COQ8B (ADCK4) is a mitochondrial atypical kinase-like protein of the UbiB/ADCK family and the closest paralog of COQ8A (ADCK3); both are co-orthologs of yeast Coq8p and arose by duplication at the emergence of chordates. It is required for the biosynthesis of coenzyme Q10 (ubiquinone), an essential lipid-soluble electron carrier of the respiratory chain, and it supports the assembly and activity of the multi-subunit COQ metabolon (complex Q / CoQ synthome), interacting with COQ6, COQ7 and other COQ proteins. The protein adopts a protein kinase-like fold in which an N-terminal KxGQ motif occludes the canonical substrate-binding pocket; nucleotide (ATP) binding relieves this autoinhibition. Its best-supported catalytic activity is ATP hydrolysis: the COQ8 family lacks canonical protein kinase activity toward general substrates in trans, and reconstituted (ancestral tetrapod) COQ8B shows ATPase activity that is stimulated ten-fold by the COQ6:COQ3 pair. In the same reconstitution COQ8B increased and streamlined CoQ production in an ATP-dependent manner without stably co-eluting with the metabolon, and COQ3 (but not COQ6) was phosphorylated by COQ8B; whether this COQ3 phosphorylation is a physiological protein-kinase function is not yet established. COQ8B does not phosphorylate CoQ lipid intermediates. It localizes mainly to the mitochondrion, associated with the matrix face of the inner mitochondrial membrane, and is also detected in the cytosol and at the cell membrane. It is particularly important in kidney podocytes; loss-of-function mutations cause primary coenzyme Q10 deficiency presenting as steroid-resistant nephrotic syndrome with focal segmental glomerulosclerosis (nephrotic syndrome type 9, COQ10D9).
| GO Term | Evidence | Action | Reason |
|---|---|---|---|
| GO:0006744 ubiquinone biosynthetic process | IBA GO_REF:0000033 | ACCEPT | Summary: Phylogenetic (IBA) propagation of the core UbiB/Coq8-family role in ubiquinone biosynthesis. Correct and central to COQ8B function; corroborated by experimental IDA/IMP evidence in this gene. Supporting Evidence: file:human/COQ8B/COQ8B-uniprot.txt Atypical kinase involved in the biosynthesis of coenzyme Q, |
| GO:0005829 cytosol | IEA GO_REF:0000044 | KEEP AS NON CORE | Summary: Electronic Subcellular-Location mapping to cytosol. The UniProt record does list a cytosolic pool, so this is supported, but the core site of action is mitochondrial; keep as a non-core localization. Supporting Evidence: file:human/COQ8B/COQ8B-uniprot.txt Cytoplasm, cytosol |
| GO:0005886 plasma membrane | IEA GO_REF:0000044 | KEEP AS NON CORE | Summary: Electronic Subcellular-Location mapping to plasma/cell membrane. Consistent with the experimentally reported podocyte foot-process/cell-membrane pool, but non-core relative to the mitochondrial coenzyme Q role. Supporting Evidence: file:human/COQ8B/COQ8B-uniprot.txt Cell membrane |
| GO:0031966 mitochondrial membrane | IEA GO_REF:0000044 | ACCEPT | Summary: Electronic Subcellular-Location mapping to mitochondrial membrane; this is the core localization and is independently supported by experimental (EXP) evidence for this gene. Supporting Evidence: file:human/COQ8B/COQ8B-uniprot.txt Mitochondrion membrane |
| GO:0006744 ubiquinone biosynthetic process | IEA GO_REF:0000041 | ACCEPT | Summary: UniPathway-based electronic annotation to ubiquinone biosynthesis. Correct and core; redundant with the experimental IDA/IMP annotations. Supporting Evidence: file:human/COQ8B/COQ8B-uniprot.txt Cofactor biosynthesis; ubiquinone biosynthesis. |
| GO:0005739 mitochondrion | IDA GO_REF:0000052 | ACCEPT | Summary: Immunofluorescence (HPA) localization to mitochondrion. Consistent with the established mitochondrial localization of COQ8B; accept as a core location. Supporting Evidence: file:human/COQ8B/COQ8B-uniprot.txt Mitochondrion membrane |
| GO:0005886 plasma membrane | EXP PMID:24270420 ADCK4 mutations promote steroid-resistant nephrotic syndrome... | KEEP AS NON CORE | Summary: Experimental localization consistent with the podocyte foot-process/cell membrane pool reported by Ashraf et al. Real but non-core relative to the mitochondrial coenzyme Q role. Experimental annotation retained. Supporting Evidence: PMID:24270420 ADCK4 was expressed in glomerular podocytes and partially localized to podocyte mitochondria and foot processes |
| GO:0031966 mitochondrial membrane | EXP PMID:24270420 ADCK4 mutations promote steroid-resistant nephrotic syndrome... | ACCEPT | Summary: Experimental localization of ADCK4 to podocyte mitochondria. Supports the core mitochondrial (inner) membrane localization. Supporting Evidence: PMID:24270420 ADCK4 was expressed in glomerular podocytes and partially localized to podocyte mitochondria and foot processes |
| GO:0031966 mitochondrial membrane | EXP PMID:33988507 A subcellular map of the human kinome. | ACCEPT | Summary: Subcellular-kinome mapping assigning COQ8B to the mitochondrial membrane. Consistent with all other localization evidence; core location. Supporting Evidence: file:human/COQ8B/COQ8B-uniprot.txt Mitochondrion membrane |
| GO:0004672 protein kinase activity | IDA PMID:38425362 In vitro construction of the COQ metabolon unveils the molec... | KEEP AS NON CORE | Summary: In vitro reconstitution (with ancestral tetrapod COQ proteins) showed by intact-protein MS that COQ3, but not COQ6, is phosphorylated by COQ8B at multiple sites in the presence of ATP. The observation is real and the curator's IDA is retained, but it is a single in vitro finding with reconstructed proteins; the same family lacks canonical protein kinase activity in trans (NOT annotation, PMID:27499294), the physiological relevance of COQ3 phosphorylation is unproven, and the directly measured catalytic activity of COQ8B in the same study is ATP hydrolysis. Kept as non-core; ATP hydrolysis activity (GO:0016887) is used as the core molecular function, consistent with COQ8A. Supporting Evidence: PMID:38425362 COQ3, but not COQ6, is phosphorylated by COQ8B at multiple sites PMID:38425362 Unless otherwise stated, all the experimental work was performed using the tetrapod ancestral COQ proteins. |
| GO:0006744 ubiquinone biosynthetic process | IDA PMID:38425362 In vitro construction of the COQ metabolon unveils the molec... | ACCEPT | Summary: In vitro reconstitution of the COQ metabolon shows COQ8B increases and streamlines coenzyme Q production. Direct experimental support for the core ubiquinone biosynthetic process role. Supporting Evidence: PMID:38425362 We demonstrate that COQ8, a kinase, increases and streamlines coenzyme Q production |
| GO:0005739 mitochondrion | HTP PMID:34800366 Quantitative high-confidence human mitochondrial proteome an... | ACCEPT | Summary: High-throughput mitochondrial proteome dataset placing COQ8B in the mitochondrion. Consistent with the well-established mitochondrial localization; accept. Supporting Evidence: file:human/COQ8B/COQ8B-uniprot.txt Mitochondrion membrane |
| GO:0005739 mitochondrion | IDA PMID:33988507 A subcellular map of the human kinome. | ACCEPT | Summary: Direct localization to mitochondrion from the subcellular kinome map. Consistent with all other evidence; core location. Supporting Evidence: file:human/COQ8B/COQ8B-uniprot.txt Mitochondrion membrane |
| GO:0008289 lipid binding | ISS GO_REF:0000024 | KEEP AS NON CORE | Summary: Sequence-similarity inference of lipid binding. COQ8-family proteins do bind coenzyme Q lipid intermediates and associate with membrane lipids, so this is biologically plausible, but it is a supporting/inferred binding property rather than the core catalytic function. Keep as non-core. Supporting Evidence: PMID:27499294 COQ8 has ATPase activity and interacts with lipid CoQ intermediates |
| GO:0016887 ATP hydrolysis activity | ISS GO_REF:0000024 | ACCEPT | Summary: Sequence-similarity inference of ATPase (ATP hydrolysis) activity from the paralog COQ8A/yeast Coq8p, where ATPase activity (and the absence of canonical in-trans protein kinase activity) was demonstrated. ATPase activity has since been measured directly for COQ8B in the reconstituted COQ metabolon, where it is stimulated by the COQ6:COQ3 pair. This is the best-supported catalytic activity of COQ8B and is accepted as its core molecular function. Supporting Evidence: PMID:27499294 COQ8 has ATPase activity and interacts with lipid CoQ intermediates PMID:38425362 this pair stimulates ATPase activity of COQ8B by ten-fold |
| GO:0004672 protein kinase activity | IDA NOT PMID:27499294 Cerebellar Ataxia and Coenzyme Q Deficiency through Loss of ... | ACCEPT | Summary: NOT annotation: family-level biochemical assays (COQ8A/yeast Coq8p, applied to COQ8B by the naming/orthology framework of this paper) showed no canonical protein kinase activity in trans toward general substrates. This negation is correctly recorded and refers to general in-trans kinase behaviour; it does not contradict the later, specific ATP-dependent COQ3 phosphorylation by COQ8B (PMID:38425362). Retained as a NOT annotation. Supporting Evidence: PMID:27499294 we demonstrate that it lacks canonical protein kinase activity in trans |
| GO:0006468 protein phosphorylation | IDA NOT PMID:27499294 Cerebellar Ataxia and Coenzyme Q Deficiency through Loss of ... | ACCEPT | Summary: NOT annotation paralleling the NOT protein kinase activity: no general in-trans protein phosphorylation was detected for the COQ8 family in this study. Correctly recorded; the specific COQ3 phosphorylation by COQ8B (PMID:38425362) is a distinct, later finding on a defined substrate. Retained as a NOT annotation. Supporting Evidence: PMID:27499294 we demonstrate that it lacks canonical protein kinase activity in trans |
| GO:0006744 ubiquinone biosynthetic process | IMP PMID:27499294 Cerebellar Ataxia and Coenzyme Q Deficiency through Loss of ... | ACCEPT | Summary: Mutant-phenotype evidence that loss of COQ8 function disrupts the CoQ biosynthesis complex (complex Q) and coenzyme Q production. Supports the core ubiquinone biosynthetic process role. Experimental IMP retained. Supporting Evidence: PMID:27499294 Coq8p and COQ8A specifically maintain complex Q in yeast and mammals |
| GO:0021692 cerebellar Purkinje cell layer morphogenesis | IMP PMID:27499294 Cerebellar Ataxia and Coenzyme Q Deficiency through Loss of ... | MARK AS OVER ANNOTATED | Summary: The cerebellar Purkinje-cell phenotype in PMID:27499294 is that of the mouse Coq8a (COQ8A/ADCK3) knockout, not COQ8B; COQ8B loss-of-function disease is renal (steroid-resistant nephrotic syndrome / FSGS), not cerebellar. This IMP therefore appears to reflect the paralog rather than COQ8B and is an over-annotation. As an experimental annotation it is not removed, but it is flagged as over-annotated / likely paralog mis-attribution. Supporting Evidence: PMID:27499294 Coq8a−/− mice showed a specific defect in the cerebellar Purkinje cell (PC) layer |
| GO:0005524 ATP binding | IEA file:human/COQ8B/COQ8B-uniprot.txt | NEW | Summary: ATP binding is not among the GOA TSV rows but is strongly supported by the UniProt record: multiple annotated ATP BINDING sites and a nucleotide-gated mechanism in which nucleotide binding relieves KxGQ autoinhibition and opens the substrate-binding pocket. Core molecular function; proposed as a new annotation. Supporting Evidence: file:human/COQ8B/COQ8B-uniprot.txt Nucleotide-binding opens the substrate binding pocket |
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Download this section (compressed HTML)Q: Is the COQ3 phosphorylation observed with reconstituted ancestral COQ8B detectable for human COQ8B in mitochondria, and does it regulate COQ synthome assembly in vivo?
Q: Why does COQ8B loss cause predominantly renal (podocyte) disease whereas COQ8A loss causes cerebellar ataxia, given the shared ATPase mechanism?
Experiment: Measure ATPase activity of purified human COQ8B wild type and COQ10D9 patient variants in the presence of cardiolipin, CoQ intermediates and the COQ6:COQ3 pair, and test phospho-site mutants of COQ3 for effects on CoQ output in COQ8B-deficient podocytes.
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