with its binding partner DFRP2, associates with ribosomes that have paused or stalled during translation elongation - term: id: GO:0003924 label: GTPase activity evidence_type: IEA original_reference_id: GO_REF:0000120 qualifier: enables review: summary: DRG2 hydrolyzes GTP to GDP; GTPase activity is the core molecular function. Electronic transfer here agrees with direct experimental (IDA) evidence. action: ACCEPT reason: GTPase activity is experimentally demonstrated and is the defining catalytic function of DRG2. supported_by: - reference_id: file:human/DRG2/DRG2-uniprot.txt supporting_text: Catalyzes the conversion of GTP to GDP through hydrolysis of - term: id: GO:0005525 label: GTP binding evidence_type: IEA original_reference_id: GO_REF:0000002 qualifier: enables review: summary: DRG2 binds GTP as the substrate for its GTPase activity. GTP binding is a structural prerequisite for, and subordinate to, the catalytic GTPase function. action: KEEP_AS_NON_CORE reason: GTP binding is real but the informative core molecular function is GTPase activity; retained as a supporting non-core annotation. supported_by: - reference_id: file:human/DRG2/DRG2-uniprot.txt supporting_text: hydrolysis of the gamma-phosphate bond in GTP - term: id: GO:0005634 label: nucleus evidence_type: IEA original_reference_id: GO_REF:0000044 qualifier: located_in review: summary: DRG2 has a documented nuclear pool, consistent with the experimental (IDA) nuclear localization. action: ACCEPT reason: Nuclear localization is experimentally supported; DRG2 is both nuclear and cytoplasmic. supported_by: - reference_id: file:human/DRG2/DRG2-uniprot.txt supporting_text: 'SUBCELLULAR LOCATION: Nucleus' - term: id: GO:0005737 label: cytoplasm evidence_type: IEA original_reference_id: GO_REF:0000044 qualifier: located_in review: summary: DRG2 is cytoplasmic, consistent with its ribosome/translation association and with the experimental (IDA) cytoplasm annotation. action: ACCEPT reason: Cytoplasmic localization is experimentally supported and consistent with its function. supported_by: - reference_id: file:human/DRG2/DRG2-uniprot.txt supporting_text: Cytoplasm - term: id: GO:0005515 label: protein binding evidence_type: IPI original_reference_id: PMID:16189514 qualifier: enables review: summary: Interaction with RWDD1/DFRP2 (Q9H446), the DRG-family regulatory cofactor that stabilizes DRG2. The bare protein binding term is uninformative, though this is DRG2's key functional partner; the falcon deep-research synthesis reiterates that DFRP2 binding is essential for DRG2 protein stability and its loss leads to rapid DRG2 degradation. action: KEEP_AS_NON_CORE reason: Records the functionally important DRG2-RWDD1/DFRP2 interaction, but the term is uninformative; the regulatory relationship is described in the gene narrative. supported_by: - reference_id: file:human/DRG2/DRG2-goa.tsv supporting_text: GO:0005515 protein binding molecular_function ECO:0000353 IPI PMID:16189514 UniProtKB:Q9H446 - reference_id: file:human/DRG2/DRG2-deep-research-falcon.md supporting_text: This interaction is essential for DRG2 stability; loss of DFRP2 leads to rapid degradation of DRG2 - term: id: GO:0005515 label: protein binding evidence_type: IPI original_reference_id: PMID:25416956 qualifier: enables review: summary: Y2H interactome interaction with RWDD1/DFRP2 (Q9H446). Bare protein binding is uninformative. action: KEEP_AS_NON_CORE reason: Records the DRG2-RWDD1 interaction but uninformative term; not core. supported_by: - reference_id: file:human/DRG2/DRG2-goa.tsv supporting_text: GO:0005515 protein binding molecular_function ECO:0000353 IPI PMID:25416956 UniProtKB:Q9H446 - term: id: GO:0005515 label: protein binding evidence_type: IPI original_reference_id: PMID:28514442 qualifier: enables review: summary: Interactome interaction with RWDD1/DFRP2 (Q9H446). Bare protein binding is uninformative. action: KEEP_AS_NON_CORE reason: Records the DRG2-RWDD1 interaction but uninformative term; not core. supported_by: - reference_id: file:human/DRG2/DRG2-goa.tsv supporting_text: GO:0005515 protein binding molecular_function ECO:0000353 IPI PMID:28514442 UniProtKB:Q9H446 - term: id: GO:0005515 label: protein binding evidence_type: IPI original_reference_id: PMID:32296183 qualifier: enables review: summary: HuRI binary interactome capturing multiple DRG2 interactions including RWDD1/DFRP2 (Q9H446), JMJD7 (P0C870), EIF4A3 (P38919), NAB2 (Q15742) and TSSK3 (Q96PN8). Bare protein binding is uninformative; RWDD1 and JMJD7 are the biologically meaningful partners. action: KEEP_AS_NON_CORE reason: Records real interactions (RWDD1, JMJD7) but uninformative term; captured by the regulatory/PTM narrative. Other partners are likely incidental Y2H hits. supported_by: - reference_id: file:human/DRG2/DRG2-goa.tsv supporting_text: GO:0005515 protein binding molecular_function ECO:0000353 IPI PMID:32296183 UniProtKB:P0C870 - term: id: GO:0005515 label: protein binding evidence_type: IPI original_reference_id: PMID:32814053 qualifier: enables review: summary: Neurodegeneration interactome capturing DRG2 interactions with SPRED1 (Q7Z699) and JPH3 (Q8WXH2). Bare protein binding is uninformative and these are isolated HT hits. action: KEEP_AS_NON_CORE reason: Isolated high-throughput interactions with partners unrelated to DRG2's GTPase/translation function; uninformative term, not core. supported_by: - reference_id: file:human/DRG2/DRG2-goa.tsv supporting_text: GO:0005515 protein binding molecular_function ECO:0000353 IPI PMID:32814053 UniProtKB:Q7Z699 - term: id: GO:0005515 label: protein binding evidence_type: IPI original_reference_id: PMID:33961781 qualifier: enables review: summary: BioPlex affinity-purification capturing DRG2-RWDD1/DFRP2 (Q9H446). Bare protein binding is uninformative. action: KEEP_AS_NON_CORE reason: Records the DRG2-RWDD1 interaction but uninformative term; not core. supported_by: - reference_id: file:human/DRG2/DRG2-goa.tsv supporting_text: GO:0005515 protein binding molecular_function ECO:0000353 IPI PMID:33961781 UniProtKB:Q9H446 - term: id: GO:0005515 label: protein binding evidence_type: IPI original_reference_id: PMID:40205054 qualifier: enables review: summary: Multimodal cell-maps interactome capturing DRG2-RWDD1/DFRP2 (Q9H446). Bare protein binding is uninformative. action: KEEP_AS_NON_CORE reason: Records the DRG2-RWDD1 interaction but uninformative term; not core. supported_by: - reference_id: file:human/DRG2/DRG2-goa.tsv supporting_text: GO:0005515 protein binding molecular_function ECO:0000353 IPI PMID:40205054 UniProtKB:Q9H446 - term: id: GO:0005829 label: cytosol evidence_type: IDA original_reference_id: GO_REF:0000052 qualifier: located_in review: summary: HPA immunofluorescence cytosolic localization, consistent with DRG2's cytoplasmic site of action. action: ACCEPT reason: Direct evidence for cytosolic localization, consistent with function. supported_by: - reference_id: file:human/DRG2/DRG2-goa.tsv supporting_text: GO:0005829 cytosol cellular_component ECO:0000314 IDA - term: id: GO:0005829 label: cytosol evidence_type: TAS original_reference_id: Reactome:R-HSA-9629578 qualifier: located_in review: summary: Reactome curated cytosolic localization, consistent with the IDA cytosol annotation. action: ACCEPT reason: Correct cytosolic localization. supported_by: - reference_id: file:human/DRG2/DRG2-goa.tsv supporting_text: GO:0005829 cytosol cellular_component ECO:0000304 TAS Reactome:R-HSA-9629578 - term: id: GO:0003723 label: RNA binding evidence_type: IDA original_reference_id: PMID:29915238 qualifier: enables review: summary: DRG2 binds RNA, an activity linked to JMJD7-mediated (3S)-lysyl hydroxylation at Lys-21 and to its translation role. A real but conditional/secondary activity. action: KEEP_AS_NON_CORE reason: RNA binding is experimentally demonstrated but is a hydroxylation-dependent, secondary activity relative to the core GTPase function. supported_by: - reference_id: file:human/DRG2/DRG2-uniprot.txt supporting_text: When hydroxylated at C-3 of 'Lys-21' by JMJD7, may bind to RNA and play a role in translation - term: id: GO:0003924 label: GTPase activity evidence_type: IDA original_reference_id: PMID:29915238 qualifier: enables review: summary: Direct experimental demonstration that DRG2 hydrolyzes GTP. This is the core molecular function. action: ACCEPT reason: IDA evidence for GTP hydrolysis establishes GTPase activity as DRG2's core catalytic function. supported_by: - reference_id: file:human/DRG2/DRG2-uniprot.txt supporting_text: Catalyzes the conversion of GTP to GDP through hydrolysis of - term: id: GO:0005515 label: protein binding evidence_type: IPI original_reference_id: PMID:29915238 qualifier: enables review: summary: Direct interaction with JMJD7 (P0C870), the JmjC oxygenase that hydroxylates DRG2 at Lys-21. Bare protein binding is uninformative, but this is a biologically meaningful enzyme-substrate interaction. action: KEEP_AS_NON_CORE reason: Records the functionally relevant DRG2-JMJD7 (hydroxylase) interaction, but the term is uninformative; the PTM relationship is captured in the gene narrative. supported_by: - reference_id: file:human/DRG2/DRG2-uniprot.txt supporting_text: Interacts with JMJD7; this interaction is direct - term: id: GO:0005634 label: nucleus evidence_type: IDA original_reference_id: PMID:29915238 qualifier: located_in review: summary: Direct evidence for nuclear localization of DRG2. action: ACCEPT reason: Experimentally supported nuclear pool. supported_by: - reference_id: file:human/DRG2/DRG2-goa.tsv supporting_text: GO:0005634 nucleus cellular_component ECO:0000314 IDA PMID:29915238 - term: id: GO:0005737 label: cytoplasm evidence_type: IDA original_reference_id: PMID:29915238 qualifier: located_in review: summary: Direct evidence for cytoplasmic localization of DRG2. action: ACCEPT reason: Experimentally supported cytoplasmic localization, consistent with function. supported_by: - reference_id: file:human/DRG2/DRG2-goa.tsv supporting_text: GO:0005737 cytoplasm cellular_component ECO:0000314 IDA PMID:29915238 - term: id: GO:0016020 label: membrane evidence_type: HDA original_reference_id: PMID:19946888 qualifier: located_in review: summary: DRG2 appeared in a high-throughput NK-cell membrane-proteome dataset. Generic, non-specific localization for a cytosolic/nuclear GTPase. action: MARK_AS_OVER_ANNOTATED reason: Generic "membrane" from a high-throughput proteomics survey; uninformative and inconsistent with DRG2's documented cytoplasmic/nuclear localization. supported_by: - reference_id: file:human/DRG2/DRG2-goa.tsv supporting_text: GO:0016020 membrane cellular_component ECO:0007005 HDA PMID:19946888 - term: id: GO:0005525 label: GTP binding evidence_type: TAS original_reference_id: PMID:7929244 qualifier: enables review: summary: Original (1994) identification of DRG2 as a GTP-binding protein. GTP binding is real but subordinate to the GTPase catalytic function. action: KEEP_AS_NON_CORE reason: GTP binding is supported but the informative core MF is GTPase activity; retained as a supporting non-core annotation. supported_by: - reference_id: file:human/DRG2/DRG2-goa.tsv supporting_text: GO:0005525 GTP binding molecular_function ECO:0000304 TAS PMID:7929244 - term: id: GO:0007165 label: signal transduction evidence_type: TAS original_reference_id: PMID:7929244 qualifier: involved_in review: summary: A vague legacy "signal transduction" inference from the 1994 paper that identified DRG2 as a GTP-binding protein repressed in SV40-transformed fibroblasts. No specific signaling pathway is established; DRG2 is a translational GTPase, not a classical signaling GTPase. action: MARK_AS_OVER_ANNOTATED reason: Over-broad, unsupported by a defined pathway; DRG2's function is as a translational GTPase rather than a signal-transducing GTPase. supported_by: - reference_id: file:human/DRG2/DRG2-goa.tsv supporting_text: GO:0007165 signal transduction biological_process ECO:0000304 TAS PMID:7929244 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. findings: [] - id: GO_REF:0000052 title: Gene Ontology annotation based on curation of immunofluorescence data. findings: [] - id: GO_REF:0000120 title: Combined Automated Annotation using Multiple IEA Methods. findings: [] - id: PMID:16189514 title: Towards a proteome-scale map of the human protein-protein interaction network. findings: [] - id: PMID:19946888 title: Defining the membrane proteome of NK cells. findings: [] - id: PMID:25416956 title: A proteome-scale map of the human interactome network. findings: [] - id: PMID:28514442 title: Architecture of the human interactome defines protein communities and disease networks. findings: [] - id: PMID:29915238 title: The Jumonji-C oxygenase JMJD7 catalyzes (3S)-lysyl hydroxylation of TRAFAC GTPases. reference_review: relevance: HIGH correctness: VERIFIED review_notes: "Cached publication (publications/PMID_29915238.md) PubMed title matches the YAML title exactly; body explicitly names developmentally regulated GTP-binding proteins 1 and 2 (DRG1/2) as TRAFAC-family GTPases and JMJD7 substrates, supporting DRG2's core GTPase molecular function and the JMJD7 hydroxylation/RNA-binding context." findings: - statement: DRG2 is a TRAFAC GTPase that hydrolyzes GTP, binds RNA, and is a substrate of JMJD7-catalyzed (3S)-lysyl hydroxylation; interacts directly with JMJD7. reference_section_type: RESULTS - id: PMID:32296183 title: A reference map of the human binary protein interactome. findings: [] - id: PMID:32814053 title: Interactome Mapping Provides a Network of Neurodegenerative Disease Proteins and Uncovers Widespread Protein Aggregation in Affected Brains. findings: [] - id: PMID:33961781 title: Dual proteome-scale networks reveal cell-specific remodeling of the human interactome. findings: [] - id: PMID:40205054 title: Multimodal cell maps as a foundation for structural and functional genomics. findings: [] - id: PMID:7929244 title: A novel GTP-binding protein which is selectively repressed in SV40 transformed fibroblasts. reference_review: relevance: HIGH correctness: VERIFIED review_notes: "Original DRG2 cloning paper. Verified against a checkable anchor: UniProt P55039 (DRG2_HUMAN, 364 AA) cites PubMed=7929244 as its nucleotide sequence reference, and the cached abstract (364-aa, ~41 kDa GTP-binding protein with conserved G1-G5 motifs defining a new GTPase subfamily) matches DRG2. Establishes DRG2 as a GTP-binding protein, the basis for its core GTPase MF." findings: - statement: Original identification of DRG2 as a GTP-binding protein selectively repressed in SV40-transformed fibroblasts. reference_section_type: RESULTS - id: Reactome:R-HSA-9629578 title: Reactome cytosolic localization annotation for DRG2. findings: [] - id: file:human/DRG2/DRG2-deep-research-falcon.md title: Falcon deep research report for DRG2 reference_review: relevance: HIGH correctness: UNVERIFIED review_notes: "LLM-synthesized (Edison/Falcon) deep-research report; treated as UNVERIFIED pending primary-source checking. DRG2-SPECIFIC, well-anchored claims: DRG2 forms an obligate heterodimer with DFRP2/RWDD1 that stabilizes it against degradation; DRG2 is a JMJD7 substrate hydroxylated at Lys21 in the N-terminal HTH domain, which promotes RNA binding without altering stability/GTPase activity (Markolovic 2018, PMID:29915238); DRG2 localizes to cytoplasm, nucleus and Rab5-positive early endosomes; the DRG2-specific endosomal/Rab5 and PD-L1 recycling role derives from a genuine DRG2 paper (Choi 2024, doi:10.1038/s41420-024-02027-x). GENERALIZED / EXTRAPOLATED-FROM-PARALOG claims to treat cautiously: the 'general translation factor that rescues stalled/paused ribosomes and stimulates peptidyl transfer' mechanism rests on DRG1, bacterial Obg, and yeast Rbg2 orthologs plus 2024 preprints (jin2024/hawk2024, westrip2024), and the report itself states direct biochemical characterization of human DRG2 GTPase activity (e.g. K+-dependence) is limited and inferred from DRG1. The Gcn1-mediated collided-ribosome recruitment and DNAJC2/co-chaperone links are speculative. No annotation was added or removed on the basis of this report alone; it is used only to corroborate the existing ribosome/translation framing." findings: - statement: DRG2, with its paralog DRG1, is reported as a translation factor that associates with stalled/paused ribosomes via its DFRP2 partner; human-specific GTPase biochemistry is largely inferred from DRG1 and ortholog studies. reference_section_type: RESULTS - id: file:human/DRG2/DRG2-uniprot.txt title: UniProt entry P55039 (DRG2_HUMAN), Developmentally-regulated GTP-binding protein 2. findings: - statement: DRG2 is a TRAFAC-class OBG/DRG-family GTPase that hydrolyzes GTP to GDP (Mg2+ cofactor); when hydroxylated at Lys-21 by JMJD7 it may bind RNA and act in translation; stabilized by DFRP2/RWDD1; localizes to cytoplasm and nucleus. reference_section_type: OTHER core_functions: - description: Translational GTPase of the DRG/OBG family that catalyzes hydrolysis of GTP to GDP (Mg2+-dependent); functions in association with its DFRP2/RWDD1 cofactor and is implicated in regulation of translation. molecular_function: id: GO:0003924 label: GTPase activity locations: - id: GO:0005737 label: cytoplasm - id: GO:0005634 label: nucleus supported_by: - reference_id: file:human/DRG2/DRG2-uniprot.txt supporting_text: Catalyzes the conversion of GTP to GDP through hydrolysis of - reference_id: file:human/DRG2/DRG2-uniprot.txt supporting_text: Belongs to the TRAFAC class OBG-HflX-like GTPase proposed_new_terms: [] suggested_questions: - question: Does human DRG2 physically associate with translating ribosomes (as known for DRG-family GTPases) and at what step does its GTPase cycle act on translation? - question: How does DFRP2/RWDD1 binding regulate DRG2's GTPase activity, stability, and ribosome association? - question: What is the functional role of JMJD7-mediated Lys-21 hydroxylation in switching DRG2 between GTPase and RNA-binding/translation activities? suggested_experiments: - description: Ribosome co-sedimentation / polysome profiling with tagged DRG2 (with and without RWDD1) to test ribosome association and translational state dependence. - description: In vitro GTP-hydrolysis assays of DRG2 alone and in complex with DFRP2/RWDD1 to define cofactor effects on GTPase kinetics. - description: Compare RNA binding and translation phenotypes of wild-type DRG2 versus a Lys-21 hydroxylation-deficient mutant and in JMJD7-knockout cells.