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.
| GO Term | Evidence | Action | Reason |
|---|---|---|---|
| GO:0006414 translational elongation | IBA GO_REF:0000033 | MARK AS OVER ANNOTATED | 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. 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. Supporting Evidence: file:human/GTPBP2/GTPBP2-uniprot.txt Involved in the rescue of ribosome stalling due to the presence of non-functional tRNA file:human/GTPBP2/GTPBP2-deep-research-falcon.md GTPBP2 deficiency causes prolonged ribosome pausing specifically at AGA arginine codons when the cognate tRNA_Arg(UCU) is limiting |
| GO:0003924 GTPase activity | IEA GO_REF:0000002 | KEEP AS NON CORE | 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. 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. Supporting Evidence: file:human/GTPBP2/GTPBP2-uniprot.txt Has very low GTP-binding activity |
| GO:0005525 GTP binding | IEA GO_REF:0000002 | ACCEPT | Summary: GTPBP2 binds GTP, though weakly; binding is stimulated by aminoacyl-tRNA. Reason: GTP binding is directly observed (albeit weak) and is consistent with the GTPase fold. Supporting Evidence: file:human/GTPBP2/GTPBP2-uniprot.txt Has very low GTP-binding activity |
| GO:1904678 alpha-aminoacyl-tRNA binding | IEA GO_REF:0000117 | ACCEPT | Summary: GTPBP2 binds aminoacyl-tRNA; Phe-tRNA stimulates its GTP binding, indicating a functional aa-tRNA interaction. Reason: Directly supported by the observation that aa-tRNA stimulates GTPBP2 GTP binding. Supporting Evidence: file:human/GTPBP2/GTPBP2-uniprot.txt Has very low GTP-binding activity |
| GO:0005515 protein binding | IPI PMID:23455924 A Y2H-seq approach defines the human protein methyltransfera... | KEEP AS NON CORE | Summary: Y2H interactome (protein methyltransferase network) capturing GTPBP2 interactions (e.g. PRMT5/PRMT6). Bare protein binding is uninformative and unrelated to the rescue function. Reason: Records physical interactions but the generic term adds nothing to GTPBP2's ribosome-rescue function. Supporting Evidence: file:human/GTPBP2/GTPBP2-uniprot.txt O14744: PRMT5 |
| GO:0005515 protein binding | IPI PMID:32296183 A reference map of the human binary protein interactome. | KEEP AS NON CORE | Summary: Binary interactome capturing GTPBP2 interactions, including self-association. Bare protein binding. Reason: Generic term; physical interactions recorded but uninformative for core function. Supporting Evidence: file:human/GTPBP2/GTPBP2-uniprot.txt Q9BX10: GTPBP2 |
| GO:0042802 identical protein binding | IPI PMID:32296183 A reference map of the human binary protein interactome. | KEEP AS NON CORE | Summary: GTPBP2 self-association (homotypic interaction) detected in the binary interactome. Reason: Records a homodimerization-type interaction; not established as functionally central to ribosome rescue. Supporting Evidence: file:human/GTPBP2/GTPBP2-uniprot.txt Q9BX10: GTPBP2 |
| GO:0003746 translation elongation factor activity | IDA NOT PMID:30108131 Functions of unconventional mammalian translational GTPases ... | ACCEPT | 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. 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. Supporting Evidence: PMID:30108131 GTPBP2 lacked elongation activity and did not stimulate exosomal degradation file:human/GTPBP2/GTPBP2-deep-research-falcon.md This codon-specific function indicates that GTPBP2 acts as a quality control GTPase rather than a canonical elongation factor or metabolic enzyme |
| GO:0005525 GTP binding | IDA PMID:30108131 Functions of unconventional mammalian translational GTPases ... | ACCEPT | Summary: Direct demonstration that GTPBP2 binds GTP, albeit weakly, with binding stimulated by aa-tRNA. Reason: Directly demonstrated (weak) GTP binding. Supporting Evidence: file:human/GTPBP2/GTPBP2-uniprot.txt Has very low GTP-binding activity |
| GO:1904678 alpha-aminoacyl-tRNA binding | IDA PMID:30108131 Functions of unconventional mammalian translational GTPases ... | ACCEPT | Summary: Direct evidence that aminoacyl-tRNA (Phe-tRNA) interacts with GTPBP2 and stimulates its GTP binding. Reason: Directly demonstrated aa-tRNA binding. Supporting Evidence: file:human/GTPBP2/GTPBP2-uniprot.txt Has very low GTP-binding activity |
| GO:0005576 extracellular region | TAS Reactome:R-HSA-481007 | KEEP AS NON CORE | Summary: Reactome platelet-degranulation localization, reflecting detection of GTPBP2 in platelet alpha-granule releasate; not its functional compartment. Reason: Specialized platelet-biology localization peripheral to GTPBP2's cytoplasmic ribosome-rescue function. Supporting Evidence: file:human/GTPBP2/GTPBP2-uniprot.txt Involved in the rescue of ribosome stalling due to the presence of non-functional tRNA |
| GO:0031093 platelet alpha granule lumen | TAS Reactome:R-HSA-481007 | KEEP AS NON CORE | Summary: Reactome platelet alpha-granule lumen localization from platelet proteomics; a specialized context distinct from GTPBP2's core function. Reason: Specialized platelet-biology localization; peripheral and does not reflect GTPBP2's principal cytoplasmic role. Supporting Evidence: file:human/GTPBP2/GTPBP2-uniprot.txt Involved in the rescue of ribosome stalling due to the presence of non-functional tRNA |
Loading supporting content…
Download this section (compressed HTML)Q: 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?
Q: 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?
Experiment: Reconstituted ribosome-rescue assays with PELO and ABCE1 comparing GTPBP2 and HBS1L on tRNA-deficient stalled ribosomes to define GTPBP2's specific activity.
Experiment: 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.
Loading supporting content…
Download this section (compressed HTML)Loading supporting content…
Download this section (compressed HTML)Loading supporting content…
Download this section (compressed HTML)Loading supporting content…
Download this section (compressed HTML)