UQCRC2 (Cytochrome b-c1 complex subunit 2, mitochondrial; core protein II; QCR2; ubiquinol-cytochrome-c reductase complex core protein 2) is one of the two large "core" subunits (with UQCRC1/core protein 1) of mitochondrial respiratory Complex III, the cytochrome bc1 / ubiquinol-cytochrome c reductase of the electron transport chain. Complex III is an eleven-subunit, obligate-dimeric enzyme of the inner mitochondrial membrane that transfers electrons from ubiquinol to cytochrome c and couples this redox chemistry to proton translocation across the inner membrane via the protonmotive Q cycle; the catalytic redox centres reside in cytochrome b, the Rieske iron-sulfur protein UQCRFS1, and cytochrome c1, not in the core proteins. UQCRC2 is a non-catalytic structural subunit required for assembly and stability of the complex; it is a peripheral inner-membrane protein exposed to the matrix side. The two core proteins are homologous to the alpha/beta subunits of the mitochondrial-processing peptidase and retain the peptidase M16 fold, but human UQCRC2 lacks the catalytic zinc-binding motif and any peptidase activity is unproven (it has been proposed only as a possible participant in in situ processing of the UQCRFS1 Rieske precursor). Complex III assembles with Complexes I and IV into supercomplexes/respirasomes. Biallelic UQCRC2 loss-of- function variants cause mitochondrial complex III deficiency, nuclear type 5 (MC3DN5), a metabolic/neurological disorder with neonatal-onset recurrent metabolic decompensation, encephalopathy, lactic acidosis, and hepato-renal involvement.
| GO Term | Evidence | Action | Reason |
|---|---|---|---|
| GO:0005739 mitochondrion | IBA GO_REF:0000033 | ACCEPT | Summary: Phylogenetic (PAN-GO/GO_Central) inference that UQCRC2 acts in the mitochondrion. Correct but general; the informative locations are the inner membrane and respiratory chain complex III. Reason: UQCRC2 is an established mitochondrial protein, a subunit of inner-membrane Complex III. The term is accurate though non-specific; retained as a correct high-level localization. Supporting Evidence: file:human/UQCRC2/UQCRC2-uniprot.txt Mitochondrion inner membrane |
| GO:0045275 respiratory chain complex III | IBA GO_REF:0000033 | ACCEPT | Summary: Phylogenetic inference that UQCRC2 is part of respiratory chain complex III. This is a core, correct annotation: UQCRC2 (core protein 2) is one of the eleven subunits of the cytochrome bc1 complex. Reason: Well supported across orthologs and by structure; UQCRC2 is a constitutive structural subunit of Complex III. This is one of the two most informative annotations for the gene. Supporting Evidence: file:human/UQCRC2/UQCRC2-uniprot.txt Component of the ubiquinol-cytochrome c oxidoreductase (cytochrome b-c1 complex, complex III, CIII), a multisubunit enzyme composed of 11 subunits |
| GO:0004222 metalloendopeptidase activity | IEA GO_REF:0000002 | MARK AS OVER ANNOTATED | Summary: InterPro (peptidase M16 family, IPR001431) electronically maps metalloendopeptidase activity. UQCRC2 retains the M16/MPP-like fold but is a non-catalytic core subunit: it lacks the canonical M16 inverted zinc-binding motif (HXXEH), and no peptidase activity has been demonstrated for human UQCRC2. UniProt only hedges that the core proteins "seem to have preserved" MPP properties (By similarity) and that UQCRC2 "May be involved" in UQCRFS1 processing (Probable). Reason: Fold-based electronic over-annotation. A sequence scan finds no HXXEH catalytic motif in mature UQCRC2, and Reactome lists UQCRC1/UQCRC2 only as possible (not demonstrated) candidates for the UQCRFS1-processing peptidase. PAN-GO/GO_Central assigns no catalytic MF. The activity is not part of the verified core function (structural subunit of Complex III), so it should not be treated as a real molecular function. Supporting Evidence: file:human/UQCRC2/UQCRC2-uniprot.txt Belongs to the peptidase M16 family. UQCRC2/QCR2 subfamily. file:human/UQCRC2/UQCRC2-uniprot.txt May be involved in the in situ processing of UQCRFS1 into the mature Rieske protein and its mitochondrial targeting sequence (MTS)/subunit 9 when incorporated into complex III |
| GO:0005739 mitochondrion | IEA GO_REF:0000117 | ACCEPT | Summary: ARBA machine-learning electronic annotation to mitochondrion. Consistent with the well-established mitochondrial localization of UQCRC2. Reason: Correct, though general; the more specific inner-membrane / Complex III terms are the informative ones. Supporting Evidence: file:human/UQCRC2/UQCRC2-uniprot.txt Mitochondrion inner membrane |
| GO:0005743 mitochondrial inner membrane | IEA GO_REF:0000120 | ACCEPT | Summary: Combined-IEA electronic annotation (with mouse ortholog Q9DB77 and UniProt-SubCell) to mitochondrial inner membrane. Matches the curated subcellular location of UQCRC2 as a peripheral inner-membrane subunit of Complex III on the matrix side. Reason: Accurate and specific; this is a core, informative localization for UQCRC2. Supporting Evidence: file:human/UQCRC2/UQCRC2-uniprot.txt Mitochondrion inner membrane |
| GO:0006508 proteolysis | IEA GO_REF:0000002 | MARK AS OVER ANNOTATED | Summary: InterPro (peptidase M16) electronic mapping to proteolysis. This is the biological-process counterpart of the metalloendopeptidase MF IEA and rests on the same unproven premise that UQCRC2 is catalytically active. Reason: Human UQCRC2 is a non-catalytic core subunit that has lost the M16 catalytic zinc-binding motif; no proteolytic activity is demonstrated. Any involvement in UQCRFS1 maturation is speculative (only "Probable" in UniProt; Reactome lists UQCRC1/UQCRC2 only as possible candidates). This is a fold-derived over-annotation, not the gene's core process. Supporting Evidence: file:human/UQCRC2/UQCRC2-uniprot.txt May be involved in the in situ processing of UQCRFS1 into the mature Rieske protein and its mitochondrial targeting sequence (MTS)/subunit 9 when incorporated into complex III |
| GO:0046872 metal ion binding | IEA GO_REF:0000002 | MARK AS OVER ANNOTATED | Summary: InterPro (IPR011249, Metalloenzyme LuxS/M16) electronic mapping to metal ion binding, reflecting the predicted zinc-binding of the M16 peptidase fold. As with the peptidase MF, the catalytic/metal-binding site is degenerate in human UQCRC2. Reason: The metal-binding annotation is a by-product of the M16 fold prediction; the catalytic zinc-binding motif (HXXEH) is absent and no metal cofactor has been shown for UQCRC2. Not a verified molecular function. Supporting Evidence: file:human/UQCRC2/UQCRC2-uniprot.txt Belongs to the peptidase M16 family. UQCRC2/QCR2 subfamily. |
| GO:0005515 protein binding | IPI PMID:21078624 Comparison of an expanded ataxia interactome with patient me... | MARK AS OVER ANNOTATED | Summary: IntAct IPI from an expanded ataxia-interactome study, recording a binary interaction (with CACNA1A, O00555). The GO term protein binding is uninformative and this is a high-throughput interactome hit unrelated to the established Complex III function of UQCRC2. Reason: Bare protein binding conveys no specific molecular function; per curation guidelines it should not be treated as a core function. The interaction is from a large-scale interactome screen and is not shown to be physiologically relevant to UQCRC2's role as a Complex III subunit. Supporting Evidence: PMID:21078624 Comparison of an expanded ataxia interactome with patient medical records reveals a relationship between macular degeneration and ataxia. |
| GO:0005515 protein binding | IPI PMID:32814053 Interactome Mapping Provides a Network of Neurodegenerative ... | MARK AS OVER ANNOTATED | Summary: IntAct IPI from a neurodegenerative-disease interactome map (Y2H/network), recording binary interactions (e.g. SNW1, DLG-family). Uninformative protein-binding term from a large-scale screen. Reason: Bare protein binding is uninformative and these are high-throughput interactome interactions of unclear relevance to UQCRC2's Complex III function. Kept (not removed) as a valid but non-core interaction record. Supporting Evidence: PMID:32814053 Interactome Mapping Provides a Network of Neurodegenerative Disease Proteins and Uncovers Widespread Protein Aggregation in Affected Brains. |
| GO:0005515 protein binding | IPI PMID:36115835 Quantitative fragmentomics allow affinity mapping of interac... | MARK AS OVER ANNOTATED | Summary: IntAct IPI from a fragmentomics affinity-mapping study; the partners are predominantly PDZ-domain proteins (DLG1-4, MAGI1/2, SCRIB, PATJ, GRIP1/2, etc.), consistent with an affinity screen of PDZ-binding motifs rather than an in vivo mitochondrial interaction. Reason: Bare protein binding is uninformative; this cluster of PDZ-domain interactors reflects the assay design and is not evidence for a Complex III related molecular function. Retained as a non-core interaction record. Supporting Evidence: PMID:36115835 Quantitative fragmentomics allow affinity mapping of interactomes. |
| GO:0045275 respiratory chain complex III | IEA GO_REF:0000120 | ACCEPT | Summary: Combined-IEA electronic annotation (with mouse ortholog) placing UQCRC2 in respiratory chain complex III. Duplicates the IBA/IDA CIII annotations and is correct. Reason: UQCRC2 is a constitutive structural subunit of Complex III; this is a core, correct annotation. Supporting Evidence: file:human/UQCRC2/UQCRC2-uniprot.txt Component of the ubiquinol-cytochrome c oxidoreductase (cytochrome b-c1 complex, complex III, CIII), a multisubunit enzyme composed of 11 subunits |
| GO:0005739 mitochondrion | IDA GO_REF:0000052 | ACCEPT | Summary: Human Protein Atlas immunofluorescence (IDA) localizing UQCRC2 to the mitochondrion. Consistent with all other evidence. Reason: Direct localization evidence; correct though general relative to the inner-membrane/CIII terms. Supporting Evidence: file:human/UQCRC2/UQCRC2-uniprot.txt Mitochondrion inner membrane |
| GO:0005743 mitochondrial inner membrane | ISS GO_REF:0000024 | ACCEPT | Summary: ISS transfer from the yeast ortholog QCR2 (P07257) assigning mitochondrial inner membrane. Matches the curated location of human UQCRC2. Reason: Accurate, specific, core localization; consistent with experimental and electronic evidence. Supporting Evidence: file:human/UQCRC2/UQCRC2-uniprot.txt Mitochondrion inner membrane |
| GO:0005743 mitochondrial inner membrane | IDA PMID:28844695 Architecture of Human Mitochondrial Respiratory Megacomplex ... | ACCEPT | Summary: ComplexPortal IDA based on the cryo-EM structure of the human respiratory megacomplex I2III2IV2, in which UQCRC2 is resolved as an inner-membrane Complex III subunit. Reason: Direct structural evidence for inner-membrane localization within Complex III; a core, well-supported CC annotation. Supporting Evidence: PMID:28844695 Architecture of Human Mitochondrial Respiratory Megacomplex I(2)III(2)IV(2). file:human/UQCRC2/UQCRC2-uniprot.txt Mitochondrion inner membrane |
| GO:0006122 mitochondrial electron transport, ubiquinol to cytochrome c | NAS PMID:28844695 Architecture of Human Mitochondrial Respiratory Megacomplex ... | ACCEPT | Summary: ComplexPortal NAS annotation of UQCRC2 to the core Complex III process: mitochondrial electron transport from ubiquinol to cytochrome c. As a required structural subunit of CIII, UQCRC2 is a bona fide participant in this process. Reason: This is the central biological process performed by Complex III, of which UQCRC2 is an obligate subunit. Although UQCRC2 itself is non-catalytic, the inner-membrane electron-transfer / proton-pumping activity requires the assembled complex including the core proteins. This is the most specific and informative BP for the gene. Supporting Evidence: file:human/UQCRC2/UQCRC2-uniprot.txt The cytochrome b-c1 complex catalyzes electron transfer from ubiquinol to cytochrome c, linking this redox reaction to translocation of protons across the mitochondrial inner membrane |
| GO:0045275 respiratory chain complex III | IPI PMID:28844695 Architecture of Human Mitochondrial Respiratory Megacomplex ... | ACCEPT | Summary: ComplexPortal IPI placing UQCRC2 in respiratory chain complex III, based on the cryo-EM megacomplex structure. Core, correct complex-membership annotation. Reason: Structural evidence that UQCRC2 is a subunit of Complex III; one of the two most informative annotations for this gene. Supporting Evidence: PMID:28844695 Architecture of Human Mitochondrial Respiratory Megacomplex I(2)III(2)IV(2). file:human/UQCRC2/UQCRC2-uniprot.txt Component of the ubiquinol-cytochrome c oxidoreductase (cytochrome b-c1 complex, complex III, CIII), a multisubunit enzyme composed of 11 subunits |
| GO:0045333 cellular respiration | NAS PMID:28844695 Architecture of Human Mitochondrial Respiratory Megacomplex ... | ACCEPT | Summary: ComplexPortal NAS annotation to cellular respiration, the broad process encompassing Complex III electron transport. Accurate but more general than GO:0006122. Reason: Correct high-level process for a Complex III subunit; retained as accurate but kept non-core relative to the specific ubiquinol-to-cytochrome-c term. Supporting Evidence: file:human/UQCRC2/UQCRC2-uniprot.txt part of the mitochondrial electron transport chain which drives oxidative phosphorylation |
| GO:0005739 mitochondrion | HTP PMID:34800366 Quantitative high-confidence human mitochondrial proteome an... | ACCEPT | Summary: High-throughput annotation to mitochondrion from a quantitative high-confidence human mitochondrial proteome study. Confirms mitochondrial localization. Reason: Supported by high-confidence mitochondrial proteomics; correct though general. Supporting Evidence: PMID:34800366 Quantitative high-confidence human mitochondrial proteome and its dynamics in cellular context. |
| GO:0045275 respiratory chain complex III | IDA PMID:23168492 LYRM7/MZM1L is a UQCRFS1 chaperone involved in the last step... | ACCEPT | Summary: IDA (UniProt) of Complex III membership from a study of CIII assembly (LYRM7/MZM1L as UQCRFS1 chaperone), in which UQCRC2 features as a structural subunit of the mature/assembling complex. Reason: Consistent with all evidence that UQCRC2 is part of Complex III; core, correct annotation. Cached record is abstract-only and the paper is by the CIII-assembly group; defer to the experimental curator. Supporting Evidence: PMID:23168492 LYRM7/MZM1L is a UQCRFS1 chaperone involved in the last steps of mitochondrial Complex III assembly in human cells. |
| GO:0045275 respiratory chain complex III | IDA PMID:31536960 Rewiring of the Human Mitochondrial Interactome during Neuro... | ACCEPT | Summary: IDA (UniProt) of Complex III membership from a mitochondrial-interactome / co-fractionation study of neuronal reprogramming, which also reports the UQCRC2-RAB5IF interaction. UQCRC2 co-fractionates as a Complex III subunit. Reason: Core, correct complex-membership annotation; consistent with structural and phylogenetic evidence. Supporting Evidence: file:human/UQCRC2/UQCRC2-uniprot.txt Interacts with RAB5IF |
| GO:0005515 protein binding | IPI PMID:35101990 The cardiac-enriched microprotein mitolamban regulates mitoc... | MARK AS OVER ANNOTATED | Summary: IPI (UniProt) recording interaction with mitolamban/STMP1 (P0DP99). The mitolamban paper shows this cardiac inner-membrane microprotein co-immunoprecipitates and co-migrates with Complex III subunits (UQCRC1, UQCRC2, UQCR10) and regulates CIII assembly/activity. Biologically plausible and CIII-relevant, but the GO term protein binding is uninformative. Reason: Although this interaction is more physiologically relevant than the generic interactome hits (mitolamban is a CIII-assembly regulator), the bare protein binding term does not describe a specific molecular function and is not itself a core function of UQCRC2. Kept as a non-core interaction record rather than removed. Supporting Evidence: PMID:35101990 The four most-enriched proteins in the Mtlbn IP sample were all components of complex III of the mitochondrial respiratory chain (UQCRC1, UQCRC2, UQCR10, and UQCRFS1P1) PMID:35101990 UQCRC1, UQCRC2, and UQCR10 was confirmed |
| GO:0005515 protein binding | IPI PMID:31536960 Rewiring of the Human Mitochondrial Interactome during Neuro... | MARK AS OVER ANNOTATED | Summary: IPI (UniProt) recording the UQCRC2-RAB5IF (Q9BUV8) interaction from the mitochondrial-interactome study. UniProt curates this as a documented interaction of UQCRC2, but the GO term protein binding is uninformative. Reason: Bare protein binding conveys no specific function. The RAB5IF interaction is a curated binary interaction but does not by itself define a molecular function; retained as a non-core interaction record. Supporting Evidence: file:human/UQCRC2/UQCRC2-uniprot.txt Interacts with RAB5IF |
| GO:0005739 mitochondrion | HDA PMID:20833797 Phosphoproteome analysis of functional mitochondria isolated... | ACCEPT | Summary: High-throughput direct-assay (HDA) mitochondrion localization from a phosphoproteome study of functional mitochondria isolated from human muscle, in which UQCRC2 was identified among inner-membrane respiratory complex subunits. Reason: Supported by mitochondrial proteomics; correct though general. Supporting Evidence: PMID:20833797 phosphorylation of inner membrane protein complexes |
| GO:0005743 mitochondrial inner membrane | TAS Reactome:R-HSA-164651 | ACCEPT | Summary: Reactome TAS for inner-membrane localization, tied to the reaction for electron transfer from ubiquinol to cytochrome c of complex III (the Q cycle). Consistent with UQCRC2 as an inner-membrane CIII subunit. Reason: Authoritative traceable statement; core, correct localization. Supporting Evidence: file:human/UQCRC2/UQCRC2-uniprot.txt Mitochondrion inner membrane |
| GO:0005743 mitochondrial inner membrane | TAS Reactome:R-HSA-9837978 | ACCEPT | Summary: Reactome TAS (inner membrane) associated with a reaction in which LONP1 binds mitochondrial inner membrane proteins; a protein-quality-control reaction in which UQCRC2, as an inner-membrane protein, is a participant. The localization term itself is correct. Reason: Correct inner-membrane localization; consistent with all other evidence. Supporting Evidence: file:human/UQCRC2/UQCRC2-uniprot.txt Mitochondrion inner membrane |
| GO:0005743 mitochondrial inner membrane | TAS Reactome:R-HSA-9838004 | ACCEPT | Summary: Reactome TAS (inner membrane) associated with a reaction in which LONP1 degrades mitochondrial inner membrane proteins. The inner-membrane localization is correct. Reason: Correct localization; retained. Supporting Evidence: file:human/UQCRC2/UQCRC2-uniprot.txt Mitochondrion inner membrane |
| GO:0005743 mitochondrial inner membrane | TAS Reactome:R-HSA-9906017 | ACCEPT | Summary: Reactome TAS (inner membrane) associated with a CIII-maturation reaction in which an unknown peptidase cleaves the UQCRFS1 subunit and UQCRC1/UQCRC2 are noted only as possible candidate peptidases. The localization term is correct. Reason: Inner-membrane localization is correct. (The associated speculative peptidase role is addressed under the InterPro metalloendopeptidase/proteolysis IEAs, which are marked as over-annotations.) Supporting Evidence: file:human/UQCRC2/UQCRC2-uniprot.txt Mitochondrion inner membrane |
| GO:0005743 mitochondrial inner membrane | TAS Reactome:R-HSA-9906042 | ACCEPT | Summary: Reactome TAS (inner membrane) associated with a reaction in which TTC19 clears UQCRFS1 fragments from Complex III. Correct inner-membrane localization for UQCRC2. Reason: Correct localization; retained. Supporting Evidence: file:human/UQCRC2/UQCRC2-uniprot.txt Mitochondrion inner membrane |
| GO:0005743 mitochondrial inner membrane | TAS PMID:8288258 Assignment of the gene for the core protein II (UQCRC2) subu... | ACCEPT | Summary: TAS (ProtInc/PINC) inner-membrane localization from the paper assigning the UQCRC2 gene (core protein II of the cytochrome bc1 complex) to human chromosome 16p12. Correct localization for a CIII inner-membrane subunit. Reason: Correct, core localization consistent with all other evidence. Supporting Evidence: PMID:8288258 Assignment of the gene for the core protein II (UQCRC2) subunit of the mitochondrial cytochrome bc1 complex to human chromosome 16p12. |
| GO:0006119 oxidative phosphorylation | TAS PMID:8288258 Assignment of the gene for the core protein II (UQCRC2) subu... | ACCEPT | Summary: TAS annotation to oxidative phosphorylation. Complex III is an integral part of the OXPHOS electron transport chain, so a CIII subunit is legitimately involved in oxidative phosphorylation. More general than the specific ubiquinol-to-cytochrome-c term. Reason: Accurate high-level process for a Complex III subunit; retained as correct but non-core relative to GO:0006122. Supporting Evidence: file:human/UQCRC2/UQCRC2-uniprot.txt part of the mitochondrial electron transport chain which drives oxidative phosphorylation |
| GO:0009060 aerobic respiration | TAS PMID:8288258 Assignment of the gene for the core protein II (UQCRC2) subu... | ACCEPT | Summary: TAS annotation to aerobic respiration. As a subunit of Complex III of the aerobic electron transport chain (which passes electrons ultimately to molecular oxygen via CIV), UQCRC2 participates in aerobic respiration. Accurate but general. Reason: Correct high-level respiratory process for a CIII subunit; retained as accurate but non-core relative to the specific electron-transport term. Supporting Evidence: file:human/UQCRC2/UQCRC2-uniprot.txt cooperate to transfer electrons derived from NADH and succinate to molecular oxygen |
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Download this section (compressed HTML)Q: Does human UQCRC2 retain any residual peptidase activity toward the UQCRFS1 Rieske precursor during Complex III assembly, or is UQCRFS1 processing entirely dependent on other peptidases?
Q: Are any of the reported PDZ-domain / interactome interactions of UQCRC2 (e.g. DLG family, MAGI, SCRIB) physiologically relevant, or artifacts of the affinity/network assays?
Experiment: Reconstitute Complex III assembly in cells expressing catalytic-site (M16 motif) UQCRC2 variants to test whether any residual metallopeptidase capacity contributes to UQCRFS1 maturation.
Experiment: Structurally and biochemically define the UQCRC2-mitolamban (STMP1) and UQCRC2-RAB5IF interactions within assembling Complex III to clarify their roles in CIII biogenesis and supercomplex formation.
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