Holocarboxylase synthetase (HLCS) is the human biotin--protein ligase that covalently attaches biotin to the biotin-dependent carboxylases, converting their inactive apo forms into active holoenzymes. It catalyses a two-step reaction, first activating biotin with ATP to form biotinyl-5'-AMP and then transferring biotin to a specific lysine within the biotin carboxyl carrier domain of each substrate. A single HLCS activates all of the human biotin-dependent carboxylases in both the cytosol and the mitochondria, including pyruvate carboxylase (PC), propionyl-CoA carboxylase (PCCA/PCCB), 3-methylcrotonyl-CoA carboxylase (MCCC1/MCCC2), and the acetyl-CoA carboxylases (ACACA and ACACB). Through these carboxylases it is essential for gluconeogenesis and anaplerosis, odd-chain fatty acid and propionate metabolism, leucine catabolism, and fatty acid synthesis. Loss-of-function variants cause holocarboxylase synthetase deficiency (neonatal/early-onset multiple carboxylase deficiency), an autosomal recessive, biotin-responsive disorder characterized by ketoacidosis, lactic acidosis, hyperammonemia, organic aciduria, and dermatological manifestations. HLCS has additionally been reported to enter the nucleus and biotinylate histones, a proposed chromatin/gene-regulatory role whose in vivo physiological significance remains debated.
| GO Term | Evidence | Action | Reason |
|---|---|---|---|
| GO:0004077 biotin--[biotin carboxyl-carrier protein] ligase activity | IBA GO_REF:0000033 | ACCEPT | Summary: Phylogenetic (IBA) assertion of the core molecular function, biotin--protein ligase activity. This is the defining, disease-relevant function of HLCS and is strongly supported by direct experimental evidence. Reason: Core molecular function. HLCS catalyses the covalent attachment of biotin to the biotin-dependent carboxylases; the IBA is consistent with abundant human experimental evidence. Supporting Evidence: PMID:7753853 Holocarboxylase synthetase (HCS) catalyzes the biotinylation of the four biotin-dependent carboxylases in human cells. |
| GO:0005737 cytoplasm | IBA GO_REF:0000033 | ACCEPT | Summary: Phylogenetic (IBA) assignment of cytoplasmic localization. HLCS acts in the cytosol (activating ACACA and, en route, mitochondrial apocarboxylases) as well as the mitochondrion; cytoplasmic localization is well supported. Reason: Consistent with direct experimental localization of HLCS to the cytosol and with a single HLCS acting in both cytoplasm and mitochondria. Supporting Evidence: PMID:7753853 a single HCS is targeted to the mitochondria and cytoplasm |
| GO:0004077 biotin--[biotin carboxyl-carrier protein] ligase activity | IEA GO_REF:0000120 | ACCEPT | Summary: Electronic (IEA, combined-method) assertion of the core biotin--protein ligase activity, with RHEA/EC cross-references (EC 6.3.4.9/.10/.11/.15). Redundant with the experimental annotations and correct. Reason: Correct core molecular function, consistent with UniProt catalytic-activity records and experimental data. Supporting Evidence: PMID:7753853 Holocarboxylase synthetase (HCS) catalyzes the biotinylation of the four biotin-dependent carboxylases in human cells. |
| GO:0005737 cytoplasm | IEA GO_REF:0000044 | ACCEPT | Summary: Electronic localization to cytoplasm derived from the UniProt Subcellular Location vocabulary (SL-0086). Consistent with experimental cytosolic localization. Reason: HLCS is a cytoplasmic (and mitochondrial) enzyme; the SubCell-derived cytoplasm term is correct. Supporting Evidence: PMID:16780588 the HLCS gene codes for a biotin-protein ligase and was found to localize throughout the cytosol |
| GO:0005739 mitochondrion | IEA GO_REF:0000044 | ACCEPT | Summary: Electronic localization to mitochondrion from the UniProt Subcellular Location vocabulary (SL-0173). A single HLCS activates the mitochondrial apocarboxylases (PC, PCC, MCC, ACACB), so mitochondrial localization is expected and reported. Reason: Consistent with the requirement for HLCS to biotinylate mitochondrial apocarboxylases and with UniProt's SUBCELLULAR LOCATION (Cytoplasm; Mitochondrion). Supporting Evidence: PMID:7753853 a single HCS is targeted to the mitochondria and cytoplasm |
| GO:0006768 biotin metabolic process | IEA GO_REF:0000117 | ACCEPT | Summary: Electronic (ARBA) assignment of the broad biotin metabolic process. HLCS is a central enzyme of biotin utilization; the term is broad but correct. Reason: HLCS is the enzyme that incorporates biotin into apocarboxylases, a core step of biotin metabolism/utilization. The parent process term is correct although general. Supporting Evidence: PMID:7842009 Holocarboxylase synthetase (HCS) plays an essential role in biotin utilization in eukaryotic cells |
| GO:0005515 protein binding | IPI PMID:20085763 The N-terminal domain of human holocarboxylase synthetase fa... | MARK AS OVER ANNOTATED | Summary: Bare "protein binding" from an IntAct-curated pairwise interaction (partner O00763 = ACACB, an HLCS substrate). The paper concerns HLCS N-terminal domain binding its biotin-acceptor substrate, so the interaction is real, but the GO term is uninformative. Reason: Bare protein binding conveys no specific function. The underlying biology (HLCS recognizing its carboxylase substrate) is captured better by the ligase activity and enzyme/substrate-binding annotations; per curation policy the experimental IPI is retained but marked as over-annotated rather than removed. |
| GO:0005515 protein binding | IPI PMID:21044950 Genome-wide YFP fluorescence complementation screen identifi... | MARK AS OVER ANNOTATED | Summary: Bare "protein binding" from a genome-wide YFP fluorescence-complementation interaction screen (partner Q9NUX5 = POT1). High-throughput screen hit; uninformative GO term and biologically unexplained for HLCS. Reason: Uninformative bare protein-binding term derived from a high-throughput interactome screen; no established functional relevance to HLCS. Retained per policy (experimental IPI) but marked over-annotated. |
| GO:0005515 protein binding | IPI PMID:28514442 Architecture of the human interactome defines protein commun... | MARK AS OVER ANNOTATED | Summary: Bare "protein binding" from a large-scale interactome/AP-MS study (partners Q5T0L3 = SPATA46, Q86XM0 = CATSPERD). Uninformative GO term from a proteome-scale screen. Reason: Bare protein binding from a high-throughput interactome map; not an informative molecular function. Retained per policy but marked over-annotated. |
| GO:0005515 protein binding | IPI PMID:32296183 A reference map of the human binary protein interactome. | MARK AS OVER ANNOTATED | Summary: Bare "protein binding" from the HuRI binary interactome map (multiple partners incl. MED19, KRTAP5-9, SPATA46, ANKRD29). Uninformative screen-derived term. Reason: Bare protein-binding term from a proteome-scale Y2H interactome; no specific functional insight into HLCS. Retained per policy but marked over-annotated. |
| GO:0005515 protein binding | IPI PMID:33961781 Dual proteome-scale networks reveal cell-specific remodeling... | MARK AS OVER ANNOTATED | Summary: Bare "protein binding" from a proteome-scale AP-MS interactome (partners SPATA46, CATSPERD). Uninformative GO term from a high-throughput dataset. Reason: Bare protein-binding term derived from a large-scale interactome study; not functionally informative for HLCS. Retained per policy but marked over-annotated. |
| GO:0042802 identical protein binding | IEA GO_REF:0000107 | MARK AS OVER ANNOTATED | Summary: Electronic "identical protein binding" (self-association/homodimerization) transferred by orthology from the rat protein (D4AA38). Human HLCS is reported to be a monomer, so self-association is not supported for the human enzyme. Reason: Orthology-transferred (Ensembl Compara) self-binding term. UniProt records human HLCS SUBUNIT as "Monomer", so this electronic homodimerization inference is not substantiated for human HLCS. Supporting Evidence: PMID:7842009 Holocarboxylase synthetase (HCS) plays an essential role in biotin utilization in eukaryotic cells |
| GO:0070781 response to biotin | IEA GO_REF:0000107 | KEEP AS NON CORE | Summary: Electronic "response to biotin" transferred by orthology from the rat protein. Relates to the reported (and debated) role of HLCS as a nuclear biotin sensor that adjusts biotin uptake; not the core catalytic function. Reason: The biotin-sensing/response role has some direct support in human cells but is a proposed, non-essential moonlighting activity distinct from the core biotin-protein ligase function. Kept as non-core. Supporting Evidence: PMID:17904341 the nuclear translocation of HCS depends on biotin |
| GO:0006768 biotin metabolic process | TAS Reactome:R-HSA-196780 | ACCEPT | Summary: Reactome (TAS) placement of HLCS in "Biotin transport and metabolism". HLCS incorporates biotin into apocarboxylases, a central step of biotin metabolism/utilization. Broad but correct. Reason: Correct broad biological process; HLCS is a core enzyme of biotin metabolism. Supporting Evidence: PMID:7842009 Holocarboxylase synthetase (HCS) plays an essential role in biotin utilization in eukaryotic cells |
| GO:0004077 biotin--[biotin carboxyl-carrier protein] ligase activity | TAS Reactome:R-HSA-2993447 | ACCEPT | Summary: Reactome (TAS) biotin--protein ligase activity for the reaction "HLCS biotinylates 6x(PCCA:PCCB)" (biotinylation of propionyl-CoA carboxylase). Correct core molecular function on a genuine substrate. Reason: Core molecular function; PCC is an established HLCS substrate. Duplicate of the experimental ligase-activity annotations. Supporting Evidence: PMID:7753853 Holocarboxylase synthetase (HCS) catalyzes the biotinylation of the four biotin-dependent carboxylases in human cells. |
| GO:0004077 biotin--[biotin carboxyl-carrier protein] ligase activity | TAS Reactome:R-HSA-2993799 | ACCEPT | Summary: Reactome (TAS) biotin--protein ligase activity for "HLCS biotinylates 6xMCCC1:6xMCCC2" (biotinylation of 3-methylcrotonyl-CoA carboxylase). Correct core function on a genuine substrate. Reason: Core molecular function; MCC is an established HLCS substrate. Supporting Evidence: PMID:7753853 Holocarboxylase synthetase (HCS) catalyzes the biotinylation of the four biotin-dependent carboxylases in human cells. |
| GO:0004077 biotin--[biotin carboxyl-carrier protein] ligase activity | TAS Reactome:R-HSA-2993802 | ACCEPT | Summary: Reactome (TAS) biotin--protein ligase activity for "HLCS biotinylates PC:Mn2+" (biotinylation of pyruvate carboxylase). Correct core function on a genuine substrate. Reason: Core molecular function; PC is an established HLCS substrate. Supporting Evidence: PMID:7753853 Holocarboxylase synthetase (HCS) catalyzes the biotinylation of the four biotin-dependent carboxylases in human cells. |
| GO:0004077 biotin--[biotin carboxyl-carrier protein] ligase activity | TAS Reactome:R-HSA-2993814 | ACCEPT | Summary: Reactome (TAS) biotin--protein ligase activity for "HLCS biotinylates ACACA:Mn2+" (biotinylation of acetyl-CoA carboxylase 1). Correct core function on a genuine substrate. Reason: Core molecular function; ACACA is an established HLCS substrate. Supporting Evidence: PMID:7753853 Holocarboxylase synthetase (HCS) catalyzes the biotinylation of the four biotin-dependent carboxylases in human cells. |
| GO:0004077 biotin--[biotin carboxyl-carrier protein] ligase activity | TAS Reactome:R-HSA-3323184 | ACCEPT | Summary: Reactome (TAS) biotin--protein ligase activity within the disease reaction "Defective HLCS does not biotinylate ACACA:Mn2+". The annotated activity is the same core ligase function (in a defective-variant context). Correct. Reason: Same core molecular function, annotated in a disease-variant Reactome reaction; the function itself is correct. Supporting Evidence: PMID:7753853 Holocarboxylase synthetase (HCS) catalyzes the biotinylation of the four biotin-dependent carboxylases in human cells. |
| GO:0004077 biotin--[biotin carboxyl-carrier protein] ligase activity | TAS Reactome:R-HSA-4167511 | ACCEPT | Summary: Reactome (TAS) biotin--protein ligase activity for "HLCS biotinylates ACACB" (biotinylation of acetyl-CoA carboxylase 2). Correct core function on a genuine substrate. Reason: Core molecular function; ACACB is an established HLCS substrate. Supporting Evidence: PMID:7753853 Holocarboxylase synthetase (HCS) catalyzes the biotinylation of the four biotin-dependent carboxylases in human cells. |
| GO:0004077 biotin--[biotin carboxyl-carrier protein] ligase activity | TAS Reactome:R-HSA-9035987 | ACCEPT | Summary: Reactome (TAS) biotin--protein ligase activity within the disease reaction "Defective HLCS does not biotinylate 6xMCCC1:6xMCCC2". Same core ligase function in a defective-variant context. Correct. Reason: Same core molecular function annotated in a disease-variant Reactome reaction. Supporting Evidence: PMID:7753853 Holocarboxylase synthetase (HCS) catalyzes the biotinylation of the four biotin-dependent carboxylases in human cells. |
| GO:0004077 biotin--[biotin carboxyl-carrier protein] ligase activity | TAS Reactome:R-HSA-9035988 | ACCEPT | Summary: Reactome (TAS) biotin--protein ligase activity within the disease reaction "Defective HLCS does not biotinylate PC:Mn2+". Same core ligase function in a defective-variant context. Correct. Reason: Same core molecular function annotated in a disease-variant Reactome reaction. Supporting Evidence: PMID:7753853 Holocarboxylase synthetase (HCS) catalyzes the biotinylation of the four biotin-dependent carboxylases in human cells. |
| GO:0004077 biotin--[biotin carboxyl-carrier protein] ligase activity | TAS Reactome:R-HSA-9035990 | ACCEPT | Summary: Reactome (TAS) biotin--protein ligase activity within the disease reaction "Defective HLCS does not biotinylate 6x(PCCA:PCCB)". Same core ligase function in a defective-variant context. Correct. Reason: Same core molecular function annotated in a disease-variant Reactome reaction. Supporting Evidence: PMID:7753853 Holocarboxylase synthetase (HCS) catalyzes the biotinylation of the four biotin-dependent carboxylases in human cells. |
| GO:0005829 cytosol | TAS Reactome:R-HSA-3323184 | ACCEPT | Summary: Reactome (TAS) cytosolic localization. Consistent with the well-documented cytosolic localization of HLCS. Reason: HLCS acts in the cytosol; localization is directly supported experimentally. Supporting Evidence: PMID:16780588 the HLCS gene codes for a biotin-protein ligase and was found to localize throughout the cytosol |
| GO:0005829 cytosol | TAS Reactome:R-HSA-9035987 | ACCEPT | Summary: Reactome (TAS) cytosolic localization. Duplicate of the well-supported cytosolic localization of HLCS. Reason: HLCS acts in the cytosol; localization is directly supported experimentally. Supporting Evidence: PMID:16780588 the HLCS gene codes for a biotin-protein ligase and was found to localize throughout the cytosol |
| GO:0005829 cytosol | TAS Reactome:R-HSA-9035988 | ACCEPT | Summary: Reactome (TAS) cytosolic localization. Duplicate of the well-supported cytosolic localization of HLCS. Reason: HLCS acts in the cytosol; localization is directly supported experimentally. Supporting Evidence: PMID:16780588 the HLCS gene codes for a biotin-protein ligase and was found to localize throughout the cytosol |
| GO:0005829 cytosol | TAS Reactome:R-HSA-9035990 | ACCEPT | Summary: Reactome (TAS) cytosolic localization. Duplicate of the well-supported cytosolic localization of HLCS. Reason: HLCS acts in the cytosol; localization is directly supported experimentally. Supporting Evidence: PMID:16780588 the HLCS gene codes for a biotin-protein ligase and was found to localize throughout the cytosol |
| GO:0004077 biotin--[biotin carboxyl-carrier protein] ligase activity | EXP PMID:7753853 Isolation of a cDNA encoding human holocarboxylase synthetas... | ACCEPT | Summary: Direct experimental evidence for the core biotin--protein ligase activity. The human HCS cDNA complemented an E. coli birA (biotin ligase) mutant and promoted biotinylation of the biotin carboxyl carrier protein and of a propionyl-CoA carboxylase alpha fragment. Reason: Gold-standard experimental evidence for the defining molecular function of HLCS. Supporting Evidence: PMID:7753853 complementation of an Escherichia coli birA PMID:7753853 Holocarboxylase synthetase (HCS) catalyzes the biotinylation of the four biotin-dependent carboxylases in human cells. |
| GO:0004077 biotin--[biotin carboxyl-carrier protein] ligase activity | IDA PMID:14613969 Reduced histone biotinylation in multiple carboxylase defici... | ACCEPT | Summary: Direct-assay evidence that HLCS possesses biotin--protein ligase activity. This study, focused on the nuclear/histone role, also confirmed that HLCS retains biotinylating activity. Reason: Direct experimental support for the core ligase activity. Supporting Evidence: PMID:14613969 The attachment of biotin to apocarboxylases is catalyzed by holocarboxylase PMID:14613969 Nuclear HCS retains its biotinylating activity |
| GO:0043687 post-translational protein modification | IDA PMID:14613969 Reduced histone biotinylation in multiple carboxylase defici... | ACCEPT | Summary: HLCS mediates a post-translational modification (covalent attachment of biotin to lysine residues of acceptor proteins). This is the process-level view of its ligase activity; the biotinylation-specific process terms (e.g. GO:0009305 protein biotinylation) are obsolete, so this is the best available BP term. Reason: Correct process-level annotation of HLCS-catalysed protein biotinylation. Biotinylation is a bona fide post-translational modification and the annotation is directly supported. Supporting Evidence: PMID:14613969 The attachment of biotin to apocarboxylases is catalyzed by holocarboxylase |
| GO:0005829 cytosol | TAS Reactome:R-HSA-2993447 | ACCEPT | Summary: Reactome (TAS) cytosolic localization associated with the PCC-biotinylation reaction. Consistent with cytosolic HLCS. Reason: HLCS acts in the cytosol; localization is directly supported experimentally. Supporting Evidence: PMID:16780588 the HLCS gene codes for a biotin-protein ligase and was found to localize throughout the cytosol |
| GO:0005829 cytosol | TAS Reactome:R-HSA-2993799 | ACCEPT | Summary: Reactome (TAS) cytosolic localization associated with the MCC-biotinylation reaction. Consistent with cytosolic HLCS. Reason: HLCS acts in the cytosol; localization is directly supported experimentally. Supporting Evidence: PMID:16780588 the HLCS gene codes for a biotin-protein ligase and was found to localize throughout the cytosol |
| GO:0005829 cytosol | TAS Reactome:R-HSA-2993802 | ACCEPT | Summary: Reactome (TAS) cytosolic localization associated with the PC-biotinylation reaction. Consistent with cytosolic HLCS. Reason: HLCS acts in the cytosol; localization is directly supported experimentally. Supporting Evidence: PMID:16780588 the HLCS gene codes for a biotin-protein ligase and was found to localize throughout the cytosol |
| GO:0005829 cytosol | TAS Reactome:R-HSA-2993814 | ACCEPT | Summary: Reactome (TAS) cytosolic localization associated with the ACACA-biotinylation reaction. Consistent with cytosolic HLCS. Reason: HLCS acts in the cytosol; localization is directly supported experimentally. Supporting Evidence: PMID:16780588 the HLCS gene codes for a biotin-protein ligase and was found to localize throughout the cytosol |
| GO:0005829 cytosol | TAS Reactome:R-HSA-4167511 | ACCEPT | Summary: Reactome (TAS) cytosolic localization associated with the ACACB-biotinylation reaction. Consistent with cytosolic HLCS. Reason: HLCS acts in the cytosol; localization is directly supported experimentally. Supporting Evidence: PMID:16780588 the HLCS gene codes for a biotin-protein ligase and was found to localize throughout the cytosol |
| GO:0070781 response to biotin | IDA PMID:17904341 Holocarboxylase synthetase regulates expression of biotin tr... | KEEP AS NON CORE | Summary: Direct-assay evidence that HLCS responds to biotin availability - its nuclear translocation increases with biotin supplementation, and it participates in a proposed biotin-sensing/homeostasis loop that regulates the SMVT biotin transporter via histone biotinylation. This is a proposed regulatory/moonlighting role, not the core catalytic function, and its in vivo significance is debated. Reason: Experimentally observed biotin-responsive behavior, but it reflects a proposed nuclear/regulatory moonlighting role rather than the essential biotin-protein ligase function. Retained as non-core. Supporting Evidence: PMID:17904341 the nuclear translocation of HCS depends on biotin PMID:17904341 HCS senses biotin |
| GO:0000785 chromatin | IDA PMID:14613969 Reduced histone biotinylation in multiple carboxylase defici... | KEEP AS NON CORE | Summary: Direct-assay (subnuclear fractionation/immunofluorescence) evidence that a fraction of HLCS associates with chromatin, linked to the proposed histone-biotinylation role. This nuclear/chromatin function is a moonlighting activity whose in vivo physiological relevance is contested. Reason: A real experimental observation from a specific study, but chromatin association reflects a debated nuclear moonlighting role rather than the core cytosolic/mitochondrial carboxylase-activation function. Retained as non-core. Supporting Evidence: PMID:14613969 localizes to the nucleus rather than the cytoplasm PMID:14613969 biotinylate purified histones in vitro |
| GO:0004077 biotin--[biotin carboxyl-carrier protein] ligase activity | IMP PMID:18429047 Reduced half-life of holocarboxylase synthetase from patient... | ACCEPT | Summary: Mutation-based evidence that HLCS is the biotin--protein ligase. Patient cells homozygous for p.L216R lacked detectable HLCS enzyme activity, and recombinant p.L216R showed severely compromised ligase activity that could not be rescued by additional biotin, with a doubled protein turnover rate. Reason: Loss-of-function/variant analysis directly supports the core ligase activity. Supporting Evidence: PMID:18429047 the turn-over rate for the mutant protein was double that of wildtype HLCS |
| GO:0004077 biotin--[biotin carboxyl-carrier protein] ligase activity | IDA PMID:7842009 Isolation and characterization of mutations in the human hol... | ACCEPT | Summary: Direct-assay evidence for the core biotin--protein ligase activity from the original human HCS cDNA cloning/characterization, which established HLCS as essential for biotin utilization and homologous to E. coli BirA (biotin-[acetyl-CoA-carboxylase] ligase). Reason: Foundational direct experimental evidence for the defining molecular function. Supporting Evidence: PMID:7842009 Holocarboxylase synthetase (HCS) plays an essential role in biotin utilization in eukaryotic cells |
| GO:0004077 biotin--[biotin carboxyl-carrier protein] ligase activity | IDA PMID:9630604 Identification of holocarboxylase synthetase (HCS) proteins ... | ACCEPT | Summary: Direct-assay evidence for the ligase activity. Anti-HCS antibodies to the Ile128-Pro398 region inhibited HCS enzymatic activity, mapping the catalytically essential region; three cytosolic HCS proteins (86/82/76 kDa) were identified in placenta. Reason: Direct experimental support for the core molecular function. Supporting Evidence: PMID:9630604 we have identified, in human placenta, three cytosolic HCS PMID:9630604 essential for the catalytic activity of |
| GO:0005652 nuclear lamina | IDA PMID:14613969 Reduced histone biotinylation in multiple carboxylase defici... | KEEP AS NON CORE | Summary: Direct-assay (subnuclear fractionation) evidence that a fraction of HLCS associates with the nuclear lamina, part of the proposed nuclear/histone-biotinylation role. This moonlighting localization is debated and is not the core function. Reason: Real experimental observation but reflects a contested nuclear moonlighting role, not the core cytosolic/mitochondrial carboxylase-activation function. Retained as non-core. Supporting Evidence: PMID:14613969 localizes to the nucleus rather than the cytoplasm |
| GO:0005829 cytosol | IDA PMID:9630604 Identification of holocarboxylase synthetase (HCS) proteins ... | ACCEPT | Summary: Direct-assay evidence for cytosolic localization; HLCS proteins were identified as cytosolic in human placenta, and cell-free-synthesized HCS was not translocated into mitochondria, consistent with a cytosolic pool. Reason: Direct experimental support for cytosolic localization, a core compartment for HLCS. Supporting Evidence: PMID:9630604 we have identified, in human placenta, three cytosolic HCS |
| GO:0009374 biotin binding | IDA PMID:14613969 Reduced histone biotinylation in multiple carboxylase defici... | ACCEPT | Summary: Direct-assay evidence that HLCS binds biotin, the substrate it activates (as biotinyl-5'-AMP) prior to transfer to apocarboxylases. A supporting molecular function underpinning the core ligase activity. Reason: Biotin binding is an integral part of the HLCS catalytic mechanism and is directly supported; retained as a supporting molecular function. Supporting Evidence: PMID:14613969 Nuclear HCS retains its biotinylating activity |
| GO:0016363 nuclear matrix | IDA PMID:14613969 Reduced histone biotinylation in multiple carboxylase defici... | KEEP AS NON CORE | Summary: Direct-assay (subnuclear fractionation) evidence associating a fraction of HLCS with the nuclear matrix, part of the proposed nuclear/histone role. Debated moonlighting localization, not the core function. Reason: Real experimental observation but reflects the contested nuclear moonlighting role rather than the core function. Retained as non-core. Supporting Evidence: PMID:14613969 localizes to the nucleus rather than the cytoplasm |
| GO:0019899 enzyme binding | IPI PMID:19157941 N- and C-terminal domains in human holocarboxylase synthetas... | ACCEPT | Summary: Physical-interaction evidence (Y2H) with a propionyl-CoA carboxylase-derived polypeptide (p67; partner P05165 = PCCA). This captures HLCS binding to its carboxylase (apoenzyme) substrate via the N- and C-terminal domains, i.e. substrate recognition preceding biotinylation. Reason: More informative than bare protein binding - the partner PCCA is a genuine HLCS substrate (an enzyme), and the interaction reflects substrate recognition central to HLCS catalysis. Retained. Supporting Evidence: PMID:19157941 essential for biotinylation of carboxylases by HCS PMID:19157941 N- and C-termini play roles in substrate recognition |
| GO:0005829 cytosol | HDA PMID:16780588 Cell array-based intracellular localization screening reveal... | ACCEPT | Summary: High-throughput direct-assay (transfected-cell array localization screen of chromosome 21 proteins) placing HLCS in the cytosol. Consistent with the broader experimental and Reactome cytosolic annotations. Reason: Consistent cytosolic localization, corroborating multiple other lines of evidence. Supporting Evidence: PMID:16780588 the HLCS gene codes for a biotin-protein ligase and was found to localize throughout the cytosol |
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