DNAJC30 (WBSCR18) is a mitochondrial inner-membrane DnaJ/HSP40 (J-domain) protein encoded in the 7q11.23 Williams-Beuren syndrome critical region. Imported via an N-terminal transit peptide and anchored by a single transmembrane helix, it has two intertwined roles in oxidative phosphorylation. It is an auxiliary component of the ATP synthase machinery, interacting directly with MT-ATP6 and ATP5MC2 and facilitating ATP synthesis. It also acts as a chaperone in a mitochondrial complex I (NADH:ubiquinone oxidoreductase) repair mechanism, promoting the efficient exchange/turnover of N-module subunits damaged by reactive oxygen species and thereby maintaining complex I efficiency. DNAJC30 is highly expressed in brain (pyramidal neurons). Biallelic loss-of-function variants cause autosomal-recessive Leber hereditary optic neuropathy (LHONAR1), and hemizygous loss contributes to the mitochondrial dysfunction underlying neurodevelopmental features of Williams-Beuren syndrome.
| GO Term | Evidence | Action | Reason |
|---|---|---|---|
| GO:0005743 mitochondrial inner membrane | IEA GO_REF:0000044 | ACCEPT | Summary: Electronic (UniProt SubCell) localization to the mitochondrial inner membrane, corroborated by direct experimental evidence (PMID:30318146). Reason: Correct and well-supported core localization; DNAJC30 is an inner-membrane single-pass protein. Supporting Evidence: file:human/DNAJC30/DNAJC30-uniprot.txt SUBCELLULAR LOCATION: Mitochondrion inner membrane |
| GO:0005515 protein binding | IPI PMID:32296183 A reference map of the human binary protein interactome. | KEEP AS NON CORE | Summary: A large set of binary HuRI yeast two-hybrid interactions, predominantly with membrane proteins (AQP6, BEST2, EBP, MGST2, MRM1 and others) unrelated to DNAJC30's OXPHOS function. Bare protein binding is uninformative. Reason: High-throughput binary interactions, many likely membrane-protein Y2H artifacts; bare protein binding is not elevated to core and the partners do not inform the ATP-synthase/complex-I function. Supporting Evidence: file:human/DNAJC30/DNAJC30-uniprot.txt Q96LL9; Q13520: AQP6; NbExp=3; IntAct=EBI-8639143, EBI-13059134 |
| GO:0007420 brain development | IEA GO_REF:0000107 | KEEP AS NON CORE | Summary: DNAJC30 is highly expressed in brain and its loss in mice diminishes neocortical pyramidal-neuron morphology and produces Williams-syndrome-like phenotypes, via mitochondrial dysfunction. This is a downstream, organ-level consequence of its mitochondrial molecular role. Reason: Brain development is a pleiotropic downstream outcome of DNAJC30's mitochondrial OXPHOS function rather than its direct molecular activity; retained as non-core. Supporting Evidence: PMID:30318146 a novel role for mitochondria in normal human brain development and WS |
| GO:1905706 regulation of mitochondrial ATP synthesis coupled proton transport | IEA GO_REF:0000107 | ACCEPT | Summary: DNAJC30 associates with the ATP synthase complex and facilitates ATP synthesis; loss decreases the integrity of OXPHOS supercomplexes and ATP-synthase dimers. This supports a role in regulating mitochondrial ATP synthesis. Reason: Supported by direct ATP-synthase interaction (MT-ATP6, ATP5MC2) and the functional role as an auxiliary component of ATP-synthase machinery. Supporting Evidence: PMID:30318146 DNAJC30 is highly enriched in neurons and is a novel auxiliary protein of the mitochondrial ATP synthase complex |
| GO:0005739 mitochondrion | HTP PMID:34800366 Quantitative high-confidence human mitochondrial proteome an... | ACCEPT | Summary: High-throughput proteomic localization to mitochondrion, consistent with and less specific than the experimentally established inner-membrane localization. Reason: Correct compartment, though broader than the inner-membrane annotation. Supporting Evidence: file:human/DNAJC30/DNAJC30-uniprot.txt SUBCELLULAR LOCATION: Mitochondrion inner membrane |
| GO:0005515 protein binding | IPI PMID:30318146 The 7q11.23 protein DNAJC30 interacts with ATP synthase and ... | MODIFY | Summary: Direct interaction with the ATP synthase subunits MT-ATP6 (P00846) and ATP5MC2 (Q06055), establishing DNAJC30 as an auxiliary component of ATP synthase. The bare protein binding term understates this; the biologically meaningful function is binding to the ATP synthase complex. Reason: Bare protein binding is uninformative; the documented partners are ATP synthase subunits, so enzyme binding better captures the molecular interaction with the ATP synthase complex. Proposed replacements: enzyme binding Supporting Evidence: file:human/DNAJC30/DNAJC30-uniprot.txt Interacts with MT-ATP6; interaction is direct (PubMed:30318146). |
| GO:0005743 mitochondrial inner membrane | IDA PMID:30318146 The 7q11.23 protein DNAJC30 interacts with ATP synthase and ... | ACCEPT | Summary: Direct experimental demonstration of DNAJC30 at the mitochondrial inner membrane. Reason: Strongest-evidence localization; this is the core compartment of DNAJC30. Supporting Evidence: file:human/DNAJC30/DNAJC30-uniprot.txt Mitochondrion inner membrane |
| GO:0007420 brain development | ISS GO_REF:0000024 | KEEP AS NON CORE | Summary: Sequence/orthology-based brain-development annotation (from mouse P59041), same downstream-phenotype caveat as the IEA brain-development term. Reason: Downstream pleiotropic consequence of mitochondrial function rather than DNAJC30's direct molecular activity. Supporting Evidence: PMID:30318146 a novel role for mitochondria in normal human brain development and WS |
| GO:1905706 regulation of mitochondrial ATP synthesis coupled proton transport | ISS GO_REF:0000024 | ACCEPT | Summary: Orthology-based annotation (from mouse P59041) for regulation of mitochondrial ATP synthesis, consistent with the experimental ATP-synthase association. Reason: Supported by the direct ATP-synthase interaction and the role as an auxiliary ATP-synthase component. Supporting Evidence: file:human/DNAJC30/DNAJC30-uniprot.txt Associates with the ATP synthase complex (PubMed:30318146). |
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Download this section (compressed HTML)Q: Does DNAJC30 act mechanistically as a canonical J-domain co-chaperone (stimulating a mitochondrial HSP70 such as mortalin/HSPA9) during complex I subunit exchange, or by a non-canonical holdase/extraction mechanism?
Q: Are the ATP-synthase auxiliary role and the complex I repair role mediated by the same activity, and which is primarily disrupted by the LHONAR1 variants?
Experiment: Reconstitute complex I subunit exchange in vitro or in DNAJC30-knockout cells with wild-type vs LHONAR1 variants to quantify turnover of specific N-module subunits and complex I activity.
Experiment: Test DNAJC30 J-domain function (HPD-motif mutagenesis, mitochondrial HSP70 ATPase-stimulation assay) to determine whether it is a bona fide co-chaperone.
Experiment: Cross-linking/structural analysis of DNAJC30 within the ATP synthase complex to define how it contributes to ATP-synthase dimer and supercomplex integrity.
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