DNAJC19 (TIM14/TIMM14; DnaJ homolog subfamily C member 19) is a J-domain co-chaperone of the mitochondrial inner membrane. It is a single-pass inner-membrane protein with a short intermembrane-space N-terminus, one transmembrane helix, and a matrix-facing J-domain. As the J-protein of the presequence translocase-associated import motor (PAM), it stimulates the ATPase activity of matrix mitochondrial HSP70 (mortalin/HSPA9) to drive ATP-dependent translocation of presequence-bearing precursor proteins from the TIM23 channel into the matrix. It forms a regulatory heterodimeric subcomplex with PAM16/Magmas (TIMM16), which restrains its HSP70-stimulating activity, and is tethered to the TIM23 translocase. DNAJC19 also associates with the prohibitin complex via PHB2 and has been implicated in cardiolipin remodeling. Biallelic loss-of-function variants cause dilated cardiomyopathy with ataxia (DCMA) syndrome / 3-methylglutaconic aciduria type 5.
| GO Term | Evidence | Action | Reason |
|---|---|---|---|
| GO:0001405 PAM complex, Tim23 associated import motor | IBA GO_REF:0000033 | ACCEPT | Summary: DNAJC19 is the J-protein component of the presequence translocase-associated import motor (PAM), the matrix-side motor of the TIM23 complex. Well supported for the human protein by co-immunoprecipitation with translocon components. Reason: The PAM complex is the defining functional context of DNAJC19; human DNAJC19 co-precipitates with Magmas, hTim44 and hTim23 as part of the human translocon, and the orthology-based IBA is corroborated by direct experimental evidence. Supporting Evidence: PMID:20053669 Pull down of Magmas along with other translocon components such as hTim44, hTim23, DnaJC19 provides direct evidence for the association of Magmas with the human translocon |
| GO:0001671 ATPase activator activity | IBA GO_REF:0000033 | ACCEPT | Summary: As a J-domain protein, DNAJC19 stimulates the ATPase activity of mitochondrial HSP70 (mortalin), the core molecular function that powers presequence import. Directly demonstrated for the human protein. Reason: Human DNAJC19 directly stimulates human Mortalin (mtHSP70) ATPase activity via its J-domain; this is the central molecular function of the gene and is experimentally supported, not merely inferred. Supporting Evidence: PMID:20053669 we have observed upto 70% reduction in ATPase stimulating activity of human Mortalin by Magmas:DnaJC19 complex PMID:19564938 J-domain containing proteins, DnaJs, usually enhance the ATPase activity of Hsp70 chaperones |
| GO:0030150 protein import into mitochondrial matrix | IBA GO_REF:0000033 | ACCEPT | Summary: DNAJC19 participates in ATP-dependent import of precursor proteins across the inner membrane into the matrix, as the J-protein driving the import motor. The core biological process for the gene. Reason: The motor activity of the PAM complex that DNAJC19 enables drives matrix protein import; this BP is the direct outcome of its ATPase-activator function and is supported by orthology and human experimental work. Supporting Evidence: PMID:19564938 The latter role is played by the membrane-bound J-domain-containing protein named Tim14/Pam18 |
| GO:0005743 mitochondrial inner membrane | IEA GO_REF:0000120 | ACCEPT | Summary: Electronic annotation of inner-membrane localization, consistent with the experimentally supported single-pass inner-membrane topology of DNAJC19. Reason: Correct compartment; agrees with UniProt subcellular location and the IDA inner-membrane annotation. Supporting Evidence: file:human/DNAJC19/DNAJC19-uniprot.txt SUBCELLULAR LOCATION: Mitochondrion inner membrane |
| GO:0098800 inner mitochondrial membrane protein complex | IEA GO_REF:0000107 | KEEP AS NON CORE | Summary: DNAJC19 is part of inner-membrane protein complexes (TIM23/PAM). This generic complex term is correct but less informative than the specific PAM/TIM23 complex annotations. Reason: Correct but generic; the specific PAM complex and TIM23 translocase complex annotations capture the same information more precisely. Supporting Evidence: file:human/DNAJC19/DNAJC19-uniprot.txt SUBCELLULAR LOCATION: Mitochondrion inner membrane |
| GO:0099617 matrix side of mitochondrial inner membrane | IEA GO_REF:0000107 | ACCEPT | Summary: The J-domain of DNAJC19 faces the matrix side of the inner membrane, consistent with its topology and its role stimulating matrix mtHSP70. Reason: Accurate sub-membrane localization matching the protein's topology, where the catalytic J-domain projects into the matrix to engage mtHSP70. Supporting Evidence: file:human/DNAJC19/DNAJC19-uniprot.txt Matrix side |
| GO:1900208 regulation of cardiolipin metabolic process | IEA GO_REF:0000107 | KEEP AS NON CORE | Summary: DNAJC19 has been implicated in cardiolipin remodeling through its association with the prohibitin complex (via PHB2). By-similarity/inferred; relevant to the DCMA disease phenotype but secondary to the import-motor function. Reason: The cardiolipin-remodeling role is supported only by similarity and the prohibitin interaction; it is disease-relevant but not the core, experimentally established molecular function of DNAJC19. Supporting Evidence: file:human/DNAJC19/DNAJC19-uniprot.txt forms a complex with prohibitins to regulate cardiolipin remodeling |
| GO:0005743 mitochondrial inner membrane | NAS PMID:10339406 Genetic and structural characterization of the human mitocho... | ACCEPT | Summary: Inner-membrane localization asserted from the structural/genetic characterization of the human inner-membrane translocase. Consistent with all other evidence. Reason: Correct localization, redundant with the IEA and IDA inner-membrane annotations for the same compartment. Supporting Evidence: file:human/DNAJC19/DNAJC19-uniprot.txt SUBCELLULAR LOCATION: Mitochondrion inner membrane |
| GO:0005744 TIM23 mitochondrial import inner membrane translocase complex | NAS PMID:10339406 Genetic and structural characterization of the human mitocho... | ACCEPT | Summary: DNAJC19 is part of the TIM23 inner-membrane presequence translocase, tethered via its subcomplex with PAM16/Magmas. Supported by human translocon co-immunoprecipitation. Reason: Human DNAJC19 co-precipitates with TIM23 translocon components (hTim23, hTim44, Magmas); membership in the TIM23 translocase complex is well established. Supporting Evidence: PMID:20053669 Pull down of Magmas along with other translocon components such as hTim44, hTim23, DnaJC19 provides direct evidence for the association of Magmas with the human translocon |
| GO:0006886 intracellular protein transport | NAS PMID:10339406 Genetic and structural characterization of the human mitocho... | KEEP AS NON CORE | Summary: Generic protein-transport process term. DNAJC19's specific role is import of precursors into the mitochondrial matrix, captured more precisely by GO:0030150. Reason: Correct but a high-level parent of the specific 'protein import into mitochondrial matrix' process; non-core because a more precise term applies. Supporting Evidence: PMID:19564938 The latter role is played by the membrane-bound J-domain-containing protein named Tim14/Pam18 |
| GO:0030150 protein import into mitochondrial matrix | NAS PMID:16055927 Mutation of DNAJC19, a human homologue of yeast inner mitoch... | ACCEPT | Summary: The same core import process as the IBA annotation, asserted in the DCMA disease report describing DNAJC19 as an inner-membrane import co-chaperone. Reason: Matrix protein import is the core biological process of DNAJC19, consistent across orthology, biochemistry and the disease description. Supporting Evidence: file:human/DNAJC19/DNAJC19-uniprot.txt required for the translocation of transit peptide-containing proteins from the inner membrane into the mitochondrial matrix |
| GO:0005739 mitochondrion | HTP PMID:34800366 Quantitative high-confidence human mitochondrial proteome an... | KEEP AS NON CORE | Summary: High-throughput proteomic detection of DNAJC19 in mitochondria. Correct but less specific than the inner-membrane annotations. Reason: Accurate but generic organelle localization; the inner-membrane / matrix-side annotations are more informative. Supporting Evidence: file:human/DNAJC19/DNAJC19-uniprot.txt SUBCELLULAR LOCATION: Mitochondrion inner membrane |
| GO:0098800 inner mitochondrial membrane protein complex | ISS GO_REF:0000024 | KEEP AS NON CORE | Summary: By-similarity assertion of inner-membrane complex membership, duplicating the IEA annotation of the same term. Correct but generic. Reason: Correct but generic complex term; more precise PAM/TIM23 complex annotations supersede it. Supporting Evidence: file:human/DNAJC19/DNAJC19-uniprot.txt SUBCELLULAR LOCATION: Mitochondrion inner membrane |
| GO:0099617 matrix side of mitochondrial inner membrane | ISS GO_REF:0000024 | ACCEPT | Summary: By-similarity assertion of matrix-side localization, duplicating the IEA annotation. Matches the protein's topology. Reason: Accurate sub-membrane localization consistent with the matrix-facing J-domain topology. Supporting Evidence: file:human/DNAJC19/DNAJC19-uniprot.txt Matrix side |
| GO:1900208 regulation of cardiolipin metabolic process | ISS GO_REF:0000024 | KEEP AS NON CORE | Summary: By-similarity cardiolipin-remodeling annotation, duplicating the IEA version. Implicated through the prohibitin complex; disease-relevant but secondary. Reason: Supported only by similarity and the prohibitin interaction; not the core experimentally established function. Supporting Evidence: file:human/DNAJC19/DNAJC19-uniprot.txt forms a complex with prohibitins to regulate cardiolipin remodeling |
| GO:0005515 protein binding | IPI PMID:19564938 The mitochondrial protein translocation motor: structural co... | KEEP AS NON CORE | Summary: IPI interaction with PAM16/Magmas (Q9Y3D7). DNAJC19 forms a heterodimeric J/J-like subcomplex with PAM16; the bare 'protein binding' term is uninformative, but the interaction is real and central to its regulation. Reason: Per curation guidelines bare protein binding is uninformative and not elevated to core, but the documented DNAJC19-PAM16 interaction (the regulatory module of the import motor) is genuine; the IPI partner Q9Y3D7 is TIMM16/PAM16/Magmas. Supporting Evidence: file:human/DNAJC19/DNAJC19-uniprot.txt Interacts with TIMM16/PAM16 |
| GO:0005515 protein binding | IPI PMID:20053669 Role of Magmas in protein transport and human mitochondria b... | KEEP AS NON CORE | Summary: IPI interaction with PAM16/Magmas (Q9Y3D7) demonstrated in human mitochondria by reciprocal co-immunoprecipitation. The bare term is uninformative but the interaction is genuine and functionally important. Reason: Bare protein binding is uninformative; the underlying DNAJC19-Magmas subcomplex interaction is real (it regulates DNAJC19's ATPase-stimulating activity) and is retained as non-core. Supporting Evidence: PMID:20053669 we have observed upto 70% reduction in ATPase stimulating activity of human Mortalin by Magmas:DnaJC19 complex |
| GO:0005743 mitochondrial inner membrane | IDA PMID:20053669 Role of Magmas in protein transport and human mitochondria b... | ACCEPT | Summary: Direct experimental evidence localizing DNAJC19 to the mitochondrial inner membrane as part of the human translocon. The strongest localization annotation. Reason: IDA-supported inner-membrane localization, fully consistent with the protein's single-pass inner-membrane topology and translocon membership. Supporting Evidence: file:human/DNAJC19/DNAJC19-uniprot.txt SUBCELLULAR LOCATION: Mitochondrion inner membrane |
| GO:0032991 protein-containing complex | IDA PMID:19564938 The mitochondrial protein translocation motor: structural co... | KEEP AS NON CORE | Summary: Generic complex-membership annotation reflecting the DNAJC19-PAM16 heterodimer. Correct but uninformative relative to the specific PAM/TIM23 complex terms. Reason: Accurate but generic; subsumed by the specific PAM complex and TIM23 translocase annotations. Supporting Evidence: PMID:19564938 heterodimeric complexes and that these complexes interact with yeast mtHsp |
| GO:0032991 protein-containing complex | IDA PMID:20053669 Role of Magmas in protein transport and human mitochondria b... | KEEP AS NON CORE | Summary: Generic complex-membership annotation from the human translocon co-IP. Correct but uninformative relative to the specific complex terms. Reason: Accurate but generic; the specific PAM/TIM23 complex annotations are more informative. Supporting Evidence: PMID:20053669 Pull down of Magmas along with other translocon components such as hTim44, hTim23, DnaJC19 provides direct evidence for the association of Magmas with the human translocon |
| GO:0005739 mitochondrion | IDA PMID:12592411 Characterization of the human heart mitochondrial proteome. | KEEP AS NON CORE | Summary: Direct detection of DNAJC19 in the human heart mitochondrial proteome. Correct but less specific than the inner-membrane annotations. Reason: Accurate but generic organelle localization; the inner-membrane / matrix-side annotations are more precise. Supporting Evidence: file:human/DNAJC19/DNAJC19-uniprot.txt SUBCELLULAR LOCATION: Mitochondrion inner membrane |
| GO:0016020 membrane | NAS PMID:16055927 Mutation of DNAJC19, a human homologue of yeast inner mitoch... | KEEP AS NON CORE | Summary: High-level membrane localization asserted in the DCMA disease report. Correct but very generic relative to the inner-membrane annotations. Reason: Correct but a generic parent term; superseded by the specific inner-membrane localization. Supporting Evidence: file:human/DNAJC19/DNAJC19-uniprot.txt SUBCELLULAR LOCATION: Mitochondrion inner membrane |
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Download this section (compressed HTML)Q: Does DNAJC19's prohibitin/cardiolipin-remodeling role represent a function separable from its import-motor activity, and which one underlies the DCMA cardiomyopathy?
Q: How does the DNAJC19-PAM16 (Magmas) heterodimer dynamically regulate mtHSP70 ATPase stimulation during active import versus resting states?
Experiment: Reconstitute the human import motor in vitro with purified DNAJC19, PAM16, mtHSP70 and GRPEL to measure DNAJC19-dependent ATPase stimulation and precursor translocation, including disease-variant proteins.
Experiment: Conditional DNAJC19 depletion in cardiomyocytes followed by mitochondrial import assays and cardiolipin profiling to dissect import-motor versus cardiolipin-remodeling contributions to the DCMA phenotype.
Experiment: Cryo-EM of the human TIM23-PAM holo-translocase to define how the DNAJC19 J-domain engages mtHSP70 at the matrix exit of the channel.
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