id: P41214 gene_symbol: EIF2D product_type: PROTEIN status: COMPLETE taxon: id: NCBITaxon:9606 label: Homo sapiens description: 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. alternative_products: - name: '1' id: P41214-1 - name: '2' id: P41214-2 sequence_note: VSP_006300 existing_annotations: - term: id: GO:0001731 label: formation of translation preinitiation complex evidence_type: IBA original_reference_id: GO_REF:0000033 qualifier: involved_in review: summary: Phylogenetic transfer of preinitiation-complex formation, consistent with EIF2D delivering tRNA onto 40S/mRNA complexes for (re)initiation. action: ACCEPT reason: Corroborated by direct experimental evidence that eIF2D delivers tRNA to the 40S P-site. supported_by: - reference_id: file:human/EIF2D/EIF2D-uniprot.txt supporting_text: Translation initiation factor that is able to deliver tRNA to the P-site of the eukaryotic ribosome in a GTP-independent manner. - term: id: GO:0003743 label: translation initiation factor activity evidence_type: IBA original_reference_id: GO_REF:0000033 qualifier: enables review: 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. action: ACCEPT reason: Supported by both phylogenetic inference and direct biochemical evidence (PMID:20566627); this is the core molecular function. supported_by: - reference_id: file:human/EIF2D/EIF2D-uniprot.txt supporting_text: Translation initiation factor that is able to deliver tRNA to the P-site of the eukaryotic ribosome in a GTP-independent manner. - term: id: GO:0001731 label: formation of translation preinitiation complex evidence_type: IEA original_reference_id: GO_REF:0000002 qualifier: involved_in review: summary: InterPro-based assignment of preinitiation-complex formation, redundant with and consistent with the IBA/IDA evidence. action: ACCEPT reason: Consistent with EIF2D's documented role in assembling tRNA onto 40S/mRNA complexes. supported_by: - reference_id: file:human/EIF2D/EIF2D-uniprot.txt supporting_text: Translation initiation factor that is able to deliver tRNA to the P-site of the eukaryotic ribosome in a GTP-independent manner. - term: id: GO:0003723 label: RNA binding evidence_type: IEA original_reference_id: GO_REF:0000002 qualifier: enables review: 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. action: KEEP_AS_NON_CORE reason: Correct but generic; the specific informative function is GTP-independent P-site tRNA delivery (initiation factor activity). supported_by: - reference_id: file:human/EIF2D/EIF2D-uniprot.txt supporting_text: includes an SUI1 domain present also in translation initiation factor eIF1 - term: id: GO:0003743 label: translation initiation factor activity evidence_type: IEA original_reference_id: GO_REF:0000002 qualifier: enables review: summary: InterPro-based assignment of translation initiation factor activity, redundant with the IBA and IDA evidence for this core function. action: ACCEPT reason: Agrees with direct experimental evidence; core molecular function. supported_by: - reference_id: file:human/EIF2D/EIF2D-uniprot.txt supporting_text: Translation initiation factor that is able to deliver tRNA to the P-site of the eukaryotic ribosome in a GTP-independent manner. - term: id: GO:0005737 label: cytoplasm evidence_type: IEA original_reference_id: GO_REF:0000044 qualifier: located_in review: summary: Automated cytoplasmic localization, consistent with the experimentally determined site of action. action: ACCEPT reason: Agrees with IDA cytoplasm/cytosol evidence; EIF2D acts on cytoplasmic ribosomes. supported_by: - reference_id: file:human/EIF2D/EIF2D-uniprot.txt supporting_text: 'SUBCELLULAR LOCATION: Cytoplasm' - term: id: GO:0006413 label: translational initiation evidence_type: IEA original_reference_id: GO_REF:0000002 qualifier: involved_in review: summary: General translational initiation, assigned from domain content. EIF2D's specific role is non-canonical, eIF2-independent P-site tRNA delivery. action: KEEP_AS_NON_CORE reason: Correct parent process but less informative than the specific GTP-independent (re)initiation/recycling role. supported_by: - reference_id: file:human/EIF2D/EIF2D-uniprot.txt supporting_text: Translation initiation factor that is able to deliver tRNA to the P-site of the eukaryotic ribosome in a GTP-independent manner. - term: id: GO:0043933 label: protein-containing complex organization evidence_type: IEA original_reference_id: GO_REF:0000117 qualifier: involved_in review: summary: Automated (ARBA) assignment of protein-containing complex organization, a very general process term that is uninformative for EIF2D. action: MARK_AS_OVER_ANNOTATED reason: Generic complex-organization term not specific to EIF2D's documented tRNA-delivery/recycling function; uninformative. supported_by: - reference_id: file:human/EIF2D/EIF2D-goa.tsv supporting_text: GO:0043933 protein-containing complex organization biological_process ECO:0000256 IEA GO_REF:0000117 ARBA:ARBA00026287 - term: id: GO:0005829 label: cytosol evidence_type: IDA original_reference_id: GO_REF:0000052 qualifier: located_in review: summary: Direct immunofluorescence (HPA) cytosolic localization, consistent with the cytoplasmic site of action. action: ACCEPT reason: IDA-supported cytosolic localization agrees with EIF2D's role on cytoplasmic ribosomes. supported_by: - reference_id: file:human/EIF2D/EIF2D-goa.tsv supporting_text: GO:0005829 cytosol cellular_component ECO:0000314 IDA GO_REF:0000052 - term: id: GO:0075522 label: IRES-dependent viral translational initiation evidence_type: IDA original_reference_id: PMID:20713520 qualifier: involved_in review: 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. action: KEEP_AS_NON_CORE reason: A genuine but specialized application of EIF2D's P-site tRNA delivery activity; non-core relative to cellular reinitiation/recycling. supported_by: - reference_id: PMID:20713520 supporting_text: 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 - term: id: GO:0001731 label: formation of translation preinitiation complex evidence_type: IDA original_reference_id: PMID:20713520 qualifier: involved_in review: summary: Direct evidence that Ligatin (eIF2D) assembles initiator tRNA onto 40S/mRNA complexes. action: ACCEPT reason: Direct experimental support for EIF2D's role in assembling the tRNA-loaded 40S complex. supported_by: - reference_id: PMID:20713520 supporting_text: promote efficient eIF2-independent recruitment of Met-tRNA(Met)(i) to 40S/mRNA complexes - term: id: GO:0032790 label: ribosome disassembly evidence_type: IDA original_reference_id: PMID:20713520 qualifier: involved_in review: 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). action: ACCEPT reason: Direct experimental support for EIF2D's role in 40S recycling/recovery. supported_by: - reference_id: PMID:20713520 supporting_text: 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 - term: id: GO:0003743 label: translation initiation factor activity evidence_type: IDA original_reference_id: PMID:20566627 qualifier: enables review: 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. action: ACCEPT reason: Direct experimental evidence for EIF2D's defining initiation-factor activity. supported_by: - reference_id: PMID:20566627 supporting_text: the tRNA binding to the P-site of 40 S ribosomes by a novel GTP-independent factor eIF2D - term: id: GO:0005737 label: cytoplasm evidence_type: IDA original_reference_id: PMID:20566627 qualifier: located_in review: summary: Direct evidence for cytoplasmic localization of eIF2D. action: ACCEPT reason: IDA-supported cytoplasmic localization consistent with EIF2D's site of action. supported_by: - reference_id: file:human/EIF2D/EIF2D-uniprot.txt supporting_text: 'SUBCELLULAR LOCATION: Cytoplasm' - term: id: GO:0005737 label: cytoplasm evidence_type: TAS original_reference_id: PMID:2482295 qualifier: located_in review: 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. action: ACCEPT 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. supported_by: - reference_id: PMID:2482295 supporting_text: a punctate immunofluorescence pattern within the cytosol of U937 cells - term: id: GO:0006886 label: intracellular protein transport evidence_type: TAS original_reference_id: PMID:2482295 qualifier: involved_in review: 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. action: REMOVE 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. supported_by: - reference_id: PMID:2482295 supporting_text: encoding ligatin, a trafficking receptor for phosphoglycoproteins - term: id: GO:0038023 label: signaling receptor activity evidence_type: TAS original_reference_id: PMID:2482295 qualifier: enables review: 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. action: REMOVE reason: Based on a superseded identity; EIF2D is a translation factor, not a signaling receptor. The activity is not supported by any current evidence. supported_by: - reference_id: PMID:2482295 supporting_text: encoding ligatin, a trafficking receptor for phosphoglycoproteins references: - id: GO_REF:0000002 title: Gene Ontology annotation through association of InterPro records with GO terms findings: [] - id: GO_REF:0000033 title: Annotation inferences using phylogenetic trees findings: [] - id: GO_REF:0000044 title: Gene Ontology annotation based on UniProtKB/Swiss-Prot Subcellular Location vocabulary mapping findings: [] - id: GO_REF:0000052 title: Gene Ontology annotation based on curation of immunofluorescence data findings: [] - id: GO_REF:0000117 title: Electronic Gene Ontology annotations created by ARBA machine learning models findings: [] - id: PMID:20566627 title: GTP-independent tRNA delivery to the ribosomal P-site by a novel eukaryotic translation factor. reference_review: relevance: HIGH correctness: VERIFIED review_notes: "Cached publications/PMID_20566627.md title matches YAML; defines eIF2D's GTP-independent P-site tRNA delivery. GOA anchors this PMID to GO:0003743 (translation initiation factor activity, IDA), the core MF supported by this reference." findings: - statement: eIF2D binds tRNA to the P-site of 40S ribosomes in a GTP-independent manner after the AUG codon is positioned in the P-site, and uniquely delivers elongator (non-Met) tRNAs as well. reference_section_type: ABSTRACT - id: PMID:20713520 title: Activities of Ligatin and MCT-1/DENR in eukaryotic translation initiation and ribosomal recycling. reference_review: relevance: HIGH correctness: VERIFIED review_notes: "Cached publications/PMID_20713520.md title matches YAML; establishes Ligatin/eIF2D roles in eIF2-independent initiator-tRNA recruitment and 40S recycling. GOA anchors this PMID to GO:0032790 (ribosome disassembly) and GO:0001731 (IDA), supporting the recycling core function." findings: - statement: Ligatin (eIF2D) promotes eIF2-independent recruitment of initiator tRNA to 40S/mRNA complexes when the start codon is in the P-site, and promotes release of deacylated tRNA and mRNA from recycled 40S subunits after ABCE1-mediated ribosome dissociation. reference_section_type: ABSTRACT - id: PMID:2482295 title: Molecular cloning of the cDNA for ligatin. findings: - statement: The 1989 paper describes "ligatin" as a trafficking receptor for phosphoglycoproteins; this identity has since been superseded by the characterization of EIF2D/Ligatin as a non-canonical translation factor. reference_section_type: ABSTRACT core_functions: - description: Non-canonical translation factor that delivers initiator and elongator tRNA into the 40S ribosomal P-site in a GTP-independent and eIF2-independent manner when the start codon is already positioned in the P-site, driving (re)initiation on specialized mRNAs. molecular_function: id: GO:0003743 label: translation initiation factor activity locations: - id: GO:0005737 label: cytoplasm supported_by: - reference_id: PMID:20566627 supporting_text: the tRNA binding to the P-site of 40 S ribosomes by a novel GTP-independent factor eIF2D - reference_id: file:human/EIF2D/EIF2D-uniprot.txt supporting_text: Translation initiation factor that is able to deliver tRNA to the P-site of the eukaryotic ribosome in a GTP-independent manner. - description: Promotes recycling/recovery of post-termination 40S ribosomal subunits by promoting dissociation of deacylated tRNA and mRNA after ABCE1-mediated ribosome splitting. molecular_function: id: GO:0003743 label: translation initiation factor activity locations: - id: GO:0005737 label: cytoplasm supported_by: - reference_id: file:human/EIF2D/EIF2D-uniprot.txt supporting_text: can promote release of deacylated tRNA and mRNA from recycled 40S subunits following ABCE1-mediated dissociation of post-termination ribosomal complexes proposed_new_terms: [] suggested_questions: - question: 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? - question: What is the physiological significance of EIF2D's unique ability to deliver elongator (non-Met) tRNAs to the P-site? suggested_experiments: - description: Ribosome profiling in EIF2D-knockout cells (with and without MCTS1/DENR co-depletion) to define EIF2D-specific translational targets and recycling defects. - description: Reconstituted 40S recycling and P-site tRNA delivery assays comparing EIF2D with the MCTS1-DENR complex to quantify functional overlap and differences.