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.
| GO Term | Evidence | Action | Reason |
|---|---|---|---|
| GO:0005515 protein binding | IPI PMID:36115835 Quantitative fragmentomics allow affinity mapping of interac... | REMOVE | Summary: Generic protein binding to GRID2IP does not identify an informative ABCC6 molecular function. 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. Supporting Evidence: PMID:36115835 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. |
| GO:0005515 protein binding | IPI PMID:36115835 Quantitative fragmentomics allow affinity mapping of interac... | REMOVE | Summary: Generic protein binding to MPDZ does not identify an informative ABCC6 molecular function. 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. Supporting Evidence: PMID:36115835 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. |
| GO:0005515 protein binding | IPI PMID:36115835 Quantitative fragmentomics allow affinity mapping of interac... | MODIFY | Summary: The ABCC6 C-terminal peptide binds a PDZ domain of DLG4; PDZ domain binding is more informative than generic protein binding. 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. Proposed replacements: PDZ domain binding Supporting Evidence: PMID:36115835 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. |
| GO:0005515 protein binding | IPI PMID:36115835 Quantitative fragmentomics allow affinity mapping of interac... | REMOVE | Summary: Generic protein binding to APBA1 does not identify an informative ABCC6 molecular function. 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. Supporting Evidence: PMID:36115835 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. |
| GO:0005515 protein binding | IPI PMID:36115835 Quantitative fragmentomics allow affinity mapping of interac... | REMOVE | Summary: Generic protein binding to TJP1 does not identify an informative ABCC6 molecular function. 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. Supporting Evidence: PMID:36115835 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. |
| GO:0005515 protein binding | IPI PMID:36115835 Quantitative fragmentomics allow affinity mapping of interac... | REMOVE | Summary: Generic protein binding to DLG1 does not identify an informative ABCC6 molecular function. 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. Supporting Evidence: PMID:36115835 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. |
| GO:0005515 protein binding | IPI PMID:36115835 Quantitative fragmentomics allow affinity mapping of interac... | REMOVE | Summary: Generic protein binding to IL16 does not identify an informative ABCC6 molecular function. 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. Supporting Evidence: PMID:36115835 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. |
| GO:0005515 protein binding | IPI PMID:36115835 Quantitative fragmentomics allow affinity mapping of interac... | REMOVE | Summary: Generic protein binding to SCRIB does not identify an informative ABCC6 molecular function. 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. Supporting Evidence: PMID:36115835 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. |
| GO:0005515 protein binding | IPI PMID:36115835 Quantitative fragmentomics allow affinity mapping of interac... | REMOVE | Summary: Generic protein binding to DLG2 does not identify an informative ABCC6 molecular function. 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. Supporting Evidence: PMID:36115835 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. |
| GO:0005515 protein binding | IPI PMID:36115835 Quantitative fragmentomics allow affinity mapping of interac... | MODIFY | Summary: The ABCC6 C-terminal peptide binds a PDZ domain of NHERF3; PDZ domain binding is more informative than generic protein binding. 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. Proposed replacements: PDZ domain binding Supporting Evidence: PMID:36115835 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. |
| GO:0005515 protein binding | IPI PMID:36115835 Quantitative fragmentomics allow affinity mapping of interac... | REMOVE | Summary: Generic protein binding to FRMPD2 does not identify an informative ABCC6 molecular function. 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. Supporting Evidence: PMID:36115835 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. |
| GO:0005515 protein binding | IPI PMID:36115835 Quantitative fragmentomics allow affinity mapping of interac... | MODIFY | Summary: The ABCC6 C-terminal peptide binds a PDZ domain of MAGI2; PDZ domain binding is more informative than generic protein binding. 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. Proposed replacements: PDZ domain binding Supporting Evidence: PMID:36115835 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. |
| GO:0005515 protein binding | IPI PMID:36115835 Quantitative fragmentomics allow affinity mapping of interac... | MODIFY | Summary: The ABCC6 C-terminal peptide binds a PDZ domain of NHERF4; PDZ domain binding is more informative than generic protein binding. 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. Proposed replacements: PDZ domain binding Supporting Evidence: PMID:36115835 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. |
| GO:0005515 protein binding | IPI PMID:36115835 Quantitative fragmentomics allow affinity mapping of interac... | REMOVE | Summary: Generic protein binding to LNX2 does not identify an informative ABCC6 molecular function. 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. Supporting Evidence: PMID:36115835 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. |
| GO:0005515 protein binding | IPI PMID:36115835 Quantitative fragmentomics allow affinity mapping of interac... | REMOVE | Summary: Generic protein binding to Inadl does not identify an informative ABCC6 molecular function. 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. Supporting Evidence: PMID:36115835 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. |
| GO:0005515 protein binding | IPI PMID:36115835 Quantitative fragmentomics allow affinity mapping of interac... | REMOVE | Summary: Generic protein binding to LNX1 does not identify an informative ABCC6 molecular function. 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. Supporting Evidence: PMID:36115835 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. |
| GO:0005515 protein binding | IPI PMID:36115835 Quantitative fragmentomics allow affinity mapping of interac... | REMOVE | Summary: Generic protein binding to DLG3 does not identify an informative ABCC6 molecular function. 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. Supporting Evidence: PMID:36115835 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. |
| GO:0005515 protein binding | IPI PMID:36115835 Quantitative fragmentomics allow affinity mapping of interac... | REMOVE | Summary: Generic protein binding to MAGI1 does not identify an informative ABCC6 molecular function. 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. Supporting Evidence: PMID:36115835 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. |
| GO:0005515 protein binding | IPI PMID:36115835 Quantitative fragmentomics allow affinity mapping of interac... | REMOVE | Summary: Generic protein binding to APBA2 does not identify an informative ABCC6 molecular function. 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. Supporting Evidence: PMID:36115835 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. |
| GO:0005515 protein binding | IPI PMID:36115835 Quantitative fragmentomics allow affinity mapping of interac... | REMOVE | Summary: Generic protein binding to GRIP2 does not identify an informative ABCC6 molecular function. 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. Supporting Evidence: PMID:36115835 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. |
| GO:0005515 protein binding | IPI PMID:36115835 Quantitative fragmentomics allow affinity mapping of interac... | MODIFY | Summary: The ABCC6 C-terminal peptide binds a PDZ domain of DFNB31; PDZ domain binding is more informative than generic protein binding. 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. Proposed replacements: PDZ domain binding Supporting Evidence: PMID:36115835 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. |
| GO:0005515 protein binding | IPI PMID:36115835 Quantitative fragmentomics allow affinity mapping of interac... | REMOVE | Summary: Generic protein binding to GRIP1 does not identify an informative ABCC6 molecular function. 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. Supporting Evidence: PMID:36115835 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. |
| GO:0005524 ATP binding | IDA PMID:11880368 Loss of ATP-dependent transport activity in pseudoxanthoma e... | ACCEPT | Summary: ATP binding is intrinsic to the ABCC6 nucleotide-binding domains. 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. Supporting Evidence: PMID:11880368 In isolated membranes ATP binding as well as ATP-dependent active transport by ABCC6 was demonstrated. |
| GO:0005524 ATP binding | IEA GO_REF:0000002 | ACCEPT | Summary: ATP binding is intrinsic to the ABCC6 nucleotide-binding domains. 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. Propagation Review Root cause: NO FAILURE CORE Sources checked: InterPro:IPR003439 SUPPORTS TRANSFER The matched ABC ATP-binding domain supports nucleotide binding/catalysis. InterPro:IPR011527 SUPPORTS TRANSFER The matched ABC ATP-binding domain supports nucleotide binding/catalysis. InterPro:IPR017871 SUPPORTS TRANSFER The matched ABC ATP-binding domain supports nucleotide binding/catalysis. InterPro:IPR036640 SUPPORTS TRANSFER The matched ABC ATP-binding domain supports nucleotide binding/catalysis. Supporting Evidence: PMID:11880368 In isolated membranes ATP binding as well as ATP-dependent active transport by ABCC6 was demonstrated. |
| GO:0005524 ATP binding | TAS PMID:8912525 The anthracycline resistance-associated (ara) gene, a novel ... | ACCEPT | Summary: ATP binding is intrinsic to the ABCC6 nucleotide-binding domains. 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. Supporting Evidence: PMID:11880368 In isolated membranes ATP binding as well as ATP-dependent active transport by ABCC6 was demonstrated. |
| GO:0005576 extracellular region | IDA PMID:28592560 Ectopic calcification in pseudoxanthoma elasticum responds t... | MARK AS OVER ANNOTATED | Summary: The paper concerns extracellular metabolites and calcification, not localization of ABCC6 protein outside the cell. 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. Supporting Evidence: PMID:28592560 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. PMID:23625951 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). |
| GO:0005789 endoplasmic reticulum membrane | IEA GO_REF:0000044 | KEEP AS NON CORE | Summary: The ER membrane mapping is supported for the short URG7 alternative product. 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. Propagation Review Root cause: NO FAILURE NON CORE Sources checked: UniProtKB-SubCell:SL-0097 SUPPORTS TRANSFER This subcellular-location vocabulary maps to the stated compartment. The originating location applies to URG7 O95255-2, not unrestricted full-length ABCC6 localization. Supporting Evidence: PMID:23912081 The results demonstrate that URG7 is N-glycosylated and located to the endoplasmic reticulum membrane with an Nlumen-Ccytosol orientation. |
| GO:0005886 plasma membrane | IBA GO_REF:0000033 | ACCEPT | Summary: Full-length ABCC6 is a plasma-membrane transporter. 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. Propagation Review Root cause: NO FAILURE CORE Sources checked: PANTHER:PTN002795584 SUPPORTS TRANSFER 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. Supporting Evidence: PMID:23625951 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). PMID:12901863 human ABCC6, when expressed by retroviral transduction in polarized mammalian (MDCKII) cells, is exclusively localized to the basolateral membrane. |
| GO:0005886 plasma membrane | IDA GO_REF:0000052 | ACCEPT | Summary: Full-length ABCC6 is a plasma-membrane transporter. 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. Supporting Evidence: PMID:23625951 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). PMID:12901863 human ABCC6, when expressed by retroviral transduction in polarized mammalian (MDCKII) cells, is exclusively localized to the basolateral membrane. |
| GO:0005886 plasma membrane | TAS PMID:10835642 Mutations in a gene encoding an ABC transporter cause pseudo... | ACCEPT | Summary: Full-length ABCC6 is a plasma-membrane transporter. 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. Supporting Evidence: PMID:23625951 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). PMID:12901863 human ABCC6, when expressed by retroviral transduction in polarized mammalian (MDCKII) cells, is exclusively localized to the basolateral membrane. |
| GO:0005886 plasma membrane | TAS Reactome:R-HSA-1454916 | ACCEPT | Summary: Full-length ABCC6 is a plasma-membrane transporter. 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. Supporting Evidence: PMID:23625951 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). PMID:12901863 human ABCC6, when expressed by retroviral transduction in polarized mammalian (MDCKII) cells, is exclusively localized to the basolateral membrane. |
| GO:0005886 plasma membrane | TAS Reactome:R-HSA-5690340 | ACCEPT | Summary: Full-length ABCC6 is a plasma-membrane transporter. 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. Supporting Evidence: PMID:23625951 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). PMID:12901863 human ABCC6, when expressed by retroviral transduction in polarized mammalian (MDCKII) cells, is exclusively localized to the basolateral membrane. |
| GO:0009410 response to xenobiotic stimulus | IEA GO_REF:0000117 | KEEP AS NON CORE | Summary: Heterologous ABCC6 expression can confer limited resistance to xenobiotic anticancer agents. 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. Propagation Review Root cause: NO FAILURE NON CORE Sources checked: ARBA:ARBA00092608 UNRESOLVED 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. Supporting Evidence: PMID:12414644 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. |
| GO:0009410 response to xenobiotic stimulus | TAS PMID:8912525 The anthracycline resistance-associated (ara) gene, a novel ... | KEEP AS NON CORE | Summary: Heterologous ABCC6 expression can confer limited resistance to xenobiotic anticancer agents. 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. Supporting Evidence: PMID:12414644 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. |
| GO:0009925 basal plasma membrane | IDA PMID:35307651 Localization of Xenobiotic Transporters Expressed at the Hum... | ACCEPT | Summary: Human tissue staining places MRP6 at the basal membrane of Sertoli cells. 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. Supporting Evidence: PMID:35307651 OCTN2, multidrug resistance protein (MRP) 3, MRP6, and MRP7 localized to SC basal membranes and peritubular myoid cells (PMCs) surrounding the seminiferous tubules. |
| GO:0009925 basal plasma membrane | IEA GO_REF:0000044 | ACCEPT | Summary: Human tissue staining places MRP6 at the basal membrane of Sertoli cells. 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. Propagation Review Root cause: NO FAILURE CORE Sources checked: UniProtKB-SubCell:SL-0024 SUPPORTS TRANSFER This subcellular-location vocabulary maps to the stated compartment. Direct human localization independently supports the compartment. Supporting Evidence: PMID:35307651 OCTN2, multidrug resistance protein (MRP) 3, MRP6, and MRP7 localized to SC basal membranes and peritubular myoid cells (PMCs) surrounding the seminiferous tubules. |
| GO:0010467 gene expression | IDA PMID:28592560 Ectopic calcification in pseudoxanthoma elasticum responds t... | MARK AS OVER ANNOTATED | Summary: Altered expression of other enzymes after ABCC6 deficiency does not make ABCC6 a gene-expression component. 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. Supporting Evidence: PMID:28592560 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. |
| GO:0015431 ABC-type glutathione S-conjugate transporter activity | EXP PMID:12414644 Characterization of the drug resistance and transport proper... | ACCEPT | Summary: Human ABCC6 directly catalyzes ATP-dependent export of glutathione S-conjugates in membrane-vesicle assays. 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. Supporting Evidence: PMID:11880368 We found that glutathione conjugates, including leukotriene C(4) and N-ethylmaleimide S-glutathione (NEM-GS), were actively transported by human ABCC6. PMID:11880368 Our data indicate that human ABCC6 is a primary active transporter for organic anions. |
| GO:0015431 ABC-type glutathione S-conjugate transporter activity | IDA PMID:11880368 Loss of ATP-dependent transport activity in pseudoxanthoma e... | ACCEPT | Summary: Human ABCC6 directly catalyzes ATP-dependent export of glutathione S-conjugates in membrane-vesicle assays. 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. Supporting Evidence: PMID:11880368 We found that glutathione conjugates, including leukotriene C(4) and N-ethylmaleimide S-glutathione (NEM-GS), were actively transported by human ABCC6. PMID:11880368 Our data indicate that human ABCC6 is a primary active transporter for organic anions. |
| GO:0015431 ABC-type glutathione S-conjugate transporter activity | IEA GO_REF:0000003 | ACCEPT | Summary: Human ABCC6 directly catalyzes ATP-dependent export of glutathione S-conjugates in membrane-vesicle assays. 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. Propagation Review Root cause: NO FAILURE CORE Sources checked: EC:7.6.2.3 SUPPORTS TRANSFER EC:7.6.2.3 maps directly to ATP-dependent glutathione S-conjugate export, corroborated by human substrate assays. Supporting Evidence: PMID:11880368 We found that glutathione conjugates, including leukotriene C(4) and N-ethylmaleimide S-glutathione (NEM-GS), were actively transported by human ABCC6. PMID:11880368 Our data indicate that human ABCC6 is a primary active transporter for organic anions. |
| GO:0015867 ATP transport | IDA PMID:24277820 ABCC6 prevents ectopic mineralization seen in pseudoxanthoma... | KEEP AS NON CORE | Summary: ABCC6-dependent cellular ATP release is supported, while the route of ATP translocation remains unresolved. 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. Supporting Evidence: PMID:24277820 cells expressing ABCC6 excrete large amounts of nucleoside triphosphates, even though ABCC6 itself does not transport nucleoside triphosphates. PMID:24969777 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. |
| GO:0015867 ATP transport | IDA PMID:24969777 ABCC6-mediated ATP secretion by the liver is the main source... | KEEP AS NON CORE | Summary: ABCC6-dependent cellular ATP release is supported, while the route of ATP translocation remains unresolved. 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. Supporting Evidence: PMID:24277820 cells expressing ABCC6 excrete large amounts of nucleoside triphosphates, even though ABCC6 itself does not transport nucleoside triphosphates. PMID:24969777 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. |
| GO:0016020 membrane | IEA GO_REF:0000002 | ACCEPT | Summary: ABCC6 is a multi-pass integral membrane transporter. 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. Propagation Review Root cause: NO FAILURE CORE Sources checked: InterPro:IPR005292 SUPPORTS TRANSFER The matched ABC/MRP transmembrane domain supports membrane transport architecture; physiological substrate identity is not inferred from this match. InterPro:IPR011527 SUPPORTS TRANSFER The matched ABC/MRP transmembrane domain supports membrane transport architecture; physiological substrate identity is not inferred from this match. InterPro:IPR036640 SUPPORTS TRANSFER The matched ABC/MRP transmembrane domain supports membrane transport architecture; physiological substrate identity is not inferred from this match. Supporting Evidence: PMID:23625951 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). |
| GO:0016323 basolateral plasma membrane | IBA GO_REF:0000033 | ACCEPT | Summary: The canonical transporter localizes to the basolateral plasma membrane. 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. Propagation Review Root cause: NO FAILURE CORE Sources checked: PANTHER:PTN009085618 SUPPORTS TRANSFER 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. Supporting Evidence: PMID:12901863 human ABCC6, when expressed by retroviral transduction in polarized mammalian (MDCKII) cells, is exclusively localized to the basolateral membrane. PMID:23625951 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). |
| GO:0016323 basolateral plasma membrane | IDA PMID:12901863 Subcellular localization and N-glycosylation of human ABCC6,... | ACCEPT | Summary: The canonical transporter localizes to the basolateral plasma membrane. 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. Supporting Evidence: PMID:12901863 human ABCC6, when expressed by retroviral transduction in polarized mammalian (MDCKII) cells, is exclusively localized to the basolateral membrane. PMID:23625951 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). |
| GO:0016323 basolateral plasma membrane | IEA GO_REF:0000120 | ACCEPT | Summary: The canonical transporter localizes to the basolateral plasma membrane. 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. Propagation Review Root cause: NO FAILURE CORE Sources checked: ARBA:ARBA00086715 UNRESOLVED 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. UniProtKB:Q9R1S7 SUPPORTS TRANSFER Mouse basolateral localization agrees with independently demonstrated human basolateral localization; transfer is biologically compatible. ensembl:ENSMUSP00000002850 UNRESOLVED 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. UniProtKB-SubCell:SL-0026 SUPPORTS TRANSFER This subcellular-location vocabulary maps to the stated compartment. Direct human localization independently supports the compartment. Supporting Evidence: PMID:12901863 human ABCC6, when expressed by retroviral transduction in polarized mammalian (MDCKII) cells, is exclusively localized to the basolateral membrane. PMID:23625951 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). |
| GO:0016887 ATP hydrolysis activity | IEA GO_REF:0000002 | ACCEPT | Summary: ATP hydrolysis drives the ABCC6 transport cycle. 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. Propagation Review Root cause: NO FAILURE CORE Sources checked: InterPro:IPR003439 SUPPORTS TRANSFER The matched ABC ATP-binding domain supports nucleotide binding/catalysis. InterPro:IPR017871 SUPPORTS TRANSFER The matched ABC ATP-binding domain supports nucleotide binding/catalysis. Supporting Evidence: PMID:11880368 In isolated membranes ATP binding as well as ATP-dependent active transport by ABCC6 was demonstrated. PMID:11880368 Our data indicate that human ABCC6 is a primary active transporter for organic anions. |
| GO:0022857 transmembrane transporter activity | IEA GO_REF:0000002 | ACCEPT | Summary: ABCC6 catalyzes transmembrane transport. 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. Propagation Review Root cause: NO FAILURE CORE Sources checked: InterPro:IPR005292 SUPPORTS TRANSFER The matched ABC/MRP transmembrane domain supports membrane transport architecture; physiological substrate identity is not inferred from this match. Supporting Evidence: PMID:11880368 We found that glutathione conjugates, including leukotriene C(4) and N-ethylmaleimide S-glutathione (NEM-GS), were actively transported by human ABCC6. |
| GO:0030505 inorganic diphosphate transport | IEA GO_REF:0000107 | MARK AS OVER ANNOTATED | Summary: The traced mouse study demonstrates oral PPi uptake and rescue, not ABCC6-mediated PPi transport. 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. Propagation Review Root cause: SOURCE BAD Failure modes: ROLE CONFLATION Sources checked: UniProtKB:Q9R1S7 SOURCE BAD 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. ensembl:ENSMUSP00000002850 UNRESOLVED 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. Supporting Evidence: PMID:28592560 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). PMID:28701330 though the exact molecular mechanism of ATP release and the actual substrate of ABCC6 is not known. |
| GO:0030643 intracellular phosphate ion homeostasis | IEA GO_REF:0000107 | UNDECIDED | Summary: The specific intracellular inorganic-phosphate claim could not be verified from the traced source. 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. Propagation Review Root cause: UNRESOLVED Sources checked: UniProtKB:Q9R1S7 UNRESOLVED QuickGO traces mouse IMP to PMID:24277820. The abstract concerns extracellular PPi; unavailable full text prevents verification of the specific intracellular phosphate measurement. ensembl:ENSMUSP00000002850 UNRESOLVED 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. Supporting Evidence: PMID:24277820 cells expressing ABCC6 excrete large amounts of nucleoside triphosphates, even though ABCC6 itself does not transport nucleoside triphosphates. |
| GO:0032026 response to magnesium ion | IEA GO_REF:0000107 | KEEP AS NON CORE | Summary: Mineralization susceptibility in Abcc6-deficient mice changes under a phosphate-rich, magnesium-reduced diet. 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. Propagation Review Root cause: NO FAILURE NON CORE Sources checked: UniProtKB:Q9R1S7 SUPPORTS TRANSFER 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. ensembl:ENSMUSP00000002850 UNRESOLVED 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. Supporting Evidence: PMID:24732453 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. |
| GO:0042626 ATPase-coupled transmembrane transporter activity | IDA PMID:11880368 Loss of ATP-dependent transport activity in pseudoxanthoma e... | ACCEPT | Summary: ABCC6 is an ATPase-coupled primary active membrane transporter. 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. Supporting Evidence: PMID:11880368 In isolated membranes ATP binding as well as ATP-dependent active transport by ABCC6 was demonstrated. PMID:11880368 Our data indicate that human ABCC6 is a primary active transporter for organic anions. |
| GO:0042626 ATPase-coupled transmembrane transporter activity | TAS PMID:8912525 The anthracycline resistance-associated (ara) gene, a novel ... | ACCEPT | Summary: ABCC6 is an ATPase-coupled primary active membrane transporter. 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. Supporting Evidence: PMID:11880368 In isolated membranes ATP binding as well as ATP-dependent active transport by ABCC6 was demonstrated. PMID:11880368 Our data indicate that human ABCC6 is a primary active transporter for organic anions. |
| GO:0042626 ATPase-coupled transmembrane transporter activity | TAS Reactome:R-HSA-1454916 | ACCEPT | Summary: ABCC6 is an ATPase-coupled primary active membrane transporter. 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. Supporting Evidence: PMID:11880368 In isolated membranes ATP binding as well as ATP-dependent active transport by ABCC6 was demonstrated. PMID:11880368 Our data indicate that human ABCC6 is a primary active transporter for organic anions. |
| GO:0042626 ATPase-coupled transmembrane transporter activity | TAS Reactome:R-HSA-5690340 | ACCEPT | Summary: ABCC6 is an ATPase-coupled primary active membrane transporter. 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. Supporting Evidence: PMID:11880368 In isolated membranes ATP binding as well as ATP-dependent active transport by ABCC6 was demonstrated. PMID:11880368 Our data indicate that human ABCC6 is a primary active transporter for organic anions. |
| GO:0046034 ATP metabolic process | IDA PMID:28592560 Ectopic calcification in pseudoxanthoma elasticum responds t... | KEEP AS NON CORE | Summary: ABCC6-dependent export affects extracellular ATP metabolism, alongside ATP use by the transporter itself. 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. Supporting Evidence: PMID:28592560 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. PMID:11880368 In isolated membranes ATP binding as well as ATP-dependent active transport by ABCC6 was demonstrated. |
| GO:0046942 carboxylic acid transport | IEA GO_REF:0000117 | ACCEPT | Summary: Transport of defined organic-anion substrates supports carboxylic-acid transport at a broad level. 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. Propagation Review Root cause: NO FAILURE CORE Sources checked: ARBA:ARBA00027271 UNRESOLVED 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. Supporting Evidence: PMID:11880368 We found that glutathione conjugates, including leukotriene C(4) and N-ethylmaleimide S-glutathione (NEM-GS), were actively transported by human ABCC6. |
| GO:0055062 phosphate ion homeostasis | IDA PMID:28592560 Ectopic calcification in pseudoxanthoma elasticum responds t... | MARK AS OVER ANNOTATED | Summary: The mechanistic evidence concerns extracellular pyrophosphate availability and mineralization rather than phosphate-ion steady-state regulation. 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. Supporting Evidence: PMID:28592560 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. PMID:24732453 No difference in serum calcium, inorganic phosphate or pyrophosphate concentrations was noted (Table 1). |
| GO:0055062 phosphate ion homeostasis | IEA GO_REF:0000120 | MARK AS OVER ANNOTATED | Summary: The mechanistic evidence concerns extracellular pyrophosphate availability and mineralization rather than phosphate-ion steady-state regulation. 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. Propagation Review Root cause: SOURCE BAD Failure modes: ROLE CONFLATION Sources checked: ARBA:ARBA00027627 UNRESOLVED 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. UniProtKB:Q9R1S7 SOURCE BAD 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. ensembl:ENSMUSP00000002850 UNRESOLVED 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. Supporting Evidence: PMID:28592560 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. PMID:24732453 No difference in serum calcium, inorganic phosphate or pyrophosphate concentrations was noted (Table 1). |
| GO:0055074 calcium ion homeostasis | IDA PMID:28592560 Ectopic calcification in pseudoxanthoma elasticum responds t... | MARK AS OVER ANNOTATED | Summary: The experiments establish abnormal tissue calcium-phosphate deposition, not a separate calcium-ion steady-state mechanism. 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. Supporting Evidence: PMID:28592560 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. PMID:24732453 No difference in serum calcium, inorganic phosphate or pyrophosphate concentrations was noted (Table 1). |
| GO:0055074 calcium ion homeostasis | IEA GO_REF:0000107 | MARK AS OVER ANNOTATED | Summary: The experiments establish abnormal tissue calcium-phosphate deposition, not a separate calcium-ion steady-state mechanism. 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. Propagation Review Root cause: TERM SCOPING PROBLEM Failure modes: GRANULARITY MISMATCH Sources checked: UniProtKB:Q9R1S7 UNRESOLVED 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. ensembl:ENSMUSP00000002850 UNRESOLVED 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. Supporting Evidence: PMID:28592560 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. PMID:24732453 No difference in serum calcium, inorganic phosphate or pyrophosphate concentrations was noted (Table 1). |
| GO:0055085 transmembrane transport | IBA GO_REF:0000033 | ACCEPT | Summary: ABCC6 directly performs transmembrane transport. 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. Propagation Review Root cause: NO FAILURE CORE Sources checked: PANTHER:PTN000657997 SUPPORTS TRANSFER 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. Supporting Evidence: PMID:11880368 Our data indicate that human ABCC6 is a primary active transporter for organic anions. PMID:11880368 We found that glutathione conjugates, including leukotriene C(4) and N-ethylmaleimide S-glutathione (NEM-GS), were actively transported by human ABCC6. |
| GO:0055085 transmembrane transport | IEA GO_REF:0000002 | ACCEPT | Summary: ABCC6 directly performs transmembrane transport. 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. Propagation Review Root cause: NO FAILURE CORE Sources checked: InterPro:IPR005292 SUPPORTS TRANSFER The matched ABC/MRP transmembrane domain supports membrane transport architecture; physiological substrate identity is not inferred from this match. InterPro:IPR011527 SUPPORTS TRANSFER The matched ABC/MRP transmembrane domain supports membrane transport architecture; physiological substrate identity is not inferred from this match. Supporting Evidence: PMID:11880368 Our data indicate that human ABCC6 is a primary active transporter for organic anions. PMID:11880368 We found that glutathione conjugates, including leukotriene C(4) and N-ethylmaleimide S-glutathione (NEM-GS), were actively transported by human ABCC6. |
| GO:0055085 transmembrane transport | TAS Reactome:R-HSA-382556 | ACCEPT | Summary: ABCC6 directly performs transmembrane transport. 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. Supporting Evidence: PMID:11880368 Our data indicate that human ABCC6 is a primary active transporter for organic anions. PMID:11880368 We found that glutathione conjugates, including leukotriene C(4) and N-ethylmaleimide S-glutathione (NEM-GS), were actively transported by human ABCC6. |
| GO:0071716 leukotriene transport | IDA PMID:11880368 Loss of ATP-dependent transport activity in pseudoxanthoma e... | KEEP AS NON CORE | Summary: Leukotriene C4 is an experimentally transported ABCC6 substrate. 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. Supporting Evidence: PMID:11880368 We found that glutathione conjugates, including leukotriene C(4) and N-ethylmaleimide S-glutathione (NEM-GS), were actively transported by human ABCC6. |
| GO:0140359 ABC-type transporter activity | IBA GO_REF:0000033 | ACCEPT | Summary: ABCC6 has the architecture and demonstrated mechanism of an ABC-type primary active transporter. 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. Propagation Review Root cause: NO FAILURE CORE Sources checked: PANTHER:PTN009085477 SUPPORTS TRANSFER 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. Supporting Evidence: PMID:11880368 Our data indicate that human ABCC6 is a primary active transporter for organic anions. PMID:11880368 In isolated membranes ATP binding as well as ATP-dependent active transport by ABCC6 was demonstrated. |
| GO:0140359 ABC-type transporter activity | IEA GO_REF:0000120 | ACCEPT | Summary: ABCC6 has the architecture and demonstrated mechanism of an ABC-type primary active transporter. 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. Propagation Review Root cause: NO FAILURE CORE Sources checked: ARBA:ARBA00086592 UNRESOLVED 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. InterPro:IPR011527 SUPPORTS TRANSFER The matched ABC/MRP transmembrane domain supports membrane transport architecture; physiological substrate identity is not inferred from this match. Supporting Evidence: PMID:11880368 Our data indicate that human ABCC6 is a primary active transporter for organic anions. PMID:11880368 In isolated membranes ATP binding as well as ATP-dependent active transport by ABCC6 was demonstrated. |
| GO:0140928 inhibition of non-skeletal tissue mineralization | IEA GO_REF:0000107 | ACCEPT | Summary: ABCC6 activity inhibits mineralization of non-skeletal tissues by sustaining extracellular anti-mineralization chemistry. 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. Propagation Review Root cause: NO FAILURE CORE Sources checked: UniProtKB:Q9R1S7 SUPPORTS TRANSFER Mouse experimental annotations trace to PMID:24732453 and PMID:28652107. Deficiency and rescue directly support anti-mineralization, concordant with human genetic and PPi evidence. ensembl:ENSMUSP00000002850 UNRESOLVED 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. Supporting Evidence: PMID:28592560 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. PMID:24969777 The plasma PPi concentrations were ≈2.5-fold lower in patients than in healthy individuals (Figure 2E). PMID:28652107 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. |
| GO:1904383 response to sodium phosphate | IEA GO_REF:0000107 | KEEP AS NON CORE | Summary: Mineralization susceptibility in Abcc6-deficient mice changes under a phosphate-rich, magnesium-reduced diet. 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. Propagation Review Root cause: NO FAILURE NON CORE Sources checked: UniProtKB:Q9R1S7 SUPPORTS TRANSFER Mouse PMID:24732453 tests a combined phosphate-rich, magnesium-poor acceleration diet. The non-core response phenotype can be transferred with that experimental scope. ensembl:ENSMUSP00000002850 UNRESOLVED 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. Supporting Evidence: PMID:24732453 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. |
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Download this section (compressed HTML)Q: What endogenous substrate is physically transported by ABCC6, and does ABCC6 directly translocate ATP or regulate another ATP-release route?
Q: 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?
Q: Which quantified C-terminal PDZ interactions occur with full-length endogenous ABCC6 and influence basolateral trafficking or physiological export?
Q: Does the original mouse intracellular-phosphate annotation have an assay distinct from the extracellular PPi measurements in PMID:24277820?
Experiment: 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.
Experiment: 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.
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