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).
| 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} |
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Download this section (compressed HTML)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?
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.
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