DNAJC15 (MCJ, "methylation-controlled J protein") is a small (150 aa) single-pass mitochondrial inner-membrane protein of the DnaJ/HSP40 subfamily C, anchored by a single transmembrane helix with its C-terminal J domain facing the matrix. It has two intertwined activities. As a J co-chaperone of the TIM23 presequence translocase import motor, it stimulates the ATPase activity of the matrix HSP70 chaperone mortalin (HSPA9) to drive presequence-protein import into the matrix; it forms a stable subcomplex with PAM16/MAGMAS, which counteracts this ATPase stimulation. Independently, MCJ associates with respiratory-chain complex I, impairs supercomplex assembly and acts as an endogenous negative regulator of the respiratory chain, restricting mitochondrial membrane potential and ATP production. DNAJC15 is highly expressed in heart, liver and kidney; its promoter is hypermethylated and silenced in many cancers, where loss of expression is associated with chemoresistance.
| GO Term | Evidence | Action | Reason |
|---|---|---|---|
| GO:0001405 PAM complex, Tim23 associated import motor | IBA GO_REF:0000033 | ACCEPT | Summary: Phylogenetic (IBA) annotation placing MCJ in the PAM (presequence translocase-associated motor) of the TIM23 complex. Experimentally supported by its interaction with PAM16/MAGMAS and the core TIM23 components and its J co-chaperone activity in import. Reason: MCJ forms a subcomplex with the import motor component MAGMAS and interacts with the core TIM23 translocase; it is a genuine PAM-associated J co-chaperone. Supporting Evidence: PMID:23263864 MCJ forms a stable subcomplex with a component of the mitochondrial import motor, MAGMAS |
| GO:0001671 ATPase activator activity | IBA GO_REF:0000033 | ACCEPT | Summary: MCJ stimulates the ATPase activity of the matrix HSP70 chaperone mortalin (HSPA9), the defining molecular function of a TIM23-motor J co-chaperone. Experimentally demonstrated for the recombinant soluble MCJ J domain. Reason: Directly supported experimentally; stimulating mortalin/HSPA9 ATPase activity is the core molecular function of MCJ as a J-domain co-chaperone. Supporting Evidence: PMID:23263864 the recombinant soluble MCJ domain stimulates the ATPase activity of the human mtHsp70 chaperone, mortalin |
| GO:0030150 protein import into mitochondrial matrix | IBA GO_REF:0000033 | ACCEPT | Summary: As a J co-chaperone of the TIM23 import motor, MCJ is required for efficient presequence-protein import into the mitochondrial matrix. Reason: Pre-protein import into mitochondria is impaired in the absence of MCJ; a core biological process for this gene. Supporting Evidence: PMID:23263864 pre-protein import into mitochondria is impaired in the absence of MCJ |
| GO:0005743 mitochondrial inner membrane | IEA GO_REF:0000120 | ACCEPT | Summary: Automated annotation of mitochondrial inner-membrane localization, consistent with the experimentally established single-pass inner-membrane topology of MCJ. Reason: MCJ is anchored in the mitochondrial inner membrane (single-pass), its core site of action; corroborated by direct experimental evidence. Supporting Evidence: PMID:23263864 It is anchored in the mitochondrial inner membrane with the C-terminal J domain facing the matrix space. |
| GO:0005515 protein binding | IPI PMID:23263864 Methylation-controlled J-protein MCJ acts in the import of p... | KEEP AS NON CORE | Summary: Curated interaction with PAM16/MAGMAS (Q9Y3D7), the import-motor partner that forms a stable subcomplex with MCJ and antagonizes its HSPA9 ATPase-stimulating activity. The bare protein binding term is uninformative, but the interaction is functionally central. Reason: Records a real, functionally important interaction (PAM16/MAGMAS), but GO:0005515 is uninformative; the functional consequence (J co-chaperone regulation) is captured by the ATPase activator activity and import annotations. Supporting Evidence: PMID:23263864 MCJ forms a stable subcomplex with a component of the mitochondrial import motor, MAGMAS |
| GO:0005515 protein binding | IPI PMID:25416956 A proteome-scale map of the human interactome network. | KEEP AS NON CORE | Summary: Yeast two-hybrid human interactome screen capturing MCJ interactions with Q8IUQ4 and Q8IZU0. The bare protein binding term is uninformative and these high-throughput partners are not characterized in the context of MCJ function. Reason: Uninformative GO:0005515 from a high-throughput Y2H screen with uncharacterized partners; not part of the established core function. Supporting Evidence: file:human/DNAJC15/DNAJC15-goa.tsv GO:0005515 protein binding molecular_function ECO:0000353 IPI PMID:25416956 UniProtKB:Q8IUQ4 |
| GO:0005515 protein binding | IPI PMID:33961781 Dual proteome-scale networks reveal cell-specific remodeling... | KEEP AS NON CORE | Summary: BioPlex affinity-purification interactome capturing the MCJ-PAM16/MAGMAS (Q9Y3D7) interaction. The bare protein binding term is uninformative. Reason: Records the real PAM16/MAGMAS interaction but GO:0005515 itself is uninformative; the functional meaning is captured elsewhere and it is not elevated to core. Supporting Evidence: file:human/DNAJC15/DNAJC15-goa.tsv GO:0005515 protein binding molecular_function ECO:0000353 IPI PMID:33961781 UniProtKB:Q9Y3D7 |
| GO:0005739 mitochondrion | IEA GO_REF:0000107 | KEEP AS NON CORE | Summary: Electronic (Ensembl orthology) annotation of mitochondrial localization, a generic parent of the specific inner-membrane localization. Reason: Correct but generic; the specific mitochondrial inner-membrane localization is the informative, core annotation. Supporting Evidence: PMID:23263864 Our results demonstrate that MCJ is located in mitochondria. |
| GO:0005743 mitochondrial inner membrane | NAS PMID:10339406 Genetic and structural characterization of the human mitocho... | ACCEPT | Summary: Non-traceable author statement (ComplexPortal) of inner-membrane localization, redundant with the experimentally established inner-membrane topology. Reason: Consistent with and corroborated by direct experimental evidence for inner-membrane anchoring; a core localization. Supporting Evidence: PMID:23263864 It is anchored in the mitochondrial inner membrane with the C-terminal J domain facing the matrix space. |
| GO:0005744 TIM23 mitochondrial import inner membrane translocase complex | NAS PMID:10339406 Genetic and structural characterization of the human mitocho... | ACCEPT | Summary: ComplexPortal annotation placing MCJ in the TIM23 translocase complex, supported by its interaction with the core TIM23 components and PAM16/MAGMAS. Reason: MCJ interacts with the core TIM23 pre-protein translocase and functions as its J co-chaperone; membership is well supported. Supporting Evidence: PMID:23263864 MCJ and MAGMAS interact with the core components of the TIM23 pre-protein translocase. |
| GO:0006886 intracellular protein transport | NAS PMID:10339406 Genetic and structural characterization of the human mitocho... | KEEP AS NON CORE | Summary: ComplexPortal annotation of intracellular protein transport, a generic parent of MCJ's specific role in mitochondrial matrix protein import. Reason: Correct but generic; the specific process (protein import into mitochondrial matrix) is the informative, core annotation. Supporting Evidence: PMID:23263864 pre-protein import into mitochondria is impaired in the absence of MCJ |
| GO:0005739 mitochondrion | HTP PMID:34800366 Quantitative high-confidence human mitochondrial proteome an... | KEEP AS NON CORE | Summary: High-throughput (FlyBase) annotation of mitochondrial localization, redundant with and consistent with the experimentally supported localization. Reason: Correct but generic mitochondrial localization; superseded by the specific inner-membrane annotation. Supporting Evidence: PMID:23263864 Our results demonstrate that MCJ is located in mitochondria. |
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Download this section (compressed HTML)Q: How is the balance between MCJ's two roles (TIM23 import co-chaperone versus complex I repressor) regulated, and do they occur in the same or distinct inner-membrane pools?
Q: Does MCJ promoter hypermethylation and silencing causally drive chemoresistance through altered mitochondrial metabolism, or through reduced protein import capacity?
Experiment: Structure-function analysis of the MCJ J domain (HPD-motif mutants) testing separately its mortalin/HSPA9 ATPase-stimulating import activity and its complex I/supercomplex regulatory activity, to determine whether the two functions are separable.
Experiment: Blue-native PAGE and respirometry in MCJ-knockout versus reconstituted cells to quantify supercomplex assembly, complex I activity and ATP output, paired with import assays for TIM23 substrates.
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