GFM1 encodes mitochondrial elongation factor G1 (EF-G1mt, mEF-G1), a nuclear-encoded translational GTPase of the EF-G/EF-2 family that is imported into the mitochondrial matrix via an N-terminal targeting presequence. On the 55S mitoribosome it catalyses the GTP-dependent translocation step of the elongation cycle, moving the A-site peptidyl-tRNA and P-site deacylated tRNA to the P and E sites together with the mRNA. In human mitochondria the two functions of bacterial EF-G are split between paralogs; EF-G1mt performs translocation only, whereas EF-G2mt (GFM2) acts with mitochondrial ribosome recycling factor in ribosome recycling. A mitochondria-specific C-terminal extension contacts the A-site tRNA acceptor arm during translocation. EF-G1mt is required for synthesis of the 13 mtDNA-encoded OXPHOS subunits, and biallelic GFM1 variants cause combined oxidative phosphorylation deficiency 1 (COXPD1), typically a rapidly progressive neonatal hepatoencephalopathy.
| GO Term | Evidence | Action | Reason |
|---|---|---|---|
| GO:0003723 RNA binding | HDA PMID:22658674 Insights into RNA biology from an atlas of mammalian mRNA-bi... | MARK AS OVER ANNOTATED | Summary: GFM1 was detected among proteins crosslinked to polyadenylated RNA in an mRNA interactome capture screen of HeLa cells. Reason: EF-G1mt contacts tRNAs, rRNA and mRNA only as a ribosome-bound translocase. Its activity is captured by translation elongation factor activity and GTPase activity. A generic RNA-binding call from a high-throughput interactome capture screen, which likely reflects crosslinking within mRNA-engaged mitoribosomes, adds no information and is not an independent RNA-binding function. Supporting Evidence: PMID:32737313 the mito-specific C-terminal extension in EF-G1mt is directly involved in translocation of the acceptor arm of the A-site tRNAmt |
| GO:0003746 translation elongation factor activity | IBA GO_REF:0000033 | ACCEPT | Summary: PAINT phylogenetic inference of translation elongation factor activity for the EF-G family node containing GFM1. Reason: EF-G1mt is the mitochondrial EF-G translocase; the IBA agrees with direct biochemical evidence on the human protein (Tsuboi et al. 2009) and with structures of human mitoribosome-EF-G1mt complexes. Supporting Evidence: PMID:19716793 EF-G1mt specifically catalyzes translocation, whereas EF-G2mt mediates ribosome recycling with human mitochondrial RRF but lacks translocation activity |
| GO:0003746 translation elongation factor activity | IDA PMID:19716793 EF-G2mt is an exclusive recycling factor in mammalian mitoch... | ACCEPT | Summary: Reconstituted translation assays with purified human factors showed that EF-G1mt catalyses translocation on mitochondrial ribosomes. Reason: This is the defining activity of GFM1 and is directly demonstrated in this paper. Supporting Evidence: PMID:19716793 EF-G1mt specifically catalyzes translocation, whereas EF-G2mt mediates ribosome recycling with human mitochondrial RRF but lacks translocation activity |
| GO:0003746 translation elongation factor activity | IEA GO_REF:0000120 | ACCEPT | Summary: Automated assignment from InterPro EF-G signatures and UniRule. Reason: Consistent with experimental evidence that EF-G1mt is the mitochondrial translocase. Supporting Evidence: PMID:19716793 EF-G1mt specifically catalyzes translocation |
| GO:0003924 GTPase activity | IBA GO_REF:0000033 | ACCEPT | Summary: PAINT inference of GTPase activity for the EF-G family. Reason: EF-G1mt is a translational GTPase whose ribosome-stimulated GTP hydrolysis drives translocation; the structure of the mitoribosome-bound factor shows the catalytic residues positioned for hydrolysis. Supporting Evidence: PMID:32737313 the binding of EF-G1mt to the 55S mitoribosome stabilizes the factor in an active conformation necessary to catalyze the hydrolysis reaction |
| GO:0003924 GTPase activity | IDA PMID:19716793 EF-G2mt is an exclusive recycling factor in mammalian mitoch... | ACCEPT | Summary: GTP hydrolysis by purified human EF-G1mt was assayed in the study that separated the translocation and recycling functions of the two mitochondrial EF-G paralogs. Reason: GTPase activity is intrinsic to the translocase mechanism; the UniProt catalytic-activity entry cites this paper. The cached record is abstract only, so the assay itself was not inspected, but the annotation is consistent with the family and structural evidence and is accepted. Supporting Evidence: file:human/GFM1/GFM1-uniprot.txt Mitochondrial GTPase that catalyzes the GTP-dependent ribosomal translocation step during translation elongation |
| GO:0003924 GTPase activity | IEA GO_REF:0000120 | ACCEPT | Summary: Automated assignment from the tr-type G domain signature and UniRule. Reason: Correct; EF-G1mt is a translational GTPase. Supporting Evidence: file:human/GFM1/GFM1-uniprot.txt Mitochondrial GTPase that catalyzes the GTP-dependent ribosomal translocation step during translation elongation |
| GO:0005515 protein binding | IPI PMID:18157088 Cooperative control of striated muscle mass and metabolism b... | REMOVE | Summary: In a yeast two-hybrid screen with MuRF1 and MuRF2 baits, GFM1 was picked up as a MuRF1 (TRIM63) prey and the interaction was tested in vitro by pull-down with a MuRF1 fragment. Reason: Uninformative protein binding term. The interaction with a cytosolic muscle E3 ligase was detected by yeast two-hybrid and in vitro pull-down with recombinant protein, has no demonstrated physiological role for EF-G1mt, and is spatially implausible for a matrix-resident translation factor. Supporting Evidence: PMID:18157088 EEF1G/EF-1Ξ³ (selected as a sophisticatedly regulated component of the translation machinery; see Belle et al, 1995) as well as its mitochondrial counterpart GFM1 |
| GO:0005515 protein binding | IPI PMID:28169297 Comparative influenza protein interactomes identify the role... | REMOVE | Summary: Affinity-purification mass spectrometry of influenza A virus proteins expressed in HEK293 cells recovered GFM1 with an influenza NS-segment protein (UniProt P03508). Reason: High-throughput virus-host interactome hit annotated with the uninformative protein binding term; it tells nothing about the function of EF-G1mt. Supporting Evidence: PMID:28169297 Here, we mapped protein interactomes between human host and several influenza A viruses (IAV). |
| GO:0005525 GTP binding | IEA GO_REF:0000120 | ACCEPT | Summary: Automated assignment from G-domain InterPro signatures. Reason: GTP binding is required for the GTPase-driven translocation mechanism; the tr-type G domain carries the conserved G1-G5 motifs. Supporting Evidence: file:human/GFM1/GFM1-uniprot.txt Mitochondrial GTPase that catalyzes the GTP-dependent ribosomal translocation step during translation elongation |
| GO:0005739 mitochondrion | HTP PMID:34800366 Quantitative high-confidence human mitochondrial proteome an... | ACCEPT | Summary: Detected in the high-confidence quantitative human mitochondrial proteome. Reason: GFM1 has a mitochondrial targeting presequence and acts on mitoribosomes in the matrix. Supporting Evidence: file:human/GFM1/GFM1-uniprot.txt SUBCELLULAR LOCATION: Mitochondrion |
| GO:0005739 mitochondrion | IBA GO_REF:0000033 | ACCEPT | Summary: PAINT inference of mitochondrial localisation for the mitochondrial EF-G subfamily. Reason: Correct; GFM1 is a mitochondrial translation factor. Supporting Evidence: PMID:32737313 we present the 2.68-3.96 Γ
cryo-EM structures of the human 55S mitoribosome in complex with the human mitochondrial elongation factor G1 (EF-G1mt) |
| GO:0005739 mitochondrion | IEA GO_REF:0000120 | ACCEPT | Summary: Automated assignment from UniProt subcellular location and UniRule. Reason: Correct. Supporting Evidence: file:human/GFM1/GFM1-uniprot.txt SUBCELLULAR LOCATION: Mitochondrion |
| GO:0005759 mitochondrial matrix | IEA GO_REF:0000117 | ACCEPT | Summary: ARBA prediction of mitochondrial matrix localisation. Reason: Mitoribosomes, on which EF-G1mt acts, are in the matrix tethered to the inner membrane; matrix is the precise compartment. Supporting Evidence: Reactome:R-HSA-5419261 GFMT1:GTP (EF-G1mt:GTP) binds ribosomes possessing a peptidyl-tRNA at the A site and an empty P site |
| GO:0005759 mitochondrial matrix | TAS Reactome:R-HSA-5419261 | ACCEPT | Summary: Reactome places the binding of GFM1:GTP to the 55S ribosome with A-site peptidyl-tRNA in the mitochondrial matrix. Reason: Correct compartment for mitochondrial translation elongation. Supporting Evidence: Reactome:R-HSA-5419261 GFMT1:GTP (EF-G1mt:GTP) binds ribosomes possessing a peptidyl-tRNA at the A site and an empty P site |
| GO:0006412 translation | IEA GO_REF:0000117 | MODIFY | Summary: ARBA assignment of the generic translation term. Reason: Correct but very general; GFM1 acts specifically in mitochondrial translational elongation. Proposed replacements: mitochondrial translational elongation Supporting Evidence: PMID:19716793 EF-G1mt specifically catalyzes translocation |
| GO:0006414 translational elongation | IEA GO_REF:0000120 | MODIFY | Summary: InterPro/UniPathway assignment of translational elongation. Reason: Correct process but GFM1 is mitochondrial-specific; the more precise child term mitochondrial translational elongation is supported experimentally. Proposed replacements: mitochondrial translational elongation Supporting Evidence: PMID:19716793 EF-G1mt specifically catalyzes translocation |
| GO:0070125 mitochondrial translational elongation | IBA GO_REF:0000033 | ACCEPT | Summary: PAINT inference of mitochondrial translational elongation. Reason: Core process of GFM1, supported by direct biochemical and structural evidence. Supporting Evidence: PMID:32737313 Our study reveals several distinct features, including mito-specific molecular interactions during EF-G1mt-mediated tRNAmt translocation on the human mitoribosome. |
| GO:0070125 mitochondrial translational elongation | IDA PMID:19716793 EF-G2mt is an exclusive recycling factor in mammalian mitoch... | ACCEPT | Summary: Purified EF-G1mt catalyses translocation in mitochondrial translation elongation. Reason: Core process, directly demonstrated. Supporting Evidence: PMID:19716793 EF-G1mt specifically catalyzes translocation, whereas EF-G2mt mediates ribosome recycling with human mitochondrial RRF but lacks translocation activity |
| GO:0070125 mitochondrial translational elongation | IEA GO_REF:0000104 | ACCEPT | Summary: UniRule transfer of mitochondrial translational elongation. Reason: Correct core process. Supporting Evidence: PMID:19716793 EF-G1mt specifically catalyzes translocation |
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Download this section (compressed HTML)Q: Why do some GFM1 variants produce an OXPHOS defect in fibroblasts but not in muscle, and does tissue-specific expression of GFM1 or GFM2 explain the hepatocerebral predominance of COXPD1?
Q: Does the mitochondria-specific lysine-rich C-terminal extension of EF-G1mt contribute to translocation fidelity or reading-frame maintenance on the leaderless mt-mRNAs?
Experiment: Reconstituted single-turnover translocation kinetics on human mitoribosomes with wild-type EF-G1mt, a C-terminal-extension deletion and COXPD1 patient variants (e.g. R250W in subdomain G'), to separate defects in GTP hydrolysis from defects in tRNA movement.
Experiment: Mitoribosome profiling in patient fibroblasts and Gfm1 mutant mouse liver to test whether EF-G1mt deficiency causes codon- or transcript-specific elongation stalls.
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