EIF2D (also called Ligatin) is a cytoplasmic non-canonical translation factor and the single-polypeptide counterpart of the MCTS1-DENR heterodimer (MCTS1 and DENR together correspond to the N- and C-terminal halves of Ligatin). Containing SUI1, PUA and SWIB modules, EIF2D delivers initiator (Met) and, uniquely, elongator (non-Met) tRNAs into the P-site of the 40S small ribosomal subunit in a GTP-independent, eIF2-independent manner, specifically when the start codon is already positioned in the P-site (as on certain IRESs, leaderless and A-rich mRNAs). In addition to its role in initiation, EIF2D promotes recycling of post-termination 40S subunits by promoting release of deacylated tRNA and mRNA following ABCE1-mediated dissociation of post-termination ribosomal complexes. It is broadly expressed and conserved across eukaryotes.
| GO Term | Evidence | Action | Reason |
|---|---|---|---|
| GO:0001731 formation of translation preinitiation complex | IBA GO_REF:0000033 | ACCEPT | Summary: Phylogenetic transfer of preinitiation-complex formation, consistent with EIF2D delivering tRNA onto 40S/mRNA complexes for (re)initiation. Reason: Corroborated by direct experimental evidence that eIF2D delivers tRNA to the 40S P-site. Supporting Evidence: file:human/EIF2D/EIF2D-uniprot.txt Translation initiation factor that is able to deliver tRNA to the P-site of the eukaryotic ribosome in a GTP-independent manner. |
| GO:0003743 translation initiation factor activity | IBA GO_REF:0000033 | ACCEPT | Summary: EIF2D's defining molecular function is non-canonical, GTP-independent delivery of tRNA to the 40S P-site; translation initiation factor activity is the appropriate core MF. Reason: Supported by both phylogenetic inference and direct biochemical evidence (PMID:20566627); this is the core molecular function. Supporting Evidence: file:human/EIF2D/EIF2D-uniprot.txt Translation initiation factor that is able to deliver tRNA to the P-site of the eukaryotic ribosome in a GTP-independent manner. |
| GO:0001731 formation of translation preinitiation complex | IEA GO_REF:0000002 | ACCEPT | Summary: InterPro-based assignment of preinitiation-complex formation, redundant with and consistent with the IBA/IDA evidence. Reason: Consistent with EIF2D's documented role in assembling tRNA onto 40S/mRNA complexes. Supporting Evidence: file:human/EIF2D/EIF2D-uniprot.txt Translation initiation factor that is able to deliver tRNA to the P-site of the eukaryotic ribosome in a GTP-independent manner. |
| GO:0003723 RNA binding | IEA GO_REF:0000002 | KEEP AS NON CORE | Summary: InterPro PUA-domain-based assignment of RNA binding. EIF2D contains a PUA RNA-binding domain and engages mRNA, so RNA binding is a reasonable parent molecular function. Reason: Correct but generic; the specific informative function is GTP-independent P-site tRNA delivery (initiation factor activity). Supporting Evidence: file:human/EIF2D/EIF2D-uniprot.txt includes an SUI1 domain present also in translation initiation factor eIF1 |
| GO:0003743 translation initiation factor activity | IEA GO_REF:0000002 | ACCEPT | Summary: InterPro-based assignment of translation initiation factor activity, redundant with the IBA and IDA evidence for this core function. Reason: Agrees with direct experimental evidence; core molecular function. Supporting Evidence: file:human/EIF2D/EIF2D-uniprot.txt Translation initiation factor that is able to deliver tRNA to the P-site of the eukaryotic ribosome in a GTP-independent manner. |
| GO:0005737 cytoplasm | IEA GO_REF:0000044 | ACCEPT | Summary: Automated cytoplasmic localization, consistent with the experimentally determined site of action. Reason: Agrees with IDA cytoplasm/cytosol evidence; EIF2D acts on cytoplasmic ribosomes. Supporting Evidence: file:human/EIF2D/EIF2D-uniprot.txt SUBCELLULAR LOCATION: Cytoplasm |
| GO:0006413 translational initiation | IEA GO_REF:0000002 | KEEP AS NON CORE | Summary: General translational initiation, assigned from domain content. EIF2D's specific role is non-canonical, eIF2-independent P-site tRNA delivery. Reason: Correct parent process but less informative than the specific GTP-independent (re)initiation/recycling role. Supporting Evidence: file:human/EIF2D/EIF2D-uniprot.txt Translation initiation factor that is able to deliver tRNA to the P-site of the eukaryotic ribosome in a GTP-independent manner. |
| GO:0043933 protein-containing complex organization | IEA GO_REF:0000117 | MARK AS OVER ANNOTATED | Summary: Automated (ARBA) assignment of protein-containing complex organization, a very general process term that is uninformative for EIF2D. Reason: Generic complex-organization term not specific to EIF2D's documented tRNA-delivery/recycling function; uninformative. Supporting Evidence: file:human/EIF2D/EIF2D-goa.tsv GO:0043933 protein-containing complex organization biological_process ECO:0000256 IEA GO_REF:0000117 ARBA:ARBA00026287 |
| GO:0005829 cytosol | IDA GO_REF:0000052 | ACCEPT | Summary: Direct immunofluorescence (HPA) cytosolic localization, consistent with the cytoplasmic site of action. Reason: IDA-supported cytosolic localization agrees with EIF2D's role on cytoplasmic ribosomes. Supporting Evidence: file:human/EIF2D/EIF2D-goa.tsv GO:0005829 cytosol cellular_component ECO:0000314 IDA GO_REF:0000052 |
| GO:0075522 IRES-dependent viral translational initiation | IDA PMID:20713520 Activities of Ligatin and MCT-1/DENR in eukaryotic translati... | KEEP AS NON CORE | Summary: EIF2D (Ligatin) promotes eIF2-independent recruitment of initiator tRNA on HCV-like IRESs and SV 26S mRNA, where the start codon is placed directly in the P-site. Reason: A genuine but specialized application of EIF2D's P-site tRNA delivery activity; non-core relative to cellular reinitiation/recycling. Supporting Evidence: PMID:20713520 promote efficient eIF2-independent recruitment of Met-tRNA(Met)(i) to 40S/mRNA complexes, if attachment of 40S subunits to the mRNA places the initiation codon directly in the P site, as on HCV-like IRESs |
| GO:0001731 formation of translation preinitiation complex | IDA PMID:20713520 Activities of Ligatin and MCT-1/DENR in eukaryotic translati... | ACCEPT | Summary: Direct evidence that Ligatin (eIF2D) assembles initiator tRNA onto 40S/mRNA complexes. Reason: Direct experimental support for EIF2D's role in assembling the tRNA-loaded 40S complex. Supporting Evidence: PMID:20713520 promote efficient eIF2-independent recruitment of Met-tRNA(Met)(i) to 40S/mRNA complexes |
| GO:0032790 ribosome disassembly | IDA PMID:20713520 Activities of Ligatin and MCT-1/DENR in eukaryotic translati... | ACCEPT | Summary: Ligatin (eIF2D) promotes release of deacylated tRNA and mRNA from recycled 40S subunits after ABCE1-mediated splitting of post-termination ribosomes (the 40S recovery/recycling step). Reason: Direct experimental support for EIF2D's role in 40S recycling/recovery. Supporting Evidence: PMID:20713520 Ligatin and MCT-1/DENR can promote release of deacylated tRNA and mRNA from recycled 40S subunits after ABCE1-mediated dissociation of post-termination ribosomes |
| GO:0003743 translation initiation factor activity | IDA PMID:20566627 GTP-independent tRNA delivery to the ribosomal P-site by a n... | ACCEPT | Summary: Direct biochemical demonstration that eIF2D delivers tRNA (including elongator tRNAs) to the 40S P-site in a GTP-independent manner; the core molecular function. Reason: Direct experimental evidence for EIF2D's defining initiation-factor activity. Supporting Evidence: PMID:20566627 the tRNA binding to the P-site of 40 S ribosomes by a novel GTP-independent factor eIF2D |
| GO:0005737 cytoplasm | IDA PMID:20566627 GTP-independent tRNA delivery to the ribosomal P-site by a n... | ACCEPT | Summary: Direct evidence for cytoplasmic localization of eIF2D. Reason: IDA-supported cytoplasmic localization consistent with EIF2D's site of action. Supporting Evidence: file:human/EIF2D/EIF2D-uniprot.txt SUBCELLULAR LOCATION: Cytoplasm |
| GO:0005737 cytoplasm | TAS PMID:2482295 Molecular cloning of the cDNA for ligatin. | ACCEPT | Summary: Cytoplasmic localization annotated from the 1989 cDNA-cloning paper that described "ligatin" as a phosphoglycoprotein trafficking receptor. The compartment happens to be correct, but the provenance reflects the historical (now superseded) receptor interpretation. Reason: Cytoplasmic localization is correct and corroborated by later IDA evidence; although the supporting reference pre-dates the identification of EIF2D/Ligatin as a translation factor, the compartment annotation itself is sound. Supporting Evidence: PMID:2482295 a punctate immunofluorescence pattern within the cytosol of U937 cells |
| GO:0006886 intracellular protein transport | TAS PMID:2482295 Molecular cloning of the cDNA for ligatin. | REMOVE | Summary: This annotation derives from the historical description of "ligatin" as a trafficking receptor for phosphoglycoproteins. Modern molecular characterization identifies EIF2D/Ligatin as a non-canonical translation factor, not a transport receptor; the protein-transport role is not supported. Reason: Based on a superseded identity of "ligatin" as a phosphoglycoprotein trafficking receptor; inconsistent with the established translation-factor function of EIF2D. No evidence supports a protein-transport role for EIF2D. Supporting Evidence: PMID:2482295 encoding ligatin, a trafficking receptor for phosphoglycoproteins |
| GO:0038023 signaling receptor activity | TAS PMID:2482295 Molecular cloning of the cDNA for ligatin. | REMOVE | Summary: Annotated as a receptor activity from the historical "ligatin = trafficking receptor for phosphoglycoproteins" description. EIF2D/Ligatin is now established as a cytoplasmic translation factor with no receptor function. Reason: Based on a superseded identity; EIF2D is a translation factor, not a signaling receptor. The activity is not supported by any current evidence. Supporting Evidence: PMID:2482295 encoding ligatin, a trafficking receptor for phosphoglycoproteins |
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Download this section (compressed HTML)Q: Under what cellular conditions (e.g. eIF2alpha phosphorylation/integrated stress response) does single-polypeptide EIF2D act versus the MCTS1-DENR heterodimer, and are their target mRNAs distinct?
Q: What is the physiological significance of EIF2D's unique ability to deliver elongator (non-Met) tRNAs to the P-site?
Experiment: Ribosome profiling in EIF2D-knockout cells (with and without MCTS1/DENR co-depletion) to define EIF2D-specific translational targets and recycling defects.
Experiment: Reconstituted 40S recycling and P-site tRNA delivery assays comparing EIF2D with the MCTS1-DENR complex to quantify functional overlap and differences.
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