DNAJC24

UniProt ID: Q6P3W2
Organism: Homo sapiens
Review Status: COMPLETE
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Gene Description

DNAJC24 (DnaJ homolog subfamily C member 24; also DPH4 / ZCSL3, Diphthamide biosynthesis protein 4) is a small cytoplasmic J-domain co-chaperone of the HSP70 system that also functions in diphthamide biosynthesis. It comprises an N-terminal J-domain (with the canonical HPD motif) and a C-terminal DPH-type CSL metal-binding domain that can coordinate either zinc or iron. Through its J-domain it stimulates the ATPase activity of HSP70-type chaperones; its CSL domain binds metal ions, and iron binding promotes oligomerization and confers redox/electron-carrier activity. DNAJC24 participates in the conserved multi-step diphthamide pathway that installs the diphthamide modification on a specific histidine of translation elongation factor 2 (EEF2), the residue targeted by diphtheria toxin and Pseudomonas exotoxin A.

Existing Annotations Review

GO Term Evidence Action Reason
GO:0001671 ATPase activator activity
IBA
GO_REF:0000033 		ACCEPT
Summary: As a J-domain protein, DNAJC24/DPH4 stimulates the ATPase activity of HSP70-type chaperones. This phylogenetic inference is directly confirmed for the human protein.
Reason: The J-domain of DPH4 catalytically stimulates HSP70 ATPase activity; this is the canonical molecular function of the gene, supported by both orthology and direct experimental evidence.
Supporting Evidence:
PMID:22367199
catalytically stimulate the ATPase activity of Hsp70
GO:0008198 ferrous iron binding
IBA
GO_REF:0000033 		ACCEPT
Summary: The CSL metal-binding domain of DPH4 binds iron (in addition to zinc), conferring redox/electron-carrier activity. Supported experimentally for the human protein.
Reason: DPH4's CSL domain binds iron in solution (loss on the C139S mutation), a genuine molecular function corroborated by direct experimental evidence.
Supporting Evidence:
PMID:22367199
Dph4 possesses the intrinsic ability to bind iron in solution
GO:0005856 cytoskeleton
IEA
GO_REF:0000044 		KEEP AS NON CORE
Summary: Cytoplasm/cytoskeleton localization is annotated from the UniProt subcellular location (by similarity). The cytoskeletal association is weakly supported.
Reason: The cytoplasm-cytoskeleton localization is by-similarity (ECO:0000250) rather than direct; DPH4 is a cytoplasmic co-chaperone, but cytoskeletal localization is not central to its characterized function.
Supporting Evidence:
file:human/DNAJC24/DNAJC24-uniprot.txt
SUBCELLULAR LOCATION: Cytoplasm, cytoskeleton
GO:0015629 actin cytoskeleton
IEA
GO_REF:0000107 		MARK AS OVER ANNOTATED
Summary: Actin-cytoskeleton localization transferred by orthology from the mouse protein. There is no direct human functional evidence linking DPH4 to the actin cytoskeleton.
Reason: This is an Ensembl-Compara orthology transfer from mouse with no direct human evidence; DPH4's characterized roles are HSP70 co-chaperone and diphthamide biosynthesis, not actin-cytoskeleton activity.
Supporting Evidence:
file:human/DNAJC24/DNAJC24-uniprot.txt
SUBCELLULAR LOCATION: Cytoplasm, cytoskeleton
GO:0017183 protein histidyl modification to diphthamide
IEA
GO_REF:0000120 		ACCEPT
Summary: DPH4 participates in the diphthamide biosynthesis pathway, a post-translational modification of a histidine in EEF2. This is the gene's defining biological process and is supported experimentally.
Reason: DPH4 plays a documented role in diphthamide biosynthesis (the EEF2 histidine modification); this is the core biological process, supported by functional studies and pathway membership.
Supporting Evidence:
file:human/DNAJC24/DNAJC24-uniprot.txt
Plays a role in the diphthamide biosynthesis, a post-translational modification of histidine which occurs in translation elongation factor 2 (EEF2)
GO:0001671 ATPase activator activity
IDA
PMID:22367199
Structure and mechanistic insights into novel iron-mediated ... 		ACCEPT
Summary: Direct experimental evidence that DPH4 stimulates the ATPase activity of HSP70-type chaperones. The core molecular function of the J-protein.
Reason: IDA evidence that DPH4's J-domain stimulates HSP70 ATPase activity confirms its canonical co-chaperone molecular function.
Supporting Evidence:
PMID:22367199
catalytically stimulate the ATPase activity of Hsp70
GO:0006457 protein folding
TAS
PMID:22367199
Structure and mechanistic insights into novel iron-mediated ... 		KEEP AS NON CORE
Summary: As an HSP70 co-chaperone, DPH4 is annotated to protein folding. This is a downstream process of the HSP70 machine it assists rather than autonomous foldase activity.
Reason: DPH4 is a J-domain co-chaperone that delivers substrates to and stimulates HSP70; protein folding is a generic downstream process, non-core relative to its ATPase-activator function and diphthamide role.
Supporting Evidence:
PMID:22367199
The J-proteins sequester and deliver unfolded proteins to Hsp70 in the ATP-bound state
GO:0008198 ferrous iron binding
IDA
PMID:22367199
Structure and mechanistic insights into novel iron-mediated ... 		ACCEPT
Summary: Direct experimental evidence that DPH4 binds iron through its CSL domain, conferring redox properties. A genuine molecular function.
Reason: IDA evidence (iron-binding lost in the C139S mutant) confirms DPH4 binds ferrous iron via its CSL metal-binding domain.
Supporting Evidence:
PMID:22367199
Dph4 possesses the intrinsic ability to bind iron in solution
GO:0008270 zinc ion binding
IDA
PMID:22367199
Structure and mechanistic insights into novel iron-mediated ... 		ACCEPT
Summary: Direct experimental and structural (NMR, PDB 2L6L) evidence that the CSL/DPH-type domain of DPH4 binds zinc ions via four conserved residues.
Reason: IDA/structural evidence that the DPH-type metal-binding domain coordinates zinc confirms this molecular function; the domain can bind either zinc or iron.
Supporting Evidence:
file:human/DNAJC24/DNAJC24-uniprot.txt
The DPH-type metal-binding (MB) domain can bind either zinc or iron ions.
GO:0032781 positive regulation of ATP-dependent activity
IDA
PMID:22367199
Structure and mechanistic insights into novel iron-mediated ... 		KEEP AS NON CORE
Summary: A process-level annotation reflecting DPH4's stimulation of HSP70 ATPase activity. Redundant with the more informative ATPase activator activity molecular function.
Reason: This generic process term captures the same underlying activity as the ATPase activator activity MF; non-core because the MF term is more informative.
Supporting Evidence:
PMID:22367199
catalytically stimulate the ATPase activity of Hsp70

Core Functions

J-domain co-chaperone that catalytically stimulates the ATPase activity of HSP70-type chaperones, delivering substrates to HSP70 in the ATP-bound state.

Molecular Function:
ATPase activator activity
Cellular Locations:
cytoplasm
Supporting Evidence:

Component of the diphthamide biosynthesis pathway that installs the diphthamide modification on a specific histidine of translation elongation factor 2 (EEF2); its CSL domain binds zinc/iron and the iron-bound form is redox-active.

Directly Involved In:
protein histidyl modification to diphthamide
Cellular Locations:
cytoplasm
Supporting Evidence:
  • file:human/DNAJC24/DNAJC24-uniprot.txt
    Plays a role in the diphthamide biosynthesis, a post-translational modification of histidine which occurs in translation elongation factor 2 (EEF2)
  • PMID:22367199
    Dph4 possesses the intrinsic ability to bind iron in solution

References

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:0000107
Automatic transfer of experimentally verified manual GO annotation data to orthologs using Ensembl Compara
GO_REF:0000120
Combined Automated Annotation using Multiple IEA Methods
PMID:22367199
Structure and mechanistic insights into novel iron-mediated moonlighting functions of human J-protein cochaperone, Dph4.
  • DPH4 is a J-protein co-chaperone whose J-domain catalytically stimulates HSP70 ATPase activity; its CSL domain binds zinc or iron, and the iron-bound form is redox-active with electron-carrier activity, supporting moonlighting roles including diphthamide biosynthesis.
PMID:22509046
Immunotoxin resistance via reversible methylation of the DPH4 promoter is a unique survival strategy.
  • DPH4 is required for diphthamide biosynthesis on EEF2; silencing DPH4 (via promoter methylation) confers resistance to immunotoxins/diphtheria-toxin-like agents that ADP-ribosylate the diphthamide residue.
file:human/DNAJC24/DNAJC24-uniprot.txt
UniProt entry Q6P3W2 (DJC24_HUMAN), DnaJ homolog subfamily C member 24 (DPH4)
  • Stimulates the ATPase activity of HSP70-type chaperones (enhanced by iron binding); CSL domain binds zinc or iron; iron-bound form is redox-active; participates in diphthamide biosynthesis on EEF2; cytoplasmic.

Suggested Questions for Experts

Q: Which HSP70 paralog(s) does DPH4 stimulate in vivo, and is the J-domain co-chaperone activity required for diphthamide biosynthesis or separable from it?

Q: Is the iron-dependent redox/electron-carrier activity of DPH4 physiologically relevant to the radical-SAM chemistry of the diphthamide pathway (e.g. DPH1-DPH2)?

Suggested Experiments

Experiment: Reconstitute the diphthamide pathway in vitro with DPH1-DPH7 and test whether DPH4 J-domain (HPD) mutants or iron-binding (C139S) mutants impair EEF2 diphthamide formation.

Experiment: Measure DPH4-stimulated ATPase activity of candidate HSP70 partners (HSPA8, HSPA9) and map which clients require DPH4 hand-off.

Experiment: Knockout DPH4 in cells and assay EEF2 diphthamidation and sensitivity to diphtheria toxin / Pseudomonas exotoxin A to confirm its in-vivo pathway role.

📚 Additional Documentation

Notes

(DNAJC24-notes.md)

DNAJC24 (Q6P3W2) research notes

Small cytoplasmic J-domain co-chaperone of the HSP70 system that also functions in
diphthamide biosynthesis. Also named DPH4 / ZCSL3.

Architecture

  • N-terminal J-domain (canonical HPD motif) that stimulates HSP70 ATPase activity.
  • C-terminal DPH-type CSL metal-binding domain coordinating Zn or Fe; iron binding
    promotes oligomerization and confers redox/electron-carrier activity. [PMID:22367199;
    PMID:22509046]

Function

  • Component of the conserved multi-step diphthamide pathway that installs the
    diphthamide modification on a specific histidine of translation elongation factor 2
    (EEF2) — the residue targeted by diphtheria toxin and Pseudomonas exotoxin A.
    [UniProt Q6P3W2; PMID:22367199]

Curation calls

  • Core MFs: ATPase activator activity (GO:0001671, stimulates HSP70); protein histidyl
    modification to diphthamide (GO:0017183).
  • An actin-cytoskeleton annotation (orthology transfer) marked over-annotated.

Pn Notes

(DNAJC24-pn-notes.md)

DNAJC24 PN Consistency Notes

  • Generated: 2026-06-18
  • Project: PROTEOSTASIS
  • Scope: PN consistency rereview against local AIGR review and available deep-research artifacts
  • UniProt: Q6P3W2
  • AIGR review status: COMPLETE
  • Review batch: proteostasis-batch-2026-06-07b
  • Batch change status: added

Source Files Checked

Deep Research Files

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

AIGR Review Snapshot

  • Description: DNAJC24 (DnaJ homolog subfamily C member 24; also DPH4 / ZCSL3, Diphthamide biosynthesis protein 4) is a small cytoplasmic J-domain co-chaperone of the HSP70 system that also functions in diphthamide biosynthesis. It comprises an N-terminal J-domain (with the canonical HPD motif) and a C-terminal DPH-type CSL metal-binding domain that can coordinate either zinc or iron. Through its J-domain it stimulates the ATPase activity of HSP70-type chaperones; its CSL domain binds metal ions, and iron binding promotes oligomerization and confers redox/electron-carrier activity. DNAJC24 participates in the conserved multi-step diphthamide pathway that installs the diphthamide modification on a specific histidine of translation elongation factor 2 (EEF2), the residue targeted by diphtheria toxin and Pseudomonas exotoxin A.
  • Existing/core annotation action counts: ACCEPT: 6; KEEP_AS_NON_CORE: 3; MARK_AS_OVER_ANNOTATED: 1

PN Consistency Summary

  • Consistency: Deep research, notes, and review YAML are fully self-consistent: DPH4 is a J-domain co-chaperone that stimulates HSP70 ATPase (IDA + IBA, PMID:22367199) and a diphthamide-biosynthesis factor (GO:0017183). The PN "J-domain HSP70 cochaperone" placement agrees with the review's HSP70-cochaperone framing. No contradictions.
  • PN story / NEW pressure: PN asserts Hsp70 protein binding (GO:0030544, verified real). GOA does NOT contain GO:0030544; closest is GO:0001671 ATPase activator activity (IDA). DPH4's J-domain HSP70 interaction is experimentally supported, so GO:0030544 is a defensible, specific ADD (J-proteins bind Hsp70). Not over-reaching for this gene — but note GO:0001671 already captures the functional consequence; GO:0030544 would be a complementary, narrower MF.
  • Evidence alignment: PN row carries no reference titles; review anchors on PMID:22367199 (structure/iron-mediated moonlighting) and PMID:22509046 (diphthamide/EF2). Both VERIFIED in YAML. No divergence.
  • Verdict: Consistent. GO:0030544 is a defensible ADD (new_to_goa). Diphthamide role correctly kept distinct from chaperone family inference.

Full Consistency Review

  • UniProt: Q6P3W2 (DPH4 / ZCSL3) · batch: proteostasis-batch-2026-06-07b · review status: COMPLETE
  • PN placement: Cytonuclear proteostasis|Chaperone|HSP70 system|J-domain containing HSP70 cochaperone ; PN-node mapping: type=mapped, scope=ok_for_propagation_to_go, GO:0030544 Hsp70 protein binding (projected new_to_goa); group/class/branch=no_mapping.
  • Consistency: Deep research, notes, and review YAML are fully self-consistent: DPH4 is a J-domain co-chaperone that stimulates HSP70 ATPase (IDA + IBA, PMID:22367199) and a diphthamide-biosynthesis factor (GO:0017183). The PN "J-domain HSP70 cochaperone" placement agrees with the review's HSP70-cochaperone framing. No contradictions.
  • PN story / NEW pressure: PN asserts Hsp70 protein binding (GO:0030544, verified real). GOA does NOT contain GO:0030544; closest is GO:0001671 ATPase activator activity (IDA). DPH4's J-domain HSP70 interaction is experimentally supported, so GO:0030544 is a defensible, specific ADD (J-proteins bind Hsp70). Not over-reaching for this gene — but note GO:0001671 already captures the functional consequence; GO:0030544 would be a complementary, narrower MF.
  • Mapping strategy: Does not change node status. Projection (new_to_goa) is accurate — GO:0030544 genuinely absent from GOA. Term is appropriately specific (not over-broad), since DPH4's HSP70 interaction is real.
  • Evidence alignment: PN row carries no reference titles; review anchors on PMID:22367199 (structure/iron-mediated moonlighting) and PMID:22509046 (diphthamide/EF2). Both VERIFIED in YAML. No divergence.
  • Verdict: Consistent. GO:0030544 is a defensible ADD (new_to_goa). Diphthamide role correctly kept distinct from chaperone family inference.

PN Dossier Context

  • review_batch: proteostasis-batch-2026-06-07b
  • review_yaml: genes/human/DNAJC24/DNAJC24-ai-review.yaml
  • PN workbook rows: 1

PN row 1: Cytonuclear proteostasis | Chaperone | HSP70 system | J-domain containing HSP70 cochaperone

  • UniProt: Q6P3W2
  • In branches: CY
  • PN-node mapping records (path + ancestors):
    • [type] Cytonuclear proteostasis|Chaperone|HSP70 system|J-domain containing HSP70 cochaperone
      status=mapped scope=ok_for_propagation_to_go GO=[GO:0030544 Hsp70 protein binding]
      rationale: In the PN hierarchy, this type denotes J-domain cochaperones assigned to the HSP70 system. Their shared mechanistic role is direct interaction with HSP70-family chaperones, making Hsp70 protein binding the most defensible GO target in the current cache.
    • [group] Cytonuclear proteostasis|Chaperone|HSP70 system
      status=no_mapping scope= GO=[]
      rationale: Reviewed as a broad PN category rather than a specific GO class. The member genes span multiple activities, complexes, or contexts, so propagation from this node would overstate the shared biology; use narrower child or gene-level curations.
    • [class] Cytonuclear proteostasis|Chaperone
      status=no_mapping scope= GO=[]
      rationale: Reviewed as a broad PN category rather than a specific GO class. The member genes span multiple activities, complexes, or contexts, so propagation from this node would overstate the shared biology; use narrower child or gene-level curations.
    • [branch] Cytonuclear proteostasis
      status=no_mapping scope= GO=[]
      rationale: Reviewed as a top-level PN branch. This is a systems/taxonomy umbrella, not a direct GO assertion; narrower child curations carry any propagating GO mappings.

Projected GO annotations (1)

  • GO:0030544 Hsp70 protein binding | scope=ok_for_propagation_to_go | goa_status=new_to_goa | from=Cytonuclear proteostasis|Chaperone|HSP70 system|J-domain containing HSP70 cochaperone

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: Q6P3W2
gene_symbol: DNAJC24
product_type: PROTEIN
status: COMPLETE
taxon:
  id: NCBITaxon:9606
  label: Homo sapiens
description: DNAJC24 (DnaJ homolog subfamily C member 24; also DPH4 / ZCSL3, Diphthamide biosynthesis protein 4) is a small cytoplasmic J-domain co-chaperone of the HSP70 system that also functions in diphthamide biosynthesis. It comprises an N-terminal J-domain (with the canonical HPD motif) and a C-terminal DPH-type CSL metal-binding domain that can coordinate either zinc or iron. Through its J-domain it stimulates the ATPase activity of HSP70-type chaperones; its CSL domain binds metal ions, and iron binding promotes oligomerization and confers redox/electron-carrier activity. DNAJC24 participates in the conserved multi-step diphthamide pathway that installs the diphthamide modification on a specific histidine of translation elongation factor 2 (EEF2), the residue targeted by diphtheria toxin and Pseudomonas exotoxin A.
alternative_products:
- name: '1'
  id: Q6P3W2-1
- name: '2'
  id: Q6P3W2-2
  sequence_note: VSP_056274
existing_annotations:
- term:
    id: GO:0001671
    label: ATPase activator activity
  evidence_type: IBA
  original_reference_id: GO_REF:0000033
  qualifier: enables
  review:
    summary: As a J-domain protein, DNAJC24/DPH4 stimulates the ATPase activity of HSP70-type chaperones. This phylogenetic inference is directly confirmed for the human protein.
    action: ACCEPT
    reason: The J-domain of DPH4 catalytically stimulates HSP70 ATPase activity; this is the canonical molecular function of the gene, supported by both orthology and direct experimental evidence.
    supported_by:
    - reference_id: PMID:22367199
      supporting_text: catalytically stimulate the ATPase activity of Hsp70
- term:
    id: GO:0008198
    label: ferrous iron binding
  evidence_type: IBA
  original_reference_id: GO_REF:0000033
  qualifier: enables
  review:
    summary: The CSL metal-binding domain of DPH4 binds iron (in addition to zinc), conferring redox/electron-carrier activity. Supported experimentally for the human protein.
    action: ACCEPT
    reason: DPH4's CSL domain binds iron in solution (loss on the C139S mutation), a genuine molecular function corroborated by direct experimental evidence.
    supported_by:
    - reference_id: PMID:22367199
      supporting_text: Dph4 possesses the intrinsic ability to bind iron in solution
- term:
    id: GO:0005856
    label: cytoskeleton
  evidence_type: IEA
  original_reference_id: GO_REF:0000044
  qualifier: located_in
  review:
    summary: Cytoplasm/cytoskeleton localization is annotated from the UniProt subcellular location (by similarity). The cytoskeletal association is weakly supported.
    action: KEEP_AS_NON_CORE
    reason: The cytoplasm-cytoskeleton localization is by-similarity (ECO:0000250) rather than direct; DPH4 is a cytoplasmic co-chaperone, but cytoskeletal localization is not central to its characterized function.
    supported_by:
    - reference_id: file:human/DNAJC24/DNAJC24-uniprot.txt
      supporting_text: 'SUBCELLULAR LOCATION: Cytoplasm, cytoskeleton'
- term:
    id: GO:0015629
    label: actin cytoskeleton
  evidence_type: IEA
  original_reference_id: GO_REF:0000107
  qualifier: is_active_in
  review:
    summary: Actin-cytoskeleton localization transferred by orthology from the mouse protein. There is no direct human functional evidence linking DPH4 to the actin cytoskeleton.
    action: MARK_AS_OVER_ANNOTATED
    reason: This is an Ensembl-Compara orthology transfer from mouse with no direct human evidence; DPH4's characterized roles are HSP70 co-chaperone and diphthamide biosynthesis, not actin-cytoskeleton activity.
    supported_by:
    - reference_id: file:human/DNAJC24/DNAJC24-uniprot.txt
      supporting_text: 'SUBCELLULAR LOCATION: Cytoplasm, cytoskeleton'
- term:
    id: GO:0017183
    label: protein histidyl modification to diphthamide
  evidence_type: IEA
  original_reference_id: GO_REF:0000120
  qualifier: involved_in
  review:
    summary: DPH4 participates in the diphthamide biosynthesis pathway, a post-translational modification of a histidine in EEF2. This is the gene's defining biological process and is supported experimentally.
    action: ACCEPT
    reason: DPH4 plays a documented role in diphthamide biosynthesis (the EEF2 histidine modification); this is the core biological process, supported by functional studies and pathway membership.
    supported_by:
    - reference_id: file:human/DNAJC24/DNAJC24-uniprot.txt
      supporting_text: Plays a role in the diphthamide biosynthesis, a post-translational modification of histidine which occurs in translation elongation factor 2 (EEF2)
- term:
    id: GO:0001671
    label: ATPase activator activity
  evidence_type: IDA
  original_reference_id: PMID:22367199
  qualifier: enables
  review:
    summary: Direct experimental evidence that DPH4 stimulates the ATPase activity of HSP70-type chaperones. The core molecular function of the J-protein.
    action: ACCEPT
    reason: IDA evidence that DPH4's J-domain stimulates HSP70 ATPase activity confirms its canonical co-chaperone molecular function.
    supported_by:
    - reference_id: PMID:22367199
      supporting_text: catalytically stimulate the ATPase activity of Hsp70
- term:
    id: GO:0006457
    label: protein folding
  evidence_type: TAS
  original_reference_id: PMID:22367199
  qualifier: involved_in
  review:
    summary: As an HSP70 co-chaperone, DPH4 is annotated to protein folding. This is a downstream process of the HSP70 machine it assists rather than autonomous foldase activity.
    action: KEEP_AS_NON_CORE
    reason: DPH4 is a J-domain co-chaperone that delivers substrates to and stimulates HSP70; protein folding is a generic downstream process, non-core relative to its ATPase-activator function and diphthamide role.
    supported_by:
    - reference_id: PMID:22367199
      supporting_text: The J-proteins sequester and deliver unfolded proteins to Hsp70 in the ATP-bound state
- term:
    id: GO:0008198
    label: ferrous iron binding
  evidence_type: IDA
  original_reference_id: PMID:22367199
  qualifier: enables
  review:
    summary: Direct experimental evidence that DPH4 binds iron through its CSL domain, conferring redox properties. A genuine molecular function.
    action: ACCEPT
    reason: IDA evidence (iron-binding lost in the C139S mutant) confirms DPH4 binds ferrous iron via its CSL metal-binding domain.
    supported_by:
    - reference_id: PMID:22367199
      supporting_text: Dph4 possesses the intrinsic ability to bind iron in solution
- term:
    id: GO:0008270
    label: zinc ion binding
  evidence_type: IDA
  original_reference_id: PMID:22367199
  qualifier: enables
  review:
    summary: Direct experimental and structural (NMR, PDB 2L6L) evidence that the CSL/DPH-type domain of DPH4 binds zinc ions via four conserved residues.
    action: ACCEPT
    reason: IDA/structural evidence that the DPH-type metal-binding domain coordinates zinc confirms this molecular function; the domain can bind either zinc or iron.
    supported_by:
    - reference_id: file:human/DNAJC24/DNAJC24-uniprot.txt
      supporting_text: The DPH-type metal-binding (MB) domain can bind either zinc or iron ions.
- term:
    id: GO:0032781
    label: positive regulation of ATP-dependent activity
  evidence_type: IDA
  original_reference_id: PMID:22367199
  qualifier: involved_in
  review:
    summary: A process-level annotation reflecting DPH4's stimulation of HSP70 ATPase activity. Redundant with the more informative ATPase activator activity molecular function.
    action: KEEP_AS_NON_CORE
    reason: This generic process term captures the same underlying activity as the ATPase activator activity MF; non-core because the MF term is more informative.
    supported_by:
    - reference_id: PMID:22367199
      supporting_text: catalytically stimulate the ATPase activity of Hsp70
references:
- 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:0000107
  title: Automatic transfer of experimentally verified manual GO annotation data to orthologs using Ensembl Compara
  findings: []
- id: GO_REF:0000120
  title: Combined Automated Annotation using Multiple IEA Methods
  findings: []
- id: PMID:22367199
  title: Structure and mechanistic insights into novel iron-mediated moonlighting functions of human J-protein cochaperone, Dph4.
  reference_review:
    relevance: HIGH
    correctness: VERIFIED
    review_notes: "Cached publication title matches the YAML title; the text establishes DPH4 as a J-protein cochaperone whose J-domain stimulates HSP70 ATPase activity, with an iron/zinc-binding redox-active CSL domain, supporting the ATPase-activator MF and diphthamide-biosynthesis role. Primary reference cited in core_functions.supported_by."
  findings:
  - statement: DPH4 is a J-protein co-chaperone whose J-domain catalytically stimulates HSP70 ATPase activity; its CSL domain binds zinc or iron, and the iron-bound form is redox-active with electron-carrier activity, supporting moonlighting roles including diphthamide biosynthesis.
    reference_section_type: RESULTS
- id: PMID:22509046
  title: Immunotoxin resistance via reversible methylation of the DPH4 promoter is a unique survival strategy.
  reference_review:
    relevance: MEDIUM
    correctness: VERIFIED
    review_notes: "Cached publication title matches the YAML title; the text confirms DPH4 is required for diphthamide biosynthesis on EF2 and that DPH4 silencing renders EF2 refractory to immunotoxins, corroborating the diphthamide-biosynthesis biological-process role (functional/disease context rather than direct MF characterization)."
  findings:
  - statement: DPH4 is required for diphthamide biosynthesis on EEF2; silencing DPH4 (via promoter methylation) confers resistance to immunotoxins/diphtheria-toxin-like agents that ADP-ribosylate the diphthamide residue.
    reference_section_type: RESULTS
- id: file:human/DNAJC24/DNAJC24-uniprot.txt
  title: UniProt entry Q6P3W2 (DJC24_HUMAN), DnaJ homolog subfamily C member 24 (DPH4)
  findings:
  - statement: Stimulates the ATPase activity of HSP70-type chaperones (enhanced by iron binding); CSL domain binds zinc or iron; iron-bound form is redox-active; participates in diphthamide biosynthesis on EEF2; cytoplasmic.
    reference_section_type: OTHER
core_functions:
- description: J-domain co-chaperone that catalytically stimulates the ATPase activity of HSP70-type chaperones, delivering substrates to HSP70 in the ATP-bound state.
  molecular_function:
    id: GO:0001671
    label: ATPase activator activity
  locations:
  - id: GO:0005737
    label: cytoplasm
  supported_by:
  - reference_id: PMID:22367199
    supporting_text: catalytically stimulate the ATPase activity of Hsp70
- description: Component of the diphthamide biosynthesis pathway that installs the diphthamide modification on a specific histidine of translation elongation factor 2 (EEF2); its CSL domain binds zinc/iron and the iron-bound form is redox-active.
  locations:
  - id: GO:0005737
    label: cytoplasm
  supported_by:
  - reference_id: file:human/DNAJC24/DNAJC24-uniprot.txt
    supporting_text: Plays a role in the diphthamide biosynthesis, a post-translational modification of histidine which occurs in translation elongation factor 2 (EEF2)
  - reference_id: PMID:22367199
    supporting_text: Dph4 possesses the intrinsic ability to bind iron in solution
  directly_involved_in:
  - id: GO:0017183
    label: protein histidyl modification to diphthamide
proposed_new_terms: []
suggested_questions:
- question: Which HSP70 paralog(s) does DPH4 stimulate in vivo, and is the J-domain co-chaperone activity required for diphthamide biosynthesis or separable from it?
- question: Is the iron-dependent redox/electron-carrier activity of DPH4 physiologically relevant to the radical-SAM chemistry of the diphthamide pathway (e.g. DPH1-DPH2)?
suggested_experiments:
- description: Reconstitute the diphthamide pathway in vitro with DPH1-DPH7 and test whether DPH4 J-domain (HPD) mutants or iron-binding (C139S) mutants impair EEF2 diphthamide formation.
- description: Measure DPH4-stimulated ATPase activity of candidate HSP70 partners (HSPA8, HSPA9) and map which clients require DPH4 hand-off.
- description: Knockout DPH4 in cells and assay EEF2 diphthamidation and sensitivity to diphtheria toxin / Pseudomonas exotoxin A to confirm its in-vivo pathway role.