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.