MCCC2 encodes the beta (carboxyltransferase) subunit of mitochondrial 3-methylcrotonyl-CoA carboxylase (MCC; EC 6.4.1.4), a biotin-dependent carboxylase of the leucine catabolic pathway. MCC catalyzes the ATP- and bicarbonate-dependent carboxylation of 3-methylcrotonyl-CoA to 3-methylglutaconyl-CoA. The holoenzyme is an alpha6-beta6 dodecamer in which the biotin-containing alpha subunit (MCCC1) carries out biotin carboxylation and shuttles the carboxyl group as carboxybiotin, while the non-biotin-containing beta subunit encoded by MCCC2 binds the acyl-CoA substrate and provides the carboxyltransferase activity that transfers the carboxyl group to 3-methylcrotonyl-CoA. The mature protein is imported into the mitochondrial matrix via a cleavable N-terminal presequence and belongs to the AccD/PCCB carboxyltransferase family, with N- and C-terminal CoA carboxyltransferase domains. Biallelic loss-of-function variants in MCCC2 (or in MCCC1) cause 3-methylcrotonyl-CoA carboxylase deficiency (3-methylcrotonylglycinuria), an autosomal recessive organic aciduria of leucine catabolism with a highly variable phenotype ranging from asymptomatic to severe neonatal metabolic decompensation.
| GO Term | Evidence | Action | Reason |
|---|---|---|---|
| GO:0004485 methylcrotonoyl-CoA carboxylase activity | IBA GO_REF:0000033 | ACCEPT | Summary: Phylogenetic (IBA) inference of the core molecular function of MCCC2, the carboxyltransferase subunit of 3-methylcrotonyl-CoA carboxylase. The `contributes_to` qualifier is appropriate because catalysis is a property of the assembled alpha6-beta6 holoenzyme; the beta subunit binds the acyl-CoA substrate and provides the carboxyltransferase activity but requires the biotin-carrying alpha subunit (MCCC1) for the complete reaction. Reason: This is the correct, well-supported core molecular function, consistent across IBA, experimental (IDA), and EC-based evidence and confirmed by direct enzymatic characterization of the recombinant human enzyme. Supporting Evidence: PMID:17360195 protocol has been developed to purify the active MCCC which appears to reside in PMID:11170888 the Ξ² subunits contain the binding site for the acyl-CoA substrate |
| GO:0005739 mitochondrion | IBA GO_REF:0000033 | ACCEPT | Summary: Phylogenetic inference that MCCC2 is active in the mitochondrion. This is the correct broad localization; the more specific and better-supported location is the mitochondrial matrix. Reason: Correct compartment. Retained as the general parent of the more specific mitochondrial matrix location, which is where MCC actually functions. Supporting Evidence: PMID:16023992 are imported into the mitochondrial matrix by the classical pathway involving |
| GO:0006552 L-leucine catabolic process | IBA GO_REF:0000033 | ACCEPT | Summary: Phylogenetic inference that MCCC2 participates in L-leucine catabolism. MCC catalyzes the committed carboxylation step (3-methylcrotonyl-CoA to 3-methylglutaconyl-CoA) of the leucine degradation pathway. Reason: This is the core biological process for MCCC2, supported experimentally (IMP, TAS) and by pathway assignment. Correct and specific. Supporting Evidence: PMID:11170888 an enzyme of leucine catabolism |
| GO:1905202 methylcrotonoyl-CoA carboxylase complex | IBA GO_REF:0000033 | ACCEPT | Summary: Phylogenetic inference that MCCC2 is part of the methylcrotonoyl-CoA carboxylase complex. MCCC2 (beta) assembles with MCCC1 (alpha) into the alpha6-beta6 dodecameric holoenzyme. Reason: Correct and core. This complex-membership term captures the functional unit better than a generic protein binding annotation and is supported by direct complex characterization. Supporting Evidence: PMID:17360195 in the recombinant human MCCC, the PMID:11170888 MCC, an heteromeric enzyme consisting of Ξ± (biotin-containing) and Ξ² subunits |
| GO:0004485 methylcrotonoyl-CoA carboxylase activity | IEA GO_REF:0000120 | ACCEPT | Summary: Electronic annotation (mapped from EC 6.4.1.4 / RHEA:13589 and orthology) of the methylcrotonoyl-CoA carboxylase molecular function. Reason: The EC/RHEA mapping to GO:0004485 is correct and matches the experimentally confirmed catalytic activity. (Note the `enables` qualifier here versus the more precise `contributes_to` used elsewhere; the activity is a holoenzyme property.) Supporting Evidence: PMID:17360195 74+/-7microM) similar to those reported for the native enzyme. |
| GO:0005759 mitochondrial matrix | IEA GO_REF:0000120 | ACCEPT | Summary: Electronic annotation (orthology / UniProtKB-SubCell SL-0170) placing MCCC2 in the mitochondrial matrix. Reason: Correct and matches direct experimental evidence that MCC is imported into and functions in the mitochondrial matrix. Supporting Evidence: PMID:16023992 are imported into the mitochondrial matrix by the classical pathway involving |
| GO:0016874 ligase activity | IEA GO_REF:0000002 | KEEP AS NON CORE | Summary: InterPro-to-GO electronic annotation of ligase activity, the broad parent class of the methylcrotonoyl-CoA carboxylase (carboxylase/ligase) activity. EC 6.4.1.4 is a carbon-carbon ligase. Reason: Not wrong (GO:0004485 is a subclass of GO:0016874, ligase activity), but much less informative than the specific carboxylase activity term. Retained as a correct parent, marked non-core. Supporting Evidence: PMID:22869039 biotin carboxylase (BC), carboxyltransferase (CT), and |
| GO:0005515 protein binding | IPI PMID:17360195 Expression, purification, characterization of human 3-methyl... | MARK AS OVER ANNOTATED | Summary: IPI protein-binding annotation with the MCCC1 alpha subunit (Q96RQ3) as the interaction partner. This reflects the physiological intra-holoenzyme alpha-beta interaction. Reason: The generic `protein binding` term is uninformative and does not convey the actual function. The biologically meaningful interaction (with MCCC1) is captured far better by the methylcrotonoyl-CoA carboxylase complex term (GO:1905202). Per curation policy this bare IPI is marked as over-annotated rather than removed. Supporting Evidence: PMID:11170888 MCC, an heteromeric enzyme consisting of Ξ± (biotin-containing) and Ξ² subunits |
| GO:0005515 protein binding | IPI PMID:27499296 Mitochondrial Protein Interaction Mapping Identifies Regulat... | MARK AS OVER ANNOTATED | Summary: IPI protein-binding annotation (MCCC1, Q96RQ3) derived from a large-scale mitochondrial protein interaction mapping study. Reason: Bare `protein binding` is uninformative; the relevant interaction with the MCCC1 alpha subunit is better represented by the carboxylase complex term (GO:1905202). Marked as over-annotated per policy rather than removed. Supporting Evidence: PMID:27499296 Mitochondrial Protein Interaction Mapping Identifies Regulators of Respiratory |
| GO:0005515 protein binding | IPI PMID:33961781 Dual proteome-scale networks reveal cell-specific remodeling... | MARK AS OVER ANNOTATED | Summary: IPI protein-binding annotation (MCCC1, Q96RQ3) from a proteome-scale interactome study. Reason: Uninformative `protein binding` term; the meaningful MCCC1 interaction is captured by GO:1905202. Marked as over-annotated per policy. Supporting Evidence: PMID:33961781 Dual proteome-scale networks reveal cell-specific remodeling of the human |
| GO:0005515 protein binding | IPI PMID:35156780 CFTR interactome mapping using the mammalian membrane two-hy... | MARK AS OVER ANNOTATED | Summary: IPI protein-binding annotation with CFTR (P13569) recovered from a CFTR-interactome mammalian membrane two-hybrid screen. Reason: Generic `protein binding`, and the CFTR partner is from a high-throughput CFTR-interactome screen with no established biological relationship to this mitochondrial matrix metabolic enzyme. Uninformative; marked as over-annotated per policy (not removed, as it is an experimental IPI whose full text is not verifiable here). Supporting Evidence: PMID:35156780 CFTR interactome mapping using the mammalian membrane two-hybrid |
| GO:0005515 protein binding | IPI PMID:36012204 Differential CFTR-Interactome Proximity Labeling Procedures ... | MARK AS OVER ANNOTATED | Summary: IPI protein-binding annotation with CFTR (P13569) from a differential CFTR-interactome proximity-labeling study. Reason: Generic, uninformative `protein binding` from a CFTR proximity-labeling screen; not indicative of MCCC2's function. Marked as over-annotated per policy. Supporting Evidence: PMID:36012204 Differential CFTR-Interactome Proximity Labeling Procedures Identify Enrichment |
| GO:0005515 protein binding | IPI PMID:40205054 Multimodal cell maps as a foundation for structural and func... | MARK AS OVER ANNOTATED | Summary: IPI protein-binding annotation (MCCC1, Q96RQ3) from a multimodal cell-map structural/functional genomics study. Reason: Bare `protein binding`; the MCCC1 interaction is better captured by the carboxylase complex term. Marked as over-annotated per policy. Supporting Evidence: PMID:40205054 Multimodal cell maps as a foundation for structural and functional genomics |
| GO:0006552 L-leucine catabolic process | IEA GO_REF:0000120 | ACCEPT | Summary: Electronic annotation (orthology / UniPathway UPA00363) of participation in L-leucine catabolism. Reason: Correct core biological process, consistent with the pathway assignment and experimental evidence. Supporting Evidence: PMID:11170888 an enzyme of leucine catabolism |
| GO:0015936 coenzyme A metabolic process | IEA GO_REF:0000107 | MARK AS OVER ANNOTATED | Summary: Electronic annotation transferred from a rat ortholog assigning coenzyme A metabolic process. MCC uses acyl-CoA substrates but does not synthesize, degrade, or interconvert coenzyme A itself. Reason: This is a tangential/over-broad mapping. CoA is the carrier scaffold of the substrate, not a metabolite processed by MCC; the enzyme carboxylates the acyl moiety (leucine catabolism), it does not perform coenzyme A metabolism. The accurate process terms are L-leucine / branched-chain amino acid catabolism. Supporting Evidence: PMID:11170888 the enzyme converting 3-methylcrotonoyl-CoA to 3-methylglutaconyl-CoA |
| GO:0005759 mitochondrial matrix | IDA PMID:17360195 Expression, purification, characterization of human 3-methyl... | ACCEPT | Summary: Direct assay (ComplexPortal-curated) placing MCCC2 in the mitochondrial matrix, the compartment where the MCC holoenzyme functions. Reason: Correct and core cellular location, corroborated by mitochondrial import studies and multiple independent annotations. Supporting Evidence: PMID:16023992 are imported into the mitochondrial matrix by the classical pathway involving |
| GO:0009083 branched-chain amino acid catabolic process | NAS PMID:17360195 Expression, purification, characterization of human 3-methyl... | KEEP AS NON CORE | Summary: Non-traceable author statement that MCCC2 participates in branched-chain amino acid catabolism. Leucine is a branched-chain amino acid, so this is the broader parent of the L-leucine catabolic process term. Reason: Correct but less specific than GO:0006552 (L-leucine catabolic process), which is a subclass of branched-chain amino acid catabolic process. Retained as a valid parent, marked non-core. Supporting Evidence: PMID:11170888 an enzyme of leucine catabolism |
| GO:1905202 methylcrotonoyl-CoA carboxylase complex | IPI PMID:17360195 Expression, purification, characterization of human 3-methyl... | ACCEPT | Summary: Interaction-based (ComplexPortal-curated) assignment of MCCC2 as part of the methylcrotonoyl-CoA carboxylase complex, based on characterization of the assembled alpha/beta enzyme. Reason: Correct and core. Captures the functional holoenzyme unit; supported by direct purification and characterization of the alpha-beta complex. Supporting Evidence: PMID:17360195 in the recombinant human MCCC, the |
| GO:0005739 mitochondrion | IDA GO_REF:0000052 | ACCEPT | Summary: Direct immunofluorescence (HPA) localization to the mitochondrion. Reason: Correct compartment; consistent with matrix localization. Retained as the broader parent of mitochondrial matrix. Supporting Evidence: PMID:16023992 are imported into the mitochondrial matrix by the classical pathway involving |
| GO:0006552 L-leucine catabolic process | IMP PMID:9544913 3-Methylcrotonyl-coenzyme A carboxylase deficiency in Amish/... | ACCEPT | Summary: Mutant-phenotype evidence linking MCC deficiency to disrupted leucine catabolism, from characterization of MCC-deficient Amish/Mennonite adults with the diagnostic acylcarnitine/organic-acid profile of impaired leucine degradation. Reason: Core biological process supported by loss-of-function/mutant evidence. Do not overrule this experimental annotation; the curator had access to the full clinical/enzymatic characterization. Supporting Evidence: PMID:9544913 Isolated 3-methylcrotonyl coenzyme A carboxylase (MCC) deficiency was documented |
| GO:0005739 mitochondrion | HTP PMID:34800366 Quantitative high-confidence human mitochondrial proteome an... | ACCEPT | Summary: High-throughput proteomic detection of MCCC2 in a high-confidence human mitochondrial proteome (MitoCoP). Reason: Consistent with the well-established mitochondrial (matrix) localization. Correct compartment; retained as the broad parent of mitochondrial matrix. Supporting Evidence: PMID:34800366 mitochondrial high-confidence proteome of >1,100 proteins (MitoCoP). |
| GO:0005759 mitochondrial matrix | TAS Reactome:R-HSA-9909466 | ACCEPT | Summary: Reactome traceable-author-statement placing MCCC2 in the mitochondrial matrix (context of the 3-MCC deficiency pathway). Reason: Correct and core location, consistent with experimental matrix localization. Supporting Evidence: PMID:16023992 are imported into the mitochondrial matrix by the classical pathway involving |
| GO:1905202 methylcrotonoyl-CoA carboxylase complex | IDA PMID:17360195 Expression, purification, characterization of human 3-methyl... | ACCEPT | Summary: Direct-assay assignment (ParkinsonsUK-UCL) of MCCC2 as part of the methylcrotonoyl-CoA carboxylase complex, from purification/characterization of the assembled enzyme. Reason: Correct and core complex-membership annotation, supported by direct characterization of the alpha-beta holoenzyme. Supporting Evidence: PMID:17360195 protocol has been developed to purify the active MCCC which appears to reside in |
| GO:0004485 methylcrotonoyl-CoA carboxylase activity | IDA PMID:17360195 Expression, purification, characterization of human 3-methyl... | ACCEPT | Summary: Direct enzymatic characterization of purified recombinant human MCC establishing methylcrotonoyl-CoA carboxylase activity, with measured kinetic parameters (kcat ~4.0 s-1; KM ATP 45 uM; KM 3-methylcrotonyl-CoA 74 uM). The `contributes_to` qualifier correctly reflects that catalysis is a holoenzyme property to which the beta carboxyltransferase subunit contributes. Reason: This is the strongest, experimentally demonstrated core molecular function of MCCC2. Directly measured activity of the recombinant human enzyme. Supporting Evidence: PMID:17360195 74+/-7microM) similar to those reported for the native enzyme. |
| GO:0004485 methylcrotonoyl-CoA carboxylase activity | NAS PMID:11170888 The molecular basis of 3-methylcrotonylglycinuria, a disorde... | ACCEPT | Summary: Non-traceable author statement attributing methylcrotonoyl-CoA carboxylase activity to the MCC alpha/beta enzyme; the beta subunit provides the acyl-CoA-binding carboxyltransferase function. Reason: Correct core molecular function; the `contributes_to` qualifier is appropriate given the holoenzyme nature of catalysis. Corroborated by the IDA annotation. Supporting Evidence: PMID:11170888 the Ξ² subunits contain the binding site for the acyl-CoA substrate |
| GO:0004485 methylcrotonoyl-CoA carboxylase activity | NAS PMID:11181649 The molecular basis of human 3-methylcrotonyl-CoA carboxylas... | ACCEPT | Summary: Non-traceable author statement attributing methylcrotonoyl-CoA carboxylase activity to MCC, from the parallel molecular characterization of human MCC deficiency. Reason: Correct core molecular function; duplicate support for GO:0004485 with the appropriate `contributes_to` qualifier. (Abstract-only cache; deferring to the annotating curator, consistent with the well-established enzymology.) Supporting Evidence: PMID:11170888 the Ξ² subunits contain the binding site for the acyl-CoA substrate |
| GO:1905202 methylcrotonoyl-CoA carboxylase complex | NAS PMID:11170888 The molecular basis of 3-methylcrotonylglycinuria, a disorde... | ACCEPT | Summary: Non-traceable author statement that MCCC2 (beta) is part of the MCC alpha/beta complex. Reason: Correct and core; MCC is a heteromeric alpha-beta enzyme and MCCC2 is the beta component. Supporting Evidence: PMID:11170888 MCC, an heteromeric enzyme consisting of Ξ± (biotin-containing) and Ξ² subunits |
| GO:1905202 methylcrotonoyl-CoA carboxylase complex | NAS PMID:11181649 The molecular basis of human 3-methylcrotonyl-CoA carboxylas... | ACCEPT | Summary: Non-traceable author statement that MCCC2 is part of the methylcrotonoyl-CoA carboxylase complex. Reason: Correct and core complex membership; duplicate support consistent with the heteromeric alpha-beta architecture of MCC. Supporting Evidence: PMID:11170888 MCC, an heteromeric enzyme consisting of Ξ± (biotin-containing) and Ξ² subunits |
| GO:1905202 methylcrotonoyl-CoA carboxylase complex | TAS PMID:22869039 Structure and function of biotin-dependent carboxylases. | ACCEPT | Summary: Traceable-author-statement (review of biotin-dependent carboxylase structure/function) that MCC is a multi-subunit carboxylase built from biotin carboxylase, carboxyltransferase, and biotin-carboxyl-carrier components. Reason: Correct and core; MCCC2 is the carboxyltransferase subunit of the MCC complex, whose holoenzyme architecture is described in this structural review. Supporting Evidence: PMID:22869039 biotin carboxylase (BC), carboxyltransferase (CT), and |
| GO:0005739 mitochondrion | IDA PMID:11170888 The molecular basis of 3-methylcrotonylglycinuria, a disorde... | ACCEPT | Summary: Direct-assay mitochondrial localization consistent with the matrix location of the MCC enzyme. Reason: Correct compartment; retained as the broad parent of mitochondrial matrix. Supporting Evidence: PMID:16023992 are imported into the mitochondrial matrix by the classical pathway involving |
| GO:0005759 mitochondrial matrix | IDA PMID:16023992 Mitochondrial targeting signals and mature peptides of 3-met... | ACCEPT | Summary: Direct experimental evidence that MCCbeta is imported into the mitochondrial matrix via a cleavable N-terminal targeting presequence (cleavage at Ala22/Tyr23). Reason: Strong, direct experimental support for the core matrix localization, including definition of the transit peptide. Supporting Evidence: PMID:16023992 are imported into the mitochondrial matrix by the classical pathway involving |
| GO:0005759 mitochondrial matrix | TAS Reactome:R-HSA-3065959 | ACCEPT | Summary: Reactome TAS placing MCCC2 in the mitochondrial matrix (carboxylase degradation reaction context). Reason: Correct core location, consistent with direct experimental matrix localization. Supporting Evidence: PMID:16023992 are imported into the mitochondrial matrix by the classical pathway involving |
| GO:0005759 mitochondrial matrix | TAS Reactome:R-HSA-3323111 | ACCEPT | Summary: Reactome TAS placing MCCC2 in the mitochondrial matrix. Reason: Correct core location consistent with experimental evidence. Supporting Evidence: PMID:16023992 are imported into the mitochondrial matrix by the classical pathway involving |
| GO:0005759 mitochondrial matrix | TAS Reactome:R-HSA-508308 | ACCEPT | Summary: Reactome TAS placing MCCC2 in the mitochondrial matrix (carboxylation reaction context). Reason: Correct core location; MCC catalyzes its reaction in the matrix. Supporting Evidence: PMID:16023992 are imported into the mitochondrial matrix by the classical pathway involving |
| GO:0005759 mitochondrial matrix | TAS Reactome:R-HSA-70773 | ACCEPT | Summary: Reactome TAS placing MCCC2 in the mitochondrial matrix (MCC reaction context). Reason: Correct core location, consistent with experimental matrix localization. Supporting Evidence: PMID:16023992 are imported into the mitochondrial matrix by the classical pathway involving |
| GO:0005829 cytosol | TAS Reactome:R-HSA-2993799 | MARK AS OVER ANNOTATED | Summary: Reactome TAS annotating MCCC2 to the cytosol, arising from the modeled HLCS-mediated biotinylation / cytosol-to-matrix translocation steps of the nascent carboxylase rather than a steady-state functional location. Reason: MCCC2 is a matrix enzyme imported via a cleavable presequence; any cytosolic presence is a transient import/processing intermediate captured in Reactome's biotinylation-and-translocation model, not a site of function. The functional localization is the mitochondrial matrix. Supporting Evidence: PMID:16023992 are imported into the mitochondrial matrix by the classical pathway involving |
| GO:0005829 cytosol | TAS Reactome:R-HSA-3323111 | MARK AS OVER ANNOTATED | Summary: Reactome TAS annotating MCCC2 to the cytosol, from the modeled translocation of cytosolic (apo) carboxylases to the mitochondrial matrix. Reason: Reflects a transient pre-import state in the Reactome model, not a functional cytosolic localization. Mature functional MCC resides in the mitochondrial matrix. Supporting Evidence: PMID:16023992 are imported into the mitochondrial matrix by the classical pathway involving |
| GO:0005829 cytosol | TAS Reactome:R-HSA-9035987 | MARK AS OVER ANNOTATED | Summary: Reactome TAS annotating MCCC2 to the cytosol, in the context of defective HLCS failing to biotinylate the cytosolic apo-carboxylase. Reason: A transient pre-import/biotinylation intermediate in the Reactome model rather than a functional location. Functional MCC is in the mitochondrial matrix. Supporting Evidence: PMID:16023992 are imported into the mitochondrial matrix by the classical pathway involving |
| GO:0005739 mitochondrion | NAS PMID:11181649 The molecular basis of human 3-methylcrotonyl-CoA carboxylas... | ACCEPT | Summary: Non-traceable author statement of mitochondrial localization for MCCC2. Reason: Correct compartment consistent with the established mitochondrial matrix localization; retained as the broad parent term. Supporting Evidence: PMID:16023992 are imported into the mitochondrial matrix by the classical pathway involving |
| GO:0006552 L-leucine catabolic process | TAS PMID:11170888 The molecular basis of 3-methylcrotonylglycinuria, a disorde... | ACCEPT | Summary: Traceable-author-statement that MCC (and thus MCCC2) is an enzyme of leucine catabolism, with in vivo confirmation via a fungal MCCA-null model. Reason: Core biological process, directly supported in the cited paper (including a genetic model demonstrating involvement of MCC in leucine catabolism). Supporting Evidence: PMID:11170888 we use a fungal model for MCG carrying an MCCA null allele, to demonstrate, in vivo, the specific involvement of MCC in leucine catabolism |
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