id: Q96KC8 gene_symbol: DNAJC1 product_type: PROTEIN status: COMPLETE taxon: id: NCBITaxon:9606 label: Homo sapiens description: DNAJC1 (MTJ1/ERdj1, human homolog HTJ1) is a single-pass type I endoplasmic reticulum (and nuclear/microsomal) membrane protein of the DNAJC subfamily of J-domain co-chaperones. Its N-terminal J domain faces the ER lumen and stimulates the ATPase activity of the ER HSP70 chaperone BiP (HSPA5), while its large cytosolic C-terminal region associates with ribosomes and modulates protein synthesis, and contains two SANT (Myb-like) domains. Through its second SANT domain it binds the serpin SERPINA3/alpha-1-antichymotrypsin and the inter-alpha-trypsin inhibitor heavy chain ITIH4, modulating their protease-inhibitory/processing behavior. DNAJC1 thereby couples the ER-membrane BiP chaperone system to translation and to regulation of secreted protease/protease-inhibitor activity. existing_annotations: - term: id: GO:0012505 label: endomembrane system evidence_type: IBA original_reference_id: GO_REF:0000033 qualifier: is_active_in review: summary: DNAJC1 is an integral ER/nuclear membrane protein and thus acts within the endomembrane system. A general but correct localization. action: ACCEPT reason: Consistent with DNAJC1's documented ER/nuclear/microsomal membrane localization; a broad but accurate site-of-action term. supported_by: - reference_id: file:human/DNAJC1/DNAJC1-uniprot.txt supporting_text: 'SUBCELLULAR LOCATION: Endoplasmic reticulum membrane' - term: id: GO:0001671 label: ATPase activator activity evidence_type: IEA original_reference_id: GO_REF:0000117 qualifier: enables review: summary: Rule-based electronic annotation of ATPase activator activity, redundant with the experimentally supported TAS annotation that DNAJC1's lumenal J domain stimulates BiP/HSPA5 ATPase activity. action: ACCEPT reason: J-domain stimulation of BiP ATPase is the core molecular function of DNAJC1 and is supported by experimental TAS evidence; the IEA call is correct. supported_by: - reference_id: PMID:14668352 supporting_text: its lumenal J-domain stimulates the - term: id: GO:0005789 label: endoplasmic reticulum membrane evidence_type: IEA original_reference_id: GO_REF:0000044 qualifier: located_in review: summary: Automated ER-membrane localization derived from the UniProt subcellular-location annotation; DNAJC1 is a single-pass type I ER-membrane protein. action: ACCEPT reason: ER membrane is the correct, documented localization for this single-pass membrane J-protein. supported_by: - reference_id: file:human/DNAJC1/DNAJC1-uniprot.txt supporting_text: 'SUBCELLULAR LOCATION: Endoplasmic reticulum membrane' - term: id: GO:0031965 label: nuclear membrane evidence_type: IEA original_reference_id: GO_REF:0000044 qualifier: located_in review: summary: Automated nuclear-membrane localization from the UniProt annotation; DNAJC1 is also found in the nuclear (contiguous with ER) membrane. action: ACCEPT reason: Nuclear-membrane localization is documented in UniProt and consistent with DNAJC1's ER/nuclear-envelope membrane residence. supported_by: - reference_id: file:human/DNAJC1/DNAJC1-uniprot.txt supporting_text: Nucleus membrane - term: id: GO:0051246 label: regulation of protein metabolic process evidence_type: IEA original_reference_id: GO_REF:0000117 qualifier: involved_in review: summary: Rule-based electronic annotation that DNAJC1 regulates a protein metabolic process, broadly consistent with its roles in BiP-assisted folding, translation modulation and SANT2-mediated protease/secretion regulation. action: KEEP_AS_NON_CORE reason: A very general process term that subsumes DNAJC1's more specific roles; retained as non-core because the informative functions are captured by specific terms. supported_by: - reference_id: file:human/DNAJC1/DNAJC1-uniprot.txt supporting_text: May modulate protein synthesis - term: id: GO:0005515 label: protein binding evidence_type: IPI original_reference_id: PMID:14668352 qualifier: enables review: summary: Specific interaction of the DNAJC1 SANT2 domain with the serpin SERPINA3/alpha-1-antichymotrypsin (P01011). Bare protein binding is uninformative, but this records a functionally characterized SANT2 interaction. action: KEEP_AS_NON_CORE reason: Records a real, characterized SANT2-SERPINA3 interaction; bare protein binding is uninformative per curation guidelines, and the functional consequence is captured by the proteolysis/secretion process terms. supported_by: - reference_id: file:human/DNAJC1/DNAJC1-goa.tsv supporting_text: GO:0005515 protein binding molecular_function ECO:0000353 IPI PMID:14668352 UniProtKB:P01011 - term: id: GO:0005515 label: protein binding evidence_type: IPI original_reference_id: PMID:28514442 qualifier: enables review: summary: Human interactome community study capturing DNAJC1 with RMND1 (Q9NWS8). Bare protein binding is uninformative. action: KEEP_AS_NON_CORE reason: Records a real high-throughput interaction but bare protein binding is uninformative and the partner does not define DNAJC1's core function. supported_by: - reference_id: file:human/DNAJC1/DNAJC1-goa.tsv supporting_text: GO:0005515 protein binding molecular_function ECO:0000353 IPI PMID:28514442 UniProtKB:Q9NWS8 - term: id: GO:0005515 label: protein binding evidence_type: IPI original_reference_id: PMID:32296183 qualifier: enables review: summary: Binary interactome map capturing DNAJC1 with multiple membrane partners (e.g. TNFRSF10C O14798, ATP6V0C P27449, CYP4F2 P78329, AGTRAP, CMTM7, TMEM201, PLP2). Bare protein binding is uninformative. action: KEEP_AS_NON_CORE reason: Records real high-throughput interactions with membrane proteins but bare protein binding is uninformative; none define DNAJC1's core function. supported_by: - reference_id: file:human/DNAJC1/DNAJC1-goa.tsv supporting_text: GO:0005515 protein binding molecular_function ECO:0000353 IPI PMID:32296183 UniProtKB:O14798 - term: id: GO:0005515 label: protein binding evidence_type: IPI original_reference_id: PMID:32814053 qualifier: enables review: summary: Neurodegeneration interactome screen capturing DNAJC1 with LAMP2 (P13473-2) and SH3GLB1 (Q9Y371). Bare protein binding is uninformative. action: KEEP_AS_NON_CORE reason: Records real high-throughput interactions but bare protein binding is uninformative and the partners do not define DNAJC1's core function. supported_by: - reference_id: file:human/DNAJC1/DNAJC1-goa.tsv supporting_text: GO:0005515 protein binding molecular_function ECO:0000353 IPI PMID:32814053 UniProtKB:P13473-2 - term: id: GO:0005515 label: protein binding evidence_type: IPI original_reference_id: PMID:33961781 qualifier: enables review: summary: BioPlex affinity-purification interactome capturing DNAJC1 with RMND1 (Q9NWS8). Bare protein binding is uninformative. action: KEEP_AS_NON_CORE reason: Records a real high-throughput interaction but bare protein binding is uninformative as a core MF. supported_by: - reference_id: file:human/DNAJC1/DNAJC1-goa.tsv supporting_text: GO:0005515 protein binding molecular_function ECO:0000353 IPI PMID:33961781 UniProtKB:Q9NWS8 - term: id: GO:0005515 label: protein binding evidence_type: IPI original_reference_id: PMID:35156780 qualifier: enables review: summary: CFTR interactome (membrane two-hybrid) capturing DNAJC1 with CFTR (P13569). Bare protein binding is uninformative, though CFTR is an ER quality-control/ERAD substrate plausibly handled by the BiP/ERdj1 system. action: KEEP_AS_NON_CORE reason: Records a real interactome interaction with a known ERAD substrate; bare protein binding is uninformative as a core MF. supported_by: - reference_id: file:human/DNAJC1/DNAJC1-goa.tsv supporting_text: GO:0005515 protein binding molecular_function ECO:0000353 IPI PMID:35156780 UniProtKB:P13569 - term: id: GO:0005515 label: protein binding evidence_type: IPI original_reference_id: PMID:36012204 qualifier: enables review: summary: CFTR proximity-labeling interactome again capturing DNAJC1 with CFTR (P13569). Bare protein binding is uninformative. action: KEEP_AS_NON_CORE reason: Records a real proximity-labeling interaction with CFTR; bare protein binding is uninformative as a core MF. supported_by: - reference_id: file:human/DNAJC1/DNAJC1-goa.tsv supporting_text: GO:0005515 protein binding molecular_function ECO:0000353 IPI PMID:36012204 UniProtKB:P13569 - term: id: GO:0005783 label: endoplasmic reticulum evidence_type: IEA original_reference_id: GO_REF:0000107 qualifier: located_in review: summary: Ensembl ortholog-projected ER localization, consistent with the experimentally supported ER membrane localization. action: ACCEPT reason: Correct compartment; agrees with ISS/IEA ER membrane evidence. supported_by: - reference_id: file:human/DNAJC1/DNAJC1-uniprot.txt supporting_text: 'SUBCELLULAR LOCATION: Endoplasmic reticulum membrane' - term: id: GO:0005886 label: plasma membrane evidence_type: IEA original_reference_id: GO_REF:0000107 qualifier: located_in review: summary: Ensembl ortholog-projected plasma-membrane localization. DNAJC1 is an ER/nuclear-envelope membrane protein; a plasma-membrane localization is not supported and conflicts with its documented topology and residence. action: MARK_AS_OVER_ANNOTATED reason: Orthology-projected plasma-membrane localization conflicts with DNAJC1's established ER/nuclear membrane residence; likely an over-annotation. supported_by: - reference_id: file:human/DNAJC1/DNAJC1-goa.tsv supporting_text: GO:0005886 plasma membrane cellular_component ECO:0000265 IEA GO_REF:0000107 - term: id: GO:0051087 label: protein-folding chaperone binding evidence_type: IEA original_reference_id: GO_REF:0000107 qualifier: enables review: summary: Orthology-projected chaperone-binding molecular function. DNAJC1's J domain binds the chaperone BiP/HSPA5, so this term is correct. action: ACCEPT reason: DNAJC1 binds the HSP70 chaperone BiP via its J domain; chaperone binding is a genuine molecular function consistent with experimental data. supported_by: - reference_id: file:human/DNAJC1/DNAJC1-uniprot.txt supporting_text: Interacts (via J domain) with HSPA5 - term: id: GO:0016020 label: membrane evidence_type: HDA original_reference_id: PMID:19946888 qualifier: located_in review: summary: High-throughput membrane-proteome (NK cell) detection of DNAJC1, consistent with its membrane residence but uninformative as to compartment. action: KEEP_AS_NON_CORE reason: Generic membrane localization from a proteomics screen; correct but less informative than the specific ER/nuclear membrane annotations. supported_by: - reference_id: file:human/DNAJC1/DNAJC1-goa.tsv supporting_text: GO:0016020 membrane cellular_component ECO:0007005 HDA PMID:19946888 - term: id: GO:0005515 label: protein binding evidence_type: IPI original_reference_id: PMID:16271702 qualifier: enables review: summary: Specific interaction of the DNAJC1 SANT2 domain with inter-alpha-trypsin inhibitor heavy chain 4 (ITIH4, Q14624); SANT2 protects ITIH4 from kallikrein cleavage. Bare protein binding is uninformative but records a functionally characterized SANT2 interaction. action: KEEP_AS_NON_CORE reason: Records a real, characterized SANT2-ITIH4 interaction; bare protein binding is uninformative per curation guidelines, with the functional consequence captured by the proteolysis-regulation term. supported_by: - reference_id: file:human/DNAJC1/DNAJC1-goa.tsv supporting_text: GO:0005515 protein binding molecular_function ECO:0000353 IPI PMID:16271702 UniProtKB:Q14624 - term: id: GO:0001671 label: ATPase activator activity evidence_type: TAS original_reference_id: PMID:14668352 qualifier: enables review: summary: The lumenal J domain of DNAJC1/MTJ1 stimulates the ATPase activity of the ER HSP70 chaperone BiP/GRP78. This is the core molecular function of DNAJC1 as a J-protein co-chaperone. action: ACCEPT reason: J-domain stimulation of BiP ATPase is the defining co-chaperone activity of DNAJC1 and is experimentally documented. supported_by: - reference_id: PMID:14668352 supporting_text: its lumenal J-domain stimulates the - term: id: GO:0005783 label: endoplasmic reticulum evidence_type: ISS original_reference_id: GO_REF:0000024 qualifier: located_in review: summary: Sequence/ortholog-based ER localization, consistent with DNAJC1's established ER-membrane residence. action: ACCEPT reason: ISS ER localization agrees with the documented ER membrane localization. supported_by: - reference_id: file:human/DNAJC1/DNAJC1-uniprot.txt supporting_text: 'SUBCELLULAR LOCATION: Endoplasmic reticulum membrane' - term: id: GO:0045861 label: negative regulation of proteolysis evidence_type: TAS original_reference_id: PMID:14668352 qualifier: involved_in review: summary: The DNAJC1 SANT2 domain binds SERPINA3/alpha-1-antichymotrypsin and alters its serpin inhibitory activity (and protects ITIH4 from kallikrein cleavage), modulating proteolysis. A documented, specialized process role. action: KEEP_AS_NON_CORE reason: A genuine, experimentally supported SANT2-mediated function, but specialized/peripheral relative to DNAJC1's core BiP co-chaperone and translation-modulation roles. supported_by: - reference_id: PMID:14668352 supporting_text: results in an apparent loss of ACT inhibitory - term: id: GO:0050708 label: regulation of protein secretion evidence_type: IDA original_reference_id: PMID:14668352 qualifier: involved_in review: summary: DNAJC1's SANT2-mediated modulation of the serpin SERPINA3 is interpreted as regulation of protein secretion. A specialized process role supported by direct experiment. action: KEEP_AS_NON_CORE reason: Experimentally supported but specialized SANT2-domain function; peripheral to DNAJC1's core co-chaperone/translation-modulation activities. supported_by: - reference_id: PMID:14668352 supporting_text: results in an apparent loss of ACT inhibitory references: - id: GO_REF:0000024 title: Manual transfer of experimentally-verified manual GO annotation data to orthologs by curator judgment of sequence similarity findings: [] - id: GO_REF:0000033 title: Annotation inferences using phylogenetic trees findings: [] - id: GO_REF:0000044 title: Gene Ontology annotation based on UniProtKB/Swiss-Prot Subcellular Location vocabulary mapping findings: [] - id: GO_REF: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:14668352 title: The SANT2 domain of the murine tumor cell DnaJ-like protein 1 human homologue interacts with alpha1-antichymotrypsin and kinetically interferes with its serpin inhibitory activity. reference_review: relevance: HIGH correctness: VERIFIED review_notes: Cached publication title matches PubMed; body confirms DNAJC1/MTJ1/ERdj1's lumenal J-domain stimulates BiP/GRP78 ATPase and its SANT2 domain binds SERPINA3. GOA anchors this PMID to GO:0001671 (ATPase activator activity, TAS) and GO:0050708/GO:0045861, supporting the gene's core ER co-chaperone function. findings: - statement: The lumenal J domain of DNAJC1/MTJ1 stimulates the ATPase activity of BiP/GRP78; its cytosolic SANT2 domain binds SERPINA3/alpha-1-antichymotrypsin and interferes with its serpin inhibitory activity. reference_section_type: RESULTS - id: PMID:16271702 title: BIP co-chaperone MTJ1/ERDJ1 interacts with inter-alpha-trypsin inhibitor heavy chain 4. findings: - statement: The DNAJC1 (MTJ1/ERdj1) SANT2 domain binds ITIH4 and protects an ITIH4 C-terminal fragment from kallikrein cleavage. reference_section_type: RESULTS - id: PMID:19946888 title: Defining the membrane proteome of NK cells. findings: [] - id: PMID:28514442 title: Architecture of the human interactome defines protein communities and disease networks. findings: [] - id: PMID:32296183 title: A reference map of the human binary protein interactome. findings: [] - id: PMID:32814053 title: Interactome Mapping Provides a Network of Neurodegenerative Disease Proteins and Uncovers Widespread Protein Aggregation in Affected Brains. findings: [] - id: PMID:33961781 title: Dual proteome-scale networks reveal cell-specific remodeling of the human interactome. findings: [] - id: PMID:35156780 title: CFTR interactome mapping using the mammalian membrane two-hybrid high-throughput screening system. findings: [] - id: PMID:36012204 title: Differential CFTR-Interactome Proximity Labeling Procedures Identify Enrichment in Multiple SLC Transporters. findings: [] core_functions: - description: ER-membrane J-domain co-chaperone whose lumenal J domain stimulates the ATPase activity of the ER HSP70 chaperone BiP (HSPA5), coupling client folding to BiP's ATP cycle at the ER membrane. molecular_function: id: GO:0001671 label: ATPase activator activity locations: - id: GO:0005789 label: endoplasmic reticulum membrane supported_by: - reference_id: PMID:14668352 supporting_text: its lumenal J-domain stimulates the - reference_id: file:human/DNAJC1/DNAJC1-uniprot.txt supporting_text: Interacts (via J domain) with HSPA5 - description: Binds the ER HSP70 chaperone BiP/HSPA5 (via its J domain) as a co-chaperone; in addition its cytosolic domain associates with ribosomes and is proposed to modulate protein synthesis at the ER membrane. molecular_function: id: GO:0051087 label: protein-folding chaperone binding locations: - id: GO:0005789 label: endoplasmic reticulum membrane supported_by: - reference_id: file:human/DNAJC1/DNAJC1-uniprot.txt supporting_text: Interacts (via J domain) with HSPA5 - reference_id: file:human/DNAJC1/DNAJC1-uniprot.txt supporting_text: Interacts (via cytosolic domain) with ribosomes proposed_new_terms: [] suggested_questions: - question: How does DNAJC1 ribosome association at the ER membrane mechanistically regulate translation, and is this coupled to BiP-assisted co-translational folding? - question: What is the physiological significance of the SANT2-mediated regulation of secreted serpins/protease inhibitors (SERPINA3, ITIH4) by an ER-membrane chaperone? suggested_experiments: - description: Ribosome profiling and polysome analysis in DNAJC1-depleted versus control cells to test its proposed role in translation/protein-synthesis modulation at the ER. - description: Reconstituted BiP ATPase assays with the DNAJC1 lumenal J domain (wild-type versus HPD-motif mutant) to quantify its co-chaperone activity, and co-IP/structural mapping of the cytosolic ribosome-binding region.