TUFM encodes mitochondrial elongation factor Tu (mtEF-Tu), a nuclear-encoded translational GTPase of the TRAFAC class that is imported into the mitochondrial matrix. In its GTP-bound form it binds aminoacyl-tRNAs and delivers them to the A site of the 55S mitoribosome; codon recognition triggers GTP hydrolysis and release of EF-Tu-GDP, which is recycled to the GTP form by the nucleotide exchange factor EF-Ts (TSFM), with which it forms a stable EF-Tu-Ts complex. It is therefore required for elongation during synthesis of the 13 mtDNA-encoded OXPHOS subunits. mtEF-Tu has also been visualised bound to late large-subunit assembly intermediates together with GTPBP5. Biallelic TUFM variants cause combined oxidative phosphorylation deficiency 4 (COXPD4), a neonatal lactic acidosis with rapidly progressive encephalopathy and leukodystrophy and defective mitochondrial translation. A second, less well characterised role has been reported in which TUFM associates with NLRX1 and the ATG5-ATG12/ATG16L1 complex, dampening RIG-I-like receptor type I interferon signalling and promoting autophagy, and is co-opted by several viral proteins to induce mitophagy.
| GO Term | Evidence | Action | Reason |
|---|---|---|---|
| GO:0000287 magnesium ion binding | ISS GO_REF:0000024 | KEEP AS NON CORE | Summary: Transfer from E. coli EF-Tu, in which Mg2+ is coordinated with the bound guanine nucleotide. Reason: Mg2+ is a cofactor of nucleotide binding in translational GTPases, so the inference is plausible, but it is a cofactor-level detail rather than a core function. |
| GO:0003723 RNA binding | HDA PMID:22658674 Insights into RNA biology from an atlas of mammalian mRNA-bi... | KEEP AS NON CORE | Summary: Detected in mRNA interactome capture. Reason: mtEF-Tu binds aminoacyl-tRNA, so RNA binding is true, but the informative activity is captured by translation elongation factor activity. The interactome hit probably reflects crosslinking in translating mitoribosomes. Supporting Evidence: file:human/TUFM/TUFM-uniprot.txt GTP hydrolase that promotes the GTP-dependent binding of aminoacyl-tRNA to the A-site of ribosomes during protein biosynthesis |
| GO:0003746 translation elongation factor activity | IBA GO_REF:0000033 | ACCEPT | Summary: PAINT inference of translation elongation factor activity for EF-Tu family members. Reason: Core molecular function, supported by activity of recombinant mammalian mtEF-Tu in poly(U)-directed polymerization and by structural data. Supporting Evidence: PMID:8547323 The expressed form of the factor is active in the poly(U)-directed polymerization of phenylalanine although it is less active than the native EF-Tu.Tsmt complex PMID:34135318 It was recently shown that during translation, mtEF-Tu·GTP delivers aminoacylated-tRNA to the mitoribosome in a manner similar to its bacterial EF-Tu counterparts |
| GO:0003746 translation elongation factor activity | IDA PMID:9332382 The human mitochondrial elongation factor tu (EF-Tu) gene: c... | ACCEPT | Summary: Ling et al. 1997 report the human EF-Tu cDNA and gene and describe it as a component of the mitochondrial translational apparatus. Reason: The cached abstract describes cloning and genomic mapping and does not itself report an activity assay, but the full text was read by the curator and the function is not in doubt (bovine and human mtEF-Tu are 95% identical, and the recombinant factor is active). Accepted, deferring to the curator. Supporting Evidence: PMID:9332382 The human mitochondrial elongation factor Tu (EF-Tu) is nuclear-encoded and functions in the translational apparatus of mitochondria PMID:8547323 The expressed form of the factor is active in the poly(U)-directed polymerization of phenylalanine although it is less active than the native EF-Tu.Tsmt complex |
| GO:0003746 translation elongation factor activity | IEA GO_REF:0000002 | ACCEPT | Summary: InterPro EF-Tu family (IPR004541) mapping to translation elongation factor activity. Reason: Correct; consistent with biochemical and structural data. Supporting Evidence: PMID:8547323 The expressed form of the factor is active in the poly(U)-directed polymerization of phenylalanine although it is less active than the native EF-Tu.Tsmt complex |
| GO:0003924 GTPase activity | IEA GO_REF:0000002 | ACCEPT | Summary: InterPro translational GTPase domain mapping to GTPase activity. Reason: mtEF-Tu hydrolyses GTP on codon recognition; GTPase activity is a component of its elongation factor function. Supporting Evidence: file:human/TUFM/TUFM-uniprot.txt GTP hydrolase that promotes the GTP-dependent binding of aminoacyl-tRNA to the A-site of ribosomes during protein biosynthesis |
| GO:0003924 GTPase activity | ISS GO_REF:0000024 | ACCEPT | Summary: Transfer of GTPase activity from bovine (P49410) or E. coli (P0CE47) EF-Tu. Reason: mtEF-Tu hydrolyses GTP on codon recognition; GTPase activity is a component of its elongation factor function. Supporting Evidence: file:human/TUFM/TUFM-uniprot.txt GTP hydrolase that promotes the GTP-dependent binding of aminoacyl-tRNA to the A-site of ribosomes during protein biosynthesis PMID:34135318 It was recently shown that during translation, mtEF-Tu·GTP delivers aminoacylated-tRNA to the mitoribosome in a manner similar to its bacterial EF-Tu counterparts |
| GO:0003924 GTPase activity | ISS GO_REF:0000024 | ACCEPT | Summary: Transfer of GTPase activity from bovine (P49410) or E. coli (P0CE47) EF-Tu. Reason: mtEF-Tu hydrolyses GTP on codon recognition; GTPase activity is a component of its elongation factor function. Supporting Evidence: file:human/TUFM/TUFM-uniprot.txt GTP hydrolase that promotes the GTP-dependent binding of aminoacyl-tRNA to the A-site of ribosomes during protein biosynthesis PMID:34135318 It was recently shown that during translation, mtEF-Tu·GTP delivers aminoacylated-tRNA to the mitoribosome in a manner similar to its bacterial EF-Tu counterparts |
| GO:0005515 protein binding | IPI PMID:11741979 Interaction of the C-terminal domain of p43 and the alpha su... | REMOVE | Summary: Chang et al. 2001 studied binding of the C-terminal domain of p43 (EMAP II precursor) to the ATP synthase alpha subunit. Reason: The abstract states that the "p43" studied is the protein associated with the multi-tRNA synthetase complex and the precursor of EMAP II, which is AIMP1, not TUFM (whose UniProt alternative name is also "P43"). The annotation appears to arise from this name collision. Independently, generic protein binding is uninformative. Supporting Evidence: PMID:11741979 Human p43 is associated with macromolecular tRNA synthase complex and known as a precursor of endothelial monocyte-activating polypeptide II (EMAP II) file:human/TUFM/TUFM-uniprot.txt AltName: Full=P43 |
| GO:0005515 protein binding | IPI PMID:25416956 A proteome-scale map of the human interactome network. | REMOVE | Summary: Binary yeast two-hybrid hit in the HuRI/CCSB human interactome map (ARL6IP1, FUNDC1, FAM9B or CMTM5). Reason: Generic protein binding is uninformative. These are high-throughput Y2H hits with membrane or nuclear proteins with no established link to mtEF-Tu function in the matrix. Removal does not dispute the reported interaction. |
| GO:0005515 protein binding | IPI PMID:25416956 A proteome-scale map of the human interactome network. | REMOVE | Summary: Binary yeast two-hybrid hit in the HuRI/CCSB human interactome map (ARL6IP1, FUNDC1, FAM9B or CMTM5). Reason: Generic protein binding is uninformative. These are high-throughput Y2H hits with membrane or nuclear proteins with no established link to mtEF-Tu function in the matrix. Removal does not dispute the reported interaction. |
| GO:0005515 protein binding | IPI PMID:25416956 A proteome-scale map of the human interactome network. | REMOVE | Summary: Binary yeast two-hybrid hit in the HuRI/CCSB human interactome map (ARL6IP1, FUNDC1, FAM9B or CMTM5). Reason: Generic protein binding is uninformative. These are high-throughput Y2H hits with membrane or nuclear proteins with no established link to mtEF-Tu function in the matrix. Removal does not dispute the reported interaction. |
| GO:0005515 protein binding | IPI PMID:25416956 A proteome-scale map of the human interactome network. | REMOVE | Summary: Binary yeast two-hybrid hit in the HuRI/CCSB human interactome map (ARL6IP1, FUNDC1, FAM9B or CMTM5). Reason: Generic protein binding is uninformative. These are high-throughput Y2H hits with membrane or nuclear proteins with no established link to mtEF-Tu function in the matrix. Removal does not dispute the reported interaction. |
| GO:0005515 protein binding | IPI PMID:28611246 Inhibition of Avian Influenza A Virus Replication in Human C... | REMOVE | Summary: Kuo et al. 2017 report binding of TUFM to avian influenza PB2 (PB2-627E) and to NLRX1 in the context of TUFM acting as a restriction factor. Reason: Generic protein binding is uninformative. The NLRX1 and viral PB2 interactions bear on the proposed autophagy/antiviral role, but no specific molecular function of TUFM is established by them. Removal does not dispute the interactions. Supporting Evidence: PMID:28611246 we found that Tu elongation factor, mitochondrial (TUFM, also known as EF-Tu, P43, or COXPD4), can act as a selective PB2627E restriction factor |
| GO:0005515 protein binding | IPI PMID:28611246 Inhibition of Avian Influenza A Virus Replication in Human C... | REMOVE | Summary: Kuo et al. 2017 report binding of TUFM to avian influenza PB2 (PB2-627E) and to NLRX1 in the context of TUFM acting as a restriction factor. Reason: Generic protein binding is uninformative. The NLRX1 and viral PB2 interactions bear on the proposed autophagy/antiviral role, but no specific molecular function of TUFM is established by them. Removal does not dispute the interactions. Supporting Evidence: PMID:28611246 we found that Tu elongation factor, mitochondrial (TUFM, also known as EF-Tu, P43, or COXPD4), can act as a selective PB2627E restriction factor |
| GO:0005515 protein binding | IPI PMID:31515488 Extensive disruption of protein interactions by genetic vari... | REMOVE | Summary: Binary Y2H hit with FAM9B in a variant-interaction screen. Reason: Generic protein binding is uninformative. High-throughput Y2H with no functional context. |
| GO:0005525 GTP binding | IEA GO_REF:0000002 | ACCEPT | Summary: GTP binding by the EF-Tu G-domain. Reason: mtEF-Tu binds aminoacyl-tRNA in its GTP-bound state; GTP binding is intrinsic to its function. Supporting Evidence: PMID:34135318 It was recently shown that during translation, mtEF-Tu·GTP delivers aminoacylated-tRNA to the mitoribosome in a manner similar to its bacterial EF-Tu counterparts |
| GO:0005525 GTP binding | ISS GO_REF:0000024 | ACCEPT | Summary: GTP binding by the EF-Tu G-domain. Reason: mtEF-Tu binds aminoacyl-tRNA in its GTP-bound state; GTP binding is intrinsic to its function. Supporting Evidence: PMID:34135318 It was recently shown that during translation, mtEF-Tu·GTP delivers aminoacylated-tRNA to the mitoribosome in a manner similar to its bacterial EF-Tu counterparts |
| GO:0005739 mitochondrion | HDA PMID:20833797 Phosphoproteome analysis of functional mitochondria isolated... | ACCEPT | Summary: Detected in a phosphoproteome of isolated human mitochondria. Reason: Consistent with matrix localization. Supporting Evidence: PMID:20833797 we identified 155 distinct phosphorylation sites in 77 mitochondrial phosphoproteins |
| 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 matrix localization. Supporting Evidence: PMID:34800366 mitochondrial high-confidence proteome of >1,100 proteins (MitoCoP). |
| GO:0005739 mitochondrion | IBA GO_REF:0000033 | ACCEPT | Summary: PAINT inference that mitochondrial EF-Tu orthologs act in the mitochondrion. Reason: Correct; TUFM is imported into mitochondria (N-terminal transit peptide) and acts in the matrix on the mitoribosome. Supporting Evidence: PMID:8547323 the transit peptide for the mitochondrial localization of this protein is 43 amino acids in length |
| GO:0005739 mitochondrion | IDA GO_REF:0000052 | ACCEPT | Summary: Human Protein Atlas immunofluorescence localizes TUFM to mitochondria. Reason: Correct; TUFM is imported into mitochondria (N-terminal transit peptide) and acts in the matrix on the mitoribosome. Supporting Evidence: PMID:8547323 the transit peptide for the mitochondrial localization of this protein is 43 amino acids in length |
| GO:0005739 mitochondrion | IDA PMID:9332382 The human mitochondrial elongation factor tu (EF-Tu) gene: c... | ACCEPT | Summary: Ling et al. 1997 describe EF-Tu as a nuclear-encoded mitochondrial protein with an N-terminal leader sequence. Reason: Correct; TUFM is imported into mitochondria (N-terminal transit peptide) and acts in the matrix on the mitoribosome. Supporting Evidence: PMID:9332382 The human mitochondrial elongation factor Tu (EF-Tu) is nuclear-encoded and functions in the translational apparatus of mitochondria |
| GO:0005741 mitochondrial outer membrane | TAS Reactome:R-HSA-9754763 | MARK AS OVER ANNOTATED | Summary: Reactome SARS-CoV-2 M protein events place TUFM at the mitochondrial outer membrane / MAM. Reason: mtEF-Tu is imported via an N-terminal transit peptide and acts in the matrix. The Reactome event explicitly assumes that the viral M interaction occurs at the mitochondria-associated ER membrane; an outer-membrane-accessible pool of TUFM is inferred from its proposed autophagy role rather than shown by submitochondrial fractionation. Not wrong as a hypothesis, but over-states the evidence. Supporting Evidence: Reactome:R-HSA-9754763 This Reactome event shows binding of the ER-localized SARS-CoV-2 M protein to mitochondrial TUFM assuming that this interaction occurs at the mitochondria-associated endoplasmic reticulum membrane (MAM) |
| GO:0005741 mitochondrial outer membrane | TAS Reactome:R-HSA-9754775 | MARK AS OVER ANNOTATED | Summary: Reactome SARS-CoV-2 M protein events place TUFM at the mitochondrial outer membrane / MAM. Reason: mtEF-Tu is imported via an N-terminal transit peptide and acts in the matrix. The Reactome event explicitly assumes that the viral M interaction occurs at the mitochondria-associated ER membrane; an outer-membrane-accessible pool of TUFM is inferred from its proposed autophagy role rather than shown by submitochondrial fractionation. Not wrong as a hypothesis, but over-states the evidence. Supporting Evidence: Reactome:R-HSA-9754763 This Reactome event shows binding of the ER-localized SARS-CoV-2 M protein to mitochondrial TUFM assuming that this interaction occurs at the mitochondria-associated endoplasmic reticulum membrane (MAM) |
| GO:0005759 mitochondrial matrix | EXP PMID:22749352 The mitochondrial proteins NLRX1 and TUFM form a complex tha... | ACCEPT | Summary: Lei et al. 2012 localized TUFM to mitochondria and studied its NLRX1 complex. Reason: Matrix is the correct primary location of mtEF-Tu; UniProt cites this paper for "Mitochondrion matrix". Supporting Evidence: file:human/TUFM/TUFM-uniprot.txt SUBCELLULAR LOCATION: Mitochondrion matrix |
| GO:0005759 mitochondrial matrix | IEA GO_REF:0000044 | ACCEPT | Summary: UniProt SubCell mapping to mitochondrial matrix. Reason: Correct; mtEF-Tu acts on matrix mitoribosomes. Supporting Evidence: PMID:34135318 It was recently shown that during translation, mtEF-Tu·GTP delivers aminoacylated-tRNA to the mitoribosome in a manner similar to its bacterial EF-Tu counterparts |
| GO:0006414 translational elongation | IDA PMID:9332382 The human mitochondrial elongation factor tu (EF-Tu) gene: c... | ACCEPT | Summary: Ling et al. 1997 describe EF-Tu as functioning in the mitochondrial translational apparatus. Reason: Correct; the more specific mitochondrial translational elongation (GO:0070125) is also annotated. Supporting Evidence: PMID:9332382 The human mitochondrial elongation factor Tu (EF-Tu) is nuclear-encoded and functions in the translational apparatus of mitochondria |
| GO:0006414 translational elongation | IEA GO_REF:0000120 | ACCEPT | Summary: InterPro/UniPathway mapping to translational elongation. Reason: Correct, but the informative process is mitochondrial translational elongation (GO:0070125), also annotated. |
| GO:0016020 membrane | HDA PMID:19946888 Defining the membrane proteome of NK cells. | MARK AS OVER ANNOTATED | Summary: Detected in a membrane proteome of NK cells. Reason: mtEF-Tu is an abundant soluble matrix protein; membrane-fraction detection is expected from mitoribosome association with the inner membrane and contamination, and the generic term adds nothing. |
| GO:0032543 mitochondrial translation | ISS GO_REF:0000024 | ACCEPT | Summary: Transfer of mitochondrial translation from bovine mtEF-Tu. Reason: Core process; TUFM mutation causes defective mitochondrial translation, complemented in mammalian cells. Supporting Evidence: PMID:17160893 Genetic investigation involving patients with defective mitochondrial translation led us to the discovery of novel mutations in the mitochondrial elongation factor G1 (EFG1) in one affected baby and, for the first time, in the mitochondrial elongation factor Tu (EFTu) in another one PMID:17160893 Yeast and mammalian cell systems proved the pathogenic role of the mutant alleles by functional complementation in vivo |
| GO:0042645 mitochondrial nucleoid | IDA PMID:18063578 The layered structure of human mitochondrial DNA nucleoids. | KEEP AS NON CORE | Summary: Bogenhagen et al. 2008 found TUFM in native mtDNA nucleoid preparations. Reason: The authors place translation in the peripheral layer of nucleoids; association of an elongation factor there is plausible but peripheral to its function. Supporting Evidence: PMID:18063578 replication and transcription occur in the central core, whereas translation and complex assembly may occur in the peripheral region |
| GO:0070062 extracellular exosome | HDA PMID:20458337 MHC class II-associated proteins in B-cell exosomes and pote... | MARK AS OVER ANNOTATED | Summary: Detected in a proteomic survey of B-cell exosomes. Reason: mtEF-Tu is an abundant matrix protein; detection in exosome preparations is not evidence of a function there. |
| GO:0070125 mitochondrial translational elongation | IBA GO_REF:0000033 | ACCEPT | Summary: PAINT inference of mitochondrial translational elongation for the mitochondrial EF-Tu clade. Reason: Core process. mtEF-Tu delivers aminoacyl-tRNA to the mitoribosome during elongation, recombinant mammalian mtEF-Tu supports poly(U)-directed polymerization, and TUFM-mutant patients have defective mitochondrial translation. Supporting Evidence: PMID:34135318 It was recently shown that during translation, mtEF-Tu·GTP delivers aminoacylated-tRNA to the mitoribosome in a manner similar to its bacterial EF-Tu counterparts PMID:8547323 The expressed form of the factor is active in the poly(U)-directed polymerization of phenylalanine although it is less active than the native EF-Tu.Tsmt complex PMID:17160893 Genetic investigation involving patients with defective mitochondrial translation led us to the discovery of novel mutations in the mitochondrial elongation factor G1 (EFG1) in one affected baby and, for the first time, in the mitochondrial elongation factor Tu (EFTu) in another one |
| GO:1902775 mitochondrial large ribosomal subunit assembly | IDA PMID:34135318 Structural basis for late maturation steps of the human mito... | KEEP AS NON CORE | Summary: Cryo-EM structure of GTPBP5-bound late mt-LSU assembly intermediates shows mtEF-Tu bound to the particle. Reason: Direct structural evidence that mtEF-Tu binds mt-LSU assembly intermediates, in a non-canonical mode, together with GTPBP5; the authors propose that it helps accommodate GTPBP5. The functional contribution is inferred from the structure rather than tested, so this is kept as a secondary role alongside its core elongation function. Supporting Evidence: PMID:34135318 In the GTPBP5IP dataset, mtEF-Tu is present in approximately 75% of the GTPBP5-containing pre-ribosomal particles PMID:34135318 this suggests that mtEF-Tu hydrolysis—stimulated by bL12m and uL10m—is used to accommodate GTPBP5 on the maturating mt-LSU |
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Download this section (compressed HTML)Q: Is the reported role of TUFM in restraining RIG-I-like receptor signalling and promoting autophagy (with NLRX1 and ATG5-ATG12/ATG16L1) separable from its elongation function, and which pool of TUFM is accessible to cytosolic or outer-membrane partners given its matrix import?
Q: Does mtEF-Tu GTP hydrolysis actively position GTPBP5 during late mt-LSU assembly, or is its binding to assembly intermediates incidental?
Experiment: Protease-protection and submitochondrial fractionation of endogenous TUFM, combined with separation-of-function mutants that retain elongation activity, to test whether the antiviral/autophagy phenotypes require an extra-matrix pool.
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