TSFM encodes mitochondrial elongation factor Ts (EF-Ts), a nuclear-encoded matrix protein of the EF-Ts family. It is the guanine nucleotide exchange factor for mitochondrial elongation factor Tu (TUFM): it binds EF-Tu-GDP released from the mitoribosome, promotes exchange of GDP for GTP, and forms a stable EF-Tu-Ts complex, so regenerating EF-Tu-GTP for aminoacyl-tRNA delivery during elongation of the 13 mtDNA-encoded OXPHOS subunits. Mature EF-Ts also stabilises EF-Tu; in patient cells, loss of EF-Ts lowers EF-Tu levels, and the translation defect can be rescued by overexpressing either factor. Biallelic TSFM variants cause combined oxidative phosphorylation deficiency 3 (COXPD3), with presentations ranging from fatal neonatal encephalomyopathy, hepatopathy or hypertrophic cardiomyopathy to juvenile-onset Leigh syndrome, ataxia, neuropathy and optic atrophy.
| GO Term | Evidence | Action | Reason |
|---|---|---|---|
| GO:0003723 RNA binding | HDA PMID:22681889 The mRNA-bound proteome and its global occupancy profile on ... | MARK AS OVER ANNOTATED | Summary: Detected in mRNA-bound proteome capture. Reason: EF-Ts has no known RNA-binding activity; it acts on EF-Tu, and any RNA crosslinking likely reflects its association with the aminoacyl-tRNA-EF-Tu-GTP complex or translating mitoribosomes. Not supported as a function of TSFM itself. Supporting Evidence: file:human/TSFM/TSFM-uniprot.txt Associates with the EF-Tu.GDP complex and induces the exchange of GDP to GTP |
| GO:0003746 translation elongation factor activity | IBA GO_REF:0000033 | ACCEPT | Summary: Translation elongation factor activity assigned to EF-Ts family members. Reason: EF-Ts is a translation elongation factor; its specific activity is guanine nucleotide exchange on EF-Tu (GO:0005085, also annotated), and it remains bound to the ternary complex until GTP hydrolysis on the ribosome. Accepted as the broader, conventional elongation-factor term. Supporting Evidence: file:human/TSFM/TSFM-uniprot.txt Associates with the EF-Tu.GDP complex and induces the exchange of GDP to GTP PMID:7615523 The mature form of EF-Tsmt forms a complex with E. coli elongation factor Tu. This complex is active in poly(U)-directed polymerization of phenylalanine |
| GO:0003746 translation elongation factor activity | IEA GO_REF:0000120 | ACCEPT | Summary: Translation elongation factor activity assigned to EF-Ts family members. Reason: EF-Ts is a translation elongation factor; its specific activity is guanine nucleotide exchange on EF-Tu (GO:0005085, also annotated), and it remains bound to the ternary complex until GTP hydrolysis on the ribosome. Accepted as the broader, conventional elongation-factor term. Supporting Evidence: file:human/TSFM/TSFM-uniprot.txt Associates with the EF-Tu.GDP complex and induces the exchange of GDP to GTP PMID:7615523 The mature form of EF-Tsmt forms a complex with E. coli elongation factor Tu. This complex is active in poly(U)-directed polymerization of phenylalanine |
| GO:0005085 guanyl-nucleotide exchange factor activity | ISS GO_REF:0000024 | ACCEPT | Summary: Transfer of guanyl-nucleotide exchange factor activity from the bovine/mouse ortholog. Reason: Core molecular function. EF-Ts is the GEF for mtEF-Tu, binding EF-Tu-GDP and promoting exchange for GTP; the human disease variant R333W lies in the subdomain that contacts EF-Tu, and EF-Tu is destabilised when EF-Ts is lost. Supporting Evidence: file:human/TSFM/TSFM-uniprot.txt Associates with the EF-Tu.GDP complex and induces the exchange of GDP to GTP PMID:17033963 EFTs functions as a guanine nucleotide exchange factor for EFTu, another translation elongation factor that brings aminoacylated transfer RNAs to the ribosomal A site as a ternary complex with guanosine triphosphate |
| GO:0005515 protein binding | IPI PMID:25910212 Widespread macromolecular interaction perturbations in human... | REMOVE | Summary: High-throughput binary interactome hits (CCDC89, CEP70, CPLX2, GAS8, GOLGA6L9, KRTAP1-1, MDFI, RALBP1). Reason: Generic protein binding is uninformative. These are high-throughput binary yeast two-hybrid hits with cytoskeletal, centrosomal, keratin-associated and other non-mitochondrial proteins, with no link to the matrix function of EF-Ts; the expected functional partner, TUFM, is not among them. Removal does not dispute the reported interaction. |
| GO:0005515 protein binding | IPI PMID:25910212 Widespread macromolecular interaction perturbations in human... | REMOVE | Summary: High-throughput binary interactome hits (CCDC89, CEP70, CPLX2, GAS8, GOLGA6L9, KRTAP1-1, MDFI, RALBP1). Reason: Generic protein binding is uninformative. These are high-throughput binary yeast two-hybrid hits with cytoskeletal, centrosomal, keratin-associated and other non-mitochondrial proteins, with no link to the matrix function of EF-Ts; the expected functional partner, TUFM, is not among them. Removal does not dispute the reported interaction. |
| GO:0005515 protein binding | IPI PMID:32296183 A reference map of the human binary protein interactome. | REMOVE | Summary: High-throughput binary interactome hits (CCDC89, CEP70, CPLX2, GAS8, GOLGA6L9, KRTAP1-1, MDFI, RALBP1). Reason: Generic protein binding is uninformative. These are high-throughput binary yeast two-hybrid hits with cytoskeletal, centrosomal, keratin-associated and other non-mitochondrial proteins, with no link to the matrix function of EF-Ts; the expected functional partner, TUFM, is not among them. Removal does not dispute the reported interaction. |
| GO:0005515 protein binding | IPI PMID:32296183 A reference map of the human binary protein interactome. | REMOVE | Summary: High-throughput binary interactome hits (CCDC89, CEP70, CPLX2, GAS8, GOLGA6L9, KRTAP1-1, MDFI, RALBP1). Reason: Generic protein binding is uninformative. These are high-throughput binary yeast two-hybrid hits with cytoskeletal, centrosomal, keratin-associated and other non-mitochondrial proteins, with no link to the matrix function of EF-Ts; the expected functional partner, TUFM, is not among them. Removal does not dispute the reported interaction. |
| GO:0005515 protein binding | IPI PMID:32296183 A reference map of the human binary protein interactome. | REMOVE | Summary: High-throughput binary interactome hits (CCDC89, CEP70, CPLX2, GAS8, GOLGA6L9, KRTAP1-1, MDFI, RALBP1). Reason: Generic protein binding is uninformative. These are high-throughput binary yeast two-hybrid hits with cytoskeletal, centrosomal, keratin-associated and other non-mitochondrial proteins, with no link to the matrix function of EF-Ts; the expected functional partner, TUFM, is not among them. Removal does not dispute the reported interaction. |
| GO:0005515 protein binding | IPI PMID:32296183 A reference map of the human binary protein interactome. | REMOVE | Summary: High-throughput binary interactome hits (CCDC89, CEP70, CPLX2, GAS8, GOLGA6L9, KRTAP1-1, MDFI, RALBP1). Reason: Generic protein binding is uninformative. These are high-throughput binary yeast two-hybrid hits with cytoskeletal, centrosomal, keratin-associated and other non-mitochondrial proteins, with no link to the matrix function of EF-Ts; the expected functional partner, TUFM, is not among them. Removal does not dispute the reported interaction. |
| GO:0005515 protein binding | IPI PMID:32296183 A reference map of the human binary protein interactome. | REMOVE | Summary: High-throughput binary interactome hits (CCDC89, CEP70, CPLX2, GAS8, GOLGA6L9, KRTAP1-1, MDFI, RALBP1). Reason: Generic protein binding is uninformative. These are high-throughput binary yeast two-hybrid hits with cytoskeletal, centrosomal, keratin-associated and other non-mitochondrial proteins, with no link to the matrix function of EF-Ts; the expected functional partner, TUFM, is not among them. Removal does not dispute the reported interaction. |
| GO:0005515 protein binding | IPI PMID:32296183 A reference map of the human binary protein interactome. | REMOVE | Summary: High-throughput binary interactome hits (CCDC89, CEP70, CPLX2, GAS8, GOLGA6L9, KRTAP1-1, MDFI, RALBP1). Reason: Generic protein binding is uninformative. These are high-throughput binary yeast two-hybrid hits with cytoskeletal, centrosomal, keratin-associated and other non-mitochondrial proteins, with no link to the matrix function of EF-Ts; the expected functional partner, TUFM, is not among them. Removal does not dispute the reported interaction. |
| GO:0005515 protein binding | IPI PMID:32296183 A reference map of the human binary protein interactome. | REMOVE | Summary: High-throughput binary interactome hits (CCDC89, CEP70, CPLX2, GAS8, GOLGA6L9, KRTAP1-1, MDFI, RALBP1). Reason: Generic protein binding is uninformative. These are high-throughput binary yeast two-hybrid hits with cytoskeletal, centrosomal, keratin-associated and other non-mitochondrial proteins, with no link to the matrix function of EF-Ts; the expected functional partner, TUFM, is not among them. Removal does not dispute the reported interaction. |
| GO:0005515 protein binding | IPI PMID:32296183 A reference map of the human binary protein interactome. | REMOVE | Summary: High-throughput binary interactome hits (CCDC89, CEP70, CPLX2, GAS8, GOLGA6L9, KRTAP1-1, MDFI, RALBP1). Reason: Generic protein binding is uninformative. These are high-throughput binary yeast two-hybrid hits with cytoskeletal, centrosomal, keratin-associated and other non-mitochondrial proteins, with no link to the matrix function of EF-Ts; the expected functional partner, TUFM, is not among them. Removal does not dispute the reported interaction. |
| 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: Correct. 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-Ts orthologs act in mitochondria. Reason: Correct; EF-Ts acts in the matrix on mtEF-Tu. Supporting Evidence: PMID:17033963 The 13 polypeptides encoded in mitochondrial DNA (mtDNA) are synthesized in the mitochondrial matrix on a dedicated protein-translation apparatus that resembles that found in prokaryotes |
| GO:0005739 mitochondrion | IDA GO_REF:0000052 | ACCEPT | Summary: Human Protein Atlas immunofluorescence localizes TSFM to mitochondria. Reason: Correct. |
| GO:0005739 mitochondrion | IEA GO_REF:0000120 | ACCEPT | Summary: UniRule/ARBA mapping to mitochondrion. Reason: Correct. |
| GO:0005739 mitochondrion | TAS PMID:7615523 Cloning and expression of mitochondrial translational elonga... | ACCEPT | Summary: Xin et al. 1995 describe EF-Tsmt as a mitochondrial protein with an N-terminal signal peptide. Reason: Correct. Supporting Evidence: PMID:7615523 includes a 55-amino acid signal peptide and a mature protein of 283 residues |
| GO:0005759 mitochondrial matrix | IEA GO_REF:0000044 | ACCEPT | Summary: Mitochondrial matrix localization, by SubCell mapping and by similarity to the bovine/mouse factor. Reason: Core location; mitochondrial translation takes place in the matrix. Supporting Evidence: PMID:17033963 The 13 polypeptides encoded in mitochondrial DNA (mtDNA) are synthesized in the mitochondrial matrix on a dedicated protein-translation apparatus that resembles that found in prokaryotes |
| GO:0005759 mitochondrial matrix | ISS GO_REF:0000024 | ACCEPT | Summary: Mitochondrial matrix localization, by SubCell mapping and by similarity to the bovine/mouse factor. Reason: Core location; mitochondrial translation takes place in the matrix. Supporting Evidence: PMID:17033963 The 13 polypeptides encoded in mitochondrial DNA (mtDNA) are synthesized in the mitochondrial matrix on a dedicated protein-translation apparatus that resembles that found in prokaryotes |
| GO:0006414 translational elongation | IEA GO_REF:0000120 | ACCEPT | Summary: InterPro/UniRule mapping to translational elongation. Reason: Correct, but mitochondrial translational elongation (GO:0070125) is the informative term and is also annotated. |
| GO:0032543 mitochondrial translation | IEA GO_REF:0000117 | ACCEPT | Summary: ARBA mapping to mitochondrial translation. Reason: Correct; the more specific elongation term is also annotated. Supporting Evidence: PMID:27677415 we rescued the normal molecular phenotype by expression of the wild-type TSFM cDNA in patient's fibroblasts |
| GO:0070125 mitochondrial translational elongation | IBA GO_REF:0000033 | ACCEPT | Summary: PAINT inference of mitochondrial translational elongation. Reason: Core process. EF-Ts regenerates EF-Tu-GTP for each elongation cycle; TSFM mutations cause a mitochondrial translation defect rescued by EF-Ts or EF-Tu. Supporting Evidence: PMID:17033963 EFTs functions as a guanine nucleotide exchange factor for EFTu, another translation elongation factor that brings aminoacylated transfer RNAs to the ribosomal A site as a ternary complex with guanosine triphosphate PMID:17033963 These phenotypes and the translation defect were rescued by retroviral expression of either EFTs or EFTu |
| GO:0070125 mitochondrial translational elongation | IDA PMID:27677415 Molecular-genetic characterization and rescue of a TSFM muta... | ACCEPT | Summary: Emperador et al. 2016: a homozygous TSFM missense mutation causes a mitochondrial translation defect rescued by wild-type TSFM cDNA. Reason: Core process, with cDNA rescue in patient fibroblasts. UniProt cites this paper for participation in mitochondrial translation. Supporting Evidence: PMID:27677415 we rescued the normal molecular phenotype by expression of the wild-type TSFM cDNA in patient's fibroblasts |
| GO:0070125 mitochondrial translational elongation | TAS PMID:7615523 Cloning and expression of mitochondrial translational elonga... | ACCEPT | Summary: Xin et al. 1995 cloned bovine and human EF-Tsmt and showed that recombinant bovine EF-Tsmt in complex with EF-Tu supports poly(U)-directed polymerization. Reason: Core process. Supporting Evidence: PMID:7615523 The mature form of EF-Tsmt forms a complex with E. coli elongation factor Tu. This complex is active in poly(U)-directed polymerization of phenylalanine |
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Download this section (compressed HTML)Q: Do COXPD3 variants act mainly by reducing EF-Ts nucleotide-exchange activity or by destabilising the EF-Tu-Ts complex, given that EF-Tu overexpression alone rescues the translation defect?
Q: Why does the same TSFM variant (R333W) produce encephalomyopathy, cardiomyopathy or hepatopathy in different families?
Experiment: In vitro GDP/GTP exchange kinetics of recombinant human mtEF-Tu with wild-type and disease-variant EF-Ts, alongside complex-stability measurements, to separate catalytic from stabilising defects.
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