id: O95255 gene_symbol: ABCC6 product_type: PROTEIN status: COMPLETE taxon: id: NCBITaxon:9606 label: Homo sapiens description: >- ABCC6 (MRP6) is an ATP-dependent organic-anion transporter expressed prominently at the basolateral membrane of hepatocytes. Human ABCC6 transports glutathione conjugates, including leukotriene C4, in membrane assays. Its principal physiological role is to support extracellular nucleotide release and inhibit ectopic mineralization. Released ATP is converted by ENPP1 to AMP and inorganic pyrophosphate (PPi), an inhibitor of calcium-phosphate crystal growth. Direct ATP passage through ABCC6 and the principal endogenous transported substrate remain unresolved. ABCC6 deficiency lowers circulating PPi, while local cellular pathways also influence mineralization. Biallelic pathogenic variants cause pseudoxanthoma elasticum and can cause generalized arterial calcification of infancy, affecting skin, eyes and arteries. The short alternative product URG7 has a distinct ER-membrane location and is not equivalent to the full-length transporter. alternative_products: - name: '1' id: O95255-1 - name: 2 (URG7 {ECO:0000303|PubMed:23912081}) id: O95255-2 sequence_note: VSP_047315, VSP_047316 - name: 3 (Delta19Delta24) id: O95255-3 sequence_note: VSP_057077, VSP_057078 existing_annotations: - term: id: GO:0005515 label: protein binding evidence_type: IPI original_reference_id: PMID:36115835 qualifier: enables supporting_entities: - UniProtKB:A4D2P6 review: summary: >- Generic protein binding to GRID2IP does not identify an informative ABCC6 molecular function. action: REMOVE reason: >- Remove the uninformative GO:0005515 assignment under the generic-binding policy; this does not assert that the reported interaction is false. Full text and Supplementary Dataset 1 were inspected. The ABCC6 peptide has composite pKd=0 for the assayed GRID2IP domains (50463, 61669), with no quantified positive domain affinity recovered for this partner. Matching IntAct records label the interactions non-negative but report kd:1.0x10(molar), unlike quantified micromolar values. The available assay does not establish a more specific positive molecular function for this partner. Only sampled domains and a 10-residue peptide were assayed, and the paper distinguishes unquantifiable weak affinities; neither zero composite pKd nor the export placeholder is treated as universal nonbinding. This residual affinity/export question is retained in the source audit and does not determine removal of the generic term. supported_by: - &id001 reference_id: PMID:36115835 supporting_text: >- We quantified 18,332 unique dissociation constants, whereas 46,825 PDZ-PBM affinities representing 72% of the explored space remained below the assay’s quantification threshold. - term: id: GO:0005515 label: protein binding evidence_type: IPI original_reference_id: PMID:36115835 qualifier: enables supporting_entities: - UniProtKB:O75970 review: summary: >- Generic protein binding to MPDZ does not identify an informative ABCC6 molecular function. action: REMOVE reason: >- Remove the uninformative GO:0005515 assignment under the generic-binding policy; this does not assert that the reported interaction is false. Full text and Supplementary Dataset 1 were inspected. The ABCC6 peptide has composite pKd=0 for the assayed MPDZ domains (47034, 55754, 56606), with no quantified positive domain affinity recovered for this partner. Matching IntAct records label the interactions non-negative but report kd:1.0x10(molar), unlike quantified micromolar values. The available assay does not establish a more specific positive molecular function for this partner. Only sampled domains and a 10-residue peptide were assayed, and the paper distinguishes unquantifiable weak affinities; neither zero composite pKd nor the export placeholder is treated as universal nonbinding. This residual affinity/export question is retained in the source audit and does not determine removal of the generic term. supported_by: - *id001 - term: id: GO:0005515 label: protein binding evidence_type: IPI original_reference_id: PMID:36115835 qualifier: enables supporting_entities: - UniProtKB:P78352 review: summary: >- The ABCC6 C-terminal peptide binds a PDZ domain of DLG4; PDZ domain binding is more informative than generic protein binding. action: MODIFY reason: >- Primary Supplementary Dataset 1 identifies O95255 peptide YRLAQESGLV (residues 1494-1503) and quantified affinity for DLG4_2 (row 16646, pKd 3.5488). This supports GO:0030165 at the fragment-assay level, without demonstrating a full-length cellular complex or a role for this partner in ATP release. The source audit records all measured domains and the IntAct discrepancy; other unquantified domains do not negate this positive domain result. This ancillary tail interaction is not included as a core transport function. supported_by: - *id001 proposed_replacement_terms: - id: GO:0030165 label: PDZ domain binding - term: id: GO:0005515 label: protein binding evidence_type: IPI original_reference_id: PMID:36115835 qualifier: enables supporting_entities: - UniProtKB:Q02410 review: summary: >- Generic protein binding to APBA1 does not identify an informative ABCC6 molecular function. action: REMOVE reason: >- Remove the uninformative GO:0005515 assignment under the generic-binding policy; this does not assert that the reported interaction is false. Full text and Supplementary Dataset 1 were inspected. The ABCC6 peptide has composite pKd=0 for the assayed APBA1 domains (49724, 57285), with no quantified positive domain affinity recovered for this partner. Matching IntAct records label the interactions non-negative but report kd:1.0x10(molar), unlike quantified micromolar values. The available assay does not establish a more specific positive molecular function for this partner. Only sampled domains and a 10-residue peptide were assayed, and the paper distinguishes unquantifiable weak affinities; neither zero composite pKd nor the export placeholder is treated as universal nonbinding. This residual affinity/export question is retained in the source audit and does not determine removal of the generic term. supported_by: - *id001 - term: id: GO:0005515 label: protein binding evidence_type: IPI original_reference_id: PMID:36115835 qualifier: enables supporting_entities: - UniProtKB:Q07157 review: summary: >- Generic protein binding to TJP1 does not identify an informative ABCC6 molecular function. action: REMOVE reason: >- Remove the uninformative GO:0005515 assignment under the generic-binding policy; this does not assert that the reported interaction is false. Full text and Supplementary Dataset 1 were inspected. The ABCC6 peptide has composite pKd=0 for the assayed TJP1 domains (52369, 59502), with no quantified positive domain affinity recovered for this partner. Matching IntAct records label the interactions non-negative but report kd:1.0x10(molar), unlike quantified micromolar values. The available assay does not establish a more specific positive molecular function for this partner. Only sampled domains and a 10-residue peptide were assayed, and the paper distinguishes unquantifiable weak affinities; neither zero composite pKd nor the export placeholder is treated as universal nonbinding. This residual affinity/export question is retained in the source audit and does not determine removal of the generic term. supported_by: - *id001 - term: id: GO:0005515 label: protein binding evidence_type: IPI original_reference_id: PMID:36115835 qualifier: enables supporting_entities: - UniProtKB:Q12959 review: summary: >- Generic protein binding to DLG1 does not identify an informative ABCC6 molecular function. action: REMOVE reason: >- Remove the uninformative GO:0005515 assignment under the generic-binding policy; this does not assert that the reported interaction is false. Full text and Supplementary Dataset 1 were inspected. The ABCC6 peptide has composite pKd=0 for the assayed DLG1 domains (39815, 55062, 62943), with no quantified positive domain affinity recovered for this partner. Matching IntAct records label the interactions non-negative but report kd:1.0x10(molar), unlike quantified micromolar values. The available assay does not establish a more specific positive molecular function for this partner. Only sampled domains and a 10-residue peptide were assayed, and the paper distinguishes unquantifiable weak affinities; neither zero composite pKd nor the export placeholder is treated as universal nonbinding. This residual affinity/export question is retained in the source audit and does not determine removal of the generic term. supported_by: - *id001 - term: id: GO:0005515 label: protein binding evidence_type: IPI original_reference_id: PMID:36115835 qualifier: enables supporting_entities: - UniProtKB:Q14005 review: summary: >- Generic protein binding to IL16 does not identify an informative ABCC6 molecular function. action: REMOVE reason: >- Remove the uninformative GO:0005515 assignment under the generic-binding policy; this does not assert that the reported interaction is false. Full text and Supplementary Dataset 1 were inspected. The ABCC6 peptide has composite pKd=0 for the assayed IL16 domains (48744, 49937, 60770), with no quantified positive domain affinity recovered for this partner. Matching IntAct records label the interactions non-negative but report kd:1.0x10(molar), unlike quantified micromolar values. The available assay does not establish a more specific positive molecular function for this partner. Only sampled domains and a 10-residue peptide were assayed, and the paper distinguishes unquantifiable weak affinities; neither zero composite pKd nor the export placeholder is treated as universal nonbinding. This residual affinity/export question is retained in the source audit and does not determine removal of the generic term. supported_by: - *id001 - term: id: GO:0005515 label: protein binding evidence_type: IPI original_reference_id: PMID:36115835 qualifier: enables supporting_entities: - UniProtKB:Q14160 review: summary: >- Generic protein binding to SCRIB does not identify an informative ABCC6 molecular function. action: REMOVE reason: >- Remove the uninformative GO:0005515 assignment under the generic-binding policy; this does not assert that the reported interaction is false. Full text and Supplementary Dataset 1 were inspected. The ABCC6 peptide has composite pKd=0 for the assayed SCRIB domains (48823, 52177, 62177), with no quantified positive domain affinity recovered for this partner. Matching IntAct records label the interactions non-negative but report kd:1.0x10(molar), unlike quantified micromolar values. The available assay does not establish a more specific positive molecular function for this partner. Only sampled domains and a 10-residue peptide were assayed, and the paper distinguishes unquantifiable weak affinities; neither zero composite pKd nor the export placeholder is treated as universal nonbinding. This residual affinity/export question is retained in the source audit and does not determine removal of the generic term. supported_by: - *id001 - term: id: GO:0005515 label: protein binding evidence_type: IPI original_reference_id: PMID:36115835 qualifier: enables supporting_entities: - UniProtKB:Q15700 review: summary: >- Generic protein binding to DLG2 does not identify an informative ABCC6 molecular function. action: REMOVE reason: >- Remove the uninformative GO:0005515 assignment under the generic-binding policy; this does not assert that the reported interaction is false. Full text and Supplementary Dataset 1 were inspected. The ABCC6 peptide has composite pKd=0 for the assayed DLG2 domains (44443, 63935), with no quantified positive domain affinity recovered for this partner. Matching IntAct records label the interactions non-negative but report kd:1.0x10(molar), unlike quantified micromolar values. The available assay does not establish a more specific positive molecular function for this partner. Only sampled domains and a 10-residue peptide were assayed, and the paper distinguishes unquantifiable weak affinities; neither zero composite pKd nor the export placeholder is treated as universal nonbinding. This residual affinity/export question is retained in the source audit and does not determine removal of the generic term. supported_by: - *id001 - term: id: GO:0005515 label: protein binding evidence_type: IPI original_reference_id: PMID:36115835 qualifier: enables supporting_entities: - UniProtKB:Q5T2W1 review: summary: >- The ABCC6 C-terminal peptide binds a PDZ domain of NHERF3; PDZ domain binding is more informative than generic protein binding. action: MODIFY reason: >- Primary Supplementary Dataset 1 identifies O95255 peptide YRLAQESGLV (residues 1494-1503) and quantified affinity for NHERF3_1 (row 12780, pKd 3.7629). This supports GO:0030165 at the fragment-assay level, without demonstrating a full-length cellular complex or a role for this partner in ATP release. The source audit records all measured domains and the IntAct discrepancy; other unquantified domains do not negate this positive domain result. This ancillary tail interaction is not included as a core transport function. supported_by: - *id001 proposed_replacement_terms: - id: GO:0030165 label: PDZ domain binding - term: id: GO:0005515 label: protein binding evidence_type: IPI original_reference_id: PMID:36115835 qualifier: enables supporting_entities: - UniProtKB:Q68DX3 review: summary: >- Generic protein binding to FRMPD2 does not identify an informative ABCC6 molecular function. action: REMOVE reason: >- Remove the uninformative GO:0005515 assignment under the generic-binding policy; this does not assert that the reported interaction is false. Full text and Supplementary Dataset 1 were inspected. The ABCC6 peptide has composite pKd=0 for the assayed FRMPD2 domains (42786, 56680, 61158), with no quantified positive domain affinity recovered for this partner. Matching IntAct records label the interactions non-negative but report kd:1.0x10(molar), unlike quantified micromolar values. The available assay does not establish a more specific positive molecular function for this partner. Only sampled domains and a 10-residue peptide were assayed, and the paper distinguishes unquantifiable weak affinities; neither zero composite pKd nor the export placeholder is treated as universal nonbinding. This residual affinity/export question is retained in the source audit and does not determine removal of the generic term. supported_by: - *id001 - term: id: GO:0005515 label: protein binding evidence_type: IPI original_reference_id: PMID:36115835 qualifier: enables supporting_entities: - UniProtKB:Q86UL8 review: summary: >- The ABCC6 C-terminal peptide binds a PDZ domain of MAGI2; PDZ domain binding is more informative than generic protein binding. action: MODIFY reason: >- Primary Supplementary Dataset 1 identifies O95255 peptide YRLAQESGLV (residues 1494-1503) and quantified affinity for MAGI2_4 (row 10921, pKd 3.8891); MAGI2_5 (row 15495, pKd 3.6070). This supports GO:0030165 at the fragment-assay level, without demonstrating a full-length cellular complex or a role for this partner in ATP release. The source audit records all measured domains and the IntAct discrepancy; other unquantified domains do not negate this positive domain result. This ancillary tail interaction is not included as a core transport function. supported_by: - *id001 proposed_replacement_terms: - id: GO:0030165 label: PDZ domain binding - term: id: GO:0005515 label: protein binding evidence_type: IPI original_reference_id: PMID:36115835 qualifier: enables supporting_entities: - UniProtKB:Q86UT5 review: summary: >- The ABCC6 C-terminal peptide binds a PDZ domain of NHERF4; PDZ domain binding is more informative than generic protein binding. action: MODIFY reason: >- Primary Supplementary Dataset 1 identifies O95255 peptide YRLAQESGLV (residues 1494-1503) and quantified affinity for NHERF4_1 (row 17477, pKd 3.5094). This supports GO:0030165 at the fragment-assay level, without demonstrating a full-length cellular complex or a role for this partner in ATP release. The source audit records all measured domains and the IntAct discrepancy; other unquantified domains do not negate this positive domain result. This ancillary tail interaction is not included as a core transport function. supported_by: - *id001 proposed_replacement_terms: - id: GO:0030165 label: PDZ domain binding - term: id: GO:0005515 label: protein binding evidence_type: IPI original_reference_id: PMID:36115835 qualifier: enables supporting_entities: - UniProtKB:Q8N448 review: summary: >- Generic protein binding to LNX2 does not identify an informative ABCC6 molecular function. action: REMOVE reason: >- Remove the uninformative GO:0005515 assignment under the generic-binding policy; this does not assert that the reported interaction is false. Full text and Supplementary Dataset 1 were inspected. The ABCC6 peptide has composite pKd=0 for the assayed LNX2 domains (62719, 65120), with no quantified positive domain affinity recovered for this partner. Matching IntAct records label the interactions non-negative but report kd:1.0x10(molar), unlike quantified micromolar values. The available assay does not establish a more specific positive molecular function for this partner. Only sampled domains and a 10-residue peptide were assayed, and the paper distinguishes unquantifiable weak affinities; neither zero composite pKd nor the export placeholder is treated as universal nonbinding. This residual affinity/export question is retained in the source audit and does not determine removal of the generic term. supported_by: - *id001 - term: id: GO:0005515 label: protein binding evidence_type: IPI original_reference_id: PMID:36115835 qualifier: enables supporting_entities: - UniProtKB:Q8NI35 review: summary: >- Generic protein binding to Inadl does not identify an informative ABCC6 molecular function. action: REMOVE reason: >- Remove the uninformative GO:0005515 assignment under the generic-binding policy; this does not assert that the reported interaction is false. Full text and Supplementary Dataset 1 were inspected. The ABCC6 peptide has composite pKd=0 for the assayed Inadl domains (37552, 40120, 41900, 43903, 44160, 48978, 54404, 59067, 61453), with no quantified positive domain affinity recovered for this partner. Matching IntAct records label the interactions non-negative but report kd:1.0x10(molar), unlike quantified micromolar values. The available assay does not establish a more specific positive molecular function for this partner. Only sampled domains and a 10-residue peptide were assayed, and the paper distinguishes unquantifiable weak affinities; neither zero composite pKd nor the export placeholder is treated as universal nonbinding. This residual affinity/export question is retained in the source audit and does not determine removal of the generic term. supported_by: - *id001 - term: id: GO:0005515 label: protein binding evidence_type: IPI original_reference_id: PMID:36115835 qualifier: enables supporting_entities: - UniProtKB:Q8TBB1 review: summary: >- Generic protein binding to LNX1 does not identify an informative ABCC6 molecular function. action: REMOVE reason: >- Remove the uninformative GO:0005515 assignment under the generic-binding policy; this does not assert that the reported interaction is false. Full text and Supplementary Dataset 1 were inspected. The ABCC6 peptide has composite pKd=0 for the assayed LNX1 domains (34831, 41961, 53303), with no quantified positive domain affinity recovered for this partner. Matching IntAct records label the interactions non-negative but report kd:1.0x10(molar), unlike quantified micromolar values. The available assay does not establish a more specific positive molecular function for this partner. Only sampled domains and a 10-residue peptide were assayed, and the paper distinguishes unquantifiable weak affinities; neither zero composite pKd nor the export placeholder is treated as universal nonbinding. This residual affinity/export question is retained in the source audit and does not determine removal of the generic term. supported_by: - *id001 - term: id: GO:0005515 label: protein binding evidence_type: IPI original_reference_id: PMID:36115835 qualifier: enables supporting_entities: - UniProtKB:Q92796 review: summary: >- Generic protein binding to DLG3 does not identify an informative ABCC6 molecular function. action: REMOVE reason: >- Remove the uninformative GO:0005515 assignment under the generic-binding policy; this does not assert that the reported interaction is false. Full text and Supplementary Dataset 1 were inspected. The ABCC6 peptide has composite pKd=0 for the assayed DLG3 domains (34954, 53944, 58869), with no quantified positive domain affinity recovered for this partner. Matching IntAct records label the interactions non-negative but report kd:1.0x10(molar), unlike quantified micromolar values. The available assay does not establish a more specific positive molecular function for this partner. Only sampled domains and a 10-residue peptide were assayed, and the paper distinguishes unquantifiable weak affinities; neither zero composite pKd nor the export placeholder is treated as universal nonbinding. This residual affinity/export question is retained in the source audit and does not determine removal of the generic term. supported_by: - *id001 - term: id: GO:0005515 label: protein binding evidence_type: IPI original_reference_id: PMID:36115835 qualifier: enables supporting_entities: - UniProtKB:Q96QZ7 review: summary: >- Generic protein binding to MAGI1 does not identify an informative ABCC6 molecular function. action: REMOVE reason: >- Remove the uninformative GO:0005515 assignment under the generic-binding policy; this does not assert that the reported interaction is false. Full text and Supplementary Dataset 1 were inspected. The ABCC6 peptide has composite pKd=0 for the assayed MAGI1 domains (37650, 52750), with no quantified positive domain affinity recovered for this partner. Matching IntAct records label the interactions non-negative but report kd:1.0x10(molar), unlike quantified micromolar values. The available assay does not establish a more specific positive molecular function for this partner. Only sampled domains and a 10-residue peptide were assayed, and the paper distinguishes unquantifiable weak affinities; neither zero composite pKd nor the export placeholder is treated as universal nonbinding. This residual affinity/export question is retained in the source audit and does not determine removal of the generic term. supported_by: - *id001 - term: id: GO:0005515 label: protein binding evidence_type: IPI original_reference_id: PMID:36115835 qualifier: enables supporting_entities: - UniProtKB:Q99767 review: summary: >- Generic protein binding to APBA2 does not identify an informative ABCC6 molecular function. action: REMOVE reason: >- Remove the uninformative GO:0005515 assignment under the generic-binding policy; this does not assert that the reported interaction is false. Full text and Supplementary Dataset 1 were inspected. The ABCC6 peptide has composite pKd=0 for the assayed APBA2 domains (39467, 49809), with no quantified positive domain affinity recovered for this partner. Matching IntAct records label the interactions non-negative but report kd:1.0x10(molar), unlike quantified micromolar values. The available assay does not establish a more specific positive molecular function for this partner. Only sampled domains and a 10-residue peptide were assayed, and the paper distinguishes unquantifiable weak affinities; neither zero composite pKd nor the export placeholder is treated as universal nonbinding. This residual affinity/export question is retained in the source audit and does not determine removal of the generic term. supported_by: - *id001 - term: id: GO:0005515 label: protein binding evidence_type: IPI original_reference_id: PMID:36115835 qualifier: enables supporting_entities: - UniProtKB:Q9C0E4 review: summary: >- Generic protein binding to GRIP2 does not identify an informative ABCC6 molecular function. action: REMOVE reason: >- Remove the uninformative GO:0005515 assignment under the generic-binding policy; this does not assert that the reported interaction is false. Full text and Supplementary Dataset 1 were inspected. The ABCC6 peptide has composite pKd=0 for the assayed GRIP2 domains (41004, 45022, 46813, 48995, 51806), with no quantified positive domain affinity recovered for this partner. Matching IntAct records label the interactions non-negative but report kd:1.0x10(molar), unlike quantified micromolar values. The available assay does not establish a more specific positive molecular function for this partner. Only sampled domains and a 10-residue peptide were assayed, and the paper distinguishes unquantifiable weak affinities; neither zero composite pKd nor the export placeholder is treated as universal nonbinding. This residual affinity/export question is retained in the source audit and does not determine removal of the generic term. supported_by: - *id001 - term: id: GO:0005515 label: protein binding evidence_type: IPI original_reference_id: PMID:36115835 qualifier: enables supporting_entities: - UniProtKB:Q9P202 review: summary: >- The ABCC6 C-terminal peptide binds a PDZ domain of DFNB31; PDZ domain binding is more informative than generic protein binding. action: MODIFY reason: >- Primary Supplementary Dataset 1 identifies O95255 peptide YRLAQESGLV (residues 1494-1503) and quantified affinity for DFNB31_3 (row 10236, pKd 3.9407). This supports GO:0030165 at the fragment-assay level, without demonstrating a full-length cellular complex or a role for this partner in ATP release. The source audit records all measured domains and the IntAct discrepancy; other unquantified domains do not negate this positive domain result. This ancillary tail interaction is not included as a core transport function. supported_by: - *id001 proposed_replacement_terms: - id: GO:0030165 label: PDZ domain binding - term: id: GO:0005515 label: protein binding evidence_type: IPI original_reference_id: PMID:36115835 qualifier: enables supporting_entities: - UniProtKB:Q9Y3R0 review: summary: >- Generic protein binding to GRIP1 does not identify an informative ABCC6 molecular function. action: REMOVE reason: >- Remove the uninformative GO:0005515 assignment under the generic-binding policy; this does not assert that the reported interaction is false. Full text and Supplementary Dataset 1 were inspected. The ABCC6 peptide has composite pKd=0 for the assayed GRIP1 domains (38341, 38977, 39483, 44501, 47821), with no quantified positive domain affinity recovered for this partner. Matching IntAct records label the interactions non-negative but report kd:1.0x10(molar), unlike quantified micromolar values. The available assay does not establish a more specific positive molecular function for this partner. Only sampled domains and a 10-residue peptide were assayed, and the paper distinguishes unquantifiable weak affinities; neither zero composite pKd nor the export placeholder is treated as universal nonbinding. This residual affinity/export question is retained in the source audit and does not determine removal of the generic term. supported_by: - *id001 - term: id: GO:0005524 label: ATP binding evidence_type: IDA original_reference_id: PMID:11880368 qualifier: enables review: summary: >- ATP binding is intrinsic to the ABCC6 nucleotide-binding domains. action: ACCEPT reason: >- PMID:11880368 directly reports ATP binding in membranes expressing full-length human ABCC6 and normal MgATP binding in the tested transport-deficient variants. This is energy-coupling nucleotide recognition, not evidence that ATP is the transported substrate. supported_by: - &id002 reference_id: PMID:11880368 supporting_text: >- In isolated membranes ATP binding as well as ATP-dependent active transport by ABCC6 was demonstrated. - term: id: GO:0005524 label: ATP binding evidence_type: IEA original_reference_id: GO_REF:0000002 qualifier: enables supporting_entities: - InterPro:IPR003439 - InterPro:IPR011527 - InterPro:IPR017871 - InterPro:IPR036640 review: summary: >- ATP binding is intrinsic to the ABCC6 nucleotide-binding domains. action: ACCEPT reason: >- The matched ABC nucleotide-binding domains/signatures support ATP recognition, independently corroborated by full-length human ABCC6 assays in PMID:11880368. Domain membership does not identify ATP as transport cargo. supported_by: - *id002 propagation_review: root_cause: NO_FAILURE_CORE source_entities: - source_id: InterPro:IPR003439 source_status: SUPPORTS_TRANSFER comment: >- The matched ABC ATP-binding domain supports nucleotide binding/catalysis. - source_id: InterPro:IPR011527 source_status: SUPPORTS_TRANSFER comment: >- The matched ABC ATP-binding domain supports nucleotide binding/catalysis. - source_id: InterPro:IPR017871 source_status: SUPPORTS_TRANSFER comment: >- The matched ABC ATP-binding domain supports nucleotide binding/catalysis. - source_id: InterPro:IPR036640 source_status: SUPPORTS_TRANSFER comment: >- The matched ABC ATP-binding domain supports nucleotide binding/catalysis. - term: id: GO:0005524 label: ATP binding evidence_type: TAS original_reference_id: PMID:8912525 qualifier: enables review: summary: >- ATP binding is intrinsic to the ABCC6 nucleotide-binding domains. action: ACCEPT reason: >- The original ARA paper describes an ATP-binding site in a partial sequence. Retain this author-statement assignment with independent confirmation from later full-length human ABCC6 assays; the historical small ARA product is not used to infer full-length architecture. supported_by: - *id002 - term: id: GO:0005576 label: extracellular region evidence_type: IDA original_reference_id: PMID:28592560 qualifier: is_active_in review: summary: >- The paper concerns extracellular metabolites and calcification, not localization of ABCC6 protein outside the cell. action: MARK_AS_OVER_ANNOTATED reason: >- The complete source was examined: extracellular PPi, nucleotide metabolism and local/systemic mineralization are its outcomes. ABCC6 itself executes transport at the plasma membrane, independently localized in native human liver. GO:0005576 denotes space outside the plasma membrane; extracellular metabolites and extracellular loops do not demonstrate an extracellular site of action for the complete transporter. The compartment assignment overshoots this evidence without denying the extracellular effects of the released metabolites. supported_by: - &id012 reference_id: PMID:28592560 supporting_text: >- Here, both genetic and metabolic analyses provide compelling evidence that ABCC6 acts in concert with ENPP1 and CD73 to regulate extracellular PPi, a major physiologic inhibitor of calcification. - &id003 reference_id: PMID:23625951 supporting_text: >- Our results show unambiguously that in frozen sections of mouse and human livers, Abcc6/ABCC6 is colocalized with the plasma membrane markers cadherin (Figure 1A, D) and catenin (not shown) as well as the basolateral membrane marker Na,K-ATPase (Figure 1B). - term: id: GO:0005789 label: endoplasmic reticulum membrane evidence_type: IEA original_reference_id: GO_REF:0000044 qualifier: located_in supporting_entities: - UniProtKB-SubCell:SL-0097 review: summary: >- The ER membrane mapping is supported for the short URG7 alternative product. action: KEEP_AS_NON_CORE reason: >- UniProt SL-0097 traces to the URG7 isoform (O95255-2), whose ER localization and N-lumen/C-cytosol topology are reported directly in PMID:23912081. Its abstract is sufficient for this positive location; detailed methods remain unavailable. The seeded tuple lacks an isoform flag and is preserved as supplied; this review scopes the assignment explicitly to URG7, not the predominant full-length basolateral transporter. supported_by: - reference_id: PMID:23912081 supporting_text: >- The results demonstrate that URG7 is N-glycosylated and located to the endoplasmic reticulum membrane with an Nlumen-Ccytosol orientation. propagation_review: root_cause: NO_FAILURE_NON_CORE source_entities: - source_id: UniProtKB-SubCell:SL-0097 source_status: SUPPORTS_TRANSFER comment: >- This subcellular-location vocabulary maps to the stated compartment. The originating location applies to URG7 O95255-2, not unrestricted full-length ABCC6 localization. - term: id: GO:0005886 label: plasma membrane evidence_type: IBA original_reference_id: GO_REF:0000033 qualifier: is_active_in supporting_entities: - FB:FBgn0032456 - MGI:MGI:102676 - MGI:MGI:1351634 - MGI:MGI:1352447 - MGI:MGI:1352629 - MGI:MGI:1352630 - MGI:MGI:1923658 - PANTHER:PTN002795584 - RGD:2366 - RGD:3112 - RGD:3786 - RGD:3787 - RGD:620268 - RGD:71101 - UniProtKB:O15438 - UniProtKB:O60706 - UniProtKB:O95255 - UniProtKB:P33527 - UniProtKB:Q09428 - UniProtKB:Q92887 - WB:WBGene00003407 review: summary: >- Full-length ABCC6 is a plasma-membrane transporter. action: ACCEPT reason: >- The traced PAINT ancestral node agrees with direct native human liver and polarized-cell plasma-membrane localization. The more precise basolateral compartment is compatible with this parent term; no target-specific localization loss is evident. supported_by: - *id003 - &id004 reference_id: PMID:12901863 supporting_text: >- human ABCC6, when expressed by retroviral transduction in polarized mammalian (MDCKII) cells, is exclusively localized to the basolateral membrane. propagation_review: root_cause: NO_FAILURE_CORE source_entities: - source_id: PANTHER:PTN002795584 source_status: SUPPORTS_TRANSFER comment: >- The seeded ancestral PAINT node supports plasma membrane. Human transport/localization evidence is compatible with retention of this inherited function. The node was traced; the complete PAINT tree was not re-curated, and target inclusion among descendants is not circularity. - term: id: GO:0005886 label: plasma membrane evidence_type: IDA original_reference_id: GO_REF:0000052 qualifier: located_in review: summary: >- Full-length ABCC6 is a plasma-membrane transporter. action: ACCEPT reason: >- Retain the immunofluorescence-curated location, independently corroborated by native human liver staining with plasma-membrane markers. The broad compartment is compatible with the more specific basolateral distribution. supported_by: - *id003 - *id004 - term: id: GO:0005886 label: plasma membrane evidence_type: TAS original_reference_id: PMID:10835642 qualifier: located_in review: summary: >- Full-length ABCC6 is a plasma-membrane transporter. action: ACCEPT reason: >- Retain the gene-discovery paper author statement about this membrane ABC transporter, independently corroborated by later direct native human localization. The gene-discovery abstract alone is not represented as a compartment-marker assay. supported_by: - *id003 - *id004 - term: id: GO:0005886 label: plasma membrane evidence_type: TAS original_reference_id: Reactome:R-HSA-1454916 qualifier: located_in review: summary: >- Full-length ABCC6 is a plasma-membrane transporter. action: ACCEPT reason: >- The ABCC-family Reactome transport pathway places this transporter at the plasma membrane, consistent with native human immunostaining and polarized-cell evidence. The family pathway is not used to assign every ABCC substrate to ABCC6. supported_by: - *id003 - *id004 - term: id: GO:0005886 label: plasma membrane evidence_type: TAS original_reference_id: Reactome:R-HSA-5690340 qualifier: located_in review: summary: >- Full-length ABCC6 is a plasma-membrane transporter. action: ACCEPT reason: >- This Reactome disease event describes failure of mutant ABCC6 to export organic anions. The disease-event title does not negate normal protein location; native human immunostaining independently supports plasma-membrane localization. supported_by: - *id003 - *id004 - term: id: GO:0009410 label: response to xenobiotic stimulus evidence_type: IEA original_reference_id: GO_REF:0000117 qualifier: involved_in supporting_entities: - ARBA:ARBA00092608 review: summary: >- Heterologous ABCC6 expression can confer limited resistance to xenobiotic anticancer agents. action: KEEP_AS_NON_CORE reason: >- PMID:12414644 reports low resistance to defined compounds in transfected cells, supporting this context. The early ARA association and electronic rule do not establish xenobiotic response as the principal physiological role; systemic anti-mineralization is better grounded. Rule predicates were not independently re-curated. supported_by: - &id005 reference_id: PMID:12414644 supporting_text: >- Analysis of the drug sensitivity of MRP6-transfected cells revealed low levels of resistance to several natural product agents, including etoposide, teniposide, doxorubicin, and daunorubicin. propagation_review: root_cause: NO_FAILURE_NON_CORE source_entities: - source_id: ARBA:ARBA00092608 source_status: UNRESOLVED comment: >- The rule identifier was traced from the seed, but its complete predicates were not independently audited. The action rests on the named primary evidence, not an assumption about the rule. - term: id: GO:0009410 label: response to xenobiotic stimulus evidence_type: TAS original_reference_id: PMID:8912525 qualifier: involved_in review: summary: >- Heterologous ABCC6 expression can confer limited resistance to xenobiotic anticancer agents. action: KEEP_AS_NON_CORE reason: >- PMID:12414644 reports low resistance to defined compounds in transfected cells, supporting this context. The early ARA association and electronic rule do not establish xenobiotic response as the principal physiological role; systemic anti-mineralization is better grounded. Rule predicates were not independently re-curated. supported_by: - *id005 - term: id: GO:0009925 label: basal plasma membrane evidence_type: IDA original_reference_id: PMID:35307651 qualifier: located_in review: summary: >- Human tissue staining places MRP6 at the basal membrane of Sertoli cells. action: ACCEPT reason: >- The primary study explicitly names MRP6 and reports Sertoli basal-membrane and peritubular myoid-cell staining. This direct human evidence supports the basal subcompartment and SL-0024 mapping, while not demonstrating any particular testicular transported substrate. supported_by: - &id006 reference_id: PMID:35307651 supporting_text: >- OCTN2, multidrug resistance protein (MRP) 3, MRP6, and MRP7 localized to SC basal membranes and peritubular myoid cells (PMCs) surrounding the seminiferous tubules. - term: id: GO:0009925 label: basal plasma membrane evidence_type: IEA original_reference_id: GO_REF:0000044 qualifier: located_in supporting_entities: - UniProtKB-SubCell:SL-0024 review: summary: >- Human tissue staining places MRP6 at the basal membrane of Sertoli cells. action: ACCEPT reason: >- The primary study explicitly names MRP6 and reports Sertoli basal-membrane and peritubular myoid-cell staining. This direct human evidence supports the basal subcompartment and SL-0024 mapping, while not demonstrating any particular testicular transported substrate. supported_by: - *id006 propagation_review: root_cause: NO_FAILURE_CORE source_entities: - source_id: UniProtKB-SubCell:SL-0024 source_status: SUPPORTS_TRANSFER comment: >- This subcellular-location vocabulary maps to the stated compartment. Direct human localization independently supports the compartment. - term: id: GO:0010467 label: gene expression evidence_type: IDA original_reference_id: PMID:28592560 qualifier: involved_in review: summary: >- Altered expression of other enzymes after ABCC6 deficiency does not make ABCC6 a gene-expression component. action: MARK_AS_OVER_ANNOTATED reason: >- The full paper measures ENPP1, CD73 and TNAP changes in patient fibroblasts and models a metabolic/signaling pathway. GO:0010467 means producing a mature RNA/protein product from a gene. ABCC6 performs membrane transport; the gene-expression readouts are downstream responses, not evidence it executes transcription, RNA processing or translation. No substitute transcriptional function is proposed. supported_by: - &id011 reference_id: PMID:28592560 supporting_text: >- We demonstrate that ABCC6Mut/Mut cells have the intrinsic capacity to calcify in vitro and have altered activity of enzymes involved in ATP catabolism—specifically, increased ENPP1 and TNAP and decreased CD73 enzymatic activities. - term: id: GO:0015431 label: ABC-type glutathione S-conjugate transporter activity evidence_type: EXP original_reference_id: PMID:12414644 qualifier: enables review: summary: >- Human ABCC6 directly catalyzes ATP-dependent export of glutathione S-conjugates in membrane-vesicle assays. action: ACCEPT reason: >- Independent human-expression experiments in PMID:11880368 and PMID:12414644 identify leukotriene C4 and artificial glutathione conjugates as substrates. EC:7.6.2.3 matches this chemistry. The primary abstracts explicitly support these positive transport results; unavailable full methods are not reconstructed. This established substrate capability does not identify the major endogenous cargo responsible for mineralization control. supported_by: - &id007 reference_id: PMID:11880368 supporting_text: >- We found that glutathione conjugates, including leukotriene C(4) and N-ethylmaleimide S-glutathione (NEM-GS), were actively transported by human ABCC6. - &id008 reference_id: PMID:11880368 supporting_text: >- Our data indicate that human ABCC6 is a primary active transporter for organic anions. - term: id: GO:0015431 label: ABC-type glutathione S-conjugate transporter activity evidence_type: IDA original_reference_id: PMID:11880368 qualifier: enables review: summary: >- Human ABCC6 directly catalyzes ATP-dependent export of glutathione S-conjugates in membrane-vesicle assays. action: ACCEPT reason: >- Independent human-expression experiments in PMID:11880368 and PMID:12414644 identify leukotriene C4 and artificial glutathione conjugates as substrates. EC:7.6.2.3 matches this chemistry. The primary abstracts explicitly support these positive transport results; unavailable full methods are not reconstructed. This established substrate capability does not identify the major endogenous cargo responsible for mineralization control. supported_by: - *id007 - *id008 - term: id: GO:0015431 label: ABC-type glutathione S-conjugate transporter activity evidence_type: IEA original_reference_id: GO_REF:0000003 qualifier: enables supporting_entities: - EC:7.6.2.3 review: summary: >- Human ABCC6 directly catalyzes ATP-dependent export of glutathione S-conjugates in membrane-vesicle assays. action: ACCEPT reason: >- Independent human-expression experiments in PMID:11880368 and PMID:12414644 identify leukotriene C4 and artificial glutathione conjugates as substrates. EC:7.6.2.3 matches this chemistry. The primary abstracts explicitly support these positive transport results; unavailable full methods are not reconstructed. This established substrate capability does not identify the major endogenous cargo responsible for mineralization control. supported_by: - *id007 - *id008 propagation_review: root_cause: NO_FAILURE_CORE source_entities: - source_id: EC:7.6.2.3 source_status: SUPPORTS_TRANSFER comment: >- EC:7.6.2.3 maps directly to ATP-dependent glutathione S-conjugate export, corroborated by human substrate assays. - term: id: GO:0015867 label: ATP transport evidence_type: IDA original_reference_id: PMID:24277820 qualifier: involved_in review: summary: >- ABCC6-dependent cellular ATP release is supported, while the route of ATP translocation remains unresolved. action: KEEP_AS_NON_CORE reason: >- Retain the experimentally curated release-associated biological process as non-core, rather than a defined direct transport step performed by ABCC6. The accessible original abstract reports that human and rat ABCC6 expression promotes cellular nucleoside-triphosphate release while explicitly distinguishing this from transport by ABCC6 itself; uninspected full-text methods are not asserted. Full PMID:24969777 independently supports ABCC6-dependent ATP release and allows an indirect vesicular or channel mechanism. This preserves the positive cellular result without assigning ATP as ABCC6 cargo or making ATP transport a demonstrated core molecular mechanism. supported_by: - &id009 reference_id: PMID:24277820 supporting_text: >- cells expressing ABCC6 excrete large amounts of nucleoside triphosphates, even though ABCC6 itself does not transport nucleoside triphosphates. - &id010 reference_id: PMID:24969777 supporting_text: >- Factors could be missing in vitro, however, that allows ABCC6 to transport ATP in vivo, or ABCC6 could indirectly stimulate ATP release by regulating vesicular transport or ion channels. - term: id: GO:0015867 label: ATP transport evidence_type: IDA original_reference_id: PMID:24969777 qualifier: involved_in review: summary: >- ABCC6-dependent cellular ATP release is supported, while the route of ATP translocation remains unresolved. action: KEEP_AS_NON_CORE reason: >- The full source directly measures ATP appearance after inducible rat ABCC6 expression in human HEK293 and HeLa cells, and relates mouse hepatic ATP release to extracellular AMP/PPi production. Retain this experimentally curated release-associated biological process as non-core. The authors could not demonstrate nucleoside-triphosphate transport in vesicles and allow either a missing factor in vivo or indirect stimulation of a vesicular/channel route. ABCC6 dependence therefore supports the cellular release association without establishing the entity that translocates ATP; it does not assign ATP as ABCC6 cargo or define direct ATP transport as its core mechanism. supported_by: - *id009 - *id010 - term: id: GO:0016020 label: membrane evidence_type: IEA original_reference_id: GO_REF:0000002 qualifier: located_in supporting_entities: - InterPro:IPR005292 - InterPro:IPR011527 - InterPro:IPR036640 review: summary: >- ABCC6 is a multi-pass integral membrane transporter. action: ACCEPT reason: >- The matched MRP/ABC transmembrane domains support membrane association; direct localization provides the more precise plasma-membrane context. This broad annotation is correct, including for alternative membrane products. supported_by: - *id003 propagation_review: root_cause: NO_FAILURE_CORE source_entities: - source_id: InterPro:IPR005292 source_status: SUPPORTS_TRANSFER comment: >- The matched ABC/MRP transmembrane domain supports membrane transport architecture; physiological substrate identity is not inferred from this match. - source_id: InterPro:IPR011527 source_status: SUPPORTS_TRANSFER comment: >- The matched ABC/MRP transmembrane domain supports membrane transport architecture; physiological substrate identity is not inferred from this match. - source_id: InterPro:IPR036640 source_status: SUPPORTS_TRANSFER comment: >- The matched ABC/MRP transmembrane domain supports membrane transport architecture; physiological substrate identity is not inferred from this match. - term: id: GO:0016323 label: basolateral plasma membrane evidence_type: IBA original_reference_id: GO_REF:0000033 qualifier: is_active_in supporting_entities: - MGI:MGI:1351634 - PANTHER:PTN009085618 - RGD:3112 - RGD:620268 - UniProtKB:O95255 - UniProtKB:P33527 review: summary: >- The canonical transporter localizes to the basolateral plasma membrane. action: ACCEPT reason: >- The traced basolateral PAINT node agrees with human ABCC6 localization in polarized MDCKII cells and native human hepatocytes. Retaining this inherited compartment does not extend the assignment to the distinct short URG7 product. supported_by: - *id004 - *id003 propagation_review: root_cause: NO_FAILURE_CORE source_entities: - source_id: PANTHER:PTN009085618 source_status: SUPPORTS_TRANSFER comment: >- The seeded ancestral PAINT node supports basolateral plasma membrane. Human transport/localization evidence is compatible with retention of this inherited function. The node was traced; the complete PAINT tree was not re-curated, and target inclusion among descendants is not circularity. - term: id: GO:0016323 label: basolateral plasma membrane evidence_type: IDA original_reference_id: PMID:12901863 qualifier: located_in review: summary: >- The canonical transporter localizes to the basolateral plasma membrane. action: ACCEPT reason: >- The original PMID:12901863 abstract directly reports basolateral human ABCC6 in polarized MDCKII cells, and native human liver staining independently corroborates it. The abstract supports this positive location, while uninspected full methods are not asserted. supported_by: - *id004 - *id003 - term: id: GO:0016323 label: basolateral plasma membrane evidence_type: IEA original_reference_id: GO_REF:0000120 qualifier: located_in supporting_entities: - ARBA:ARBA00086715 - UniProtKB:Q9R1S7 - ensembl:ENSMUSP00000002850 - UniProtKB-SubCell:SL-0026 review: summary: >- The canonical transporter localizes to the basolateral plasma membrane. action: ACCEPT reason: >- SL-0026 and the mouse ortholog mapping agree with direct human basolateral localization. The complete ARBA predicates and separate Ensembl chain were not re-curated; neither is needed to infer the known human location. supported_by: - *id004 - *id003 propagation_review: root_cause: NO_FAILURE_CORE source_entities: - source_id: ARBA:ARBA00086715 source_status: UNRESOLVED comment: >- The rule identifier was traced from the seed, but its complete predicates were not independently audited. The action rests on the named primary evidence, not an assumption about the rule. - source_id: UniProtKB:Q9R1S7 source_status: SUPPORTS_TRANSFER comment: >- Mouse basolateral localization agrees with independently demonstrated human basolateral localization; transfer is biologically compatible. - source_id: ensembl:ENSMUSP00000002850 source_status: UNRESOLVED comment: >- The Ensembl mouse protein identifier was preserved from the seed. The proximate ortholog and its experimental references are assessed in the UniProt source entry; a separate Ensembl transfer chain was not reconstructed. - source_id: UniProtKB-SubCell:SL-0026 source_status: SUPPORTS_TRANSFER comment: >- This subcellular-location vocabulary maps to the stated compartment. Direct human localization independently supports the compartment. - term: id: GO:0016887 label: ATP hydrolysis activity evidence_type: IEA original_reference_id: GO_REF:0000002 qualifier: enables supporting_entities: - InterPro:IPR003439 - InterPro:IPR017871 review: summary: >- ATP hydrolysis drives the ABCC6 transport cycle. action: ACCEPT reason: >- The ATP-binding cassette catalytic domains and ATP-dependent organic-anion transport establish the coupled ATPase mechanism. Retain the catalytic-component term without treating energy-source ATP as evidence for an ATP cargo. supported_by: - *id002 - *id008 propagation_review: root_cause: NO_FAILURE_CORE source_entities: - source_id: InterPro:IPR003439 source_status: SUPPORTS_TRANSFER comment: >- The matched ABC ATP-binding domain supports nucleotide binding/catalysis. - source_id: InterPro:IPR017871 source_status: SUPPORTS_TRANSFER comment: >- The matched ABC ATP-binding domain supports nucleotide binding/catalysis. - term: id: GO:0022857 label: transmembrane transporter activity evidence_type: IEA original_reference_id: GO_REF:0000002 qualifier: enables supporting_entities: - InterPro:IPR005292 review: summary: >- ABCC6 catalyzes transmembrane transport. action: ACCEPT reason: >- The MRP-family domain mapping is supported by direct human vesicle transport. This is a valid broad parent of ABC-type glutathione-conjugate transport; the precise physiological substrate remains unresolved. supported_by: - *id007 propagation_review: root_cause: NO_FAILURE_CORE source_entities: - source_id: InterPro:IPR005292 source_status: SUPPORTS_TRANSFER comment: >- The matched ABC/MRP transmembrane domain supports membrane transport architecture; physiological substrate identity is not inferred from this match. - term: id: GO:0030505 label: inorganic diphosphate transport evidence_type: IEA original_reference_id: GO_REF:0000107 qualifier: involved_in supporting_entities: - UniProtKB:Q9R1S7 - ensembl:ENSMUSP00000002850 review: summary: >- The traced mouse study demonstrates oral PPi uptake and rescue, not ABCC6-mediated PPi transport. action: MARK_AS_OVER_ANNOTATED reason: >- QuickGO traces mouse Q9R1S7 IDA/IMP to PMID:28701330. The full study measures oral PPi absorption in humans and mice and attenuation of calcification in Abcc6-deficient mice. It does not assign the uptake step to ABCC6; absence of ABCC6 does not prevent the reported supplementation effect. Known ABCC6-dependent ATP release followed by extracellular ENPP1 hydrolysis is distinct from directed movement of PPi. The related 2017 mechanistic paper explicitly labels possible PPi secretion as untested. The source process therefore exceeds its evidence and should not propagate to human. supported_by: - reference_id: PMID:28592560 supporting_text: >- In theory, ABCC6 could also contribute to the secretion of PPi, although this is not directly inferred from the data, and there is already an established plasma membrane PPi transporter, ANK (37). - reference_id: PMID:28701330 supporting_text: >- though the exact molecular mechanism of ATP release and the actual substrate of ABCC6 is not known. propagation_review: root_cause: SOURCE_BAD source_entities: - source_id: UniProtKB:Q9R1S7 source_status: SOURCE_BAD comment: >- QuickGO traces mouse IDA/IMP to PMID:28701330. Full text shows oral PPi uptake and rescue in deficient mice, not ABCC6-mediated PPi movement; the source process itself overshoots its cited experiment. - source_id: ensembl:ENSMUSP00000002850 source_status: UNRESOLVED comment: >- The Ensembl mouse protein identifier was preserved from the seed. The proximate ortholog and its experimental references are assessed in the UniProt source entry; a separate Ensembl transfer chain was not reconstructed. failure_modes: - ROLE_CONFLATION - term: id: GO:0030643 label: intracellular phosphate ion homeostasis evidence_type: IEA original_reference_id: GO_REF:0000107 qualifier: involved_in supporting_entities: - UniProtKB:Q9R1S7 - ensembl:ENSMUSP00000002850 review: summary: >- The specific intracellular inorganic-phosphate claim could not be verified from the traced source. action: UNDECIDED reason: >- Mouse Q9R1S7 IMP traces to PMID:24277820, whose full text remained inaccessible after supported retrieval attempts. The abstract establishes extracellular PPi generation and plasma PPi changes, not a measured intracellular phosphate-ion steady state. GO:0030643 is specific to intracellular phosphate. Do not infer that experiment from extracellular PPi results or reject the source solely from its abstract; leave this transfer unresolved pending the relevant full methods/results. supported_by: - *id009 propagation_review: root_cause: UNRESOLVED source_entities: - source_id: UniProtKB:Q9R1S7 source_status: UNRESOLVED comment: >- QuickGO traces mouse IMP to PMID:24277820. The abstract concerns extracellular PPi; unavailable full text prevents verification of the specific intracellular phosphate measurement. - source_id: ensembl:ENSMUSP00000002850 source_status: UNRESOLVED comment: >- The Ensembl mouse protein identifier was preserved from the seed. The proximate ortholog and its experimental references are assessed in the UniProt source entry; a separate Ensembl transfer chain was not reconstructed. - term: id: GO:0032026 label: response to magnesium ion evidence_type: IEA original_reference_id: GO_REF:0000107 qualifier: involved_in supporting_entities: - UniProtKB:Q9R1S7 - ensembl:ENSMUSP00000002850 review: summary: >- Mineralization susceptibility in Abcc6-deficient mice changes under a phosphate-rich, magnesium-reduced diet. action: KEEP_AS_NON_CORE reason: >- PMID:24732453 tests an acceleration diet changing phosphate and magnesium together and demonstrates genotype-dependent nephrocalcinosis. Retain the broad stimulus-response context as a downstream physiological phenotype, not a dedicated ABCC6 magnesium or sodium-phosphate sensor/transport function. The experiment does not isolate a molecular response to either ion separately. supported_by: - &id014 reference_id: PMID:24732453 supporting_text: >- However, if these mice were placed on an “acceleration diet” enriched in phosphate and reduced in magnesium (21, 22), acceleration of the mineralization process was observed. propagation_review: root_cause: NO_FAILURE_NON_CORE source_entities: - source_id: UniProtKB:Q9R1S7 source_status: SUPPORTS_TRANSFER comment: >- Mouse IMP/IGI PMID:24732453 measures calcification under combined high-phosphate/low-magnesium dietary stress; transferable as a non-core susceptibility phenotype, not a magnesium transport mechanism. - source_id: ensembl:ENSMUSP00000002850 source_status: UNRESOLVED comment: >- The Ensembl mouse protein identifier was preserved from the seed. The proximate ortholog and its experimental references are assessed in the UniProt source entry; a separate Ensembl transfer chain was not reconstructed. - term: id: GO:0042626 label: ATPase-coupled transmembrane transporter activity evidence_type: IDA original_reference_id: PMID:11880368 qualifier: enables review: summary: >- ABCC6 is an ATPase-coupled primary active membrane transporter. action: ACCEPT reason: >- The original human membrane study demonstrates ATP-dependent active organic-anion transport. This directly supports the coupled transport mechanism, with the more specific ABC-type activity represented in the core account. supported_by: - *id002 - *id008 - term: id: GO:0042626 label: ATPase-coupled transmembrane transporter activity evidence_type: TAS original_reference_id: PMID:8912525 qualifier: enables review: summary: >- ABCC6 is an ATPase-coupled primary active membrane transporter. action: ACCEPT reason: >- The early ARA partial sequence and resistance association support an ABC-family author statement, with the full-length mechanism independently demonstrated by the later human membrane assays. Do not infer complete architecture from the partial sequence. supported_by: - *id002 - *id008 - term: id: GO:0042626 label: ATPase-coupled transmembrane transporter activity evidence_type: TAS original_reference_id: Reactome:R-HSA-1454916 qualifier: enables review: summary: >- ABCC6 is an ATPase-coupled primary active membrane transporter. action: ACCEPT reason: >- The normal ABCC-family Reactome pathway describes ATP-coupled organic-anion transport. Direct human ABCC6 membrane assays independently support the mechanism without assigning every family substrate to ABCC6. supported_by: - *id002 - *id008 - term: id: GO:0042626 label: ATPase-coupled transmembrane transporter activity evidence_type: TAS original_reference_id: Reactome:R-HSA-5690340 qualifier: enables review: summary: >- ABCC6 is an ATPase-coupled primary active membrane transporter. action: ACCEPT reason: >- The Reactome mutant event describes loss of normal organic-anion transport in disease. Retain the normal gene-product function because direct human wild-type assays support it; the mutant event is not itself a new wild-type assay. supported_by: - *id002 - *id008 - term: id: GO:0046034 label: ATP metabolic process evidence_type: IDA original_reference_id: PMID:28592560 qualifier: involved_in review: summary: >- ABCC6-dependent export affects extracellular ATP metabolism, alongside ATP use by the transporter itself. action: KEEP_AS_NON_CORE reason: >- The full paper documents changes in ATP-catabolizing ENPP1/CD73/TNAP activities in ABCC6-deficient fibroblasts. ABCC6 also uses ATP for transport, so the broad ATP-metabolic-process label is compatible with its biology. It is retained outside the core summary to avoid implying that ABCC6 itself catalyzes extracellular ATP-to-AMP/PPi conversion, which is performed by ENPP1. supported_by: - *id011 - *id002 - term: id: GO:0046942 label: carboxylic acid transport evidence_type: IEA original_reference_id: GO_REF:0000117 qualifier: involved_in supporting_entities: - ARBA:ARBA00027271 review: summary: >- Transport of defined organic-anion substrates supports carboxylic-acid transport at a broad level. action: ACCEPT reason: >- ABCC6 directly transports glutathione conjugates including leukotriene C4, which carry carboxylate groups. This supports the broad process independently of the ARBA rule; it does not imply unrestricted organic-acid specificity or prove a major physiological cargo. The exact rule predicates were not audited. supported_by: - *id007 propagation_review: root_cause: NO_FAILURE_CORE source_entities: - source_id: ARBA:ARBA00027271 source_status: UNRESOLVED comment: >- The rule identifier was traced from the seed, but its complete predicates were not independently audited. The action rests on the named primary evidence, not an assumption about the rule. - term: id: GO:0055062 label: phosphate ion homeostasis evidence_type: IDA original_reference_id: PMID:28592560 qualifier: involved_in review: summary: >- The mechanistic evidence concerns extracellular pyrophosphate availability and mineralization rather than phosphate-ion steady-state regulation. action: MARK_AS_OVER_ANNOTATED reason: >- GO:0055062 denotes maintenance of phosphate-ion levels. The full 2017 studies assess PPi, ATP-catabolizing enzymes and calcium-phosphate deposition; pyrophosphate is a distinct chemical species, not interchangeable with inorganic phosphate. The mouse dietary study reports no serum phosphate difference in the compared groups. These findings support anti-mineralization, already represented by GO:0140928, but do not establish phosphate-ion homeostasis as a separate ABCC6 process. Mouse evidence includes independent studies as well as human-derived transfers, so the chain is not simply circular. supported_by: - *id012 - &id013 reference_id: PMID:24732453 supporting_text: >- No difference in serum calcium, inorganic phosphate or pyrophosphate concentrations was noted (Table 1). - term: id: GO:0055062 label: phosphate ion homeostasis evidence_type: IEA original_reference_id: GO_REF:0000120 qualifier: involved_in supporting_entities: - ARBA:ARBA00027627 - UniProtKB:Q9R1S7 - ensembl:ENSMUSP00000002850 review: summary: >- The mechanistic evidence concerns extracellular pyrophosphate availability and mineralization rather than phosphate-ion steady-state regulation. action: MARK_AS_OVER_ANNOTATED reason: >- GO:0055062 denotes maintenance of phosphate-ion levels. The full 2017 studies assess PPi, ATP-catabolizing enzymes and calcium-phosphate deposition; pyrophosphate is a distinct chemical species, not interchangeable with inorganic phosphate. The mouse dietary study reports no serum phosphate difference in the compared groups. These findings support anti-mineralization, already represented by GO:0140928, but do not establish phosphate-ion homeostasis as a separate ABCC6 process. Mouse evidence includes independent studies as well as human-derived transfers, so the chain is not simply circular. supported_by: - *id012 - *id013 propagation_review: root_cause: SOURCE_BAD source_entities: - source_id: ARBA:ARBA00027627 source_status: UNRESOLVED comment: >- The rule identifier was traced from the seed, but its complete predicates were not independently audited. The action rests on the named primary evidence, not an assumption about the rule. - source_id: UniProtKB:Q9R1S7 source_status: SOURCE_BAD comment: >- The mouse record combines independent PPi/mineralization studies PMID:28652107/28701330 with transfers from human PMID:28592560. These do not establish phosphate-ion steady-state regulation; PPi and Pi must remain distinct. - source_id: ensembl:ENSMUSP00000002850 source_status: UNRESOLVED comment: >- The Ensembl mouse protein identifier was preserved from the seed. The proximate ortholog and its experimental references are assessed in the UniProt source entry; a separate Ensembl transfer chain was not reconstructed. failure_modes: - ROLE_CONFLATION - term: id: GO:0055074 label: calcium ion homeostasis evidence_type: IDA original_reference_id: PMID:28592560 qualifier: involved_in review: summary: >- The experiments establish abnormal tissue calcium-phosphate deposition, not a separate calcium-ion steady-state mechanism. action: MARK_AS_OVER_ANNOTATED reason: >- GO:0055074 denotes maintenance of an internal steady-state level of calcium ions. Full PMID:28592560 measures calcification in human patient fibroblasts and mouse tissues, with micro-CT and calcium-phosphate deposition as readouts; it does not establish a distinct free-calcium-ion homeostasis assay. Mouse PMID:24732453 quantifies calcium extracted from deposits and reports unchanged serum calcium despite nephrocalcinosis. These are strong anti-mineralization results, already captured by GO:0140928, but do not separately resolve calcium-ion homeostasis. This scoping judgment matches the phosphate-ion assessment and does not deny the calcium-deposition phenotype or require ABCC6 itself to be an ion transporter. supported_by: - *id012 - *id013 - term: id: GO:0055074 label: calcium ion homeostasis evidence_type: IEA original_reference_id: GO_REF:0000107 qualifier: involved_in supporting_entities: - UniProtKB:Q9R1S7 - ensembl:ENSMUSP00000002850 review: summary: >- The experiments establish abnormal tissue calcium-phosphate deposition, not a separate calcium-ion steady-state mechanism. action: MARK_AS_OVER_ANNOTATED reason: >- GO:0055074 denotes maintenance of an internal steady-state level of calcium ions. Full PMID:28592560 measures calcification in human patient fibroblasts and mouse tissues, with micro-CT and calcium-phosphate deposition as readouts; it does not establish a distinct free-calcium-ion homeostasis assay. Mouse PMID:24732453 quantifies calcium extracted from deposits and reports unchanged serum calcium despite nephrocalcinosis. These are strong anti-mineralization results, already captured by GO:0140928, but do not separately resolve calcium-ion homeostasis. This scoping judgment matches the phosphate-ion assessment and does not deny the calcium-deposition phenotype or require ABCC6 itself to be an ion transporter. supported_by: - *id012 - *id013 propagation_review: root_cause: TERM_SCOPING_PROBLEM source_entities: - source_id: UniProtKB:Q9R1S7 source_status: UNRESOLVED comment: >- Mouse PMID:24732453/28701330 and genetic interaction PMID:28592560 support tissue calcium-phosphate deposition and its rescue. Deposited calcium measurement is distinct from calcium-ion steady-state control. The donor biology is relevant, but this more general ion-homeostasis interpretation remains insufficiently resolved; independent mouse evidence means the chain is not simply circular. - source_id: ensembl:ENSMUSP00000002850 source_status: UNRESOLVED comment: >- The Ensembl mouse protein identifier was preserved from the seed. The proximate ortholog and its experimental references are assessed in the UniProt source entry; a separate Ensembl transfer chain was not reconstructed. failure_modes: - GRANULARITY_MISMATCH - term: id: GO:0055085 label: transmembrane transport evidence_type: IBA original_reference_id: GO_REF:0000033 qualifier: involved_in supporting_entities: - AGI_LocusCode:AT1G30400 - AGI_LocusCode:AT2G34660 - CGD:CAL0000178329 - FB:FBgn0010549 - FB:FBgn0032456 - MGI:MGI:102676 - MGI:MGI:1352447 - MGI:MGI:1352630 - MGI:MGI:88388 - PANTHER:PTN000657997 - PomBase:SPAC30.04c - PomBase:SPAC3F10.11c - PomBase:SPBC359.05 - RGD:2332 - RGD:2366 - RGD:3112 - RGD:3787 - RGD:620268 - RGD:71101 - SGD:S000001027 - SGD:S000002542 - UniProtKB:A7KVC2 - UniProtKB:O15438 - UniProtKB:O15439 - UniProtKB:O15440 - UniProtKB:O60706 - UniProtKB:P13569 - UniProtKB:P33527 - UniProtKB:Q10RX7 - UniProtKB:Q92887 - UniProtKB:Q96J66 - ZFIN:ZDB-GENE-050517-17 review: summary: >- ABCC6 directly performs transmembrane transport. action: ACCEPT reason: >- Conserved ABC/MRP transmembrane architecture and direct human vesicular transport support the PAINT, domain-mapping and Reactome process assertions. This broad process is inherited with the transporter function; no specific physiological substrate is inferred from family membership. supported_by: - *id008 - *id007 propagation_review: root_cause: NO_FAILURE_CORE source_entities: - source_id: PANTHER:PTN000657997 source_status: SUPPORTS_TRANSFER comment: >- The seeded ancestral PAINT node supports transmembrane transport. Human transport/localization evidence is compatible with retention of this inherited function. The node was traced; the complete PAINT tree was not re-curated, and target inclusion among descendants is not circularity. - term: id: GO:0055085 label: transmembrane transport evidence_type: IEA original_reference_id: GO_REF:0000002 qualifier: involved_in supporting_entities: - InterPro:IPR005292 - InterPro:IPR011527 review: summary: >- ABCC6 directly performs transmembrane transport. action: ACCEPT reason: >- Conserved ABC/MRP transmembrane architecture and direct human vesicular transport support the PAINT, domain-mapping and Reactome process assertions. This broad process is inherited with the transporter function; no specific physiological substrate is inferred from family membership. supported_by: - *id008 - *id007 propagation_review: root_cause: NO_FAILURE_CORE source_entities: - source_id: InterPro:IPR005292 source_status: SUPPORTS_TRANSFER comment: >- The matched ABC/MRP transmembrane domain supports membrane transport architecture; physiological substrate identity is not inferred from this match. - source_id: InterPro:IPR011527 source_status: SUPPORTS_TRANSFER comment: >- The matched ABC/MRP transmembrane domain supports membrane transport architecture; physiological substrate identity is not inferred from this match. - term: id: GO:0055085 label: transmembrane transport evidence_type: TAS original_reference_id: Reactome:R-HSA-382556 qualifier: involved_in review: summary: >- ABCC6 directly performs transmembrane transport. action: ACCEPT reason: >- Conserved ABC/MRP transmembrane architecture and direct human vesicular transport support the PAINT, domain-mapping and Reactome process assertions. This broad process is inherited with the transporter function; no specific physiological substrate is inferred from family membership. supported_by: - *id008 - *id007 - term: id: GO:0071716 label: leukotriene transport evidence_type: IDA original_reference_id: PMID:11880368 qualifier: involved_in review: summary: >- Leukotriene C4 is an experimentally transported ABCC6 substrate. action: KEEP_AS_NON_CORE reason: >- The human ABCC6 membrane assay explicitly transports leukotriene C4. Keep the substrate-specific process as an in vitro capability without making leukotriene signaling or inflammatory physiology a core role; the physiological cargo responsible for anti-mineralization has not been established. supported_by: - *id007 - term: id: GO:0140359 label: ABC-type transporter activity evidence_type: IBA original_reference_id: GO_REF:0000033 qualifier: enables supporting_entities: - AGI_LocusCode:AT1G30400 - AGI_LocusCode:AT2G34660 - AGI_LocusCode:AT3G13080 - AGI_LocusCode:AT3G62700 - FB:FBgn0032026 - FB:FBgn0038740 - MGI:MGI:102676 - MGI:MGI:1351644 - PANTHER:PTN009085477 - PomBase:SPAC3F10.11c - PomBase:SPBC359.05 - RGD:2366 - RGD:3112 - RGD:620268 - RGD:71101 - SGD:S000002542 - SGD:S000003513 - UniProtKB:O15438 - UniProtKB:O15439 - UniProtKB:O15440 - UniProtKB:O95255 - UniProtKB:P33527 - UniProtKB:Q5T3U5 - UniProtKB:Q6UR05 - UniProtKB:Q8HXQ5 - UniProtKB:Q92887 - UniProtKB:Q96J66 - WB:WBGene00003411 review: summary: >- ABCC6 has the architecture and demonstrated mechanism of an ABC-type primary active transporter. action: ACCEPT reason: >- The two nucleotide-binding domains and transmembrane core couple ATP use to substrate transport. Direct human glutathione-conjugate transport corroborates the conserved PAINT inference and combined electronic mapping. ABCC6 is a transporter, unlike regulatory/channel members elsewhere in the ABCC family; the annotation does not rely merely on family name. supported_by: - *id008 - *id002 propagation_review: root_cause: NO_FAILURE_CORE source_entities: - source_id: PANTHER:PTN009085477 source_status: SUPPORTS_TRANSFER comment: >- The seeded ancestral PAINT node supports ABC-type transporter activity. Human transport/localization evidence is compatible with retention of this inherited function. The node was traced; the complete PAINT tree was not re-curated, and target inclusion among descendants is not circularity. - term: id: GO:0140359 label: ABC-type transporter activity evidence_type: IEA original_reference_id: GO_REF:0000120 qualifier: enables supporting_entities: - ARBA:ARBA00086592 - InterPro:IPR011527 review: summary: >- ABCC6 has the architecture and demonstrated mechanism of an ABC-type primary active transporter. action: ACCEPT reason: >- The two nucleotide-binding domains and transmembrane core couple ATP use to substrate transport. Direct human glutathione-conjugate transport corroborates the conserved PAINT inference and combined electronic mapping. ABCC6 is a transporter, unlike regulatory/channel members elsewhere in the ABCC family; the annotation does not rely merely on family name. supported_by: - *id008 - *id002 propagation_review: root_cause: NO_FAILURE_CORE source_entities: - source_id: ARBA:ARBA00086592 source_status: UNRESOLVED comment: >- The rule identifier was traced from the seed, but its complete predicates were not independently audited. The action rests on the named primary evidence, not an assumption about the rule. - source_id: InterPro:IPR011527 source_status: SUPPORTS_TRANSFER comment: >- The matched ABC/MRP transmembrane domain supports membrane transport architecture; physiological substrate identity is not inferred from this match. - term: id: GO:0140928 label: inhibition of non-skeletal tissue mineralization evidence_type: IEA original_reference_id: GO_REF:0000107 qualifier: involved_in supporting_entities: - UniProtKB:Q9R1S7 - ensembl:ENSMUSP00000002850 review: summary: >- ABCC6 activity inhibits mineralization of non-skeletal tissues by sustaining extracellular anti-mineralization chemistry. action: ACCEPT reason: >- Independent mouse deficiency/rescue and ENPP1 interaction studies, human disease genetics and decreased patient plasma PPi support this central physiological role. ABCC6 contributes an active membrane-export step that supplies the extracellular nucleotide/PPi pathway; ENPP1 performs PPi generation. Local cellular contributions and incomplete rescue by elevated PPi show that plasma PPi alone does not explain every tissue phenotype. supported_by: - *id012 - reference_id: PMID:24969777 supporting_text: >- The plasma PPi concentrations were ≈2.5-fold lower in patients than in healthy individuals (Figure 2E). - reference_id: PMID:28652107 supporting_text: >- In contrast, although significantly reduced mineralization was noted in Abcc6-/- mice expressing human ENPP1, small mineralization foci were still evident despite increased plasma PPi levels. propagation_review: root_cause: NO_FAILURE_CORE source_entities: - source_id: UniProtKB:Q9R1S7 source_status: SUPPORTS_TRANSFER comment: >- Mouse experimental annotations trace to PMID:24732453 and PMID:28652107. Deficiency and rescue directly support anti-mineralization, concordant with human genetic and PPi evidence. - source_id: ensembl:ENSMUSP00000002850 source_status: UNRESOLVED comment: >- The Ensembl mouse protein identifier was preserved from the seed. The proximate ortholog and its experimental references are assessed in the UniProt source entry; a separate Ensembl transfer chain was not reconstructed. - term: id: GO:1904383 label: response to sodium phosphate evidence_type: IEA original_reference_id: GO_REF:0000107 qualifier: involved_in supporting_entities: - UniProtKB:Q9R1S7 - ensembl:ENSMUSP00000002850 review: summary: >- Mineralization susceptibility in Abcc6-deficient mice changes under a phosphate-rich, magnesium-reduced diet. action: KEEP_AS_NON_CORE reason: >- PMID:24732453 tests an acceleration diet changing phosphate and magnesium together and demonstrates genotype-dependent nephrocalcinosis. Retain the broad stimulus-response context as a downstream physiological phenotype, not a dedicated ABCC6 magnesium or sodium-phosphate sensor/transport function. The experiment does not isolate a molecular response to either ion separately. supported_by: - *id014 propagation_review: root_cause: NO_FAILURE_NON_CORE source_entities: - source_id: UniProtKB:Q9R1S7 source_status: SUPPORTS_TRANSFER comment: >- Mouse PMID:24732453 tests a combined phosphate-rich, magnesium-poor acceleration diet. The non-core response phenotype can be transferred with that experimental scope. - source_id: ensembl:ENSMUSP00000002850 source_status: UNRESOLVED comment: >- The Ensembl mouse protein identifier was preserved from the seed. The proximate ortholog and its experimental references are assessed in the UniProt source entry; a separate Ensembl transfer chain was not reconstructed. references: - id: GO_REF:0000002 title: Gene Ontology annotation through association of InterPro records with GO terms findings: [] - id: GO_REF:0000003 title: Gene Ontology annotation based on Enzyme Commission mapping findings: [] - id: GO_REF:0000033 title: Annotation inferences using phylogenetic trees findings: [] - id: GO_REF:0000044 title: Gene Ontology annotation based on UniProtKB/Swiss-Prot Subcellular Location vocabulary mapping, accompanied by conservative changes to GO terms applied by UniProt findings: [] - id: GO_REF:0000052 title: Gene Ontology annotation based on curation of immunofluorescence data findings: [] - id: GO_REF:0000107 title: Automatic transfer of experimentally verified manual GO annotation data to orthologs using Ensembl Compara findings: [] - id: GO_REF:0000117 title: Electronic Gene Ontology annotations created by ARBA machine learning models findings: [] - id: GO_REF:0000120 title: Combined Automated Annotation using Multiple IEA Methods findings: [] - id: PMID:10835642 title: Mutations in a gene encoding an ABC transporter cause pseudoxanthoma elasticum. findings: [] full_text_unavailable: true reference_review: relevance: MEDIUM correctness: VERIFIED review_notes: >- Fetched PubMed identity verified; abstract only. Human PXE gene discovery supports disease causality. Historical dominant-phenotype language is not used to assert dominant ABCC6 Mendelian inheritance. - id: PMID:11880368 title: Loss of ATP-dependent transport activity in pseudoxanthoma elasticum-associated mutants of human ABCC6 (MRP6). findings: - statement: >- Human full-length expression and vesicular transport establish ATP binding and glutathione-conjugate export supporting_text: >- We found that glutathione conjugates, including leukotriene C(4) and N-ethylmaleimide S-glutathione (NEM-GS), were actively transported by human ABCC6. full_text_unavailable: true reference_review: relevance: HIGH correctness: VERIFIED review_notes: >- PubMed/Entrez identity verified by the supported publication fetch. Human full-length expression and vesicular transport establish ATP binding and glutathione-conjugate export; abstract only, no reconstructed methods. - id: PMID:12414644 title: Characterization of the drug resistance and transport properties of multidrug resistance protein 6 (MRP6, ABCC6). findings: - statement: >- Human MRP6 in CHO vesicles supports defined substrate export and limited drug resistance supporting_text: >- Analysis of the drug sensitivity of MRP6-transfected cells revealed low levels of resistance to several natural product agents, including etoposide, teniposide, doxorubicin, and daunorubicin. full_text_unavailable: true reference_review: relevance: HIGH correctness: VERIFIED review_notes: >- PubMed/Entrez identity verified by the supported publication fetch. Human MRP6 in CHO vesicles supports defined substrate export and limited drug resistance; abstract only. - id: PMID:12901863 title: Subcellular localization and N-glycosylation of human ABCC6, expressed in MDCKII cells. findings: - statement: >- Human protein in polarized canine MDCKII host cells establishes basolateral location supporting_text: >- human ABCC6, when expressed by retroviral transduction in polarized mammalian (MDCKII) cells, is exclusively localized to the basolateral membrane. full_text_unavailable: true reference_review: relevance: HIGH correctness: VERIFIED review_notes: >- PubMed/Entrez identity verified by the supported publication fetch. Human protein in polarized canine MDCKII host cells establishes basolateral location; abstract only. - id: PMID:24277820 title: ABCC6 prevents ectopic mineralization seen in pseudoxanthoma elasticum by inducing cellular nucleotide release. findings: - statement: >- Abstract explicitly distinguishes ABCC6-dependent NTP release from direct NTP translocation. Human/rat expression and mouse PPi evidence. Full-text retrieval failed supporting_text: >- cells expressing ABCC6 excrete large amounts of nucleoside triphosphates, even though ABCC6 itself does not transport nucleoside triphosphates. full_text_unavailable: true reference_review: relevance: HIGH correctness: VERIFIED review_notes: >- PubMed/Entrez identity verified by the supported publication fetch. Abstract explicitly distinguishes ABCC6-dependent NTP release from direct NTP translocation. Human/rat expression and mouse PPi evidence. Full-text retrieval failed; intracellular phosphate claim remains unresolved. - id: PMID:24969777 title: ABCC6-mediated ATP secretion by the liver is the main source of the mineralization inhibitor inorganic pyrophosphate in the systemic circulation-brief report. findings: - statement: >- Full text read. Rat ABCC6 in human cell lines, mouse hepatocytes/perfusion, and human patient PPi are distinct experimental contexts. No direct ATP substrate assertion. supporting_text: >- Factors could be missing in vitro, however, that allows ABCC6 to transport ATP in vivo, or ABCC6 could indirectly stimulate ATP release by regulating vesicular transport or ion channels. full_text_unavailable: false reference_review: relevance: HIGH correctness: VERIFIED review_notes: >- PubMed/Entrez identity verified by the supported publication fetch. Full text read. Rat ABCC6 in human cell lines, mouse hepatocytes/perfusion, and human patient PPi are distinct experimental contexts. No direct ATP substrate assertion. - id: PMID:28592560 title: Ectopic calcification in pseudoxanthoma elasticum responds to inhibition of tissue-nonspecific alkaline phosphatase. findings: - statement: >- Full text read. Patient fibroblasts and mouse genetic/metabolic studies support PPi/mineralization and TNAP effects. Proposed AMP/PPi secretion is explicitly hypothetical supporting_text: >- Here, both genetic and metabolic analyses provide compelling evidence that ABCC6 acts in concert with ENPP1 and CD73 to regulate extracellular PPi, a major physiologic inhibitor of calcification. full_text_unavailable: false reference_review: relevance: HIGH correctness: VERIFIED review_notes: >- PubMed/Entrez identity verified by the supported publication fetch. Full text read. Patient fibroblasts and mouse genetic/metabolic studies support PPi/mineralization and TNAP effects. Proposed AMP/PPi secretion is explicitly hypothetical; no extracellular ABCC6 location or direct gene-expression machinery is demonstrated. - id: PMID:35307651 title: Localization of Xenobiotic Transporters Expressed at the Human Blood-Testis Barrier. findings: - statement: >- Full text confirms human MRP6 basal Sertoli/peritubular staining. This does not establish specific substrate transport across the blood-testis barrier. supporting_text: >- OCTN2, multidrug resistance protein (MRP) 3, MRP6, and MRP7 localized to SC basal membranes and peritubular myoid cells (PMCs) surrounding the seminiferous tubules. full_text_unavailable: false reference_review: relevance: HIGH correctness: VERIFIED review_notes: >- PubMed/Entrez identity verified by the supported publication fetch. Full text confirms human MRP6 basal Sertoli/peritubular staining. This does not establish specific substrate transport across the blood-testis barrier. - id: PMID:36115835 title: Quantitative fragmentomics allow affinity mapping of interactomes. findings: - statement: >- Full paper and publisher Supplementary Dataset 1 inspected. ABCC6 target peptide, exact domain rows and IntAct exports are tabulated in the source audit. Quantified positives are separated from zero-coded affinities/10-molar export placeholders supporting_text: >- We quantified 18,332 unique dissociation constants, whereas 46,825 PDZ-PBM affinities representing 72% of the explored space remained below the assay’s quantification threshold. full_text_unavailable: false reference_review: relevance: HIGH correctness: VERIFIED review_notes: >- PubMed/Entrez identity verified by the supported publication fetch. Full paper and publisher Supplementary Dataset 1 inspected. ABCC6 target peptide, exact domain rows and IntAct exports are tabulated in the source audit. Quantified positives are separated from zero-coded affinities/10-molar export placeholders; this is not full-length cellular binding evidence. - id: PMID:8912525 title: The anthracycline resistance-associated (ara) gene, a novel gene associated with multidrug resistance in a human leukaemia cell line. findings: [] full_text_unavailable: true reference_review: relevance: MEDIUM correctness: VERIFIED review_notes: >- Fetched PubMed identity verified; abstract only. Historical ARA partial sequence and coexpression association; modern full-length function is independently supported. - id: Reactome:R-HSA-1454916 title: The ABCC family mediates organic anion transport findings: [] - id: Reactome:R-HSA-382556 title: ABC-family proteins mediated transport findings: [] - id: Reactome:R-HSA-5690340 title: Defective ABCC6 does not transport organic anion from cytosol to extracellular region findings: [] - id: PMID:23625951 title: ABCC6 is a basolateral plasma membrane protein. findings: - statement: >- Full text read: native human/mouse liver and primary mouse hepatocyte staining supports basolateral localization and disputes earlier MAM attribution for full-length protein. Does not negate URG7 isoform ER data. supporting_text: >- Our results show unambiguously that in frozen sections of mouse and human livers, Abcc6/ABCC6 is colocalized with the plasma membrane markers cadherin (Figure 1A, D) and catenin (not shown) as well as the basolateral membrane marker Na,K-ATPase (Figure 1B). full_text_unavailable: false reference_review: relevance: HIGH correctness: VERIFIED review_notes: >- PubMed/Entrez identity verified by the supported publication fetch. Full text read: native human/mouse liver and primary mouse hepatocyte staining supports basolateral localization and disputes earlier MAM attribution for full-length protein. Does not negate URG7 isoform ER data. - id: PMID:23912081 title: The hepatitis B x antigen anti-apoptotic effector URG7 is localized to the endoplasmic reticulum membrane. findings: - statement: >- Abstract directly establishes human URG7 ER topology supporting_text: >- The results demonstrate that URG7 is N-glycosylated and located to the endoplasmic reticulum membrane with an Nlumen-Ccytosol orientation. full_text_unavailable: true reference_review: relevance: HIGH correctness: VERIFIED review_notes: >- PubMed/Entrez identity verified by the supported publication fetch. Abstract directly establishes human URG7 ER topology; applies to the short alternative product, not full-length ABCC6. Anti-apoptotic tail mechanism is a proposal. - id: PMID:24732453 title: 'Genetic modulation of nephrocalcinosis in mouse models of ectopic mineralization: the Abcc6(tm1Jfk) and Enpp1(asj) mutant mice.' findings: - statement: >- Full text read. Combined phosphate/magnesium diet and Abcc6/Enpp1 genetic effects on nephrocalcinosis supporting_text: >- No difference in serum calcium, inorganic phosphate or pyrophosphate concentrations was noted (Table 1). full_text_unavailable: false reference_review: relevance: HIGH correctness: VERIFIED review_notes: >- PubMed/Entrez identity verified by the supported publication fetch. Full text read. Combined phosphate/magnesium diet and Abcc6/Enpp1 genetic effects on nephrocalcinosis; serum ion levels unchanged in the compared groups. - id: PMID:28701330 title: Oral administration of pyrophosphate inhibits connective tissue calcification. findings: - statement: >- Full text read. Oral PPi absorption and rescue do not identify ABCC6 as PPi transporter supporting_text: >- though the exact molecular mechanism of ATP release and the actual substrate of ABCC6 is not known. full_text_unavailable: false reference_review: relevance: HIGH correctness: VERIFIED review_notes: >- PubMed/Entrez identity verified by the supported publication fetch. Full text read. Oral PPi absorption and rescue do not identify ABCC6 as PPi transporter; the uptake and deficiency phenotypes must be distinguished. - id: PMID:28652107 title: Plasma PPi Deficiency Is the Major, but Not the Exclusive, Cause of Ectopic Mineralization in an Abcc6(-/-) Mouse Model of PXE. findings: - statement: >- Full text read. ENPP1 overexpression incompletely rescues Abcc6 deficiency, supporting a major but not exclusive role for plasma PPi. supporting_text: >- In contrast, although significantly reduced mineralization was noted in Abcc6-/- mice expressing human ENPP1, small mineralization foci were still evident despite increased plasma PPi levels. full_text_unavailable: false reference_review: relevance: HIGH correctness: VERIFIED review_notes: >- PubMed/Entrez identity verified by the supported publication fetch. Full text read. ENPP1 overexpression incompletely rescues Abcc6 deficiency, supporting a major but not exclusive role for plasma PPi. - id: PMID:22209248 title: Generalized arterial calcification of infancy and pseudoxanthoma elasticum can be caused by mutations in either ENPP1 or ABCC6. findings: - statement: >- Full human primary genetic study read. Biallelic ABCC6 cases support overlapping GACI/PXE spectrum supporting_text: >- In 14 of these patients, we detected pathogenic ABCC6 mutations (biallelic mutations in eight patients, monoallelic mutations in six patients). full_text_unavailable: false reference_review: relevance: HIGH correctness: VERIFIED review_notes: >- PubMed/Entrez identity verified by the supported publication fetch. Full human primary genetic study read. Biallelic ABCC6 cases support overlapping GACI/PXE spectrum; cases with a single identified variant do not by themselves prove dominant inheritance. - id: PMID:24840500 title: Regulation of ABCC6 trafficking and stability by a conserved C-terminal PDZ-like sequence. findings: - statement: >- Full text read: tail deletions affect biosynthesis/trafficking supporting_text: >- These data suggest that the conserved, PDZ-like sequence promotes the proper biosynthesis and trafficking of the ABCC6 protein. full_text_unavailable: false reference_review: relevance: HIGH correctness: VERIFIED review_notes: >- PubMed/Entrez identity verified by the supported publication fetch. Full text read: tail deletions affect biosynthesis/trafficking; this does not by itself identify physiological PDZ partners. - id: file:human/ABCC6/ABCC6-deep-research-falcon.md title: Falcon research report for human ABCC6 reference_review: relevance: MEDIUM correctness: UNVERIFIED review_notes: >- Genuine provider output, completed in 776.51 seconds with 1200-second wrapper limit; preserved unchanged. ATP-release versus direct-substrate distinction corroborates primary sources. Review-level and unidentified-journal references, registry claims and absence of structures were not independently adopted as primary evidence. findings: [] core_functions: - description: >- ATP-dependent organic-anion export by a basolateral ABC transporter. Glutathione conjugates are demonstrated assay substrates; the main endogenous cargo remains unresolved. ABCC6-dependent nucleotide release contributes to extracellular PPi production and prevention of ectopic mineralization, without proving direct ATP translocation. molecular_function: id: GO:0015431 label: ABC-type glutathione S-conjugate transporter activity locations: - id: GO:0016323 label: basolateral plasma membrane directly_involved_in: - id: GO:0140928 label: inhibition of non-skeletal tissue mineralization supported_by: - *id007 - *id003 - *id012 - *id010 suggested_questions: - question: >- What endogenous substrate is physically transported by ABCC6, and does ABCC6 directly translocate ATP or regulate another ATP-release route? - question: >- How should the PMID:36115835 IntAct positive interaction exports carrying a 10-molar affinity placeholder be reconciled with zero-coded, unquantified affinities in the primary supplement? - question: >- Which quantified C-terminal PDZ interactions occur with full-length endogenous ABCC6 and influence basolateral trafficking or physiological export? - question: >- Does the original mouse intracellular-phosphate annotation have an assay distinct from the extracellular PPi measurements in PMID:24277820? suggested_experiments: - description: >- Reconstitute purified full-length ABCC6 in defined membranes and distinguish ATP used for the transport cycle from ATP or other substrates physically translocated. Pair transport measurements with ATPase assays and inactive controls. - description: >- Test the five quantified source PDZ interactions using full-length endogenous proteins, matched expression compartments and C-terminal mutations; measure localization and substrate release separately from fragment affinity.