EIF2D

UniProt ID: P41214
Organism: Homo sapiens
Review Status: COMPLETE
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Gene 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.

Existing Annotations Review

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

Core Functions

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:
translation initiation factor activity
Cellular Locations:
cytoplasm
Supporting Evidence:
  • PMID:20566627
    the tRNA binding to the P-site of 40 S ribosomes by a novel GTP-independent factor eIF2D
  • 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.

Promotes recycling/recovery of post-termination 40S ribosomal subunits by promoting dissociation of deacylated tRNA and mRNA after ABCE1-mediated ribosome splitting.

Molecular Function:
translation initiation factor activity
Cellular Locations:
cytoplasm
Supporting Evidence:
  • file:human/EIF2D/EIF2D-uniprot.txt
    can promote release of deacylated tRNA and mRNA from recycled 40S subunits following ABCE1-mediated dissociation of post-termination ribosomal complexes

References

GO_REF:0000002
Gene Ontology annotation through association of InterPro records with GO terms
GO_REF:0000033
Annotation inferences using phylogenetic trees
GO_REF:0000044
Gene Ontology annotation based on UniProtKB/Swiss-Prot Subcellular Location vocabulary mapping
GO_REF:0000052
Gene Ontology annotation based on curation of immunofluorescence data
GO_REF:0000117
Electronic Gene Ontology annotations created by ARBA machine learning models
PMID:20566627
GTP-independent tRNA delivery to the ribosomal P-site by a novel eukaryotic translation factor.
  • 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.
PMID:20713520
Activities of Ligatin and MCT-1/DENR in eukaryotic translation initiation and ribosomal recycling.
  • 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.
PMID:2482295
Molecular cloning of the cDNA for ligatin.
  • 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.

Suggested Questions for Experts

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?

Suggested Experiments

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.

📚 Additional Documentation

Notes

(EIF2D-notes.md)

EIF2D (Ligatin, eIF2D) — research notes

UniProt P41214. Single-polypeptide non-canonical translation factor. Contains SUI1 + PUA + SWIB domains; it is the full-length protein of which MCTS1 (N-half) + DENR (C-half) are the split equivalent.

Core function

  • PMID:20566627
  • UniProt FUNCTION: "Translation initiation factor that is able to deliver tRNA to the P-site of the eukaryotic ribosome in a GTP-independent manner ... can promote release of deacylated tRNA and mRNA from recycled 40S subunits following ABCE1-mediated dissociation of post-termination ribosomal complexes."
  • PMID:20713520 Ligatin (= eIF2D) individually promotes eIF2-independent Met-tRNA recruitment and 40S recycling (release of deacylated tRNA/mRNA after ABCE1 splitting).

So core MF: translation initiation factor activity (GTP-independent P-site tRNA delivery); BP: ribosome recycling (40S recovery / ribosome disassembly), reinitiation, IRES init.

Historical "Ligatin = trafficking receptor" conflation

  • PMID:2482295 — this 1989 paper named "ligatin" as a phosphoglycoprotein trafficking receptor. The annotations GO:0038023 signaling receptor activity, GO:0006886 intracellular protein transport, and GO:0005737 cytoplasm (TAS PMID:2482295) derive from this. The modern molecular identity of EIF2D/Ligatin as a translation factor (Dmitriev 2010, Skabkin 2010) makes the receptor/transport functions over-annotations / mis-assignments — REMOVE or MARK_AS_OVER_ANNOTATED.

Decisions

  • translation initiation factor activity (IBA, IEA, IDA 20566627) — ACCEPT (core).
  • formation of translation preinitiation complex (IBA, IEA, IDA 20713520) — ACCEPT.
  • ribosome disassembly (IDA 20713520) — ACCEPT (recycling).
  • IRES-dependent viral translational initiation (IDA 20713520) — KEEP_AS_NON_CORE.
  • RNA binding (IEA) — KEEP_AS_NON_CORE.
  • translational initiation (IEA) / protein-containing complex organization (IEA) — KEEP_AS_NON_CORE.
  • cytosol/cytoplasm (IDA) — ACCEPT.
  • signaling receptor activity (TAS 2482295) — REMOVE (wrong "ligatin" identity).
  • intracellular protein transport (TAS 2482295) — REMOVE.
  • cytoplasm TAS 2482295 — KEEP_AS_NON_CORE (localization happens to be right but provenance is the receptor paper).

Pn Notes

(EIF2D-pn-notes.md)

EIF2D PN Consistency Notes

  • Generated: 2026-06-18
  • Project: PROTEOSTASIS
  • Scope: PN consistency rereview against local AIGR review and available deep-research artifacts
  • UniProt: P41214
  • AIGR review status: COMPLETE
  • Review batch: proteostasis-batch-2026-06-07c
  • Batch change status: added

Source Files Checked

Deep Research Files

  • No *-deep-research*.md file found in this gene directory.

AIGR Review Snapshot

  • 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.
  • Existing/core annotation action counts: ACCEPT: 11; KEEP_AS_NON_CORE: 3; MARK_AS_OVER_ANNOTATED: 1; REMOVE: 2

PN Consistency Summary

  • Consistency: Review/notes are accurate and self-consistent: EIF2D (Ligatin) is the single-polypeptide eIF2D-like factor that does GTP-independent P-site tRNA delivery and post-termination 40S recycling/reinitiation (core MF GO:0003743). This CONTRADICTS the PN "Translation termination" placement and GO:0006415 projection — EIF2D is not a release factor. (Same node mis-classification as DENR, its split-paralog partner.)
  • PN story / NEW pressure: Projected GO:0006415 translational termination is more_specific_than_existing_goa. Verified (OLS): GO:0006415 = polypeptide release at a stop codon — not EIF2D's activity. EIF2D's real roles (GO:0001731 preinitiation-complex formation, GO:0032790 ribosome disassembly/recycling, GO:0003743 initiation-factor activity) are already in GOA and reviewed. The projection over-reaches / is biologically wrong; no defensible NEW termination term.
  • Evidence alignment: Dossier carries no reference titles. Review anchors PMID:20566627 (GTP-independent P-site tRNA delivery) and PMID:20713520 (Ligatin recycling), both VERIFIED — about initiation/recycling, none about termination. Divergence by omission in dossier.
  • Verdict: Mapping mismatch — PN "translation termination" + GO:0006415 contradicts EIF2D's initiation/recycling biology already in GOA. Recommended edits: [MAP] do not project GO:0006415 to EIF2D; reclassify PN node toward reinitiation/40S recycling (GO:0001731 / GO:0032790 already in GOA).

Full Consistency Review

  • UniProt: P41214 · batch: proteostasis-batch-2026-06-07c · review status: COMPLETE
  • PN placement: Translation|Cytosolic translation|Translation termination|tRNA, mRNA release ; PN-node mapping: group Translation termination → GO:0006415 translational termination (mapped, ok_for_propagation); type tRNA, mRNA release no_mapping.
  • Consistency: Review/notes are accurate and self-consistent: EIF2D (Ligatin) is the single-polypeptide eIF2D-like factor that does GTP-independent P-site tRNA delivery and post-termination 40S recycling/reinitiation (core MF GO:0003743). This CONTRADICTS the PN "Translation termination" placement and GO:0006415 projection — EIF2D is not a release factor. (Same node mis-classification as DENR, its split-paralog partner.)
  • PN story / NEW pressure: Projected GO:0006415 translational termination is more_specific_than_existing_goa. Verified (OLS): GO:0006415 = polypeptide release at a stop codon — not EIF2D's activity. EIF2D's real roles (GO:0001731 preinitiation-complex formation, GO:0032790 ribosome disassembly/recycling, GO:0003743 initiation-factor activity) are already in GOA and reviewed. The projection over-reaches / is biologically wrong; no defensible NEW termination term.
  • Mapping strategy: Reinforces the DENR finding: the Translation termination|tRNA, mRNA release node lumps post-termination recycling/reinitiation factors (EIF2D, DENR) with genuine release factors. Recommend re-homing EIF2D under reinitiation/40S-recycling and not propagating GO:0006415.
  • Evidence alignment: Dossier carries no reference titles. Review anchors PMID:20566627 (GTP-independent P-site tRNA delivery) and PMID:20713520 (Ligatin recycling), both VERIFIED — about initiation/recycling, none about termination. Divergence by omission in dossier.
  • Verdict: Mapping mismatch — PN "translation termination" + GO:0006415 contradicts EIF2D's initiation/recycling biology already in GOA. Recommended edits: [MAP] do not project GO:0006415 to EIF2D; reclassify PN node toward reinitiation/40S recycling (GO:0001731 / GO:0032790 already in GOA).

PN Dossier Context

  • review_batch: proteostasis-batch-2026-06-07c
  • review_yaml: genes/human/EIF2D/EIF2D-ai-review.yaml
  • PN workbook rows: 1

PN row 1: Translation | Cytosolic translation | Translation termination | tRNA, mRNA release

  • UniProt: P41214
  • In branches: TR
  • PN-node mapping records (path + ancestors):
    • [type] Translation|Cytosolic translation|Translation termination|tRNA, mRNA release
      status=no_mapping scope= GO=[]
      rationale: Reviewed as a broad PN category rather than a single GO class. The member genes span multiple activities, complexes, or contexts, so direct propagation from this node would overstate the shared biology.
    • [group] Translation|Cytosolic translation|Translation termination
      status=mapped scope=ok_for_propagation_to_go GO=[GO:0006415 translational termination]
      rationale: This PN group denotes cytosolic translation termination and release factors. Translational termination is the shared process target.
    • [class] Translation|Cytosolic translation
      status=context_only scope=too_broad_to_propagate GO=[GO:0002181 cytoplasmic translation]
      rationale: The PN class Cytosolic translation is centered on the cytoplasmic translation apparatus and process, but it also houses supporting machinery such as ribosome biogenesis factors. The GO process term is a useful high-level label for the class, but propagating it to all members would over-annotate genes whose PN placement is through assembly or maturation context rather than core cytoplasmic translation.
    • [branch] Translation
      status=context_only scope=too_broad_to_propagate GO=[GO:0006412 translation]
      rationale: The PN Translation branch is organized around the translation apparatus and immediately associated cotranslational quality-control systems. GO translation is the closest high-level process label, but the PN branch also contains adjacent machinery such as ribosome biogenesis and nascent-chain handling. Keeping this relationship is useful for interpretation, but it is too broad to project safely onto every member.

Projected GO annotations (1)

  • GO:0006415 translational termination | scope=ok_for_propagation_to_go | goa_status=more_specific_than_existing_goa | from=Translation|Cytosolic translation|Translation termination

Note

This file is generated from the current PROTEOSTASIS phase-1 dossier and local gene-review artifacts. Edit the source review, PN mapping, or dossier rather than this generated note when correcting the underlying curation.

📄 View Raw YAML

 
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.