HLCS

Existing Annotations Review

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). Examined as a synthesis row (ORGANELLES policy). The GO_REF:0000044 mapping comes from a UniProt location line whose evidence is ECO:0000305 (curator inference from PMID:7842009), not an assay; the inference is the genetic argument that HLCS-deficient patients lack all four carboxylase activities, so one HLCS must reach the mitochondrion (PMID:7753853). The organelle claim holds, though direct evidence is thin. HLCS has no annotated transit peptide or membrane segment, the mitochondrial import route is unknown, and fractionation westerns were described as inconclusive. The one targeted assay, an HLCS-KLAK fusion that killed HEK293 cells as mitochondrial proteins do, cannot resolve the sub-compartment by design (PMID:29454998). The matrix location of PC, PCC and MCC is then the only pointer to a sub-compartment. That is a single, functional line, so under rule 4 the annotation stays at the root and no matrix row is added. Supporting Evidence: PMID:7753853 a single HCS is targeted to the mitochondria and cytoplasm PMID:7753853 Patients with HCS deficiency lack activity of all four carboxylases, indicating that a single HCS is targeted to the mitochondria and cytoplasm. PMID:29454998 Western blots of mitochondrial HLCS are inconclusive PMID:29454998 Rapid cell death was evident when cells were transfected with KLAKLAKKLAKLAK fusion constructs of CPT1, ACC2, UCP1, and HLCS, judged by MTT assay file:human/HLCS/HLCS-uniprot.txt Mitochondrion {ECO:0000305\|PubMed:7842009}.
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

Gene Description

Existing Annotations Review

Core Functions

References

📚 Additional Documentation

Notes

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