DNAJC5

UniProt ID: Q9H3Z4
Organism: Homo sapiens
Review Status: COMPLETE
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Gene Description

DNAJC5 (cysteine string protein alpha, CSPalpha; also CLN4) is a palmitoylated DnaJ/HSP40 co-chaperone of the presynaptic and secretory-vesicle membrane. It carries an N-terminal J domain that recruits and stimulates the constitutive HSP70 chaperone HSC70/HSPA8 and a central cysteine-string domain whose extensive palmitoylation anchors the protein to vesicle membranes. As a vesicle-localized co-chaperone it maintains the conformational integrity of the SNARE machinery, acting as a co-chaperone for SNAP-25 (with HSC70 and SGTA) and interacting with synaptotagmins, thereby supporting regulated/calcium-dependent exocytosis and the synaptic vesicle cycle and protecting nerve terminals against activity-dependent degeneration. Loss-of-function or aggregation-prone mutations in the cysteine-string domain (Leu115Arg, Leu116del) cause autosomal-dominant adult-onset neuronal ceroid lipofuscinosis (CLN4/ANCL, Kufs type).

Existing Annotations Review

GO Term Evidence Action Reason
GO:0006457 protein folding
IBA
GO_REF:0000033 		KEEP AS NON CORE
Summary: Phylogenetic inference that DNAJC5 participates in protein folding, reflecting its J-domain co-chaperone family membership. CSPalpha assists HSC70 rather than acting as an autonomous foldase.
Reason: Protein folding is a downstream outcome of the HSC70/HSP70 machine that CSPalpha supports as a J-domain co-chaperone; the informative molecular function is co-chaperone/HSP70-activator activity, so folding is retained as non-core.
Supporting Evidence:
file:human/DNAJC5/DNAJC5-uniprot.txt
Acts as a general chaperone in regulated exocytosis
GO:0016020 membrane
IBA
GO_REF:0000033 		KEEP AS NON CORE
Summary: CSPalpha is a palmitoylated, membrane-anchored co-chaperone; membrane is a correct but generic compartment.
Reason: Membrane localization is correct and palmitoylation-dependent, but the more specific and informative compartment is the synaptic/secretory vesicle membrane and presynapse; bare membrane is retained as non-core.
Supporting Evidence:
file:human/DNAJC5/DNAJC5-uniprot.txt
regulates DNAJC5 membrane attachment
GO:0098793 presynapse
IBA
GO_REF:0000033 		ACCEPT
Summary: CSPalpha acts at the presynaptic terminal on synaptic vesicles, supporting neurotransmitter release. This is a core site of action.
Reason: Strongly supported by the presynaptic/synaptic-vesicle biology of CSPalpha and its role in calcium-dependent neurotransmitter release at nerve endings.
Supporting Evidence:
file:human/DNAJC5/DNAJC5-uniprot.txt
May be involved in calcium-dependent
GO:0098693 regulation of synaptic vesicle cycle
IBA
GO_REF:0000033 		ACCEPT
Summary: CSPalpha regulates the synaptic vesicle cycle by chaperoning the exocytic SNARE machinery and supporting regulated exocytosis.
Reason: Consistent with the established presynaptic co-chaperone role of CSPalpha in maintaining release-competent synaptic vesicles.
Supporting Evidence:
file:human/DNAJC5/DNAJC5-uniprot.txt
Acts as a co-chaperone for the SNARE protein SNAP-25
GO:0005737 cytoplasm
IEA
GO_REF:0000117 		KEEP AS NON CORE
Summary: Electronic cytoplasm annotation; CSPalpha has a cytosolic pool but functions mainly on vesicle membranes.
Reason: Generic cytoplasm localization; consistent with the documented cytosol pool but less informative than the vesicle-membrane/presynapse localization.
Supporting Evidence:
file:human/DNAJC5/DNAJC5-uniprot.txt
SUBCELLULAR LOCATION: Cytoplasm, cytosol
GO:0005829 cytosol
IEA
GO_REF:0000044 		KEEP AS NON CORE
Summary: Cytosol localization from the UniProt subcellular-location mapping.
Reason: Consistent with a cytosolic pool but peripheral to the membrane-anchored functional localization.
Supporting Evidence:
file:human/DNAJC5/DNAJC5-uniprot.txt
SUBCELLULAR LOCATION: Cytoplasm, cytosol
GO:0005886 plasma membrane
IEA
GO_REF:0000044 		KEEP AS NON CORE
Summary: Plasma membrane localization, corroborated by direct IDA evidence (PMID:21820099) and by the palmitoylation-dependent membrane anchor.
Reason: CSPalpha is found at the cell membrane in addition to vesicle membranes; a genuine but non-core compartment relative to the synaptic-vesicle site of action.
Supporting Evidence:
file:human/DNAJC5/DNAJC5-uniprot.txt
Cell membrane {ECO:0000269|PubMed:21820099}
GO:0016020 membrane
IEA
GO_REF:0000044 		KEEP AS NON CORE
Summary: Generic membrane localization from UniProt subcellular-location mapping.
Reason: Correct but generic; the informative compartment is the vesicle membrane/presynapse.
Supporting Evidence:
file:human/DNAJC5/DNAJC5-uniprot.txt
regulates DNAJC5 membrane attachment
GO:0042470 melanosome
IEA
GO_REF:0000044 		KEEP AS NON CORE
Summary: Melanosome localization derived from large-scale melanosome proteomics (PMID:17081065), captured as an UniProt subcellular-location keyword.
Reason: A genuine proteomic detection in melanosome fractions but a specialized, peripheral context unrelated to CSPalpha's core synaptic co-chaperone function.
Supporting Evidence:
file:human/DNAJC5/DNAJC5-uniprot.txt
Identified by mass
GO:0042584 chromaffin granule membrane
IEA
GO_REF:0000044 		ACCEPT
Summary: Chromaffin granule (secretory vesicle) membrane localization, consistent with the secretory-vesicle role of CSPalpha in regulated exocytosis.
Reason: CSPalpha is an established component of secretory/chromaffin granule membranes where it chaperones the exocytic machinery; a relevant specific localization.
Supporting Evidence:
file:human/DNAJC5/DNAJC5-uniprot.txt
secretory vesicle,
GO:0005515 protein binding
IPI
PMID:29997244
LuTHy: a double-readout bioluminescence-based two-hybrid tec... 		KEEP AS NON CORE
Summary: Quantitative two-hybrid (LuTHy) capture of the CSPalpha-ZDHHC17 interaction. The bare protein binding term is uninformative; the partner is the palmitoyltransferase ZDHHC17, which palmitoylates CSPalpha.
Reason: Records a real, biologically meaningful interaction with the ZDHHC17 palmitoyltransferase but bare protein binding is uninformative and is not elevated to core.
Supporting Evidence:
file:human/DNAJC5/DNAJC5-uniprot.txt
Interacts with ZDHHC17 (via ANK repeats)
GO:0005515 protein binding
IPI
PMID:33961781
Dual proteome-scale networks reveal cell-specific remodeling... 		KEEP AS NON CORE
Summary: BioPlex affinity-purification interactome also capturing the CSPalpha-ZDHHC17 interaction. Bare protein binding is uninformative.
Reason: Corroborates the ZDHHC17 interaction but the bare protein binding term is uninformative; retained as non-core.
Supporting Evidence:
file:human/DNAJC5/DNAJC5-uniprot.txt
Interacts with ZDHHC17 (via ANK repeats)
GO:0006457 protein folding
IEA
GO_REF:0000107 		KEEP AS NON CORE
Summary: Ensembl-projected protein folding annotation from the mouse ortholog, reflecting the J-domain co-chaperone role.
Reason: Same rationale as the IBA protein folding annotation; a downstream process of the HSC70 machine CSPalpha assists, not its core molecular function.
Supporting Evidence:
file:human/DNAJC5/DNAJC5-uniprot.txt
Acts as a general chaperone in regulated exocytosis
GO:0008021 synaptic vesicle
IEA
GO_REF:0000107 		ACCEPT
Summary: Synaptic vesicle localization projected from the mouse ortholog; a core site for CSPalpha.
Reason: CSPalpha is a canonical synaptic-vesicle protein; this localization is central to its function.
Supporting Evidence:
file:human/DNAJC5/DNAJC5-uniprot.txt
secretory vesicle,
GO:0030672 synaptic vesicle membrane
IEA
GO_REF:0000107 		ACCEPT
Summary: CSPalpha acts on the synaptic vesicle membrane, where its palmitoylated cysteine-string domain anchors it. This is the core functional localization.
Reason: The palmitoylation-anchored, vesicle-membrane localization is where CSPalpha chaperones the exocytic machinery; strongly supported.
Supporting Evidence:
file:human/DNAJC5/DNAJC5-uniprot.txt
regulates DNAJC5 membrane attachment
GO:0031594 neuromuscular junction
IEA
GO_REF:0000107 		KEEP AS NON CORE
Summary: Neuromuscular junction localization projected from the mouse ortholog, a presynaptic site where CSPalpha operates.
Reason: A specific presynaptic site consistent with CSPalpha biology; retained as a non-core localization subsumed by the broader presynapse annotation.
Supporting Evidence:
file:human/DNAJC5/DNAJC5-uniprot.txt
important role in
GO:0043008 ATP-dependent protein binding
IEA
GO_REF:0000107 		MODIFY
Summary: ATP-dependent protein binding projected from the rat ortholog, reflecting the ATP-dependent interaction of CSPalpha with HSC70/HSPA8 via its J domain.
Reason: The interaction this captures is the J-domain-mediated, ATP-dependent recruitment of HSC70/HSPA8; the informative molecular function is HSP70/HSC70 co-chaperone (Hsp70 protein binding), which is more specific than the generic ATP-dependent protein binding term.
Proposed replacements: Hsp70 protein binding
Supporting Evidence:
file:human/DNAJC5/DNAJC5-uniprot.txt
Interacts with the chaperone complex consisting of HSC70 and
GO:0098693 regulation of synaptic vesicle cycle
IEA
GO_REF:0000107 		ACCEPT
Summary: Ensembl-projected regulation of synaptic vesicle cycle, consistent with the IBA annotation of the same term.
Reason: Redundant with the IBA annotation and well supported by CSPalpha presynaptic biology.
Supporting Evidence:
file:human/DNAJC5/DNAJC5-uniprot.txt
Acts as a co-chaperone for the SNARE protein SNAP-25
GO:0098793 presynapse
IEA
GO_REF:0000107 		ACCEPT
Summary: Ensembl-projected presynapse localization, redundant with the IBA presynapse annotation.
Reason: Core site of action; redundant with the IBA presynapse annotation.
Supporting Evidence:
file:human/DNAJC5/DNAJC5-uniprot.txt
May be involved in calcium-dependent
GO:0016020 membrane
ISS
GO_REF:0000024 		KEEP AS NON CORE
Summary: ISS membrane localization from the bovine ortholog (Q29455).
Reason: Generic membrane localization; correct but less informative than vesicle membrane.
Supporting Evidence:
file:human/DNAJC5/DNAJC5-uniprot.txt
regulates DNAJC5 membrane attachment
GO:0042470 melanosome
EXP
PMID:17081065
Proteomic and bioinformatic characterization of the biogenes... 		KEEP AS NON CORE
Summary: Experimental (mass spectrometry) detection of CSPalpha in melanosome fractions.
Reason: A genuine proteomic localization in a specialized lysosome-related organelle, peripheral to the core synaptic co-chaperone function.
Supporting Evidence:
file:human/DNAJC5/DNAJC5-uniprot.txt
Identified by mass
GO:0005829 cytosol
ISS
GO_REF:0000024 		KEEP AS NON CORE
Summary: ISS cytosol localization from the bovine ortholog.
Reason: Consistent with a cytosolic pool; peripheral to the membrane-anchored functional localization.
Supporting Evidence:
file:human/DNAJC5/DNAJC5-uniprot.txt
SUBCELLULAR LOCATION: Cytoplasm, cytosol
GO:0035577 azurophil granule membrane
TAS
Reactome:R-HSA-6798739 		KEEP AS NON CORE
Summary: Reactome neutrophil-degranulation pathway annotation placing CSPalpha on the azurophil granule membrane.
Reason: A specialized leukocyte secretory-granule context from pathway curation; peripheral to the core neuronal/secretory co-chaperone role.
Supporting Evidence:
file:human/DNAJC5/DNAJC5-uniprot.txt
secretory vesicle,
GO:0035579 specific granule membrane
TAS
Reactome:R-HSA-6799350 		KEEP AS NON CORE
Summary: Reactome neutrophil-degranulation annotation placing CSPalpha on the specific granule membrane.
Reason: Specialized leukocyte secretory-granule context; peripheral to the core function.
Supporting Evidence:
file:human/DNAJC5/DNAJC5-uniprot.txt
secretory vesicle,
GO:0006887 exocytosis
NAS
PMID:10099709
Genetics of synaptic vesicle function: toward the complete f... 		KEEP AS NON CORE
Summary: CSPalpha participates in exocytosis as a vesicle-membrane co-chaperone supporting the release machinery.
Reason: Exocytosis is a genuine process CSPalpha contributes to, but the more specific regulated/synaptic-vesicle exocytosis terms better capture its role; retained as a non-core (parent) process.
Supporting Evidence:
file:human/DNAJC5/DNAJC5-uniprot.txt
Acts as a general chaperone in regulated exocytosis
GO:0016079 synaptic vesicle exocytosis
TAS
PMID:10099709
Genetics of synaptic vesicle function: toward the complete f... 		ACCEPT
Summary: CSPalpha supports synaptic vesicle exocytosis at nerve terminals.
Reason: Well supported by CSPalpha's presynaptic role in calcium-dependent neurotransmitter release.
Supporting Evidence:
file:human/DNAJC5/DNAJC5-uniprot.txt
calcium-dependent neurotransmitter release at nerve endings
GO:0045055 regulated exocytosis
TAS
PMID:15217342
The synaptic vesicle cycle. 		ACCEPT
Summary: CSPalpha acts as a general chaperone in regulated exocytosis.
Reason: Directly stated in UniProt FUNCTION and central to CSPalpha biology in both neuronal and endocrine secretory cells.
Supporting Evidence:
file:human/DNAJC5/DNAJC5-uniprot.txt
Acts as a general chaperone in regulated exocytosis
GO:0016020 membrane
HDA
PMID:19946888
Defining the membrane proteome of NK cells. 		KEEP AS NON CORE
Summary: High-throughput proteomics detection of CSPalpha in a membrane fraction.
Reason: Generic membrane localization from large-scale data; correct but non-core.
Supporting Evidence:
file:human/DNAJC5/DNAJC5-uniprot.txt
regulates DNAJC5 membrane attachment
GO:0005886 plasma membrane
TAS
Reactome:R-HSA-6798739 		KEEP AS NON CORE
Summary: Reactome neutrophil-degranulation annotation placing CSPalpha at the plasma membrane (post-fusion).
Reason: Plasma membrane is a genuine CSPalpha compartment but this annotation derives from a specialized degranulation pathway; non-core.
Supporting Evidence:
file:human/DNAJC5/DNAJC5-uniprot.txt
Cell membrane {ECO:0000269|PubMed:21820099}
GO:0005886 plasma membrane
TAS
Reactome:R-HSA-6799350 		KEEP AS NON CORE
Summary: Reactome neutrophil-degranulation annotation placing CSPalpha at the plasma membrane.
Reason: Same as the other Reactome degranulation plasma-membrane annotation; non-core.
Supporting Evidence:
file:human/DNAJC5/DNAJC5-uniprot.txt
Cell membrane {ECO:0000269|PubMed:21820099}
GO:0005886 plasma membrane
TAS
Reactome:R-HSA-888589 		KEEP AS NON CORE
Summary: Reactome GABA-vesicle pathway annotation placing CSPalpha at the plasma membrane.
Reason: Genuine plasma-membrane compartment from pathway curation; non-core relative to the vesicle-membrane site of action.
Supporting Evidence:
file:human/DNAJC5/DNAJC5-uniprot.txt
Cell membrane {ECO:0000269|PubMed:21820099}
GO:0061202 clathrin-sculpted gamma-aminobutyric acid transport vesicle membrane
TAS
Reactome:R-HSA-888589 		ACCEPT
Summary: Reactome annotation placing CSPalpha on the clathrin-sculpted GABA transport vesicle membrane, a specific synaptic-vesicle subtype membrane.
Reason: A specific synaptic-vesicle membrane localization consistent with CSPalpha's vesicle-membrane co-chaperone role.
Supporting Evidence:
file:human/DNAJC5/DNAJC5-uniprot.txt
regulates DNAJC5 membrane attachment
GO:0061202 clathrin-sculpted gamma-aminobutyric acid transport vesicle membrane
TAS
Reactome:R-HSA-917744 		ACCEPT
Summary: Second Reactome annotation for the clathrin-sculpted GABA transport vesicle membrane.
Reason: Redundant with the other R-HSA-888589 annotation; a relevant synaptic-vesicle membrane localization.
Supporting Evidence:
file:human/DNAJC5/DNAJC5-uniprot.txt
regulates DNAJC5 membrane attachment
GO:0005739 mitochondrion
HDA
PMID:20833797
Phosphoproteome analysis of functional mitochondria isolated... 		MARK AS OVER ANNOTATED
Summary: High-throughput proteomics detection of CSPalpha in a mitochondrial fraction.
Reason: Mitochondrial localization is not supported by CSPalpha's biology (a palmitoylated vesicle-membrane/cytosolic co-chaperone) and most likely reflects fractionation cross-contamination in large-scale proteomics.
Supporting Evidence:
file:human/DNAJC5/DNAJC5-goa.tsv
mitochondrion
GO:0005765 lysosomal membrane
HDA
PMID:17897319
Integral and associated lysosomal membrane proteins. 		KEEP AS NON CORE
Summary: High-throughput proteomics detection of CSPalpha at the lysosomal membrane.
Reason: CSPalpha has documented links to lysosome-related organelles (melanosome) and unconventional secretion, so a lysosomal-membrane pool is plausible but peripheral; retained as non-core.
Supporting Evidence:
file:human/DNAJC5/DNAJC5-goa.tsv
lysosomal membrane
GO:0005886 plasma membrane
IDA
PMID:21820099
Mutations in DNAJC5, encoding cysteine-string protein alpha,... 		KEEP AS NON CORE
Summary: Direct immunolocalization of CSPalpha at the cell membrane, from the study that identified the CLN4B disease variants.
Reason: A directly observed plasma-membrane pool; genuine but non-core relative to the vesicle-membrane/presynapse site of action.
Supporting Evidence:
file:human/DNAJC5/DNAJC5-uniprot.txt
Cell membrane {ECO:0000269|PubMed:21820099}

Core Functions

Membrane-anchored HSC70/HSP70 co-chaperone that, via its J domain, recruits and stimulates HSC70/HSPA8 to chaperone the presynaptic SNARE machinery (SNAP-25), maintaining release-competent synaptic vesicles.

Molecular Function:
Hsp70 protein binding
Cellular Locations:
synaptic vesicle membrane presynapse
Supporting Evidence:
  • file:human/DNAJC5/DNAJC5-uniprot.txt
    Interacts with the chaperone complex consisting of HSC70 and
  • file:human/DNAJC5/DNAJC5-uniprot.txt
    Acts as a co-chaperone for the SNARE protein SNAP-25

General chaperone of regulated/synaptic-vesicle exocytosis that supports calcium-dependent neurotransmitter release at nerve endings and protects synapses against activity-dependent degeneration.

Molecular Function:
Hsp70 protein binding
Directly Involved In:
synaptic vesicle exocytosis
Cellular Locations:
synaptic vesicle membrane
Supporting Evidence:
  • file:human/DNAJC5/DNAJC5-uniprot.txt
    Acts as a general chaperone in regulated exocytosis
  • file:human/DNAJC5/DNAJC5-uniprot.txt
    calcium-dependent neurotransmitter release at nerve endings

References

GO_REF:0000024
Manual transfer of experimentally-verified manual GO annotation data to orthologs using Ensembl Compara
GO_REF:0000033
Annotation inferences using phylogenetic trees
GO_REF:0000044
Gene Ontology annotation through association of InterPro records with GO terms
GO_REF:0000107
Automatic transfer of experimentally verified manual GO annotation data to orthologs using Ensembl Compara
GO_REF:0000117
Electronic Gene Ontology annotations created by ARBA machine learning models
PMID:10099709
Genetics of synaptic vesicle function: toward the complete functional anatomy of an organelle.
  • Review of synaptic-vesicle protein function used as the basis for the exocytosis / synaptic-vesicle-exocytosis annotations of CSPalpha.
PMID:15217342
The synaptic vesicle cycle.
  • Review of the synaptic vesicle cycle (exocytosis followed by endocytosis and recycling) used as the basis for the regulated-exocytosis annotation.
PMID:17081065
Proteomic and bioinformatic characterization of the biogenesis and function of melanosomes.
  • CSPalpha was identified by mass spectrometry in melanosome fractions from stage I to stage IV.
PMID:17897319
Integral and associated lysosomal membrane proteins.
PMID:19946888
Defining the membrane proteome of NK cells.
PMID:20833797
Phosphoproteome analysis of functional mitochondria isolated from resting human muscle reveals extensive phosphorylation of inner membrane protein complexes and enzymes.
PMID:21820099
Mutations in DNAJC5, encoding cysteine-string protein alpha, cause autosomal-dominant adult-onset neuronal ceroid lipofuscinosis.
  • CLN4B variants Leu115Arg and Leu116del in the cysteine-string domain cause near absence of palmitoylated monomeric CSPalpha and formation of high molecular mass aggregates; CSPalpha was directly localized to the cell membrane.
PMID:29997244
LuTHy: a double-readout bioluminescence-based two-hybrid technology for quantitative mapping of protein-protein interactions in mammalian cells.
PMID:33961781
Dual proteome-scale networks reveal cell-specific remodeling of the human interactome.
Reactome:R-HSA-6798739
Neutrophil degranulation (azurophil granule membrane)
Reactome:R-HSA-6799350
Neutrophil degranulation (specific granule membrane)
Reactome:R-HSA-888589
GABA synthesis, release, reuptake and degradation
Reactome:R-HSA-917744
Clathrin-sculpted GABA transport vesicle membrane localization
file:human/DNAJC5/DNAJC5-uniprot.txt
UniProt entry Q9H3Z4 (DNJC5_HUMAN), cysteine string protein alpha
  • CSPalpha acts as a general chaperone in regulated exocytosis and a co-chaperone for SNAP-25; interacts with the HSC70/SGTA chaperone complex and with synaptotagmins; palmitoylated in its cysteine-string domain, which anchors it to vesicle membranes; CLN4B disease gene.

Suggested Questions for Experts

Q: How does palmitoylation of the cysteine-string domain coordinate CSPalpha's membrane targeting with its J-domain-dependent recruitment of HSC70 to SNARE clients?

Q: By what mechanism do the CLN4B mutations (Leu115Arg, Leu116del) cause a dominant, aggregation-prone gain of toxicity, and how does this relate to lipofuscin accumulation?

Q: Are the melanosome, lysosomal-membrane and mitochondrial proteomic localizations functionally meaningful pools of CSPalpha or fractionation artifacts?

Suggested Experiments

Experiment: Reconstituted HSC70 ATPase assays comparing wild-type CSPalpha with a J-domain HPD-motif mutant to quantify its HSP70-stimulating co-chaperone activity, and with CLN4B variants to test for loss of co-chaperone function.

Experiment: Acyl-biotin-exchange / SwissPalm-guided palmitoylation mapping in neurons combined with live imaging to correlate CSPalpha palmitoylation state with synaptic-vesicle membrane targeting and SNAP-25 chaperoning.

Experiment: Neuronal CSPalpha knockout/rescue with wild-type versus CLN4B variants to dissect the contribution of loss-of-co-chaperone function versus aggregate gain-of-toxicity to neurodegeneration.

📚 Additional Documentation

Notes

(DNAJC5-notes.md)

DNAJC5 (Q9H3Z4) research notes

Identity

  • DnaJ homolog subfamily C member 5; cysteine string protein alpha (CSPalpha/CSP); CLN4.
  • 198 aa. J domain (aa 13-82) [file:human/DNAJC5/DNAJC5-uniprot.txt "DOMAIN 13..82 /note=\"J\""].
  • Cysteine-string domain (aa ~113-136), heavily palmitoylated, mediates membrane attachment [uniprot PTM "Palmitoylated... Palmitoylation occurs probably in the cysteine-rich domain and regulates DNAJC5 membrane attachment"].

Function (UniProt FUNCTION, By similarity)

  • "Acts as a general chaperone in regulated exocytosis ... Acts as a co-chaperone for the SNARE protein SNAP-25 ... Involved in the calcium-mediated control of a late stage of exocytosis ... important role in presynaptic function ... calcium-dependent neurotransmitter release at nerve endings."
  • Interacts with HSC70/HSPA8 and SGTA chaperone complex; with synaptotagmins SYT1/5/7/9 forming a complex with SNAP25; with ZDHHC13/ZDHHC17 (palmitoyltransferases).
  • Core MF: J-domain co-chaperone (HSP70/HSC70 co-chaperone) — stimulates HSC70 ATPase, chaperones the SNARE assembly machinery (SNAP-25). This is the bona fide "ATPase activator / Hsp70 protein binding / chaperone" function. Distinct from generic protein folding (downstream).

Localization

  • Synaptic vesicle / secretory vesicle membrane, presynapse; plasma membrane; chromaffin granule membrane. Palmitoylation-dependent membrane anchor.
  • IEA melanosome (PMID:17081065 mass spec) and HDA mitochondrion (PMID:20833797), lysosomal membrane (PMID:17897319) — large-scale proteomics; non-core/peripheral.
  • Reactome neutrophil degranulation (azurophil/specific granule membrane) — peripheral, leukocyte context.

Disease

  • Autosomal-dominant adult-onset neuronal ceroid lipofuscinosis (CLN4B / ANCL / Kufs type) caused by Leu115Arg and Leu116del in the cysteine-string domain PMID:21820099. Mutants: near absence of palmitoylated monomeric forms; high MW aggregates [uniprot VARIANT].

PTM / regulation

  • Ser-10 phosphorylation (PKA) triggers order-to-disorder switch, reduces syntaxin/synaptotagmin binding without altering HSC70 interaction [PMID:27452402 from uniprot].

Curation judgment

  • Core MF: HSP70/HSC70 co-chaperone (ATPase activator / Hsp70 protein binding); the "ATP-dependent protein binding" (GO:0043008, IEA from rat ortholog) reflects this. protein folding KEEP_AS_NON_CORE (downstream). presynapse / synaptic vesicle membrane: core localizations -> ACCEPT. regulated exocytosis / synaptic vesicle cycle: genuine BP -> ACCEPT/KEEP_AS_NON_CORE.
  • The two protein binding IPI are with ZDHHC17 (Q8IUH5) -> the informative MF is the ZDHHC17/palmitoyltransferase interaction; bare protein binding KEEP_AS_NON_CORE.
  • Melanosome/mitochondrion/lysosomal membrane/granule membranes: KEEP_AS_NON_CORE or MARK_AS_OVER_ANNOTATED depending on strength; large-scale proteomics localizations not reflecting core synaptic role.

Pn Notes

(DNAJC5-pn-notes.md)

DNAJC5 PN Consistency Notes

  • Generated: 2026-06-18
  • Project: PROTEOSTASIS
  • Scope: PN consistency rereview against local AIGR review and available deep-research artifacts
  • UniProt: Q9H3Z4
  • 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: DNAJC5 (cysteine string protein alpha, CSPalpha; also CLN4) is a palmitoylated DnaJ/HSP40 co-chaperone of the presynaptic and secretory-vesicle membrane. It carries an N-terminal J domain that recruits and stimulates the constitutive HSP70 chaperone HSC70/HSPA8 and a central cysteine-string domain whose extensive palmitoylation anchors the protein to vesicle membranes. As a vesicle-localized co-chaperone it maintains the conformational integrity of the SNARE machinery, acting as a co-chaperone for SNAP-25 (with HSC70 and SGTA) and interacting with synaptotagmins, thereby supporting regulated/calcium-dependent exocytosis and the synaptic vesicle cycle and protecting nerve terminals against activity-dependent degeneration. Loss-of-function or aggregation-prone mutations in the cysteine-string domain (Leu115Arg, Leu116del) cause autosomal-dominant adult-onset neuronal ceroid lipofuscinosis (CLN4/ANCL, Kufs type).
  • Existing/core annotation action counts: ACCEPT: 11; KEEP_AS_NON_CORE: 23; MARK_AS_OVER_ANNOTATED: 1; MODIFY: 1

PN Consistency Summary

  • Consistency: Strongly consistent on MF, with one placement nuance. Deep research (notes), review and PN converge on DNAJC5/CSPalpha as a palmitoylated J-domain co-chaperone of HSC70/HSPA8 (the SNAP-25 co-chaperone with SGTA) at the synaptic/secretory vesicle membrane; CLN4 disease gene (PMID:21820099). The review's core MF is exactly GO:0030544 Hsp70 protein binding (it even MODIFIES the rat-ortholog GO:0043008 ATP-dependent protein binding → GO:0030544), matching the PN projection. Nuance: PN places CSPalpha in the ER branch, whereas the dominant biology (and the review's core localizations: synaptic vesicle membrane, presynapse) is synaptic/secretory — not ER. The secretory-vesicle/exocytic role is ER-branch-adjacent (secretory pathway), so this is a reasonable umbrella, not a contradiction.
  • PN story / NEW pressure: GO:0030544 is already the review's core MF, so the PN story is already captured (and verified real). No NEW pressure; CSPalpha's specific synaptic CSP role (regulation of synaptic vesicle cycle, synaptic vesicle exocytosis) is well annotated and goes beyond the generic J-domain MF the PN node carries.
  • Evidence alignment: PN carries no row references. Review cites the disease/mechanism literature (PMID:21820099, 10099709, 15217342, 17081065, 29997244, 33961781) plus Reactome rows; well-supported, no divergence from PN.
  • Verdict: Fully consistent; PN Hsp70-binding story already captured as core MF (GO:0030544). Recommended edits: none required; optionally [MAP] note that CSPalpha is the prototypical synaptic/secretory-vesicle CSP, so the ER-branch placement is an umbrella rather than its primary compartment.

Full Consistency Review

  • UniProt: Q9H3Z4 · batch: proteostasis-batch-2026-06-07b · review status: COMPLETE
  • PN placement: ER proteostasis|Chaperone|HSP70 system|J-domain containing HSP70 cochaperone (branch ER) ; PN-node mapping: type → mapped/ok_for_propagation_to_go GO:0030544 Hsp70 protein binding (goa_status=more_specific_than_existing_goa); all ancestor nodes no_mapping.
  • Consistency: Strongly consistent on MF, with one placement nuance. Deep research (notes), review and PN converge on DNAJC5/CSPalpha as a palmitoylated J-domain co-chaperone of HSC70/HSPA8 (the SNAP-25 co-chaperone with SGTA) at the synaptic/secretory vesicle membrane; CLN4 disease gene (PMID:21820099). The review's core MF is exactly GO:0030544 Hsp70 protein binding (it even MODIFIES the rat-ortholog GO:0043008 ATP-dependent protein binding → GO:0030544), matching the PN projection. Nuance: PN places CSPalpha in the ER branch, whereas the dominant biology (and the review's core localizations: synaptic vesicle membrane, presynapse) is synaptic/secretory — not ER. The secretory-vesicle/exocytic role is ER-branch-adjacent (secretory pathway), so this is a reasonable umbrella, not a contradiction.
  • PN story / NEW pressure: GO:0030544 is already the review's core MF, so the PN story is already captured (and verified real). No NEW pressure; CSPalpha's specific synaptic CSP role (regulation of synaptic vesicle cycle, synaptic vesicle exocytosis) is well annotated and goes beyond the generic J-domain MF the PN node carries.
  • Mapping strategy: No change to the node. GO:0030544 is the correct, defensible Hsp70-cochaperone MF (not an over-broad holdase claim). goa_status=more_specific_than_existing_goa is accurate (GOA had only the broader/ATP-dependent terms).
  • Evidence alignment: PN carries no row references. Review cites the disease/mechanism literature (PMID:21820099, 10099709, 15217342, 17081065, 29997244, 33961781) plus Reactome rows; well-supported, no divergence from PN.
  • Verdict: Fully consistent; PN Hsp70-binding story already captured as core MF (GO:0030544). Recommended edits: none required; optionally [MAP] note that CSPalpha is the prototypical synaptic/secretory-vesicle CSP, so the ER-branch placement is an umbrella rather than its primary compartment.

PN Dossier Context

  • review_batch: proteostasis-batch-2026-06-07b
  • review_yaml: genes/human/DNAJC5/DNAJC5-ai-review.yaml
  • PN workbook rows: 1

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

  • UniProt: Q9H3Z4
  • In branches: ER
  • PN-node mapping records (path + ancestors):
    • [type] ER 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] ER proteostasis|Chaperone|HSP70 system
      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.
    • [class] ER proteostasis|Chaperone
      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.
    • [branch] ER 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=more_specific_than_existing_goa | from=ER 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: Q9H3Z4
gene_symbol: DNAJC5
product_type: PROTEIN
status: COMPLETE
taxon:
  id: NCBITaxon:9606
  label: Homo sapiens
description: DNAJC5 (cysteine string protein alpha, CSPalpha; also CLN4) is a palmitoylated DnaJ/HSP40 co-chaperone of the presynaptic and secretory-vesicle membrane. It carries an N-terminal J domain that recruits and stimulates the constitutive HSP70 chaperone HSC70/HSPA8 and a central cysteine-string domain whose extensive palmitoylation anchors the protein to vesicle membranes. As a vesicle-localized co-chaperone it maintains the conformational integrity of the SNARE machinery, acting as a co-chaperone for SNAP-25 (with HSC70 and SGTA) and interacting with synaptotagmins, thereby supporting regulated/calcium-dependent exocytosis and the synaptic vesicle cycle and protecting nerve terminals against activity-dependent degeneration. Loss-of-function or aggregation-prone mutations in the cysteine-string domain (Leu115Arg, Leu116del) cause autosomal-dominant adult-onset neuronal ceroid lipofuscinosis (CLN4/ANCL, Kufs type).
alternative_products:
- name: '1'
  id: Q9H3Z4-1
- name: '2'
  id: Q9H3Z4-2
  sequence_note: VSP_001292
existing_annotations:
- term:
    id: GO:0006457
    label: protein folding
  evidence_type: IBA
  original_reference_id: GO_REF:0000033
  qualifier: involved_in
  review:
    summary: Phylogenetic inference that DNAJC5 participates in protein folding, reflecting its J-domain co-chaperone family membership. CSPalpha assists HSC70 rather than acting as an autonomous foldase.
    action: KEEP_AS_NON_CORE
    reason: Protein folding is a downstream outcome of the HSC70/HSP70 machine that CSPalpha supports as a J-domain co-chaperone; the informative molecular function is co-chaperone/HSP70-activator activity, so folding is retained as non-core.
    supported_by:
    - reference_id: file:human/DNAJC5/DNAJC5-uniprot.txt
      supporting_text: Acts as a general chaperone in regulated exocytosis
- term:
    id: GO:0016020
    label: membrane
  evidence_type: IBA
  original_reference_id: GO_REF:0000033
  qualifier: is_active_in
  review:
    summary: CSPalpha is a palmitoylated, membrane-anchored co-chaperone; membrane is a correct but generic compartment.
    action: KEEP_AS_NON_CORE
    reason: Membrane localization is correct and palmitoylation-dependent, but the more specific and informative compartment is the synaptic/secretory vesicle membrane and presynapse; bare membrane is retained as non-core.
    supported_by:
    - reference_id: file:human/DNAJC5/DNAJC5-uniprot.txt
      supporting_text: regulates DNAJC5 membrane attachment
- term:
    id: GO:0098793
    label: presynapse
  evidence_type: IBA
  original_reference_id: GO_REF:0000033
  qualifier: is_active_in
  review:
    summary: CSPalpha acts at the presynaptic terminal on synaptic vesicles, supporting neurotransmitter release. This is a core site of action.
    action: ACCEPT
    reason: Strongly supported by the presynaptic/synaptic-vesicle biology of CSPalpha and its role in calcium-dependent neurotransmitter release at nerve endings.
    supported_by:
    - reference_id: file:human/DNAJC5/DNAJC5-uniprot.txt
      supporting_text: May be involved in calcium-dependent
- term:
    id: GO:0098693
    label: regulation of synaptic vesicle cycle
  evidence_type: IBA
  original_reference_id: GO_REF:0000033
  qualifier: involved_in
  review:
    summary: CSPalpha regulates the synaptic vesicle cycle by chaperoning the exocytic SNARE machinery and supporting regulated exocytosis.
    action: ACCEPT
    reason: Consistent with the established presynaptic co-chaperone role of CSPalpha in maintaining release-competent synaptic vesicles.
    supported_by:
    - reference_id: file:human/DNAJC5/DNAJC5-uniprot.txt
      supporting_text: Acts as a co-chaperone for the SNARE protein SNAP-25
- term:
    id: GO:0005737
    label: cytoplasm
  evidence_type: IEA
  original_reference_id: GO_REF:0000117
  qualifier: located_in
  review:
    summary: Electronic cytoplasm annotation; CSPalpha has a cytosolic pool but functions mainly on vesicle membranes.
    action: KEEP_AS_NON_CORE
    reason: Generic cytoplasm localization; consistent with the documented cytosol pool but less informative than the vesicle-membrane/presynapse localization.
    supported_by:
    - reference_id: file:human/DNAJC5/DNAJC5-uniprot.txt
      supporting_text: 'SUBCELLULAR LOCATION: Cytoplasm, cytosol'
- term:
    id: GO:0005829
    label: cytosol
  evidence_type: IEA
  original_reference_id: GO_REF:0000044
  qualifier: located_in
  review:
    summary: Cytosol localization from the UniProt subcellular-location mapping.
    action: KEEP_AS_NON_CORE
    reason: Consistent with a cytosolic pool but peripheral to the membrane-anchored functional localization.
    supported_by:
    - reference_id: file:human/DNAJC5/DNAJC5-uniprot.txt
      supporting_text: 'SUBCELLULAR LOCATION: Cytoplasm, cytosol'
- term:
    id: GO:0005886
    label: plasma membrane
  evidence_type: IEA
  original_reference_id: GO_REF:0000044
  qualifier: located_in
  review:
    summary: Plasma membrane localization, corroborated by direct IDA evidence (PMID:21820099) and by the palmitoylation-dependent membrane anchor.
    action: KEEP_AS_NON_CORE
    reason: CSPalpha is found at the cell membrane in addition to vesicle membranes; a genuine but non-core compartment relative to the synaptic-vesicle site of action.
    supported_by:
    - reference_id: file:human/DNAJC5/DNAJC5-uniprot.txt
      supporting_text: Cell membrane {ECO:0000269|PubMed:21820099}
- term:
    id: GO:0016020
    label: membrane
  evidence_type: IEA
  original_reference_id: GO_REF:0000044
  qualifier: located_in
  review:
    summary: Generic membrane localization from UniProt subcellular-location mapping.
    action: KEEP_AS_NON_CORE
    reason: Correct but generic; the informative compartment is the vesicle membrane/presynapse.
    supported_by:
    - reference_id: file:human/DNAJC5/DNAJC5-uniprot.txt
      supporting_text: regulates DNAJC5 membrane attachment
- term:
    id: GO:0042470
    label: melanosome
  evidence_type: IEA
  original_reference_id: GO_REF:0000044
  qualifier: located_in
  review:
    summary: Melanosome localization derived from large-scale melanosome proteomics (PMID:17081065), captured as an UniProt subcellular-location keyword.
    action: KEEP_AS_NON_CORE
    reason: A genuine proteomic detection in melanosome fractions but a specialized, peripheral context unrelated to CSPalpha's core synaptic co-chaperone function.
    supported_by:
    - reference_id: file:human/DNAJC5/DNAJC5-uniprot.txt
      supporting_text: Identified by mass
- term:
    id: GO:0042584
    label: chromaffin granule membrane
  evidence_type: IEA
  original_reference_id: GO_REF:0000044
  qualifier: located_in
  review:
    summary: Chromaffin granule (secretory vesicle) membrane localization, consistent with the secretory-vesicle role of CSPalpha in regulated exocytosis.
    action: ACCEPT
    reason: CSPalpha is an established component of secretory/chromaffin granule membranes where it chaperones the exocytic machinery; a relevant specific localization.
    supported_by:
    - reference_id: file:human/DNAJC5/DNAJC5-uniprot.txt
      supporting_text: secretory vesicle,
- term:
    id: GO:0005515
    label: protein binding
  evidence_type: IPI
  original_reference_id: PMID:29997244
  qualifier: enables
  review:
    summary: Quantitative two-hybrid (LuTHy) capture of the CSPalpha-ZDHHC17 interaction. The bare protein binding term is uninformative; the partner is the palmitoyltransferase ZDHHC17, which palmitoylates CSPalpha.
    action: KEEP_AS_NON_CORE
    reason: Records a real, biologically meaningful interaction with the ZDHHC17 palmitoyltransferase but bare protein binding is uninformative and is not elevated to core.
    supported_by:
    - reference_id: file:human/DNAJC5/DNAJC5-uniprot.txt
      supporting_text: Interacts with ZDHHC17 (via ANK repeats)
- term:
    id: GO:0005515
    label: protein binding
  evidence_type: IPI
  original_reference_id: PMID:33961781
  qualifier: enables
  review:
    summary: BioPlex affinity-purification interactome also capturing the CSPalpha-ZDHHC17 interaction. Bare protein binding is uninformative.
    action: KEEP_AS_NON_CORE
    reason: Corroborates the ZDHHC17 interaction but the bare protein binding term is uninformative; retained as non-core.
    supported_by:
    - reference_id: file:human/DNAJC5/DNAJC5-uniprot.txt
      supporting_text: Interacts with ZDHHC17 (via ANK repeats)
- term:
    id: GO:0006457
    label: protein folding
  evidence_type: IEA
  original_reference_id: GO_REF:0000107
  qualifier: involved_in
  review:
    summary: Ensembl-projected protein folding annotation from the mouse ortholog, reflecting the J-domain co-chaperone role.
    action: KEEP_AS_NON_CORE
    reason: Same rationale as the IBA protein folding annotation; a downstream process of the HSC70 machine CSPalpha assists, not its core molecular function.
    supported_by:
    - reference_id: file:human/DNAJC5/DNAJC5-uniprot.txt
      supporting_text: Acts as a general chaperone in regulated exocytosis
- term:
    id: GO:0008021
    label: synaptic vesicle
  evidence_type: IEA
  original_reference_id: GO_REF:0000107
  qualifier: located_in
  review:
    summary: Synaptic vesicle localization projected from the mouse ortholog; a core site for CSPalpha.
    action: ACCEPT
    reason: CSPalpha is a canonical synaptic-vesicle protein; this localization is central to its function.
    supported_by:
    - reference_id: file:human/DNAJC5/DNAJC5-uniprot.txt
      supporting_text: secretory vesicle,
- term:
    id: GO:0030672
    label: synaptic vesicle membrane
  evidence_type: IEA
  original_reference_id: GO_REF:0000107
  qualifier: is_active_in
  review:
    summary: CSPalpha acts on the synaptic vesicle membrane, where its palmitoylated cysteine-string domain anchors it. This is the core functional localization.
    action: ACCEPT
    reason: The palmitoylation-anchored, vesicle-membrane localization is where CSPalpha chaperones the exocytic machinery; strongly supported.
    supported_by:
    - reference_id: file:human/DNAJC5/DNAJC5-uniprot.txt
      supporting_text: regulates DNAJC5 membrane attachment
- term:
    id: GO:0031594
    label: neuromuscular junction
  evidence_type: IEA
  original_reference_id: GO_REF:0000107
  qualifier: is_active_in
  review:
    summary: Neuromuscular junction localization projected from the mouse ortholog, a presynaptic site where CSPalpha operates.
    action: KEEP_AS_NON_CORE
    reason: A specific presynaptic site consistent with CSPalpha biology; retained as a non-core localization subsumed by the broader presynapse annotation.
    supported_by:
    - reference_id: file:human/DNAJC5/DNAJC5-uniprot.txt
      supporting_text: important role in
- term:
    id: GO:0043008
    label: ATP-dependent protein binding
  evidence_type: IEA
  original_reference_id: GO_REF:0000107
  qualifier: enables
  review:
    summary: ATP-dependent protein binding projected from the rat ortholog, reflecting the ATP-dependent interaction of CSPalpha with HSC70/HSPA8 via its J domain.
    action: MODIFY
    reason: The interaction this captures is the J-domain-mediated, ATP-dependent recruitment of HSC70/HSPA8; the informative molecular function is HSP70/HSC70 co-chaperone (Hsp70 protein binding), which is more specific than the generic ATP-dependent protein binding term.
    proposed_replacement_terms:
    - id: GO:0030544
      label: Hsp70 protein binding
    supported_by:
    - reference_id: file:human/DNAJC5/DNAJC5-uniprot.txt
      supporting_text: Interacts with the chaperone complex consisting of HSC70 and
- term:
    id: GO:0098693
    label: regulation of synaptic vesicle cycle
  evidence_type: IEA
  original_reference_id: GO_REF:0000107
  qualifier: involved_in
  review:
    summary: Ensembl-projected regulation of synaptic vesicle cycle, consistent with the IBA annotation of the same term.
    action: ACCEPT
    reason: Redundant with the IBA annotation and well supported by CSPalpha presynaptic biology.
    supported_by:
    - reference_id: file:human/DNAJC5/DNAJC5-uniprot.txt
      supporting_text: Acts as a co-chaperone for the SNARE protein SNAP-25
- term:
    id: GO:0098793
    label: presynapse
  evidence_type: IEA
  original_reference_id: GO_REF:0000107
  qualifier: is_active_in
  review:
    summary: Ensembl-projected presynapse localization, redundant with the IBA presynapse annotation.
    action: ACCEPT
    reason: Core site of action; redundant with the IBA presynapse annotation.
    supported_by:
    - reference_id: file:human/DNAJC5/DNAJC5-uniprot.txt
      supporting_text: May be involved in calcium-dependent
- term:
    id: GO:0016020
    label: membrane
  evidence_type: ISS
  original_reference_id: GO_REF:0000024
  qualifier: located_in
  review:
    summary: ISS membrane localization from the bovine ortholog (Q29455).
    action: KEEP_AS_NON_CORE
    reason: Generic membrane localization; correct but less informative than vesicle membrane.
    supported_by:
    - reference_id: file:human/DNAJC5/DNAJC5-uniprot.txt
      supporting_text: regulates DNAJC5 membrane attachment
- term:
    id: GO:0042470
    label: melanosome
  evidence_type: EXP
  original_reference_id: PMID:17081065
  qualifier: located_in
  review:
    summary: Experimental (mass spectrometry) detection of CSPalpha in melanosome fractions.
    action: KEEP_AS_NON_CORE
    reason: A genuine proteomic localization in a specialized lysosome-related organelle, peripheral to the core synaptic co-chaperone function.
    supported_by:
    - reference_id: file:human/DNAJC5/DNAJC5-uniprot.txt
      supporting_text: Identified by mass
- term:
    id: GO:0005829
    label: cytosol
  evidence_type: ISS
  original_reference_id: GO_REF:0000024
  qualifier: located_in
  review:
    summary: ISS cytosol localization from the bovine ortholog.
    action: KEEP_AS_NON_CORE
    reason: Consistent with a cytosolic pool; peripheral to the membrane-anchored functional localization.
    supported_by:
    - reference_id: file:human/DNAJC5/DNAJC5-uniprot.txt
      supporting_text: 'SUBCELLULAR LOCATION: Cytoplasm, cytosol'
- term:
    id: GO:0035577
    label: azurophil granule membrane
  evidence_type: TAS
  original_reference_id: Reactome:R-HSA-6798739
  qualifier: located_in
  review:
    summary: Reactome neutrophil-degranulation pathway annotation placing CSPalpha on the azurophil granule membrane.
    action: KEEP_AS_NON_CORE
    reason: A specialized leukocyte secretory-granule context from pathway curation; peripheral to the core neuronal/secretory co-chaperone role.
    supported_by:
    - reference_id: file:human/DNAJC5/DNAJC5-uniprot.txt
      supporting_text: secretory vesicle,
- term:
    id: GO:0035579
    label: specific granule membrane
  evidence_type: TAS
  original_reference_id: Reactome:R-HSA-6799350
  qualifier: located_in
  review:
    summary: Reactome neutrophil-degranulation annotation placing CSPalpha on the specific granule membrane.
    action: KEEP_AS_NON_CORE
    reason: Specialized leukocyte secretory-granule context; peripheral to the core function.
    supported_by:
    - reference_id: file:human/DNAJC5/DNAJC5-uniprot.txt
      supporting_text: secretory vesicle,
- term:
    id: GO:0006887
    label: exocytosis
  evidence_type: NAS
  original_reference_id: PMID:10099709
  qualifier: involved_in
  review:
    summary: CSPalpha participates in exocytosis as a vesicle-membrane co-chaperone supporting the release machinery.
    action: KEEP_AS_NON_CORE
    reason: Exocytosis is a genuine process CSPalpha contributes to, but the more specific regulated/synaptic-vesicle exocytosis terms better capture its role; retained as a non-core (parent) process.
    supported_by:
    - reference_id: file:human/DNAJC5/DNAJC5-uniprot.txt
      supporting_text: Acts as a general chaperone in regulated exocytosis
- term:
    id: GO:0016079
    label: synaptic vesicle exocytosis
  evidence_type: TAS
  original_reference_id: PMID:10099709
  qualifier: involved_in
  review:
    summary: CSPalpha supports synaptic vesicle exocytosis at nerve terminals.
    action: ACCEPT
    reason: Well supported by CSPalpha's presynaptic role in calcium-dependent neurotransmitter release.
    supported_by:
    - reference_id: file:human/DNAJC5/DNAJC5-uniprot.txt
      supporting_text: calcium-dependent neurotransmitter release at nerve endings
- term:
    id: GO:0045055
    label: regulated exocytosis
  evidence_type: TAS
  original_reference_id: PMID:15217342
  qualifier: involved_in
  review:
    summary: CSPalpha acts as a general chaperone in regulated exocytosis.
    action: ACCEPT
    reason: Directly stated in UniProt FUNCTION and central to CSPalpha biology in both neuronal and endocrine secretory cells.
    supported_by:
    - reference_id: file:human/DNAJC5/DNAJC5-uniprot.txt
      supporting_text: Acts as a general chaperone in regulated exocytosis
- term:
    id: GO:0016020
    label: membrane
  evidence_type: HDA
  original_reference_id: PMID:19946888
  qualifier: located_in
  review:
    summary: High-throughput proteomics detection of CSPalpha in a membrane fraction.
    action: KEEP_AS_NON_CORE
    reason: Generic membrane localization from large-scale data; correct but non-core.
    supported_by:
    - reference_id: file:human/DNAJC5/DNAJC5-uniprot.txt
      supporting_text: regulates DNAJC5 membrane attachment
- term:
    id: GO:0005886
    label: plasma membrane
  evidence_type: TAS
  original_reference_id: Reactome:R-HSA-6798739
  qualifier: located_in
  review:
    summary: Reactome neutrophil-degranulation annotation placing CSPalpha at the plasma membrane (post-fusion).
    action: KEEP_AS_NON_CORE
    reason: Plasma membrane is a genuine CSPalpha compartment but this annotation derives from a specialized degranulation pathway; non-core.
    supported_by:
    - reference_id: file:human/DNAJC5/DNAJC5-uniprot.txt
      supporting_text: Cell membrane {ECO:0000269|PubMed:21820099}
- term:
    id: GO:0005886
    label: plasma membrane
  evidence_type: TAS
  original_reference_id: Reactome:R-HSA-6799350
  qualifier: located_in
  review:
    summary: Reactome neutrophil-degranulation annotation placing CSPalpha at the plasma membrane.
    action: KEEP_AS_NON_CORE
    reason: Same as the other Reactome degranulation plasma-membrane annotation; non-core.
    supported_by:
    - reference_id: file:human/DNAJC5/DNAJC5-uniprot.txt
      supporting_text: Cell membrane {ECO:0000269|PubMed:21820099}
- term:
    id: GO:0005886
    label: plasma membrane
  evidence_type: TAS
  original_reference_id: Reactome:R-HSA-888589
  qualifier: located_in
  review:
    summary: Reactome GABA-vesicle pathway annotation placing CSPalpha at the plasma membrane.
    action: KEEP_AS_NON_CORE
    reason: Genuine plasma-membrane compartment from pathway curation; non-core relative to the vesicle-membrane site of action.
    supported_by:
    - reference_id: file:human/DNAJC5/DNAJC5-uniprot.txt
      supporting_text: Cell membrane {ECO:0000269|PubMed:21820099}
- term:
    id: GO:0061202
    label: clathrin-sculpted gamma-aminobutyric acid transport vesicle membrane
  evidence_type: TAS
  original_reference_id: Reactome:R-HSA-888589
  qualifier: located_in
  review:
    summary: Reactome annotation placing CSPalpha on the clathrin-sculpted GABA transport vesicle membrane, a specific synaptic-vesicle subtype membrane.
    action: ACCEPT
    reason: A specific synaptic-vesicle membrane localization consistent with CSPalpha's vesicle-membrane co-chaperone role.
    supported_by:
    - reference_id: file:human/DNAJC5/DNAJC5-uniprot.txt
      supporting_text: regulates DNAJC5 membrane attachment
- term:
    id: GO:0061202
    label: clathrin-sculpted gamma-aminobutyric acid transport vesicle membrane
  evidence_type: TAS
  original_reference_id: Reactome:R-HSA-917744
  qualifier: located_in
  review:
    summary: Second Reactome annotation for the clathrin-sculpted GABA transport vesicle membrane.
    action: ACCEPT
    reason: Redundant with the other R-HSA-888589 annotation; a relevant synaptic-vesicle membrane localization.
    supported_by:
    - reference_id: file:human/DNAJC5/DNAJC5-uniprot.txt
      supporting_text: regulates DNAJC5 membrane attachment
- term:
    id: GO:0005739
    label: mitochondrion
  evidence_type: HDA
  original_reference_id: PMID:20833797
  qualifier: located_in
  review:
    summary: High-throughput proteomics detection of CSPalpha in a mitochondrial fraction.
    action: MARK_AS_OVER_ANNOTATED
    reason: Mitochondrial localization is not supported by CSPalpha's biology (a palmitoylated vesicle-membrane/cytosolic co-chaperone) and most likely reflects fractionation cross-contamination in large-scale proteomics.
    supported_by:
    - reference_id: file:human/DNAJC5/DNAJC5-goa.tsv
      supporting_text: mitochondrion
- term:
    id: GO:0005765
    label: lysosomal membrane
  evidence_type: HDA
  original_reference_id: PMID:17897319
  qualifier: located_in
  review:
    summary: High-throughput proteomics detection of CSPalpha at the lysosomal membrane.
    action: KEEP_AS_NON_CORE
    reason: CSPalpha has documented links to lysosome-related organelles (melanosome) and unconventional secretion, so a lysosomal-membrane pool is plausible but peripheral; retained as non-core.
    supported_by:
    - reference_id: file:human/DNAJC5/DNAJC5-goa.tsv
      supporting_text: lysosomal membrane
- term:
    id: GO:0005886
    label: plasma membrane
  evidence_type: IDA
  original_reference_id: PMID:21820099
  qualifier: located_in
  review:
    summary: Direct immunolocalization of CSPalpha at the cell membrane, from the study that identified the CLN4B disease variants.
    action: KEEP_AS_NON_CORE
    reason: A directly observed plasma-membrane pool; genuine but non-core relative to the vesicle-membrane/presynapse site of action.
    supported_by:
    - reference_id: file:human/DNAJC5/DNAJC5-uniprot.txt
      supporting_text: Cell membrane {ECO:0000269|PubMed:21820099}
references:
- id: GO_REF:0000024
  title: Manual transfer of experimentally-verified manual GO annotation data to orthologs using Ensembl Compara
  findings: []
- id: GO_REF:0000033
  title: Annotation inferences using phylogenetic trees
  findings: []
- id: GO_REF:0000044
  title: Gene Ontology annotation through association of InterPro records with GO terms
  findings: []
- id: GO_REF:0000107
  title: Automatic transfer of experimentally verified manual GO annotation data to orthologs using Ensembl Compara
  findings: []
- id: GO_REF:0000117
  title: Electronic Gene Ontology annotations created by ARBA machine learning models
  findings: []
- id: PMID:10099709
  title: 'Genetics of synaptic vesicle function: toward the complete functional anatomy of an organelle.'
  findings:
  - statement: Review of synaptic-vesicle protein function used as the basis for the exocytosis / synaptic-vesicle-exocytosis annotations of CSPalpha.
    reference_section_type: ABSTRACT
- id: PMID:15217342
  title: The synaptic vesicle cycle.
  findings:
  - statement: Review of the synaptic vesicle cycle (exocytosis followed by endocytosis and recycling) used as the basis for the regulated-exocytosis annotation.
    reference_section_type: ABSTRACT
- id: PMID:17081065
  title: Proteomic and bioinformatic characterization of the biogenesis and function of melanosomes.
  findings:
  - statement: CSPalpha was identified by mass spectrometry in melanosome fractions from stage I to stage IV.
    reference_section_type: RESULTS
- id: PMID:17897319
  title: Integral and associated lysosomal membrane proteins.
  findings: []
- id: PMID:19946888
  title: Defining the membrane proteome of NK cells.
  findings: []
- id: PMID:20833797
  title: Phosphoproteome analysis of functional mitochondria isolated from resting human muscle reveals extensive phosphorylation of inner membrane protein complexes and enzymes.
  findings: []
- id: PMID:21820099
  title: Mutations in DNAJC5, encoding cysteine-string protein alpha, cause autosomal-dominant adult-onset neuronal ceroid lipofuscinosis.
  reference_review:
    relevance: HIGH
    correctness: UNVERIFIED
    review_notes: "Disease-gene reference establishing that CLN4/ANCL-causing CSPalpha variants in the cysteine-string domain abolish palmitoylated monomeric CSPalpha, underpinning the in vivo importance of DNAJC5's synaptic co-chaperone function; also the IDA source for the plasma-membrane localization. Not cached in publications/, so the identifier/content could not be checked against a cached/PubMed anchor; title is consistent with the GOA IDA plasma-membrane row but left UNVERIFIED."
  findings:
  - statement: CLN4B variants Leu115Arg and Leu116del in the cysteine-string domain cause near absence of palmitoylated monomeric CSPalpha and formation of high molecular mass aggregates; CSPalpha was directly localized to the cell membrane.
    reference_section_type: RESULTS
- id: PMID:29997244
  title: 'LuTHy: a double-readout bioluminescence-based two-hybrid technology for quantitative mapping of protein-protein interactions in mammalian cells.'
  findings: []
- id: PMID:33961781
  title: Dual proteome-scale networks reveal cell-specific remodeling of the human interactome.
  findings: []
- id: Reactome:R-HSA-6798739
  title: Neutrophil degranulation (azurophil granule membrane)
  findings: []
- id: Reactome:R-HSA-6799350
  title: Neutrophil degranulation (specific granule membrane)
  findings: []
- id: Reactome:R-HSA-888589
  title: 'GABA synthesis, release, reuptake and degradation'
  findings: []
- id: Reactome:R-HSA-917744
  title: Clathrin-sculpted GABA transport vesicle membrane localization
  findings: []
- id: file:human/DNAJC5/DNAJC5-uniprot.txt
  title: UniProt entry Q9H3Z4 (DNJC5_HUMAN), cysteine string protein alpha
  findings:
  - statement: CSPalpha acts as a general chaperone in regulated exocytosis and a co-chaperone for SNAP-25; interacts with the HSC70/SGTA chaperone complex and with synaptotagmins; palmitoylated in its cysteine-string domain, which anchors it to vesicle membranes; CLN4B disease gene.
    reference_section_type: OTHER
core_functions:
- description: Membrane-anchored HSC70/HSP70 co-chaperone that, via its J domain, recruits and stimulates HSC70/HSPA8 to chaperone the presynaptic SNARE machinery (SNAP-25), maintaining release-competent synaptic vesicles.
  molecular_function:
    id: GO:0030544
    label: Hsp70 protein binding
  locations:
  - id: GO:0030672
    label: synaptic vesicle membrane
  - id: GO:0098793
    label: presynapse
  supported_by:
  - reference_id: file:human/DNAJC5/DNAJC5-uniprot.txt
    supporting_text: Interacts with the chaperone complex consisting of HSC70 and
  - reference_id: file:human/DNAJC5/DNAJC5-uniprot.txt
    supporting_text: Acts as a co-chaperone for the SNARE protein SNAP-25
- description: General chaperone of regulated/synaptic-vesicle exocytosis that supports calcium-dependent neurotransmitter release at nerve endings and protects synapses against activity-dependent degeneration.
  molecular_function:
    id: GO:0030544
    label: Hsp70 protein binding
  locations:
  - id: GO:0030672
    label: synaptic vesicle membrane
  supported_by:
  - reference_id: file:human/DNAJC5/DNAJC5-uniprot.txt
    supporting_text: Acts as a general chaperone in regulated exocytosis
  - reference_id: file:human/DNAJC5/DNAJC5-uniprot.txt
    supporting_text: calcium-dependent neurotransmitter release at nerve endings
  directly_involved_in:
  - id: GO:0016079
    label: synaptic vesicle exocytosis
proposed_new_terms: []
suggested_questions:
- question: How does palmitoylation of the cysteine-string domain coordinate CSPalpha's membrane targeting with its J-domain-dependent recruitment of HSC70 to SNARE clients?
- question: By what mechanism do the CLN4B mutations (Leu115Arg, Leu116del) cause a dominant, aggregation-prone gain of toxicity, and how does this relate to lipofuscin accumulation?
- question: Are the melanosome, lysosomal-membrane and mitochondrial proteomic localizations functionally meaningful pools of CSPalpha or fractionation artifacts?
suggested_experiments:
- description: Reconstituted HSC70 ATPase assays comparing wild-type CSPalpha with a J-domain HPD-motif mutant to quantify its HSP70-stimulating co-chaperone activity, and with CLN4B variants to test for loss of co-chaperone function.
- description: Acyl-biotin-exchange / SwissPalm-guided palmitoylation mapping in neurons combined with live imaging to correlate CSPalpha palmitoylation state with synaptic-vesicle membrane targeting and SNAP-25 chaperoning.
- description: Neuronal CSPalpha knockout/rescue with wild-type versus CLN4B variants to dissect the contribution of loss-of-co-chaperone function versus aggregate gain-of-toxicity to neurodegeneration.