id: Q9UDY4
gene_symbol: DNAJB4
product_type: PROTEIN
status: COMPLETE
taxon:
  id: NCBITaxon:9606
  label: Homo sapiens
description: DNAJB4 (HLJ1, "human liver DnaJ-like protein"; also DNAJW) is a cytosolic
  HSP40/J-domain co-chaperone of the DNAJB subfamily and a paralog of DNAJB1. Through
  its N-terminal J domain it stimulates the ATPase activity of HSP70 (HSPA1A/HSPA1B),
  binding misfolded client proteins and delivering them to HSP70 to drive their folding,
  refolding and disaggregation. It is a homodimer, is heat-inducible, and is broadly
  expressed with high levels in striated muscle, where it localizes to the sarcomeric
  Z-disc and contributes to myofibril/Z-disc proteostasis. Biallelic loss-of-function
  variants in DNAJB4 cause an autosomal recessive congenital myopathy with early respiratory
  failure (CMYO21), reflecting its role as a muscle chaperone. It also interacts with
  the mu-opioid receptor (OPRM1) C-terminal tail and with aggregation-prone clients
  such as huntingtin and ataxin-1.
existing_annotations:
- term:
    id: GO:0006457
    label: protein folding
  evidence_type: IBA
  original_reference_id: GO_REF:0000033
  qualifier: involved_in
  review:
    summary: Phylogenetic (IBA) annotation that DNAJB4 participates in protein folding.
      As an HSP70 co-chaperone DNAJB4 assists folding rather than catalyzing it autonomously;
      folding is a downstream process outcome of its co-chaperone activity.
    action: KEEP_AS_NON_CORE
    reason: DNAJB4 is a J-protein co-chaperone that stimulates the HSP70 folding machine;
      protein folding is a real biological-process outcome but the gene's direct molecular
      role is HSP70 ATPase stimulation and client binding, so folding is non-core.
    supported_by:
    - reference_id: file:human/DNAJB4/DNAJB4-uniprot.txt
      supporting_text: Stimulates ATP hydrolysis and the folding of unfolded proteins
        mediated by HSPA1A/B
- term:
    id: GO:0051087
    label: protein-folding chaperone binding
  evidence_type: IBA
  original_reference_id: GO_REF:0000033
  qualifier: enables
  review:
    summary: DNAJB4 binds the HSP70 chaperone (HSPA1A/HSPA1B) to deliver clients and
      stimulate ATP hydrolysis. Binding the folding chaperone is central to its co-chaperone
      role and is corroborated by IPI evidence against HSP70 isoforms.
    action: ACCEPT
    reason: Direct binding to HSP70 is the structural basis of DNAJB4 co-chaperone
      activity and is supported both phylogenetically and by experimental IPI annotations
      to HSPA1A/HSPA1B.
    supported_by:
    - reference_id: file:human/DNAJB4/DNAJB4-uniprot.txt
      supporting_text: Stimulates ATP hydrolysis and the folding of unfolded proteins
        mediated by HSPA1A/B
- term:
    id: GO:0005829
    label: cytosol
  evidence_type: IBA
  original_reference_id: GO_REF:0000033
  qualifier: is_active_in
  review:
    summary: DNAJB4 is a cytosolic J-protein; cytosolic localization/site of action
      is supported by phylogeny and by direct experimental evidence (HPA IDA; PubMed:21231916;
      PubMed:18837411).
    action: ACCEPT
    reason: The cytosol is where DNAJB4 acts as an HSP70 co-chaperone; the IBA call
      agrees with multiple experimental cytosol annotations.
    supported_by:
    - reference_id: file:human/DNAJB4/DNAJB4-uniprot.txt
      supporting_text: 'SUBCELLULAR LOCATION: Cytoplasm'
- term:
    id: GO:0000122
    label: negative regulation of transcription by RNA polymerase II
  evidence_type: IBA
  original_reference_id: GO_REF:0000033
  qualifier: involved_in
  review:
    summary: Phylogenetic transfer (from PANTHER node including yeast Sis1/DnaJ family)
      assigning a transcriptional repression role. There is no direct experimental
      evidence that DNAJB4 regulates RNA polymerase II transcription in humans; this
      is most consistent with over-annotation from a divergent family branch.
    action: MARK_AS_OVER_ANNOTATED
    reason: No experimental support for a Pol II transcription-regulation role for
      DNAJB4; the term derives from IBA transfer across the broad DnaJ family and conflicts
      with DNAJB4's documented cytosolic co-chaperone function.
    supported_by:
    - reference_id: file:human/DNAJB4/DNAJB4-uniprot.txt
      supporting_text: 'SUBCELLULAR LOCATION: Cytoplasm'
- term:
    id: GO:0005737
    label: cytoplasm
  evidence_type: IEA
  original_reference_id: GO_REF:0000044
  qualifier: located_in
  review:
    summary: Automated localization to cytoplasm, consistent with the experimentally
      supported cytosolic site of action.
    action: ACCEPT
    reason: Correct compartment for this cytosolic co-chaperone; IEA agrees with stronger
      experimental and IBA cytosol/cytoplasm evidence.
    supported_by:
    - reference_id: file:human/DNAJB4/DNAJB4-uniprot.txt
      supporting_text: 'SUBCELLULAR LOCATION: Cytoplasm'
- term:
    id: GO:0005886
    label: plasma membrane
  evidence_type: IEA
  original_reference_id: GO_REF:0000044
  qualifier: located_in
  review:
    summary: Automated plasma-membrane localization derived from the UniProt cell-membrane
      annotation, which itself reflects an indirect association via the mu-opioid receptor
      (OPRM1) C-tail interaction rather than DNAJB4 being an intrinsic membrane protein.
    action: KEEP_AS_NON_CORE
    reason: Membrane association is indirect (client-mediated, via OPRM1) and context-specific;
      retained as non-core because DNAJB4 is a soluble cytosolic chaperone, not a membrane
      component.
    supported_by:
    - reference_id: file:human/DNAJB4/DNAJB4-uniprot.txt
      supporting_text: The C-terminal section interacts with the C-terminal tail of
        OPRM1
- term:
    id: GO:0006457
    label: protein folding
  evidence_type: IEA
  original_reference_id: GO_REF:0000002
  qualifier: involved_in
  review:
    summary: InterPro-based electronic annotation of protein folding, redundant with
      the IBA protein folding call and consistent with the J-protein co-chaperone role.
    action: KEEP_AS_NON_CORE
    reason: Same downstream process rationale as the IBA protein folding annotation;
      DNAJB4 assists rather than autonomously catalyzes folding.
    supported_by:
    - reference_id: file:human/DNAJB4/DNAJB4-uniprot.txt
      supporting_text: Stimulates ATP hydrolysis and the folding of unfolded proteins
        mediated by HSPA1A/B
- term:
    id: GO:0006986
    label: response to unfolded protein
  evidence_type: IEA
  original_reference_id: GO_REF:0000117
  qualifier: involved_in
  review:
    summary: DNAJB4 is heat-inducible and binds/handles unfolded and aggregation-prone
      clients as part of the stress response; participation in the response to unfolded
      protein is well supported.
    action: KEEP_AS_NON_CORE
    reason: Consistent with DNAJB4's heat-shock induction and client-handling role;
      a genuine process annotation but downstream of its molecular co-chaperone function.
    supported_by:
    - reference_id: file:human/DNAJB4/DNAJB4-uniprot.txt
      supporting_text: 'INDUCTION: By heat shock'
- term:
    id: GO:0030018
    label: Z disc
  evidence_type: IEA
  original_reference_id: GO_REF:0000044
  qualifier: located_in
  review:
    summary: Automated Z-disc localization, redundant with and corroborated by the
      experimental IDA Z-disc annotation (PubMed:36264506).
    action: ACCEPT
    reason: Z-disc localization is experimentally established and central to DNAJB4's
      muscle proteostasis role; the IEA call is correct.
    supported_by:
    - reference_id: file:human/DNAJB4/DNAJB4-uniprot.txt
      supporting_text: Cytoplasm, myofibril, sarcomere, Z line
- term:
    id: GO:0051087
    label: protein-folding chaperone binding
  evidence_type: IEA
  original_reference_id: GO_REF:0000117
  qualifier: enables
  review:
    summary: Rule-based electronic annotation of chaperone binding, redundant with
      the IBA and IPI protein-folding chaperone binding annotations (binding to HSP70).
    action: ACCEPT
    reason: Correct molecular function; DNAJB4 binds HSP70, supported by stronger IPI/IBA
      evidence.
    supported_by:
    - reference_id: file:human/DNAJB4/DNAJB4-uniprot.txt
      supporting_text: Stimulates ATP hydrolysis and the folding of unfolded proteins
        mediated by HSPA1A/B
- term:
    id: GO:0005515
    label: protein binding
  evidence_type: IPI
  original_reference_id: PMID:32296183
  qualifier: enables
  review:
    summary: High-throughput interaction capturing DNAJB4-RUVBL2 (Q9Y230). The bare
      protein binding term is uninformative and records a single interactome partner
      not central to the co-chaperone function.
    action: KEEP_AS_NON_CORE
    reason: Records a real interaction but bare protein binding is uninformative per
      curation guidelines; the RUVBL2 partner does not define DNAJB4's core chaperone
      function.
    supported_by:
    - reference_id: file:human/DNAJB4/DNAJB4-uniprot.txt
      supporting_text: 'Q9UDY4; Q9Y230: RUVBL2'
- term:
    id: GO:0005515
    label: protein binding
  evidence_type: IPI
  original_reference_id: PMID:32814053
  qualifier: enables
  review:
    summary: Neurodegeneration interactome screen capturing DNAJB4 interactions with
      aggregation-prone clients huntingtin (HTT, P42858) and ataxin-1 (ATXN1, P54253).
      Bare protein binding is uninformative, though the partners are consistent with
      DNAJB4 handling aggregation-prone substrates.
    action: KEEP_AS_NON_CORE
    reason: Real interactions with aggregation-prone clients, but bare protein binding
      is uninformative as a core MF; the meaningful function (client binding/HSP70
      delivery) is captured elsewhere.
    supported_by:
    - reference_id: file:human/DNAJB4/DNAJB4-uniprot.txt
      supporting_text: 'Q9UDY4; P42858: HTT'
- term:
    id: GO:0005654
    label: nucleoplasm
  evidence_type: IDA
  original_reference_id: GO_REF:0000052
  qualifier: located_in
  review:
    summary: HPA immunofluorescence places a pool of DNAJB4 in the nucleoplasm. This
      is a minor/secondary localization relative to its predominant cytosolic and Z-disc
      sites of action.
    action: KEEP_AS_NON_CORE
    reason: Antibody-based nucleoplasm signal is plausible but peripheral; DNAJB4's
      characterized function is cytosolic/sarcomeric, so this is non-core.
    supported_by:
    - reference_id: file:human/DNAJB4/DNAJB4-uniprot.txt
      supporting_text: 'SUBCELLULAR LOCATION: Cytoplasm'
- term:
    id: GO:0005829
    label: cytosol
  evidence_type: IDA
  original_reference_id: GO_REF:0000052
  qualifier: located_in
  review:
    summary: Direct (HPA immunofluorescence) evidence for cytosolic localization, the
      principal compartment in which DNAJB4 acts.
    action: ACCEPT
    reason: IDA-supported cytosol localization matches the documented site of co-chaperone
      action.
    supported_by:
    - reference_id: file:human/DNAJB4/DNAJB4-uniprot.txt
      supporting_text: 'SUBCELLULAR LOCATION: Cytoplasm'
- term:
    id: GO:0005886
    label: plasma membrane
  evidence_type: IDA
  original_reference_id: GO_REF:0000052
  qualifier: located_in
  review:
    summary: HPA immunofluorescence plasma-membrane signal, consistent with the membrane-associated
      pool reported via the OPRM1 interaction but secondary to the cytosolic localization.
    action: KEEP_AS_NON_CORE
    reason: Plasma-membrane association of DNAJB4 is indirect/client-mediated and context-specific;
      not part of its core cytosolic chaperone function.
    supported_by:
    - reference_id: file:human/DNAJB4/DNAJB4-uniprot.txt
      supporting_text: The C-terminal section interacts with the C-terminal tail of
        OPRM1
- term:
    id: GO:0005737
    label: cytoplasm
  evidence_type: EXP
  original_reference_id: PMID:18837411
  qualifier: located_in
  review:
    summary: Experimental (antibody-based) evidence for cytoplasmic localization of
      DNAJB4/HLJ1, consistent with its cytosolic co-chaperone role.
    action: ACCEPT
    reason: Experimental cytoplasmic localization corroborates the cytosol annotations
      and the established site of action.
    supported_by:
    - reference_id: file:human/DNAJB4/DNAJB4-uniprot.txt
      supporting_text: Cytoplasmic according to PubMed:18837411
- term:
    id: GO:0005886
    label: plasma membrane
  evidence_type: EXP
  original_reference_id: PMID:16542645
  qualifier: located_in
  review:
    summary: Membrane association reported from the study showing DNAJB4/HLJ1 binds
      the C-terminal tail of the mu-opioid receptor (OPRM1). This reflects an indirect,
      client-mediated membrane pool rather than an intrinsic membrane localization.
    action: KEEP_AS_NON_CORE
    reason: The plasma-membrane association is a consequence of binding the membrane
      protein OPRM1; DNAJB4 is a soluble cytosolic chaperone, so this is a context-specific,
      non-core localization.
    supported_by:
    - reference_id: file:human/DNAJB4/DNAJB4-uniprot.txt
      supporting_text: The C-terminal section interacts with the C-terminal tail of
        OPRM1
- term:
    id: GO:0030018
    label: Z disc
  evidence_type: IDA
  original_reference_id: PMID:36264506
  qualifier: located_in
  review:
    summary: Direct immunofluorescence demonstrates DNAJB4 localizes to the sarcomeric
      Z-disc in muscle, and it is lost from patient muscle/fibroblasts. This is a key,
      functionally relevant localization.
    action: ACCEPT
    reason: Experimentally established Z-disc localization underpins DNAJB4's role in
      myofibril/Z-disc proteostasis and is supported by loss in CMYO21 patient tissue.
    supported_by:
    - reference_id: PMID:36264506
      supporting_text: DNAJB4 normally localizes to the Z-disc and was absent from
        muscle and fibroblasts of affected patients
- term:
    id: GO:0051087
    label: protein-folding chaperone binding
  evidence_type: IPI
  original_reference_id: PMID:21231916
  qualifier: enables
  review:
    summary: Functional study of the mammalian HSP70/DNAJ machine; DNAJB4 binds HSP70
      isoforms (HSPA1A/HSPA1B) as a co-chaperone. Direct chaperone-binding evidence.
    action: ACCEPT
    reason: Binding to HSP70 chaperones is the core molecular interaction of DNAJB4
      as a J-protein co-chaperone.
    supported_by:
    - reference_id: file:human/DNAJB4/DNAJB4-goa.tsv
      supporting_text: GO:0051087 protein-folding chaperone binding molecular_function
        ECO:0000353 IPI PMID:21231916 UniProtKB:P0DMV8
- term:
    id: GO:0001671
    label: ATPase activator activity
  evidence_type: IDA
  original_reference_id: PMID:24318877
  qualifier: enables
  review:
    summary: Direct in vitro evidence that DNAJB4 (DnaJB4), as a J-protein, stimulates
      HSP70 ATPase activity (and luciferase refolding) when combined with HSP70 and
      nucleotide exchange factors. This is the core molecular function of DNAJB4.
    action: ACCEPT
    reason: J-domain stimulation of HSP70 ATP hydrolysis is the defining molecular
      activity of DNAJB4 and is experimentally demonstrated.
    supported_by:
    - reference_id: PMID:24318877
      supporting_text: we combined the Hsp70-NEF pairs with cochaperones of the J protein
        family (DnaJA1, DnaJA2, DnaJB1, and DnaJB4) to generate 16 permutations. The
        activity of the combinations in ATPase and luciferase refolding assays
- term:
    id: GO:0005829
    label: cytosol
  evidence_type: IDA
  original_reference_id: PMID:21231916
  qualifier: located_in
  review:
    summary: Direct evidence places DNAJB4 in the cytosol, consistent with all other
      localization data and its co-chaperone role.
    action: ACCEPT
    reason: IDA cytosol localization corroborates the established cytosolic site of
      action.
    supported_by:
    - reference_id: file:human/DNAJB4/DNAJB4-goa.tsv
      supporting_text: GO:0005829 cytosol cellular_component ECO:0000314 IDA PMID:21231916
- term:
    id: GO:0005515
    label: protein binding
  evidence_type: IPI
  original_reference_id: PMID:21255413
  qualifier: enables
  review:
    summary: Specific interaction with the neuron-enriched protein SDIM1 (Q6ZPB5),
      where SDIM1 attenuates cell death induced by DNAJB4 over-expression. Bare protein
      binding is uninformative as a core function but records a real, characterized
      interaction.
    action: KEEP_AS_NON_CORE
    reason: Documented DNAJB4-SDIM1 interaction; bare protein binding is uninformative
      per curation guidelines and the interaction is peripheral to the core chaperone
      function.
    supported_by:
    - reference_id: file:human/DNAJB4/DNAJB4-uniprot.txt
      supporting_text: Also interacts with SDIM1
- term:
    id: GO:0006986
    label: response to unfolded protein
  evidence_type: TAS
  original_reference_id: PMID:9546042
  qualifier: involved_in
  review:
    summary: The original cloning paper describes HLJ1/DNAJB4 as a heat-inducible HSP40,
      supporting a role in the response to unfolded protein.
    action: KEEP_AS_NON_CORE
    reason: Consistent with DNAJB4's stress-induced client-handling role; a genuine
      process annotation downstream of its molecular co-chaperone function.
    supported_by:
    - reference_id: file:human/DNAJB4/DNAJB4-uniprot.txt
      supporting_text: 'INDUCTION: By heat shock'
- term:
    id: GO:0009408
    label: response to heat
  evidence_type: TAS
  original_reference_id: PMID:9546042
  qualifier: involved_in
  review:
    summary: DNAJB4/HLJ1 is induced by heat shock, supporting involvement in the response
      to heat.
    action: KEEP_AS_NON_CORE
    reason: Heat induction is experimentally documented; participation in the heat
      response is a genuine but non-core (stress-context) process annotation.
    supported_by:
    - reference_id: file:human/DNAJB4/DNAJB4-uniprot.txt
      supporting_text: 'INDUCTION: By heat shock'
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:16542645
  title: A member of the heat shock protein 40 family, hlj1, binds to the carboxyl
    tail of the human mu opioid receptor.
  findings:
  - statement: The C-terminal portion of DNAJB4/HLJ1 interacts with the C-terminal
      tail of the human mu-opioid receptor (OPRM1), conferring a membrane-associated
      pool.
    reference_section_type: RESULTS
- id: PMID:18837411
  title: Preparation of the anti-HLJ1 monoclonal antibodies and establishment of method
    for detection of the antigen.
  findings:
  - statement: DNAJB4/HLJ1 is detected in the cytoplasm.
    reference_section_type: RESULTS
- id: PMID:21231916
  title: The diverse members of the mammalian HSP70 machine show distinct chaperone-like
    activities.
  reference_review:
    relevance: HIGH
    correctness: VERIFIED
    review_notes: Cached publication title matches PubMed; the study characterizes
      mammalian HSP40/HSP70 co-chaperones' anti-aggregation/refolding activities.
      GOA anchors this PMID to GO:0051087 (protein-folding chaperone binding, IPI)
      and GO:0005829 (cytosol, IDA), supporting DNAJB4's core co-chaperone function.
  findings:
  - statement: DNAJB4 is a cytosolic DNAJ/HSP40 co-chaperone of the HSP70 machine with
      client-dependent refolding/anti-aggregation activities.
    reference_section_type: RESULTS
- id: PMID:21255413
  title: A novel neuron-enriched protein SDIM1 is down regulated in Alzheimer's brains
    and attenuates cell death induced by DNAJB4 over-expression in neuro-progenitor
    cells.
  findings:
  - statement: SDIM1 interacts with DNAJB4 and attenuates DNAJB4 over-expression-induced
      cell death in neuro-progenitor cells.
    reference_section_type: RESULTS
- id: PMID:24318877
  title: Binding of human nucleotide exchange factors to heat shock protein 70 (Hsp70)
    generates functionally distinct complexes in vitro.
  reference_review:
    relevance: HIGH
    correctness: VERIFIED
    review_notes: Cached publication title matches PubMed; body confirms DnaJB4
      acts as a J-protein co-chaperone stimulating Hsp70 ATPase activity, and GOA
      anchors this PMID to GO:0001671 (ATPase activator activity, IDA) - the core MF.
  findings:
  - statement: DNAJB4, as a J-protein co-chaperone, stimulates HSP70 ATPase activity
      and supports luciferase refolding in combination with HSP70 and nucleotide exchange
      factors.
    reference_section_type: RESULTS
- id: PMID:32296183
  title: A reference map of the human binary protein interactome.
  findings: []
- id: PMID:32814053
  title: Interactome Mapping Provides a Network of Neurodegenerative Disease Proteins
    and Uncovers Widespread Protein Aggregation in Affected Brains.
  findings:
  - statement: DNAJB4 interacts with aggregation-prone neurodegeneration-associated
      clients including huntingtin (HTT) and ataxin-1 (ATXN1).
    reference_section_type: RESULTS
- id: PMID:36264506
  title: Loss of function variants in DNAJB4 cause a myopathy with early respiratory
    failure.
  reference_review:
    relevance: HIGH
    correctness: VERIFIED
    review_notes: Cached publication title matches PubMed; body confirms biallelic
      DNAJB4 loss-of-function causes a myopathy with respiratory failure and that
      DNAJB4 localizes to the Z-disc with a role in myofibril proteostasis. GOA
      anchors this PMID to GO:0030018 (Z disc, IDA), supporting the in-vivo function.
  findings:
  - statement: Biallelic loss-of-function DNAJB4 variants cause an autosomal recessive
      myopathy with early respiratory failure (CMYO21).
    reference_section_type: RESULTS
  - statement: DNAJB4 normally localizes to the Z-disc and is absent from patient muscle
      and fibroblasts; knockout muscle accumulates Z-disc proteins and chaperones,
      indicating a role in myofibril/Z-disc proteostasis.
    reference_section_type: RESULTS
- id: PMID:9546042
  title: Isolation of a new member of DnaJ-like heat shock protein 40 (Hsp40) from
    human liver.
  findings:
  - statement: HLJ1/DNAJB4 is a 337-residue human HSP40/DnaJ-like protein that is induced
      by heat shock.
    reference_section_type: RESULTS
core_functions:
- description: J-domain co-chaperone that stimulates the ATPase activity of HSP70 (HSPA1A/HSPA1B),
    driving HSP70-mediated folding, refolding and disaggregation of client proteins.
  molecular_function:
    id: GO:0001671
    label: ATPase activator activity
  locations:
  - id: GO:0005829
    label: cytosol
  supported_by:
  - reference_id: PMID:24318877
    supporting_text: we combined the Hsp70-NEF pairs with cochaperones of the J protein
      family (DnaJA1, DnaJA2, DnaJB1, and DnaJB4) to generate 16 permutations. The
      activity of the combinations in ATPase and luciferase refolding assays
  - reference_id: file:human/DNAJB4/DNAJB4-uniprot.txt
    supporting_text: Stimulates ATP hydrolysis and the folding of unfolded proteins
      mediated by HSPA1A/B
- description: Binds the HSP70 chaperone and misfolded/aggregation-prone client proteins,
    recruiting clients to HSP70 for folding; in striated muscle this supports myofibril
    and Z-disc proteostasis.
  molecular_function:
    id: GO:0051087
    label: protein-folding chaperone binding
  locations:
  - id: GO:0005829
    label: cytosol
  - id: GO:0030018
    label: Z disc
  supported_by:
  - reference_id: PMID:36264506
    supporting_text: DNAJB4 normally localizes to the Z-disc and was absent from muscle
      and fibroblasts of affected patients
  - reference_id: file:human/DNAJB4/DNAJB4-uniprot.txt
    supporting_text: Stimulates ATP hydrolysis and the folding of unfolded proteins
      mediated by HSPA1A/B
proposed_new_terms: []
suggested_questions:
- question: What is the specific client repertoire of DNAJB4 at the muscle Z-disc,
    and which clients accumulate/aggregate upon DNAJB4 loss to drive CMYO21 myopathology?
- question: Is DNAJB4 functionally redundant with its paralogs DNAJB1 and DNAJB6 in
    muscle, and does the Z-disc role overlap with the DNAJB6 LGMD-D1 mechanism?
suggested_experiments:
- description: Affinity purification-mass spectrometry of tagged DNAJB4 from muscle
    cells (with HSP70 as co-bait) to define its client interactome and compare with
    DNAJB6.
- description: Reconstituted ATPase and disaggregation/refolding assays comparing wild-type
    DNAJB4 with CMYO21 variants (R25Q, L262S, K286Ter) to quantify loss of HSP70-stimulating
    and client-handling activity.