Annotation inferences using phylogenetic trees
Gene Ontology annotation based on UniProtKB/Swiss-Prot Subcellular Location vocabulary mapping, accompanied by conservative changes to GO terms applied by UniProt
Mitochondrial Protein Interaction Mapping Identifies Regulators of Respiratory Chain Function.
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Affinity-enrichment mass spectrometry survey of 50 poorly characterised mitochondrial proteins, in which ADCK2 was one of the baits. ADCK2 is not discussed anywhere in the article text; the SLC25A5 interaction it supplies lives in the supplementary dataset, so the paper offers no interpretation of it.
"we assessed condition-specific protein-protein interactions for 50 select MXPs using affinity enrichment mass spectrometry"
ADCK2 Haploinsufficiency Reduces Mitochondrial Lipid Oxidation and Causes Myopathy Associated with CoQ Deficiency.
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Endogenous ADCK2 fractionates with mitochondrial markers in HEK293 cells and is absent from ER and cytosol.
"The presence of ADCK2 was not detected in the endoplasmic reticulum and cytosolic fraction."
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Protease protection places ADCK2 inside the organelle but does not discriminate matrix from inner membrane, so it supports mitochondrion and is compatible with membrane without licensing a mitochondrial inner membrane annotation.
"consistent with its presence in the mitochondrial matrix or bound to the inner mitochondrial membrane"
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The experiment that fixes the level of the biological-process term: total cellular synthesis of isoprenoid and cholesterol is unchanged in Adck2-deficient cells and only the mitochondrial fraction is depleted, so ADCK2 governs precursor delivery rather than catalysing a biosynthetic step.
"which indicated a defect in intracellular trafficking of isoprenoid and cholesterol from the cytoplasm"
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Heterologous complementation establishes functional orthology between human ADCK2 and yeast YPL109C (Cqd1) and shows the human protein is competent to restore CoQ synthesis.
"yeast strain with wild type YPL109c or human ADCK2 construct rescued CoQ6 biosynthesis"
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Deleting the yeast orthologue lowers CoQ, the phenotype the human allele complements.
"The deletion of YPL109c, the S. cerevisiae homolog of human ADCK2, caused a 40% decrease in the production of CoQ6"
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The human allele is a nonsense variant reducing transcript and protein, matching UniProt VARIANT 333..626 Missing; the assay behind the GO:0010795 row is therefore loss-of-function plus rescue rather than a direct assay of purified ADCK2.
"The mutation produced a termination codon that led to a significant decrease in ADCK2 mRNA and protein levels in dermal fibroblasts"
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Fatty acid oxidation is impaired in Adck2-deficient cells. This is a phenotype of the CoQ deficit, partially rescued by CoQ10, and is not by itself evidence of a molecular function in lipid metabolism.
"palmitate-dependent OCR decreased in permeabilized MEFs lacking Adck2 compared to WT cells"
A subcellular map of the human kinome.
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Kinome Atlas imaged epitope-tagged, ectopically expressed kinases rather than endogenous protein, so this row corroborates the mitochondrial localisation but is not load-bearing for it.
"456 epitope-tagged kinases, representing 85% of the human kinome, were expressed in HeLa cells and imaged by immunofluorescent microscopy"
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The authors state the overexpression caveat themselves.
"Although limited by possible mislocalization due to overexpression or epitope tagging"
Quantitative high-confidence human mitochondrial proteome and its dynamics in cellular context.
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MitoCoP is a curated high-confidence mitochondrial proteome, so inclusion is a filtered result rather than a raw detection; HTP is the appropriate evidence code.
"We classified >8,000 proteins in mitochondrial preparations of human cells and defined a mitochondrial high-confidence proteome of >1,100 proteins (MitoCoP)."
Mitochondrial ADCK3 employs an atypical protein kinase-like fold to enable coenzyme Q biosynthesis.
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Crystal structure of the family's archetype establishes that UbiB proteins carry features that suppress, rather than support, canonical protein kinase activity.
"we show that UbiB proteins adopt an atypical PKL fold with multiple UbiB-specific features positioned to inhibit protein kinase activity"
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An alanine of the UbiB A-rich loop actively suppresses phosphotransfer; the A339G substitution removes that suppression.
"Collectively, these results demonstrate that ADCK3 A339 inhibits protein kinase activity in vitro."
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Relevant to ADCK2 because ADCK2 naturally carries glycine at both A-rich-loop positions where COQ8A carries the suppressor alanines.
"The A339G and A337G,A339G double mutations both enabled autophosphorylation"
Cerebellar Ataxia and Coenzyme Q Deficiency through Loss of Unorthodox Kinase Activity.
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The family's two characterised members were shown not to carry canonical protein kinase activity. This is the curated basis for the NOT|enables GO:0004672 annotations that COQ8A and COQ8B both hold.
"Collectively, these results demonstrate that the enzymatic activities of mammalian COQ8A and yeast Coq8p are highly similar, and that neither catalyzes canonical protein kinase activity."
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The mechanism is steric occlusion by the KxGQ motif, which ADCK2 retains.
"Even with a nucleotide bound, the KxGQ motif is positioned to occlude the typical peptide substrate binding site and preclude in trans protein phosphorylation."
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The authors extend the inference to the whole family on the basis of the KxGQ motif, which is the specific reason this paper bears on ADCK2 rather than only on COQ8.
"we predict uPKL functionality to be conserved throughout this ancient protein family"
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Guard against over-reading the A-rich loop divergence in ADCK2: the activity that loop suppresses is cis autophosphorylation, and it is dispensable in vivo.
"showing that the autophosphorylation observed in vitro is dispensable for function in vivo"
In vitro construction of the COQ metabolon unveils the molecular determinants of coenzyme Q biosynthesis.
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A 2024 in vitro reconstitution reports that COQ8B does phosphorylate a protein substrate, partly contesting the earlier family-level negative. GOA now carries both a NOT|enables and an enables IDA for GO:0004672 on COQ8B as a result.
"COQ3, but not COQ6, is phosphorylated by COQ8B at multiple sites"
UbiB proteins regulate cellular CoQ distribution in Saccharomyces cerevisiae.
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Identifies ADCK2's yeast orthologue Cqd1 (YPL109C) and ADCK1's orthologue Cqd2 (YLR253W) as UbiB proteins with reciprocal effects on where CoQ ends up in the cell.
"we identify two highly conserved but poorly characterized mitochondrial proteins, Ypl109c (Cqd1) and Ylr253w (Cqd2), that reciprocally affect this process"
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The direction of the Cqd1 defect matches the human and mouse ADCK2 phenotype, in which only the mitochondrial CoQ pool is depleted.
"Loss of Cqd1 skews cellular CoQ distribution away from mitochondria"
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The orthology assignment used throughout this review is the authors' own, and it matches PANTHER's node structure exactly.
"it will be important to determine if functional conservation exists between Cqd1 and Cqd2 and their putative human orthologs, ADCK2 and ADCK1/5, respectively"
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Cqd1's dependence on catalytic residues is genetic, not biochemical - the protein has never been purified, so no direct activity measurement exists for this branch of the family.
"Unlike COQ8, Cqd1 is recalcitrant to recombinant protein purification"
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Rescue by Cqd1 requires the canonical phosphotransfer residues.
"depended on core protein kinase-like (PKL) family residues"
The UbiB family member Cqd1 forms a novel membrane contact site in mitochondria.
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Places ADCK2's yeast orthologue in the inner membrane at an inner-outer contact site, which is the sub-mitochondrial location human ADCK2's own data cannot yet resolve.
"we identified a novel mitochondrial contact site in Saccharomyces cerevisiae that is formed by the inner membrane protein Cqd1 and the outer membrane proteins Por1 and Om14"
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The authors expect the arrangement to be conserved to human.
"Cqd1 is highly conserved, suggesting that this complex is conserved in form and function from yeast to human"
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A second lipid-related role for the orthologue, beyond CoQ.
"Our data suggest that Cqd1 is additionally involved in phospholipid homeostasis."
Calorie Restriction Rescues Mitochondrial Dysfunction in Adck2-Deficient Skeletal Muscle.
Prenatal and progressive coenzyme Q(10) administration to mitigate muscle dysfunction in mitochondrial disease.
ADCK2 Knockdown Affects the Migration of Melanoma Cells via MYL6.
Identification of the mitochondrial protein ADCK2 as a therapeutic oncotarget of NSCLC.
Kinome-wide functional genomics screen reveals a novel mechanism of TNFalpha-induced nuclear accumulation of the HIF-1alpha transcription factor in cancer cells.
Affinage mechanistic annotation for ADCK2 (human)
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The record passed its own gates and cites five numeric PMIDs with no bioRxiv identifiers in PMID-shaped fields, but its central framing conflates CoQ biosynthesis with CoQ delivery. The isotope-labelling experiment in the paper it cites shows total cellular synthesis is unchanged and only the mitochondrial pool is depleted, so biosynthesis is not the step ADCK2 acts on.
"establishing CoQ biosynthesis as the core function from which the metabolic and developmental phenotypes derive"
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Its own summary concedes that no mechanism is available, which is consistent with this review asserting no molecular function.
"No structural model, direct kinase substrate, or biochemical mechanism linking ADCK2 to the CoQ pathway has been characterized in the available corpus."
ADCK2 bioinformatics: retention of UbiB / uPKL motifs relative to the characterised family members
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ADCK2 retains the UbiB-specific KxGQ motif that occludes the peptide-substrate groove in COQ8A, and also retains all four canonical catalytic positions, so it is neither a conventional protein kinase nor a pseudokinase by residue loss.
"ADCK2 has an intact phosphotransfer-competent active site inside a UbiB/uPKL architecture."