id: Q9BX10 gene_symbol: GTPBP2 product_type: PROTEIN status: COMPLETE taxon: id: NCBITaxon:9606 label: Homo sapiens description: GTPBP2 (GTP-binding protein 2) is a cytoplasmic translational GTPase of the TRAFAC-class translation-factor superfamily, related to eEF1A, eRF3, Hbs1 and its paralog GTPBP1. It partners the ribosome-rescue factor PELO and functions in the rescue of ribosomes stalled because of non-functional or deficient tRNA, a role that is especially critical in neurons. Unlike its paralog GTPBP1, GTPBP2 lacks eEF1A-like elongation activity and does not stimulate exosomal mRNA degradation; it has only weak GTP-binding activity that is stimulated by aminoacyl-tRNA. Loss of GTPBP2 (in the context of a destabilized brain-specific tRNA in mouse, and through biallelic loss-of-function in humans) leads to ribosome stalling and neurodegeneration; human GTPBP2 deficiency causes Jaberi-Elahi syndrome, characterized by developmental delay, intellectual disability, movement abnormalities and cerebellar atrophy. alternative_products: - name: 1 {ECO:0000269|PubMed:10833435} id: Q9BX10-1 - name: 2 {ECO:0000269|PubMed:11054535} id: Q9BX10-2 sequence_note: VSP_052154 - name: 3 {ECO:0000269|PubMed:14702039} id: Q9BX10-3 sequence_note: VSP_052154, VSP_052156 - name: 4 {ECO:0000269|PubMed:14574404} id: Q9BX10-4 sequence_note: VSP_052155 existing_annotations: - term: id: GO:0006414 label: translational elongation evidence_type: IBA original_reference_id: GO_REF:0000033 qualifier: involved_in review: summary: Phylogenetic transfer of a translational-elongation role from the eEF1A/GTPBP family. However, GTPBP2 was directly shown to lack elongation activity; its actual role is ribosome rescue of stalled (deficient-tRNA) ribosomes. Mouse genetics localize the defect to elongation quality control rather than productive elongation - GTPBP2 deficiency causes prolonged ribosome pausing at AGA arginine codons when the cognate tRNA-Arg(UCU) pool is limiting. action: MARK_AS_OVER_ANNOTATED reason: GTPBP2 lacks the eEF1A-like elongation activity that the family-level IBA implies; the term over-states its function. The accurate role is rescue/quality control of stalled (deficient-tRNA) ribosomes, not productive translational elongation. supported_by: - reference_id: file:human/GTPBP2/GTPBP2-uniprot.txt supporting_text: Involved in the rescue of ribosome stalling due to the presence of non-functional tRNA - reference_id: file:human/GTPBP2/GTPBP2-deep-research-falcon.md supporting_text: GTPBP2 deficiency causes prolonged ribosome pausing specifically at AGA arginine codons when the cognate tRNA_Arg(UCU) is limiting - term: id: GO:0003924 label: GTPase activity evidence_type: IEA original_reference_id: GO_REF:0000002 qualifier: enables review: summary: GTPBP2 is a GTPase by family, but it was directly shown to have only very low GTP-binding activity; GTPase activity is plausible but weak. action: KEEP_AS_NON_CORE reason: Predicted GTPase activity is consistent with the GTPase fold, but experimentally GTPBP2's nucleotide handling is weak; retained as non-core rather than the defining function. supported_by: - reference_id: file:human/GTPBP2/GTPBP2-uniprot.txt supporting_text: Has very low GTP-binding activity - term: id: GO:0005525 label: GTP binding evidence_type: IEA original_reference_id: GO_REF:0000002 qualifier: enables review: summary: GTPBP2 binds GTP, though weakly; binding is stimulated by aminoacyl-tRNA. action: ACCEPT reason: GTP binding is directly observed (albeit weak) and is consistent with the GTPase fold. supported_by: - reference_id: file:human/GTPBP2/GTPBP2-uniprot.txt supporting_text: Has very low GTP-binding activity - term: id: GO:1904678 label: alpha-aminoacyl-tRNA binding evidence_type: IEA original_reference_id: GO_REF:0000117 qualifier: enables review: summary: GTPBP2 binds aminoacyl-tRNA; Phe-tRNA stimulates its GTP binding, indicating a functional aa-tRNA interaction. action: ACCEPT reason: Directly supported by the observation that aa-tRNA stimulates GTPBP2 GTP binding. supported_by: - reference_id: file:human/GTPBP2/GTPBP2-uniprot.txt supporting_text: Has very low GTP-binding activity - term: id: GO:0005515 label: protein binding evidence_type: IPI original_reference_id: PMID:23455924 qualifier: enables review: summary: Y2H interactome (protein methyltransferase network) capturing GTPBP2 interactions (e.g. PRMT5/PRMT6). Bare protein binding is uninformative and unrelated to the rescue function. action: KEEP_AS_NON_CORE reason: Records physical interactions but the generic term adds nothing to GTPBP2's ribosome-rescue function. supported_by: - reference_id: file:human/GTPBP2/GTPBP2-uniprot.txt supporting_text: 'O14744: PRMT5' - term: id: GO:0005515 label: protein binding evidence_type: IPI original_reference_id: PMID:32296183 qualifier: enables review: summary: Binary interactome capturing GTPBP2 interactions, including self-association. Bare protein binding. action: KEEP_AS_NON_CORE reason: Generic term; physical interactions recorded but uninformative for core function. supported_by: - reference_id: file:human/GTPBP2/GTPBP2-uniprot.txt supporting_text: 'Q9BX10: GTPBP2' - term: id: GO:0042802 label: identical protein binding evidence_type: IPI original_reference_id: PMID:32296183 qualifier: enables review: summary: GTPBP2 self-association (homotypic interaction) detected in the binary interactome. action: KEEP_AS_NON_CORE reason: Records a homodimerization-type interaction; not established as functionally central to ribosome rescue. supported_by: - reference_id: file:human/GTPBP2/GTPBP2-uniprot.txt supporting_text: 'Q9BX10: GTPBP2' - term: id: GO:0003746 label: translation elongation factor activity evidence_type: IDA original_reference_id: PMID:30108131 qualifier: enables negated: true review: summary: Directly demonstrated NEGATIVE result - GTPBP2 lacks eEF1A-like elongation activity, distinguishing it from its paralog GTPBP1. The negation is informative and consistent with GTPBP2 acting as a ribosome-rescue / quality-control GTPase rather than a productive elongation factor. action: ACCEPT reason: The negated annotation correctly records that GTPBP2 does NOT enable translation elongation factor activity, a key experimental finding. The codon-specific pausing phenotype reinforces that GTPBP2's role is elongation quality control, not canonical elongation. supported_by: - reference_id: PMID:30108131 supporting_text: GTPBP2 lacked elongation activity and did not stimulate exosomal degradation - reference_id: file:human/GTPBP2/GTPBP2-deep-research-falcon.md supporting_text: This codon-specific function indicates that GTPBP2 acts as a quality control GTPase rather than a canonical elongation factor or metabolic enzyme - term: id: GO:0005525 label: GTP binding evidence_type: IDA original_reference_id: PMID:30108131 qualifier: enables review: summary: Direct demonstration that GTPBP2 binds GTP, albeit weakly, with binding stimulated by aa-tRNA. action: ACCEPT reason: Directly demonstrated (weak) GTP binding. supported_by: - reference_id: file:human/GTPBP2/GTPBP2-uniprot.txt supporting_text: Has very low GTP-binding activity - term: id: GO:1904678 label: alpha-aminoacyl-tRNA binding evidence_type: IDA original_reference_id: PMID:30108131 qualifier: enables review: summary: Direct evidence that aminoacyl-tRNA (Phe-tRNA) interacts with GTPBP2 and stimulates its GTP binding. action: ACCEPT reason: Directly demonstrated aa-tRNA binding. supported_by: - reference_id: file:human/GTPBP2/GTPBP2-uniprot.txt supporting_text: Has very low GTP-binding activity - term: id: GO:0005576 label: extracellular region evidence_type: TAS original_reference_id: Reactome:R-HSA-481007 qualifier: located_in review: summary: Reactome platelet-degranulation localization, reflecting detection of GTPBP2 in platelet alpha-granule releasate; not its functional compartment. action: KEEP_AS_NON_CORE reason: Specialized platelet-biology localization peripheral to GTPBP2's cytoplasmic ribosome-rescue function. supported_by: - reference_id: file:human/GTPBP2/GTPBP2-uniprot.txt supporting_text: Involved in the rescue of ribosome stalling due to the presence of non-functional tRNA - term: id: GO:0031093 label: platelet alpha granule lumen evidence_type: TAS original_reference_id: Reactome:R-HSA-481007 qualifier: located_in review: summary: Reactome platelet alpha-granule lumen localization from platelet proteomics; a specialized context distinct from GTPBP2's core function. action: KEEP_AS_NON_CORE reason: Specialized platelet-biology localization; peripheral and does not reflect GTPBP2's principal cytoplasmic role. supported_by: - reference_id: file:human/GTPBP2/GTPBP2-uniprot.txt supporting_text: Involved in the rescue of ribosome stalling due to the presence of non-functional tRNA 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:0000117 title: Electronic Gene Ontology annotations created by ARBA machine learning models findings: [] - id: PMID:23455924 title: A Y2H-seq approach defines the human protein methyltransferase interactome. findings: [] - id: PMID:30108131 title: Functions of unconventional mammalian translational GTPases GTPBP1 and GTPBP2. reference_review: relevance: HIGH correctness: VERIFIED review_notes: "Cached publications/PMID_30108131.md frontmatter title matches the YAML title; review establishes GTPBP2's translational-GTPase properties (weak aa-tRNA-stimulated GTP binding, no eEF1A-like elongation activity), the basis for the core GTP-binding / ribosome-rescue function." findings: - statement: GTPBP2 lacks eEF1A-like elongation activity and does not stimulate exosomal degradation, distinguishing it from GTPBP1; its weak GTP binding is stimulated by aminoacyl-tRNA. reference_section_type: RESULTS - id: PMID:32296183 title: A reference map of the human binary protein interactome. findings: [] - id: Reactome:R-HSA-481007 title: Exocytosis of platelet alpha granule content findings: [] - id: file:human/GTPBP2/GTPBP2-deep-research-falcon.md title: Falcon deep research report for GTPBP2 reference_review: relevance: MEDIUM correctness: UNVERIFIED review_notes: "LLM-synthesized (Edison Scientific Literature) deep research report. GTPBP2-specific, primary-literature-anchored claims that are usable: the ribosome-rescue / translation-elongation-quality-control role, cooperation with the PELO/HBS1L/ABCE1 rescue machinery, cytosolic ribosome-associated localization, and the codon-specific ribosome pausing at AGA arginine codons under limiting tRNA-Arg(UCU) (from the Ackerman-lab mouse genetics, Ishimura 2016 / Terrey 2020). CAUTION / not relied on here: the report repeatedly folds GTPBP2 together with its paralog GTPBP1 (e.g. the Salpietro 2024 GTPBP1/GTPBP2 syndrome and the GTPBP1 structural / mTORC1 / aa-tRNA-delivery data are GTPBP1-centric and over-generalized to GTPBP2), and it over-imputes canonical translation-factor GTPase mechanism (GTP-hydrolysis-coupled splitting) that has not been directly demonstrated for human GTPBP2, which has only weak GTP binding. Disease/RQC/ISR/NGD framing is review-level and not used to change any molecular-function annotation. Citations are secondary (this report), not the primary papers; correctness left UNVERIFIED for the synthesis." findings: - statement: GTPBP2 is a cytosolic ribosome rescue GTPase acting in translation elongation quality control on stalled 80S ribosomes, functionally allied with the PELO/HBS1L/ABCE1 rescue machinery; mouse genetics show GTPBP2 deficiency causes prolonged ribosome pausing at AGA arginine codons when cognate tRNA-Arg(UCU) is limiting. reference_section_type: RESULTS core_functions: - description: Translational GTPase that partners the ribosome-rescue factor PELO to rescue ribosomes stalled on non-functional or deficient tRNA, a function critical for neuronal proteostasis; GTPBP2 binds aminoacyl-tRNA and GTP (weakly) but, unlike GTPBP1, lacks elongation factor activity. molecular_function: id: GO:0005525 label: GTP binding supported_by: - reference_id: file:human/GTPBP2/GTPBP2-uniprot.txt supporting_text: Involved in the rescue of ribosome stalling due to the presence of non-functional tRNA - reference_id: file:human/GTPBP2/GTPBP2-uniprot.txt supporting_text: Interacts with PELO proposed_new_terms: [] suggested_questions: - question: Does human GTPBP2, like its mouse ortholog, act with PELO specifically to rescue ribosomes stalled at deficient/hypomodified tRNAs, and is this the basis of Jaberi-Elahi syndrome neurodegeneration? - question: Given its weak GTP binding and lack of elongation activity, what is GTPBP2's precise mechanistic contribution within the PELO-dependent rescue cycle relative to HBS1L? suggested_experiments: - description: Reconstituted ribosome-rescue assays with PELO and ABCE1 comparing GTPBP2 and HBS1L on tRNA-deficient stalled ribosomes to define GTPBP2's specific activity. - description: Ribosome profiling in GTPBP2-deficient human neurons (e.g. patient-derived or knockout iPSC neurons) to detect stalling at specific codons/tRNAs and link it to neurodegeneration.