GTPBP3 (GTP-binding protein 3, mitochondrial) is the human ortholog of bacterial MnmE and yeast MSS1, a TrmE-family TRAFAC GTPase with an N-terminal folate-binding domain, a helical domain and a G domain. After import into mitochondria (removal of an N-terminal targeting sequence) it forms a complex with the FAD-dependent enzyme MTO1 (the MnmG homolog). The GTPBP3-MTO1 complex installs 5-taurinomethyluridine (taum5U) at the wobble position U34 of five mitochondrial tRNAs (Leu(UUR), Trp, Lys, Glu, Gln), using 5,10-methylene-tetrahydrofolate and taurine as substrates and requiring GTP hydrolysis by GTPBP3. This modification supports accurate and efficient decoding of NNA/NNG codons; loss of GTPBP3 abolishes taum5U34, impairs mitochondrial translation and respiratory complexes I and IV, and biallelic GTPBP3 variants cause combined oxidative phosphorylation deficiency 23 (hypertrophic cardiomyopathy, lactic acidosis, encephalopathy). A minor splice isoform lacking the targeting sequence resides in the cytoplasm and has no known function.
| GO Term | Evidence | Action | Reason |
|---|---|---|---|
| GO:0002098 tRNA wobble uridine modification | IBA GO_REF:0000033 | ACCEPT | Summary: PAINT inference that GTPBP3 participates in wobble uridine (U34) modification, inherited from the MnmE/MSS1 clade. Human GTPBP3 is required, together with MTO1, for 5-taurinomethyluridine (taum5U) formation at U34 of five mitochondrial tRNAs. Reason: Correct and phylogenetically sound. The more specific mitochondrial child term GO:0070899 is separately annotated by IMP, so this IBA is consistent with the experimental picture; the IBA parent is retained as is. Supporting Evidence: PMID:29390138 we clearly showed that Οm5U34 was absent from five mt-tRNAs in GTPBP3 KO cells |
| GO:0003924 GTPase activity | IEA GO_REF:0000002 | ACCEPT | Summary: InterPro-based mapping of GTPase activity from the TrmE/MnmE G domain. Reason: Human GTPBP3 hydrolyses GTP in vitro (Km 9.5 uM; kcat 1.49 min-1 for the mature enzyme), so the domain-based inference is correct. Supporting Evidence: PMID:33619562 Here, we identified the mature form of hGTPBP3 and showed that hGTPBP3 is an active GTPase in vitro that is critical for tRNA modification in vivo |
| GO:0003924 GTPase activity | IMP PMID:29390138 Metabolic and chemical regulation of tRNA modification assoc... | ACCEPT | Summary: Asano et al. reconstituted taum5U34 formation in vitro with the GTPBP3-MTO1 complex in a reaction requiring GTP, and GTPBP3 knockout abolished taum5U in five mt-tRNAs. Reason: GTPase activity of GTPBP3 is directly shown elsewhere (PMID:33619562, PMID:18852288) and the GTP requirement of the reconstituted reaction is consistent with it. Accepted as a core molecular function of the protein. Supporting Evidence: PMID:29390138 we successfully reconstituted Οm5U34 formation in mt-tRNA in vitro in a system consisting of GTPBP3 and MTO1 in the presence of taurine, the methylene-THF, guanosine triphosphate (GTP) and other co-factors PMID:18852288 We show that the two most abundant GTPBP3 isoforms exhibit moderate affinity for guanine nucleotides like their bacterial homologue, MnmE, although they hydrolyze GTP at a 100-fold lower rate |
| GO:0003924 GTPase activity | IMP PMID:33619562 The human tRNA taurine modification enzyme GTPBP3 is an acti... | ACCEPT | Summary: Peng et al. purified the mature (MTS-cleaved) human GTPBP3 and showed it is an active GTPase; catalysis-defective G-domain mutants (N259A, E315A) failed to complement yeast mss1 deletion. Reason: Direct biochemical demonstration of GTP hydrolysis by the human protein with kinetic parameters, plus mutational evidence that GTP hydrolysis is required for tRNA modification in vivo. Core function. Supporting Evidence: PMID:33619562 As expected, catalysis-defective N259A and E315A mutants failed to support yeast growth in YPG medium (Figure 4C), suggesting a crucial role of GTP hydrolysis in tRNA modification in vivo |
| GO:0005515 protein binding | IPI PMID:25416956 A proteome-scale map of the human interactome network. | REMOVE | Summary: Generic protein binding from high-throughput yeast two-hybrid interactome screens (HuRI and predecessors; a neurodegeneration interactome). The reported partners (e.g. TARDBP, PARP11, DDIT4L, RALY, zinc-finger proteins) are not mitochondrial tRNA-modification partners, and MTO1, the physiological partner, is captured by the GTPBP3-MTO1 complex annotation. Reason: protein binding (GO:0005515) is uninformative about GTPBP3 function, and these binary-screen interactions with mostly nuclear/cytosolic proteins have no established functional consequence for the mitochondrial enzyme. Removal does not imply the interactions are false. The informative interaction (with MTO1) is already represented by GO:7770010 GTPBP3-MTO1 complex. |
| GO:0005515 protein binding | IPI PMID:25416956 A proteome-scale map of the human interactome network. | REMOVE | Summary: Generic protein binding from high-throughput yeast two-hybrid interactome screens (HuRI and predecessors; a neurodegeneration interactome). The reported partners (e.g. TARDBP, PARP11, DDIT4L, RALY, zinc-finger proteins) are not mitochondrial tRNA-modification partners, and MTO1, the physiological partner, is captured by the GTPBP3-MTO1 complex annotation. Reason: protein binding (GO:0005515) is uninformative about GTPBP3 function, and these binary-screen interactions with mostly nuclear/cytosolic proteins have no established functional consequence for the mitochondrial enzyme. Removal does not imply the interactions are false. The informative interaction (with MTO1) is already represented by GO:7770010 GTPBP3-MTO1 complex. |
| GO:0005515 protein binding | IPI PMID:32296183 A reference map of the human binary protein interactome. | REMOVE | Summary: Generic protein binding from high-throughput yeast two-hybrid interactome screens (HuRI and predecessors; a neurodegeneration interactome). The reported partners (e.g. TARDBP, PARP11, DDIT4L, RALY, zinc-finger proteins) are not mitochondrial tRNA-modification partners, and MTO1, the physiological partner, is captured by the GTPBP3-MTO1 complex annotation. Reason: protein binding (GO:0005515) is uninformative about GTPBP3 function, and these binary-screen interactions with mostly nuclear/cytosolic proteins have no established functional consequence for the mitochondrial enzyme. Removal does not imply the interactions are false. The informative interaction (with MTO1) is already represented by GO:7770010 GTPBP3-MTO1 complex. |
| GO:0005515 protein binding | IPI PMID:32296183 A reference map of the human binary protein interactome. | REMOVE | Summary: Generic protein binding from high-throughput yeast two-hybrid interactome screens (HuRI and predecessors; a neurodegeneration interactome). The reported partners (e.g. TARDBP, PARP11, DDIT4L, RALY, zinc-finger proteins) are not mitochondrial tRNA-modification partners, and MTO1, the physiological partner, is captured by the GTPBP3-MTO1 complex annotation. Reason: protein binding (GO:0005515) is uninformative about GTPBP3 function, and these binary-screen interactions with mostly nuclear/cytosolic proteins have no established functional consequence for the mitochondrial enzyme. Removal does not imply the interactions are false. The informative interaction (with MTO1) is already represented by GO:7770010 GTPBP3-MTO1 complex. |
| GO:0005515 protein binding | IPI PMID:32296183 A reference map of the human binary protein interactome. | REMOVE | Summary: Generic protein binding from high-throughput yeast two-hybrid interactome screens (HuRI and predecessors; a neurodegeneration interactome). The reported partners (e.g. TARDBP, PARP11, DDIT4L, RALY, zinc-finger proteins) are not mitochondrial tRNA-modification partners, and MTO1, the physiological partner, is captured by the GTPBP3-MTO1 complex annotation. Reason: protein binding (GO:0005515) is uninformative about GTPBP3 function, and these binary-screen interactions with mostly nuclear/cytosolic proteins have no established functional consequence for the mitochondrial enzyme. Removal does not imply the interactions are false. The informative interaction (with MTO1) is already represented by GO:7770010 GTPBP3-MTO1 complex. |
| GO:0005515 protein binding | IPI PMID:32296183 A reference map of the human binary protein interactome. | REMOVE | Summary: Generic protein binding from high-throughput yeast two-hybrid interactome screens (HuRI and predecessors; a neurodegeneration interactome). The reported partners (e.g. TARDBP, PARP11, DDIT4L, RALY, zinc-finger proteins) are not mitochondrial tRNA-modification partners, and MTO1, the physiological partner, is captured by the GTPBP3-MTO1 complex annotation. Reason: protein binding (GO:0005515) is uninformative about GTPBP3 function, and these binary-screen interactions with mostly nuclear/cytosolic proteins have no established functional consequence for the mitochondrial enzyme. Removal does not imply the interactions are false. The informative interaction (with MTO1) is already represented by GO:7770010 GTPBP3-MTO1 complex. |
| GO:0005515 protein binding | IPI PMID:32296183 A reference map of the human binary protein interactome. | REMOVE | Summary: Generic protein binding from high-throughput yeast two-hybrid interactome screens (HuRI and predecessors; a neurodegeneration interactome). The reported partners (e.g. TARDBP, PARP11, DDIT4L, RALY, zinc-finger proteins) are not mitochondrial tRNA-modification partners, and MTO1, the physiological partner, is captured by the GTPBP3-MTO1 complex annotation. Reason: protein binding (GO:0005515) is uninformative about GTPBP3 function, and these binary-screen interactions with mostly nuclear/cytosolic proteins have no established functional consequence for the mitochondrial enzyme. Removal does not imply the interactions are false. The informative interaction (with MTO1) is already represented by GO:7770010 GTPBP3-MTO1 complex. |
| GO:0005515 protein binding | IPI PMID:32296183 A reference map of the human binary protein interactome. | REMOVE | Summary: Generic protein binding from high-throughput yeast two-hybrid interactome screens (HuRI and predecessors; a neurodegeneration interactome). The reported partners (e.g. TARDBP, PARP11, DDIT4L, RALY, zinc-finger proteins) are not mitochondrial tRNA-modification partners, and MTO1, the physiological partner, is captured by the GTPBP3-MTO1 complex annotation. Reason: protein binding (GO:0005515) is uninformative about GTPBP3 function, and these binary-screen interactions with mostly nuclear/cytosolic proteins have no established functional consequence for the mitochondrial enzyme. Removal does not imply the interactions are false. The informative interaction (with MTO1) is already represented by GO:7770010 GTPBP3-MTO1 complex. |
| GO:0005515 protein binding | IPI PMID:32296183 A reference map of the human binary protein interactome. | REMOVE | Summary: Generic protein binding from high-throughput yeast two-hybrid interactome screens (HuRI and predecessors; a neurodegeneration interactome). The reported partners (e.g. TARDBP, PARP11, DDIT4L, RALY, zinc-finger proteins) are not mitochondrial tRNA-modification partners, and MTO1, the physiological partner, is captured by the GTPBP3-MTO1 complex annotation. Reason: protein binding (GO:0005515) is uninformative about GTPBP3 function, and these binary-screen interactions with mostly nuclear/cytosolic proteins have no established functional consequence for the mitochondrial enzyme. Removal does not imply the interactions are false. The informative interaction (with MTO1) is already represented by GO:7770010 GTPBP3-MTO1 complex. |
| GO:0005515 protein binding | IPI PMID:32296183 A reference map of the human binary protein interactome. | REMOVE | Summary: Generic protein binding from high-throughput yeast two-hybrid interactome screens (HuRI and predecessors; a neurodegeneration interactome). The reported partners (e.g. TARDBP, PARP11, DDIT4L, RALY, zinc-finger proteins) are not mitochondrial tRNA-modification partners, and MTO1, the physiological partner, is captured by the GTPBP3-MTO1 complex annotation. Reason: protein binding (GO:0005515) is uninformative about GTPBP3 function, and these binary-screen interactions with mostly nuclear/cytosolic proteins have no established functional consequence for the mitochondrial enzyme. Removal does not imply the interactions are false. The informative interaction (with MTO1) is already represented by GO:7770010 GTPBP3-MTO1 complex. |
| GO:0005515 protein binding | IPI PMID:32296183 A reference map of the human binary protein interactome. | REMOVE | Summary: Generic protein binding from high-throughput yeast two-hybrid interactome screens (HuRI and predecessors; a neurodegeneration interactome). The reported partners (e.g. TARDBP, PARP11, DDIT4L, RALY, zinc-finger proteins) are not mitochondrial tRNA-modification partners, and MTO1, the physiological partner, is captured by the GTPBP3-MTO1 complex annotation. Reason: protein binding (GO:0005515) is uninformative about GTPBP3 function, and these binary-screen interactions with mostly nuclear/cytosolic proteins have no established functional consequence for the mitochondrial enzyme. Removal does not imply the interactions are false. The informative interaction (with MTO1) is already represented by GO:7770010 GTPBP3-MTO1 complex. |
| GO:0005515 protein binding | IPI PMID:32296183 A reference map of the human binary protein interactome. | REMOVE | Summary: Generic protein binding from high-throughput yeast two-hybrid interactome screens (HuRI and predecessors; a neurodegeneration interactome). The reported partners (e.g. TARDBP, PARP11, DDIT4L, RALY, zinc-finger proteins) are not mitochondrial tRNA-modification partners, and MTO1, the physiological partner, is captured by the GTPBP3-MTO1 complex annotation. Reason: protein binding (GO:0005515) is uninformative about GTPBP3 function, and these binary-screen interactions with mostly nuclear/cytosolic proteins have no established functional consequence for the mitochondrial enzyme. Removal does not imply the interactions are false. The informative interaction (with MTO1) is already represented by GO:7770010 GTPBP3-MTO1 complex. |
| GO:0005515 protein binding | IPI PMID:32296183 A reference map of the human binary protein interactome. | REMOVE | Summary: Generic protein binding from high-throughput yeast two-hybrid interactome screens (HuRI and predecessors; a neurodegeneration interactome). The reported partners (e.g. TARDBP, PARP11, DDIT4L, RALY, zinc-finger proteins) are not mitochondrial tRNA-modification partners, and MTO1, the physiological partner, is captured by the GTPBP3-MTO1 complex annotation. Reason: protein binding (GO:0005515) is uninformative about GTPBP3 function, and these binary-screen interactions with mostly nuclear/cytosolic proteins have no established functional consequence for the mitochondrial enzyme. Removal does not imply the interactions are false. The informative interaction (with MTO1) is already represented by GO:7770010 GTPBP3-MTO1 complex. |
| GO:0005515 protein binding | IPI PMID:32296183 A reference map of the human binary protein interactome. | REMOVE | Summary: Generic protein binding from high-throughput yeast two-hybrid interactome screens (HuRI and predecessors; a neurodegeneration interactome). The reported partners (e.g. TARDBP, PARP11, DDIT4L, RALY, zinc-finger proteins) are not mitochondrial tRNA-modification partners, and MTO1, the physiological partner, is captured by the GTPBP3-MTO1 complex annotation. Reason: protein binding (GO:0005515) is uninformative about GTPBP3 function, and these binary-screen interactions with mostly nuclear/cytosolic proteins have no established functional consequence for the mitochondrial enzyme. Removal does not imply the interactions are false. The informative interaction (with MTO1) is already represented by GO:7770010 GTPBP3-MTO1 complex. |
| GO:0005515 protein binding | IPI PMID:32296183 A reference map of the human binary protein interactome. | REMOVE | Summary: Generic protein binding from high-throughput yeast two-hybrid interactome screens (HuRI and predecessors; a neurodegeneration interactome). The reported partners (e.g. TARDBP, PARP11, DDIT4L, RALY, zinc-finger proteins) are not mitochondrial tRNA-modification partners, and MTO1, the physiological partner, is captured by the GTPBP3-MTO1 complex annotation. Reason: protein binding (GO:0005515) is uninformative about GTPBP3 function, and these binary-screen interactions with mostly nuclear/cytosolic proteins have no established functional consequence for the mitochondrial enzyme. Removal does not imply the interactions are false. The informative interaction (with MTO1) is already represented by GO:7770010 GTPBP3-MTO1 complex. |
| GO:0005515 protein binding | IPI PMID:32296183 A reference map of the human binary protein interactome. | REMOVE | Summary: Generic protein binding from high-throughput yeast two-hybrid interactome screens (HuRI and predecessors; a neurodegeneration interactome). The reported partners (e.g. TARDBP, PARP11, DDIT4L, RALY, zinc-finger proteins) are not mitochondrial tRNA-modification partners, and MTO1, the physiological partner, is captured by the GTPBP3-MTO1 complex annotation. Reason: protein binding (GO:0005515) is uninformative about GTPBP3 function, and these binary-screen interactions with mostly nuclear/cytosolic proteins have no established functional consequence for the mitochondrial enzyme. Removal does not imply the interactions are false. The informative interaction (with MTO1) is already represented by GO:7770010 GTPBP3-MTO1 complex. |
| GO:0005515 protein binding | IPI PMID:32296183 A reference map of the human binary protein interactome. | REMOVE | Summary: Generic protein binding from high-throughput yeast two-hybrid interactome screens (HuRI and predecessors; a neurodegeneration interactome). The reported partners (e.g. TARDBP, PARP11, DDIT4L, RALY, zinc-finger proteins) are not mitochondrial tRNA-modification partners, and MTO1, the physiological partner, is captured by the GTPBP3-MTO1 complex annotation. Reason: protein binding (GO:0005515) is uninformative about GTPBP3 function, and these binary-screen interactions with mostly nuclear/cytosolic proteins have no established functional consequence for the mitochondrial enzyme. Removal does not imply the interactions are false. The informative interaction (with MTO1) is already represented by GO:7770010 GTPBP3-MTO1 complex. |
| GO:0005515 protein binding | IPI PMID:32296183 A reference map of the human binary protein interactome. | REMOVE | Summary: Generic protein binding from high-throughput yeast two-hybrid interactome screens (HuRI and predecessors; a neurodegeneration interactome). The reported partners (e.g. TARDBP, PARP11, DDIT4L, RALY, zinc-finger proteins) are not mitochondrial tRNA-modification partners, and MTO1, the physiological partner, is captured by the GTPBP3-MTO1 complex annotation. Reason: protein binding (GO:0005515) is uninformative about GTPBP3 function, and these binary-screen interactions with mostly nuclear/cytosolic proteins have no established functional consequence for the mitochondrial enzyme. Removal does not imply the interactions are false. The informative interaction (with MTO1) is already represented by GO:7770010 GTPBP3-MTO1 complex. |
| GO:0005515 protein binding | IPI PMID:32296183 A reference map of the human binary protein interactome. | REMOVE | Summary: Generic protein binding from high-throughput yeast two-hybrid interactome screens (HuRI and predecessors; a neurodegeneration interactome). The reported partners (e.g. TARDBP, PARP11, DDIT4L, RALY, zinc-finger proteins) are not mitochondrial tRNA-modification partners, and MTO1, the physiological partner, is captured by the GTPBP3-MTO1 complex annotation. Reason: protein binding (GO:0005515) is uninformative about GTPBP3 function, and these binary-screen interactions with mostly nuclear/cytosolic proteins have no established functional consequence for the mitochondrial enzyme. Removal does not imply the interactions are false. The informative interaction (with MTO1) is already represented by GO:7770010 GTPBP3-MTO1 complex. |
| GO:0005515 protein binding | IPI PMID:32296183 A reference map of the human binary protein interactome. | REMOVE | Summary: Generic protein binding from high-throughput yeast two-hybrid interactome screens (HuRI and predecessors; a neurodegeneration interactome). The reported partners (e.g. TARDBP, PARP11, DDIT4L, RALY, zinc-finger proteins) are not mitochondrial tRNA-modification partners, and MTO1, the physiological partner, is captured by the GTPBP3-MTO1 complex annotation. Reason: protein binding (GO:0005515) is uninformative about GTPBP3 function, and these binary-screen interactions with mostly nuclear/cytosolic proteins have no established functional consequence for the mitochondrial enzyme. Removal does not imply the interactions are false. The informative interaction (with MTO1) is already represented by GO:7770010 GTPBP3-MTO1 complex. |
| GO:0005515 protein binding | IPI PMID:32296183 A reference map of the human binary protein interactome. | REMOVE | Summary: Generic protein binding from high-throughput yeast two-hybrid interactome screens (HuRI and predecessors; a neurodegeneration interactome). The reported partners (e.g. TARDBP, PARP11, DDIT4L, RALY, zinc-finger proteins) are not mitochondrial tRNA-modification partners, and MTO1, the physiological partner, is captured by the GTPBP3-MTO1 complex annotation. Reason: protein binding (GO:0005515) is uninformative about GTPBP3 function, and these binary-screen interactions with mostly nuclear/cytosolic proteins have no established functional consequence for the mitochondrial enzyme. Removal does not imply the interactions are false. The informative interaction (with MTO1) is already represented by GO:7770010 GTPBP3-MTO1 complex. |
| GO:0005515 protein binding | IPI PMID:32296183 A reference map of the human binary protein interactome. | REMOVE | Summary: Generic protein binding from high-throughput yeast two-hybrid interactome screens (HuRI and predecessors; a neurodegeneration interactome). The reported partners (e.g. TARDBP, PARP11, DDIT4L, RALY, zinc-finger proteins) are not mitochondrial tRNA-modification partners, and MTO1, the physiological partner, is captured by the GTPBP3-MTO1 complex annotation. Reason: protein binding (GO:0005515) is uninformative about GTPBP3 function, and these binary-screen interactions with mostly nuclear/cytosolic proteins have no established functional consequence for the mitochondrial enzyme. Removal does not imply the interactions are false. The informative interaction (with MTO1) is already represented by GO:7770010 GTPBP3-MTO1 complex. |
| GO:0005515 protein binding | IPI PMID:32296183 A reference map of the human binary protein interactome. | REMOVE | Summary: Generic protein binding from high-throughput yeast two-hybrid interactome screens (HuRI and predecessors; a neurodegeneration interactome). The reported partners (e.g. TARDBP, PARP11, DDIT4L, RALY, zinc-finger proteins) are not mitochondrial tRNA-modification partners, and MTO1, the physiological partner, is captured by the GTPBP3-MTO1 complex annotation. Reason: protein binding (GO:0005515) is uninformative about GTPBP3 function, and these binary-screen interactions with mostly nuclear/cytosolic proteins have no established functional consequence for the mitochondrial enzyme. Removal does not imply the interactions are false. The informative interaction (with MTO1) is already represented by GO:7770010 GTPBP3-MTO1 complex. |
| GO:0005515 protein binding | IPI PMID:32296183 A reference map of the human binary protein interactome. | REMOVE | Summary: Generic protein binding from high-throughput yeast two-hybrid interactome screens (HuRI and predecessors; a neurodegeneration interactome). The reported partners (e.g. TARDBP, PARP11, DDIT4L, RALY, zinc-finger proteins) are not mitochondrial tRNA-modification partners, and MTO1, the physiological partner, is captured by the GTPBP3-MTO1 complex annotation. Reason: protein binding (GO:0005515) is uninformative about GTPBP3 function, and these binary-screen interactions with mostly nuclear/cytosolic proteins have no established functional consequence for the mitochondrial enzyme. Removal does not imply the interactions are false. The informative interaction (with MTO1) is already represented by GO:7770010 GTPBP3-MTO1 complex. |
| GO:0005515 protein binding | IPI PMID:32296183 A reference map of the human binary protein interactome. | REMOVE | Summary: Generic protein binding from high-throughput yeast two-hybrid interactome screens (HuRI and predecessors; a neurodegeneration interactome). The reported partners (e.g. TARDBP, PARP11, DDIT4L, RALY, zinc-finger proteins) are not mitochondrial tRNA-modification partners, and MTO1, the physiological partner, is captured by the GTPBP3-MTO1 complex annotation. Reason: protein binding (GO:0005515) is uninformative about GTPBP3 function, and these binary-screen interactions with mostly nuclear/cytosolic proteins have no established functional consequence for the mitochondrial enzyme. Removal does not imply the interactions are false. The informative interaction (with MTO1) is already represented by GO:7770010 GTPBP3-MTO1 complex. |
| GO:0005515 protein binding | IPI PMID:32814053 Interactome Mapping Provides a Network of Neurodegenerative ... | REMOVE | Summary: Generic protein binding from high-throughput yeast two-hybrid interactome screens (HuRI and predecessors; a neurodegeneration interactome). The reported partners (e.g. TARDBP, PARP11, DDIT4L, RALY, zinc-finger proteins) are not mitochondrial tRNA-modification partners, and MTO1, the physiological partner, is captured by the GTPBP3-MTO1 complex annotation. Reason: protein binding (GO:0005515) is uninformative about GTPBP3 function, and these binary-screen interactions with mostly nuclear/cytosolic proteins have no established functional consequence for the mitochondrial enzyme. Removal does not imply the interactions are false. The informative interaction (with MTO1) is already represented by GO:7770010 GTPBP3-MTO1 complex. |
| GO:0005525 GTP binding | IEA GO_REF:0000002 | ACCEPT | Summary: InterPro-based GTP binding from the G domain. Reason: GTPBP3 binds guanine nucleotides with moderate affinity and hydrolyses GTP; GTP binding is intrinsic to its GTPase activity. Supporting Evidence: PMID:18852288 We show that the two most abundant GTPBP3 isoforms exhibit moderate affinity for guanine nucleotides like their bacterial homologue, MnmE |
| GO:0005737 cytoplasm | EXP PMID:33619562 The human tRNA taurine modification enzyme GTPBP3 is an acti... | KEEP AS NON CORE | Summary: Peng et al. identified a splice variant (hGTPBP3-Iso7, UniProt isoform 4, Q969Y2-4) with a distinct N-terminus lacking a mitochondrial targeting sequence, which is expressed and localizes to the cytoplasm. Reason: The cytoplasmic localization is experimentally supported but is specific to a minor isoform that cannot complement mss1 loss and whose function is unknown. The canonical GTPBP3 proteins act in the mitochondrial matrix. Retained as non-core. Supporting Evidence: PMID:33619562 Interestingly, hGTPBP3-Iso7 localizes in the cytoplasm but not mitochondria due to its distinct N-terminus PMID:33619562 this isoform is not involved in mitochondrial tRNA modification |
| GO:0005737 cytoplasm | IBA GO_REF:0000033 | MARK AS OVER ANNOTATED | Summary: PAINT transfer of cytoplasm (is_active_in) from the bacterial MnmE branch. Bacterial MnmE acts in the cytosol, but the human (and yeast MSS1) orthologs act on mitochondrial tRNAs inside mitochondria. Reason: For human GTPBP3 the compartment in which the enzyme is active is the mitochondrion (also annotated by IBA, IDA and EXP). The only cytoplasmic pool is a minor splice isoform not involved in tRNA modification, so asserting activity in the cytoplasm for the gene product is an over-annotation. Propagation Review Root cause: PROPAGATION BAD Failure modes: COMPARTMENT OR COMPLEX MISMATCH Sources checked: PANTHER:PTN000182687 SUPPORTS SOURCE BUT NOT TARGET Ancestral MnmE-family node; cytosolic activity is correct for the bacterial branch but the eukaryotic GTPBP3/MSS1 descendants act in mitochondria. UniProtKB:P25522 SUPPORTS SOURCE BUT NOT TARGET E. coli MnmE, a cytosolic enzyme in a bacterium without mitochondria; its compartment does not transfer to the mitochondrially targeted human ortholog. Supporting Evidence: PMID:33619562 this isoform is not involved in mitochondrial tRNA modification |
| GO:0005737 cytoplasm | IEA GO_REF:0000044 | KEEP AS NON CORE | Summary: UniProt SubCell mapping of the isoform 4 cytoplasm localization. Reason: Derived from the experimentally supported cytoplasmic localization of isoform 4 (Q969Y2-4); correct for that isoform but not the core compartment of the gene product. Supporting Evidence: PMID:33619562 Interestingly, hGTPBP3-Iso7 localizes in the cytoplasm but not mitochondria due to its distinct N-terminus |
| GO:0005739 mitochondrion | EXP PMID:12370316 A human mitochondrial GTP binding protein related to tRNA mo... | ACCEPT | Summary: Li et al. 2002 cloned human GTPBP3 and showed mitochondrial localization. Reason: Consistent with all other localization evidence; GTPBP3 is a mitochondrial matrix enzyme modifying mt-tRNAs. Supporting Evidence: PMID:12370316 We showed that Gtpbp3 localizes in mitochondrion |
| GO:0005739 mitochondrion | HTP PMID:34800366 Quantitative high-confidence human mitochondrial proteome an... | ACCEPT | Summary: Detected in the high-confidence human mitochondrial proteome (MitoCoP). Reason: Consistent with low-throughput localization data. Supporting Evidence: PMID:34800366 mitochondrial high-confidence proteome of >1,100 proteins (MitoCoP). |
| GO:0005739 mitochondrion | IBA GO_REF:0000033 | ACCEPT | Summary: PAINT inference of activity in mitochondria for eukaryotic MnmE orthologs. Reason: Correct; GTPBP3 and yeast MSS1 act on mitochondrial tRNAs. Supporting Evidence: PMID:18852288 localizes exclusively to mitochondria |
| GO:0005739 mitochondrion | IDA GO_REF:0000052 | ACCEPT | Summary: Human Protein Atlas immunofluorescence localizes GTPBP3 to mitochondria. Reason: Concordant with targeted localization studies. |
| GO:0005739 mitochondrion | IDA PMID:33619562 The human tRNA taurine modification enzyme GTPBP3 is an acti... | ACCEPT | Summary: The MTS-containing GTPBP3 precursor fused to EGFP is imported into mitochondria; the pathogenic R3L MTS mutation abolishes import. Reason: Direct experimental localization. Supporting Evidence: PMID:33619562 Taken together, the above results clearly showed that R3L impaired mitochondrial localization in both HEK293T and yeast cells |
| GO:0005739 mitochondrion | IEA GO_REF:0000120 | ACCEPT | Summary: Combined automated mitochondrion annotation. Reason: Consistent with experimental data. |
| GO:0006400 tRNA modification | IEA GO_REF:0000002 | TOO GENERAL | Summary: InterPro-based tRNA modification. Reason: True but uninformative. GTPBP3 does modify tRNA, but GO:0070899 mitochondrial tRNA wobble uridine modification (an is_a descendant of GO:0006400) is accepted in this review from the IMP row and already entails this term. |
| GO:0030488 tRNA methylation | IBA GO_REF:0000033 | MARK AS OVER ANNOTATED | Summary: PAINT inference of tRNA methylation from the MnmE family. Reason: The MnmE/GTPBP3-MnmG/MTO1 reaction transfers a methylene unit from 5,10-methylene-tetrahydrofolate to C5 of U34 and condenses it with taurine (or glycine) to give a 5-taurinomethyl side chain; it does not add a methyl group to tRNA in the sense of GO:0030488 (posttranscriptional addition of methyl groups). The modification is better captured by wobble uridine modification (GO:0002098 / GO:0070899), which is annotated. Propagation Review Root cause: TERM SCOPING PROBLEM Failure modes: GRANULARITY MISMATCH Sources checked: PANTHER:PTN000182687 SUPPORTS SOURCE BUT NOT TARGET Ancestral MnmE-family node; the inherited activity is wobble uridine (c)mnm5U/taum5U formation, which GO:0002098 already captures. UniProtKB:P25522 SUPPORTS SOURCE BUT NOT TARGET E. coli MnmE seeds the node; MnmEG transfers a methylene unit and an amine to U34 rather than adding a methyl group, so tRNA methylation scopes the reaction loosely. Supporting Evidence: PMID:29390138 Here, we elucidated Οm5U biogenesis by confirming that 5,10-methylene-tetrahydrofolate and taurine are metabolic substrates for Οm5U formation catalyzed by MTO1 and GTPBP3 |
| GO:0070899 mitochondrial tRNA wobble uridine modification | IMP PMID:29390138 Metabolic and chemical regulation of tRNA modification assoc... | ACCEPT | Summary: GTPBP3 knockout HEK293T cells lack taum5U34 in five mt-tRNAs, have reduced mitochondrial translation and respiratory defects. Reason: Core biological process, directly shown by loss-of-function, in vitro reconstitution with MTO1 and patient cells with GTPBP3 mutations. Supporting Evidence: PMID:29390138 we clearly showed that Οm5U34 was absent from five mt-tRNAs in GTPBP3 KO cells PMID:25434004 Mutations in GTPBP3 are associated with a severe mitochondrial translation defect, consistent with the predicted function of the protein in catalyzing the formation of 5-taurinomethyluridine |
| GO:0070900 mitochondrial tRNA modification | IEA GO_REF:0000117 | ACCEPT | Summary: ARBA electronic annotation to mitochondrial tRNA modification. Reason: Correct parent of the experimentally supported GO:0070899. |
| GO:0160236 tRNA 5-taurinomethyluridine synthase activity | IMP PMID:29390138 Metabolic and chemical regulation of tRNA modification assoc... | ACCEPT | Summary: GTPBP3 contributes to tRNA 5-taurinomethyluridine synthase activity, which is executed by the GTPBP3-MTO1 complex using 5,10-methylene-THF, taurine, GTP and FAD. Reason: The contributes_to qualifier is appropriate - activity requires both the GTPBP3 GTPase and MTO1 (FAD-dependent) subunits, and was reconstituted in vitro with the complex. Core molecular function. Supporting Evidence: PMID:29390138 we successfully reconstituted Οm5U34 formation in mt-tRNA in vitro in a system consisting of GTPBP3 and MTO1 in the presence of taurine, the methylene-THF, guanosine triphosphate (GTP) and other co-factors |
| GO:7770010 GTPBP3-MTO1 complex | IDA PMID:33619562 The human tRNA taurine modification enzyme GTPBP3 is an acti... | ACCEPT | Summary: Endogenous MTO1 co-immunoprecipitates with endogenous GTPBP3 in HEK293T cells. Reason: Direct evidence for the GTPBP3-MTO1 complex, which is the functional unit for taum5U34 synthesis. Supporting Evidence: PMID:33619562 Using an anti-hGTPBP3 antibody in Co-IP, we confirmed that endogenous hMTO1 was indeed coprecipitated |
| GO:7770010 GTPBP3-MTO1 complex | IMP PMID:29390138 Metabolic and chemical regulation of tRNA modification assoc... | ACCEPT | Summary: The GTPBP3-MTO1 complex was isolated and used to reconstitute taum5U formation in vitro. Reason: Supports GTPBP3 membership of the complex. Supporting Evidence: PMID:29390138 we successfully reconstituted a small amount of Οm5U on mt-tRNALeu(UUR)in vitro using the GTPBP3/MTO1 complex |
Loading supporting contentβ¦
Download this section (compressed HTML)Q: How is GTP hydrolysis by GTPBP3 coupled to methylene transfer by MTO1, given that human GTPBP3 hydrolyses GTP far more slowly than bacterial MnmE and lacks potassium-stimulated G-domain activation?
Q: Does the cytoplasmic GTPBP3 splice isoform (isoform 4) have any tRNA-modification or other function outside mitochondria?
Experiment: Efficient in vitro reconstitution of taum5U34 with purified mature GTPBP3 and MTO1 and individual mt-tRNA substrates, comparing GTPase-dead GTPBP3 mutants, to define the stoichiometric role of GTP hydrolysis in the reaction.
Experiment: Isoform-specific knockout or knockdown of the cytoplasmic GTPBP3 isoform followed by tRNA modification mapping (LC-MS) of cytosolic tRNAs and proteomics.
Loading supporting contentβ¦
Download this section (compressed HTML)Loading supporting contentβ¦
Download this section (compressed HTML)Loading supporting contentβ¦
Download this section (compressed HTML)