ABCB4 is an ATP-dependent phosphatidylcholine floppase concentrated in the apical canalicular membrane of hepatocytes. Its two transmembrane and nucleotide-binding halves couple ATP utilization to movement of phosphatidylcholine from the cytosolic to the exoplasmic membrane leaflet. Bile salts extract the exposed phospholipid into bile, where it contributes to mixed lipid assemblies that reduce detergent injury and support cholesterol solubilization. Phosphatidylcholine is its established physiological lipid substrate; limited drug-substrate interactions also occur. Biallelic loss of functional ABCB4 causes progressive familial intrahepatic cholestasis type 3, and reduced expression, trafficking or transport competence can produce other cholestatic phenotypes.
| GO Term | Evidence | Action | Reason |
|---|---|---|---|
| GO:0005515 protein binding | IPI PMID:19674157 Receptor for activated C-kinase 1 regulates the cellular loc... | REMOVE | Summary: The RACK1 interaction does not define an informative molecular function of ABCB4. Reason: PMID:19674157 reports two-hybrid and GST-pulldown association with the ABCB4 linker, but unsuccessful full-length co-immunoprecipitation. Remove the generic protein-binding annotation because it does not describe the transporter activity; this does not deny the reported domain interaction. RACK1 regulates ABCB4 trafficking, so its adapter role must not be assigned to ABCB4. |
| GO:0005524 ATP binding | IEA GO_REF:0000002 | ACCEPT | Summary: ABCB4 binds ATP in its two nucleotide-binding domains. Reason: The four InterPro mappings identify ABC nucleotide-binding/transport domains. Human ABCB4 structural evidence resolves two bound ATP molecules (PMID:31873305), directly corroborating this conserved catalytic subactivity. Propagation Review Root cause: NO FAILURE CORE Sources checked: InterPro:IPR003439 SUPPORTS TRANSFER ABC nucleotide-binding/transport domain mapping; two ATP molecules are directly observed in human ABCB4 (PMID:31873305). InterPro:IPR011527 SUPPORTS TRANSFER ABC nucleotide-binding/transport domain mapping; two ATP molecules are directly observed in human ABCB4 (PMID:31873305). InterPro:IPR017871 SUPPORTS TRANSFER ABC nucleotide-binding/transport domain mapping; two ATP molecules are directly observed in human ABCB4 (PMID:31873305). InterPro:IPR036640 SUPPORTS TRANSFER ABC nucleotide-binding/transport domain mapping; two ATP molecules are directly observed in human ABCB4 (PMID:31873305). |
| GO:0005737 cytoplasm | IDA PMID:24045840 Two ABCB4 point mutations of strategic NBD-motifs do not pre... | KEEP AS NON CORE | Summary: Wild-type ABCB4 has an intracellular cytoplasmic pool in the cultured-cell assay. Reason: The accessible indexed full Results of PMID:24045840 place wild-type protein in the cytoplasm and on the cell surface of HUH7 and HEK293 cells, and Figure 3 compares wild-type and mutant distributions. Retain the observed intracellular pool without equating cytoplasm with soluble cytosol or making it the principal canalicular site. |
| GO:0005737 cytoplasm | IEA GO_REF:0000044 | KEEP AS NON CORE | Summary: The Swiss-Prot cytoplasm mapping reflects an observed intracellular pool. Reason: SL-0086 maps the location supported by wild-type cell imaging in PMID:24045840. The cytoplasmic pool is real in this expression system; polarized canalicular plasma membrane remains the core functional location. Propagation Review Root cause: NO FAILURE NON CORE Sources checked: UniProtKB-SubCell:SL-0086 SUPPORTS TRANSFER Swiss-Prot cytoplasm term supported by the wild-type intracellular pool in PMID:24045840. |
| GO:0005829 cytosol | IDA GO_REF:0000052 | KEEP AS NON CORE | Summary: The Human Protein Atlas reports additional cytosolic staining. Reason: The current ABCB4 HPA subcellular page reports supported cytosol staining with HPA049395, specifically in A-549 cells, alongside supported plasma-membrane staining. Retain this contextual antibody-based observation. It does not establish a soluble transport mechanism or a dominant hepatocyte cytosolic pool; the source and cell-line context are recorded in the notes. |
| GO:0005886 plasma membrane | EXP PMID:23468132 Bile salt-stimulated phospholipid efflux mediated by ABCB4 l... | ACCEPT | Summary: ABCB4 is an integral plasma-membrane transporter. Reason: PMID:23468132 fractionates plasma membranes from human ABCB4-expressing HEK293 cells. Predominant nonraft distribution and a smaller raft fraction both lie within the plasma membrane. |
| GO:0005886 plasma membrane | EXP PMID:28012258 Functional defect of variants in the adenosine triphosphate-... | ACCEPT | Summary: ABCB4 is an integral plasma-membrane transporter. Reason: PMID:28012258 compares wild-type and ATP-binding-motif variants that reach the plasma membrane despite impaired PC secretion. The location and catalytic defect are distinct observations. |
| GO:0005886 plasma membrane | IDA GO_REF:0000052 | ACCEPT | Summary: ABCB4 is an integral plasma-membrane transporter. Reason: The current Human Protein Atlas entry reports supported plasma-membrane staining with HPA049395 in A-549, Hep-G2 and U2OS cells. This agrees with dedicated ABCB4 localization studies; see the source URL and assay context in the notes. |
| GO:0005886 plasma membrane | IDA PMID:24045840 Two ABCB4 point mutations of strategic NBD-motifs do not pre... | ACCEPT | Summary: ABCB4 is an integral plasma-membrane transporter. Reason: PMID:24045840 directly compares cell-surface and intracellular localization of wild-type and variant ABCB4 in HUH7 and HEK293 cells. Preserved surface targeting does not imply preserved PC transport. |
| GO:0005886 plasma membrane | IDA PMID:24806754 Molecular mechanistic explanation for the spectrum of choles... | ACCEPT | Summary: ABCB4 is an integral plasma-membrane transporter. Reason: PMID:24806754 measures plasma-membrane localization independently of lipid transport. S320F has reduced surface abundance despite retained activity, whereas A286V reaches the membrane but is transport-defective. |
| GO:0005886 plasma membrane | IEA GO_REF:0000120 | ACCEPT | Summary: ABCB4 is an integral plasma-membrane transporter. Reason: The combined mouse Abcb4/Ensembl orthology and Swiss-Prot cell-membrane mapping agree with direct human plasma-membrane imaging in PMID:24045840 and PMID:24806754. The general location remains valid; the core synthesis specifies the apical domain. Propagation Review Root cause: NO FAILURE CORE Sources checked: UniProtKB:P21440 SUPPORTS TRANSFER Mouse Abcb4 orthology or Swiss-Prot cell-membrane mapping, independently corroborated by human PMID:24045840 and PMID:24806754. ensembl:ENSMUSP00000003717 SUPPORTS TRANSFER Mouse Abcb4 orthology or Swiss-Prot cell-membrane mapping, independently corroborated by human PMID:24045840 and PMID:24806754. UniProtKB-SubCell:SL-0039 SUPPORTS TRANSFER Mouse Abcb4 orthology or Swiss-Prot cell-membrane mapping, independently corroborated by human PMID:24045840 and PMID:24806754. |
| GO:0005886 plasma membrane | TAS PMID:7912658 Phosphatidylcholine translocase: a physiological role for th... | ACCEPT | Summary: ABCB4 is an integral plasma-membrane transporter. Reason: The original statement-level source PMID:7912658 studies mouse Mdr2 in yeast secretory vesicles, rather than serving as a direct human localization assay. Independent human epithelial localization in PMID:8898203 and PMID:24045840 supports retaining the broad plasma-membrane assignment. |
| GO:0005886 plasma membrane | TAS Reactome:R-HSA-1989762 | ACCEPT | Summary: ABCB4 is an integral plasma-membrane transporter. Reason: Reactome R-HSA-1989762 places ABCB4 expression in the plasma-membrane transport context. Dedicated human localization experiments in PMID:8898203 and PMID:24045840 independently support the location. |
| GO:0005886 plasma membrane | TAS Reactome:R-HSA-5678706 | ACCEPT | Summary: ABCB4 is an integral plasma-membrane transporter. Reason: Reactome R-HSA-5678706 describes the normal ABCB4 PC export step from the plasma membrane. This compartment agrees with human localization and transport measurements in PMID:8898203. |
| GO:0005886 plasma membrane | TAS Reactome:R-HSA-5678749 | ACCEPT | Summary: ABCB4 is an integral plasma-membrane transporter. Reason: Reactome R-HSA-5678749 describes failure of PC export by defective ABCB4 variants at the plasma membrane. A mutant-loss event does not negate the corresponding wild-type site; human imaging in PMID:24806754 directly separates localization from function. |
| GO:0006629 lipid metabolic process | TAS PMID:7912658 Phosphatidylcholine translocase: a physiological role for th... | MODIFY | Summary: The cited lipid activity is transbilayer PC movement. Reason: PMID:7912658 measures ATP-dependent PC redistribution across mouse Mdr2-containing membranes. Human PMID:8898203 independently establishes this physical translocation. These experiments do not show ABCB4 chemically synthesizing or degrading lipid; phospholipid translocation captures its direct contribution more precisely. Proposed replacements: phospholipid translocation |
| GO:0016020 membrane | IEA GO_REF:0000120 | ACCEPT | Summary: ABCB4 is a multipass integral membrane protein. Reason: The combined mouse orthology and InterPro membrane/ABC-domain mappings agree with the human transmembrane structure (PMID:31873305). The broad location is correct and does not imply a soluble protein. Propagation Review Root cause: NO FAILURE CORE Sources checked: UniProtKB:P21440 SUPPORTS TRANSFER Mouse Abcb4 orthology or membrane/ABC domain evidence agrees with the multipass human structure in PMID:31873305. ensembl:ENSMUSP00000003717 SUPPORTS TRANSFER Mouse Abcb4 orthology or membrane/ABC domain evidence agrees with the multipass human structure in PMID:31873305. InterPro:IPR011527 SUPPORTS TRANSFER Mouse Abcb4 orthology or membrane/ABC domain evidence agrees with the multipass human structure in PMID:31873305. InterPro:IPR036640 SUPPORTS TRANSFER Mouse Abcb4 orthology or membrane/ABC domain evidence agrees with the multipass human structure in PMID:31873305. |
| GO:0016020 membrane | TAS PMID:7912658 Phosphatidylcholine translocase: a physiological role for th... | ACCEPT | Summary: Membrane integration is essential to ABCB4 lipid translocation. Reason: PMID:7912658 studies the membrane-embedded mouse Mdr2 ortholog; human epithelial localization in PMID:8898203 and human cryo-EM in PMID:31873305 independently support the broad membrane location. |
| GO:0016324 apical plasma membrane | EXP PMID:21820390 Complementary functions of the flippase ATP8B1 and the flopp... | ACCEPT | Summary: ABCB4 acts at the apical canalicular plasma membrane. Reason: PMID:21820390 examines complementary ABCB4 and ATP8B1 activities at the canalicular surface. ABCB4 moves PC outward for bile-salt extraction; the apical membrane is its functional site. |
| GO:0016324 apical plasma membrane | EXP PMID:24594635 Functional analysis of ABCB4 mutations relates clinical outc... | ACCEPT | Summary: ABCB4 acts at the apical canalicular plasma membrane. Reason: PMID:24594635 compares MDR3 expression, subcellular localization and PC-translocating activity in patient/expressed variants. Retain the normal apical site while keeping pathogenic ER retention separate from wild-type localization. |
| GO:0016324 apical plasma membrane | EXP PMID:24723470 Phosphorylation of ABCB4 impacts its function: insights from... | ACCEPT | Summary: ABCB4 acts at the apical canalicular plasma membrane. Reason: PMID:24723470 studies polarized MDCK and HepG2 cells and distinguishes apical targeting from reduced PC secretion in N-terminal variants. This supports the location independently of the phosphorylation-dependent activity changes. |
| GO:0016324 apical plasma membrane | IBA GO_REF:0000033 | ACCEPT | Summary: ABCB4 acts at the apical canalicular plasma membrane. Reason: The PAINT assertion at PTN001199416 places apical membrane localization in an ABCB ancestral lineage. Direct human evidence in PMID:8898203 and PMID:15258199 corroborates retention in ABCB4. The target appearing among descendant experimental sources is expected, not circular. Propagation Review Root cause: NO FAILURE CORE Sources checked: PANTHER:PTN001199416 SUPPORTS TRANSFER PAINT apical-localization ancestral node; direct human apical evidence supports retention. Descendant self-inclusion is not circular. |
| GO:0016324 apical plasma membrane | IDA PMID:15258199 Bezafibrate stimulates canalicular localization of NBD-label... | ACCEPT | Summary: ABCB4 acts at the apical canalicular plasma membrane. Reason: PMID:15258199 shows ABCB4 redistribution into pseudocanaliculi between HepG2 cells after bezafibrate treatment, accompanied by increased canalicular fluorescent-PC accumulation. |
| GO:0016324 apical plasma membrane | IDA PMID:19674157 Receptor for activated C-kinase 1 regulates the cellular loc... | ACCEPT | Summary: ABCB4 acts at the apical canalicular plasma membrane. Reason: PMID:19674157 examines RACK1-dependent ABCB4 surface targeting, including polarized HepG2 cells. Suppressing RACK1 shifts ABCB4 intracellularly; this trafficking effect is consistent with its normal apical location, independently established in PMID:8898203. |
| GO:0016324 apical plasma membrane | IDA PMID:24122873 Peroxisome proliferator-activated receptor Ξ± activates human... | ACCEPT | Summary: ABCB4 acts at the apical canalicular plasma membrane. Reason: PMID:24122873 studies human ABCB4 expression and polarized hepatocyte transport under PPAR-alpha activation. The broader human apical assignment is independently established by PMID:8898203 and PMID:15258199; rat functional assays in this paper should not be relabeled as human. |
| GO:0016324 apical plasma membrane | IDA PMID:8898203 MDR1 P-glycoprotein is a lipid translocase of broad specific... | ACCEPT | Summary: ABCB4 acts at the apical canalicular plasma membrane. Reason: PMID:8898203 directly localizes transfected human MDR3/ABCB4 to the apical membrane of polarized LLC-PK1 cells before measuring apical lipid release. |
| GO:0016324 apical plasma membrane | IEA GO_REF:0000120 | ACCEPT | Summary: ABCB4 acts at the apical canalicular plasma membrane. Reason: The combined ARBA00026413 and Swiss-Prot SL-0015 sources agree with direct polarized human ABCB4 localization in PMID:8898203 and canalicular redistribution in PMID:15258199. Propagation Review Root cause: NO FAILURE CORE Sources checked: ARBA:ARBA00026413 SUPPORTS TRANSFER Apical membrane source maps to the directly observed human location in PMID:8898203 and PMID:15258199. UniProtKB-SubCell:SL-0015 SUPPORTS TRANSFER Apical membrane source maps to the directly observed human location in PMID:8898203 and PMID:15258199. |
| GO:0016887 ATP hydrolysis activity | IEA GO_REF:0000002 | ACCEPT | Summary: ATP hydrolysis powers the ABCB4 transport cycle. Reason: InterPro nucleotide-binding cassette mappings agree with Walker A perturbation of ATP-dependent efflux in PMID:17523162 and the reconstituted ATP-dependent transport assay in PMID:34385322. ATP hydrolysis is a catalytic subactivity of the transporter, not an independent physiological role. Propagation Review Root cause: NO FAILURE CORE Sources checked: InterPro:IPR003439 SUPPORTS TRANSFER ABC nucleotide-binding cassette mapping; ATP-coupling perturbation and reconstitution support the catalytic subactivity. InterPro:IPR017871 SUPPORTS TRANSFER ABC nucleotide-binding cassette mapping; ATP-coupling perturbation and reconstitution support the catalytic subactivity. |
| GO:0030136 clathrin-coated vesicle | IEA GO_REF:0000044 | UNDECIDED | Summary: Rat vesicle evidence does not resolve MDR2 from MDR1. Reason: The SL-0070 mapping traces through rat Abcb4/Q08201 to PMID:15159385. Its accessible full Results name MDR2, but C219 detects both MDR1 and MDR2. Without a discriminating assay, the clathrin-fraction signal cannot securely establish the donor-specific location or human transfer. Propagation Review Root cause: UNRESOLVED Sources checked: UniProtKB-SubCell:SL-0070 UNRESOLVED Rat Q08201 source has accessible full text, but C219 does not distinguish MDR2 from MDR1. Supporting Evidence: |
| GO:0032376 positive regulation of cholesterol transport | IDA PMID:17523162 Bile salt-dependent efflux of cellular phospholipids mediate... | KEEP AS NON CORE | Summary: ABCB4-dependent PC availability facilitates cholesterol efflux. Reason: PMID:17523162 reports taurocholate-dependent cholesterol release, but also finds that PC vesicles promote cholesterol diffusion without accepting cholesterol from ABCB4. Retain the positive effect as an indirect lipid/acceptor consequence, not direct cholesterol-transporter activity. |
| GO:0032376 positive regulation of cholesterol transport | IMP PMID:24045840 Two ABCB4 point mutations of strategic NBD-motifs do not pre... | KEEP AS NON CORE | Summary: ABCB4 variants alter the balance of PC and cholesterol release. Reason: The full Discussion of PMID:24045840 reports lower cholesterol efflux in mutant cells at absent or low taurocholate, supporting this contextual positive effect. At higher taurocholate the direction reverses; the authors propose detergent extraction after loss of lipid asymmetry. Retain as non-core with this condition dependence, not as direct cholesterol translocation. Supporting Evidence: |
| GO:0032782 bile acid secretion | IEA GO_REF:0000107 | MODIFY | Summary: ABCB4 directly supports biliary phospholipid secretion. Reason: The mouse Abcb4 source traces to IMP evidence from PMID:8106172, which establishes loss of biliary phospholipids. GO:0032782 names secretion of bile-acid steroid compounds, whereas ABCB4 moves PC. GO:0033700 phospholipid efflux preserves the measured secretion-out-of-cell context. ABCB4 performs the PC transbilayer step that enables biliary release; bile-acid export is a distinct step. Propagation Review Root cause: TERM SCOPING PROBLEM Failure modes: ROLE CONFLATION Sources checked: UniProtKB:P21440 UNRESOLVED Mouse Abcb4 orthology; its bile-acid-secretion IMP source is PMID:8106172. The verified result is biliary phospholipid loss, while human ABCB4 directly moves PC. ensembl:ENSMUSP00000003717 UNRESOLVED Mouse Abcb4 orthology; its bile-acid-secretion IMP source is PMID:8106172. The verified result is biliary phospholipid loss, while human ABCB4 directly moves PC. Proposed replacements: phospholipid efflux |
| GO:0032782 bile acid secretion | ISS GO_REF:0000024 | MODIFY | Summary: ABCB4 directly supports biliary phospholipid secretion. Reason: The mouse Abcb4 source traces to IMP evidence from PMID:8106172, which establishes loss of biliary phospholipids. GO:0032782 names secretion of bile-acid steroid compounds, whereas ABCB4 moves PC. GO:0033700 phospholipid efflux preserves the measured secretion-out-of-cell context. ABCB4 performs the PC transbilayer step that enables biliary release; bile-acid export is a distinct step. Propagation Review Root cause: TERM SCOPING PROBLEM Failure modes: ROLE CONFLATION Sources checked: UniProtKB:P21440 UNRESOLVED Mouse Abcb4 donor has IMP PMID:8106172; distinguish biliary PC loss from direct bile-acid secretion before transferring the process label. Proposed replacements: phospholipid efflux |
| GO:0042626 ATPase-coupled transmembrane transporter activity | IBA GO_REF:0000033 | ACCEPT | Summary: ABCB4 retains the ancestral ATP-coupled membrane transport mechanism. Reason: The PAINT PTN000657189 assertion encompasses ATP-dependent transport across the ABCB lineage. Human ABCB4 has direct ATP-dependent lipid-transport evidence (PMID:17523162; PMID:34385322); no target-specific loss challenges this node placement. The PC-specific activity is separately represented. Propagation Review Root cause: NO FAILURE CORE Sources checked: PANTHER:PTN000657189 SUPPORTS TRANSFER PAINT ABC transport ancestral node agrees with ATP-coupled human ABCB4 lipid flux; no node-placement or lineage-loss objection. |
| GO:0042626 ATPase-coupled transmembrane transporter activity | IDA PMID:17523162 Bile salt-dependent efflux of cellular phospholipids mediate... | ACCEPT | Summary: ABCB4 lipid efflux depends on its ATP-coupling machinery. Reason: PMID:17523162 shows loss of taurocholate-dependent phospholipid efflux for either Walker A lysine mutant. Together with purified transport in PMID:34385322, this supports the general ATPase-coupled transporter activity. |
| GO:0042626 ATPase-coupled transmembrane transporter activity | IMP PMID:8898203 MDR1 P-glycoprotein is a lipid translocase of broad specific... | ACCEPT | Summary: Human MDR3-mediated translocation is energy dependent. Reason: PMID:8898203 uses polarized cells, energy depletion and transport inhibition to distinguish transbilayer short-chain lipid movement from vesicular secretion. The more specific PC floppase activity is separately annotated; this encompassing mechanism is sound. |
| GO:0042626 ATPase-coupled transmembrane transporter activity | TAS PMID:7912658 Phosphatidylcholine translocase: a physiological role for th... | ACCEPT | Summary: The conserved Mdr2/ABCB4 lipid-transport reaction is ATP dependent. Reason: PMID:7912658 directly measures ATP/Mg-dependent PC translocation by mouse Mdr2 in yeast vesicles. This statement-level support is reinforced by direct human ABCB4 experiments in PMID:8898203 and PMID:34385322. |
| GO:0045121 membrane raft | EXP PMID:23468132 Bile salt-stimulated phospholipid efflux mediated by ABCB4 l... | KEEP AS NON CORE | Summary: ABCB4 has a minor membrane-raft pool despite predominant nonraft distribution. Reason: PMID:23468132 Figure 2 and Results report a human ABCB4 raft/nonraft distribution ratio of 0.158 in detergent-free fractionation. Thus predominantly nonraft does not mean absent from rafts. Retain the minor pool without making raft residence the defining transport site. |
| GO:0045121 membrane raft | IEA GO_REF:0000044 | KEEP AS NON CORE | Summary: ABCB4 has a minor membrane-raft pool despite predominant nonraft distribution. Reason: PMID:23468132 Figure 2 and Results report a human ABCB4 raft/nonraft distribution ratio of 0.158 in detergent-free fractionation. Thus predominantly nonraft does not mean absent from rafts. Retain the minor pool without making raft residence the defining transport site. SL-0370 maps this same location evidence. Propagation Review Root cause: NO FAILURE NON CORE Sources checked: UniProtKB-SubCell:SL-0370 SUPPORTS TRANSFER Swiss-Prot raft mapping has positive support in PMID:23468132: raft/nonraft ratio 0.158 despite predominantly nonraft localization. |
| GO:0045332 phospholipid translocation | IBA GO_REF:0000033 | ACCEPT | Summary: Phospholipid translocation is the conserved core process. Reason: PAINT PTN000657226 captures the lipid-translocation specialization directly demonstrated for human ABCB4. Human ABCB4 as a descendant evidence source is legitimate experimental grounding, not circularity; its PC translocation is independently confirmed in purified proteoliposomes. Propagation Review Root cause: NO FAILURE CORE Sources checked: PANTHER:PTN000657226 SUPPORTS TRANSFER PAINT phospholipid-translocation node is experimentally grounded in the target and retained in its lineage; self-inclusion is expected. |
| GO:0045332 phospholipid translocation | IDA PMID:8898203 MDR1 P-glycoprotein is a lipid translocase of broad specific... | ACCEPT | Summary: ABCB4 moves PC across the plasma-membrane bilayer. Reason: PMID:8898203 recovers apical short-chain PC at 15 degrees C, where vesicular secretion is suppressed, supporting transbilayer movement before extracellular albumin extraction. |
| GO:0045332 phospholipid translocation | IEA GO_REF:0000117 | ACCEPT | Summary: The ARBA phospholipid-translocation prediction agrees with direct human experiments. Reason: ARBA00026752 assigns the process that human cellular transport (PMID:8898203) and reconstitution (PMID:34385322) establish. No target-specific functional divergence argues against this transfer. Propagation Review Root cause: NO FAILURE CORE Sources checked: ARBA:ARBA00026752 SUPPORTS TRANSFER ARBA phospholipid-translocation prediction corroborated by direct human cellular and purified transport evidence. |
| GO:0045332 phospholipid translocation | IMP PMID:24806754 Molecular mechanistic explanation for the spectrum of choles... | ACCEPT | Summary: Functional variants distinguish PC translocation from surface targeting. Reason: PMID:24806754 separately measures expression, localization and lipid transport. A286V reaches the plasma membrane but cannot flop lipid, while S320F retains floppase activity with reduced surface abundance. |
| GO:0046581 intercellular canaliculus | IEA GO_REF:0000107 | ACCEPT | Summary: The bile canaliculus is the anatomical site of ABCB4 transport. Reason: The mouse Abcb4/Ensembl transfer is consistent with canalicular membrane localization in the donor record (PMID:12068294) and with human ABCB4 pseudocanalicular imaging (PMID:15258199). Retain the broad intercellular-canaliculus location; the core synthesis specifies its apical membrane. Propagation Review Root cause: NO FAILURE CORE Sources checked: UniProtKB:P21440 SUPPORTS TRANSFER Mouse Abcb4 canalicular evidence includes PMID:12068294; direct human pseudocanalicular imaging in PMID:15258199 supports conservation. ensembl:ENSMUSP00000003717 SUPPORTS TRANSFER Mouse Abcb4 canalicular evidence includes PMID:12068294; direct human pseudocanalicular imaging in PMID:15258199 supports conservation. |
| GO:0055085 transmembrane transport | IEA GO_REF:0000002 | ACCEPT | Summary: ABCB4 translocates membrane lipid. Reason: The IPR011527 ABC transporter-family mapping is broad but agrees with human ATP-dependent PC movement. The precise intramembrane direction and substrate are represented by PC floppase activity. Propagation Review Root cause: NO FAILURE CORE Sources checked: InterPro:IPR011527 SUPPORTS TRANSFER ABC transporter-family domain agrees with human PC translocation across membrane leaflets. |
| GO:0055085 transmembrane transport | TAS Reactome:R-HSA-382556 | ACCEPT | Summary: ABCB4 contributes a lipid-transport step to the ABC transport pathway. Reason: Reactome R-HSA-382556 is a broad pathway grouping, and ABCB4 performs an actual transport reaction within it. Human PC translocation experiments support this process independently of the pathway label. |
| GO:0055088 lipid homeostasis | IDA PMID:17523162 Bile salt-dependent efflux of cellular phospholipids mediate... | KEEP AS NON CORE | Summary: PC secretion contributes to biliary lipid balance. Reason: PMID:17523162 demonstrates bile-salt-dependent phospholipid output and an associated cholesterol-efflux effect. Lipid homeostasis is a valid physiological consequence, while ATP-dependent PC flopping is the molecular core. |
| GO:0061092 positive regulation of phospholipid translocation | IDA PMID:17523162 Bile salt-dependent efflux of cellular phospholipids mediate... | MODIFY | Summary: ABCB4 performs phospholipid translocation directly. Reason: PMID:17523162 tests ABCB4-dependent phospholipid output and ATP-coupling mutants. The protein is the PC translocator itself; taurocholate acts as an extracellular acceptor condition. Phospholipid translocation is more accurate than assigning ABCB4 a separate positive-regulatory role over its own reaction. Proposed replacements: phospholipid translocation |
| GO:0070062 extracellular exosome | HDA PMID:23533145 In-depth proteomic analyses of exosomes isolated from expres... | UNDECIDED | Summary: The exosome proteomic assignment needs its protein-level evidence. Reason: PMID:23533145 analyzes exosomes from expressed prostatic secretions in urine. The paper is accessible, but the ABCB4-specific supplemental peptide/protein assignment was not recovered. Preserve this experimental assertion pending that check; do not infer either a dedicated ABCB4 exosome function or absence from extracellular vesicles. |
| GO:0090554 phosphatidylcholine floppase activity | IBA GO_REF:0000033 | ACCEPT | Summary: PC floppase activity is the ABCB4 lineage specialization. Reason: The PAINT PTN000657226 assertion is directly corroborated by human cellular and proteoliposome assays. ABCB4 appearing as its own descendant evidence source is expected and does not weaken the phylogenetic inference. Propagation Review Root cause: NO FAILURE CORE Sources checked: PANTHER:PTN000657226 SUPPORTS TRANSFER PAINT PC-floppase node supported by target experimental descendant evidence and later purified human reconstitution. |
| GO:0090554 phosphatidylcholine floppase activity | IDA PMID:17523162 Bile salt-dependent efflux of cellular phospholipids mediate... | ACCEPT | Summary: ABCB4 promotes ATP-dependent PC release to extracellular bile salts. Reason: PMID:17523162 demonstrates ATP-coupling-dependent, taurocholate-stimulated PC efflux. Its cellular readout combines transbilayer movement and extracellular extraction; PMID:8898203 and purified reconstitution in PMID:34385322 independently establish the floppase mechanism. |
| GO:0090554 phosphatidylcholine floppase activity | IDA PMID:31873305 Structure of the human lipid exporter ABCB4 in a lipid envir... | ACCEPT | Summary: Human ABCB4 structure supports its PC export mechanism. Reason: PMID:31873305 resolves human ABCB4 in an ATP-bound state after substrate release. Structural snapshots support a mechanism, but are not by themselves a leaflet-resolved flux assay. Direct cellular and purified transport evidence independently establish PC floppase activity (PMID:8898203; PMID:34385322). The structural construct is isoform 2; this is not evidence that activity is unique to that isoform. |
| GO:0090554 phosphatidylcholine floppase activity | IDA PMID:8898203 MDR1 P-glycoprotein is a lipid translocase of broad specific... | ACCEPT | Summary: Human MDR3 selectively translocates the tested short-chain PC analog. Reason: PMID:8898203 distinguishes MDR3 from broad-specificity MDR1 using lipid release from polarized epithelial cells under conditions suppressing vesicular secretion. Its PC result supports outward transbilayer movement before albumin extraction. Later purified ABCB4 experiments corroborate this activity. |
| GO:0090554 phosphatidylcholine floppase activity | IEA GO_REF:0000117 | ACCEPT | Summary: The ARBA PC floppase prediction matches direct ABCB4 biochemistry. Reason: ARBA00088274 assigns the established substrate and cytosolic-to-exoplasmic direction. Human translocation and reconstitution experiments support the inference without relying only on ABC-family similarity. Propagation Review Root cause: NO FAILURE CORE Sources checked: ARBA:ARBA00088274 SUPPORTS TRANSFER ARBA prediction matches established PC substrate and outward leaflet movement. |
| GO:0090554 phosphatidylcholine floppase activity | IMP PMID:24045840 Two ABCB4 point mutations of strategic NBD-motifs do not pre... | ACCEPT | Summary: ABCB4 NBD variants reduce PC secretion despite preserved targeting. Reason: PMID:24045840 compares wild-type ABCB4 with Q-loop/A-loop variants in lipid-release assays. The decreased PC output supports functional disruption of the established floppase; increased stimulated cholesterol release must not be mistaken for an alternative directly transported substrate. |
| GO:0090554 phosphatidylcholine floppase activity | IMP PMID:24806754 Molecular mechanistic explanation for the spectrum of choles... | ACCEPT | Summary: PC floppase activity can be separated experimentally from membrane abundance. Reason: PMID:24806754 directly measures lipid transport in transfected cells and finds that surface-targeted A286V is inactive, whereas S320F retains activity but is less abundant at the plasma membrane. This is strong functional support for the wild-type activity. |
| GO:0099038 ceramide floppase activity | IDA NOT PMID:8898203 MDR1 P-glycoprotein is a lipid translocase of broad specific... | UNDECIDED | Summary: The source NOT assertion is broader than the negative lipid panel verified here. Reason: This is a negated annotation, not a positive claim of ceramide transport. PMID:8898203 Figure 4 tests short-chain sphingomyelin and glucosylceramide produced from a ceramide precursor; MDR3 lacks the MDR1-dependent enhancement for these derivatives. Those results do not directly assay movement of free ceramide as defined by this GO term. Retain the NOT flag and source row but leave the exact free-ceramide conclusion unresolved rather than infer a universal negative from PC selectivity. |
| GO:0099040 ceramide translocation | IDA NOT PMID:8898203 MDR1 P-glycoprotein is a lipid translocase of broad specific... | UNDECIDED | Summary: The source NOT assertion is broader than the negative lipid panel verified here. Reason: This is a negated annotation, not a positive claim of ceramide transport. PMID:8898203 Figure 4 tests short-chain sphingomyelin and glucosylceramide produced from a ceramide precursor; MDR3 lacks the MDR1-dependent enhancement for these derivatives. Those results do not directly assay movement of free ceramide as defined by this GO term. Retain the NOT flag and source row but leave the exact free-ceramide conclusion unresolved rather than infer a universal negative from PC selectivity. |
| GO:0120014 phospholipid transfer activity | TAS Reactome:R-HSA-5678706 | MODIFY | Summary: The Reactome PC-export event is executed by a membrane floppase. Reason: Reactome R-HSA-5678706 describes normal PC export. GO:0120014 specifically describes extracting a phospholipid and shielding it during transfer through an aqueous phase. ABCB4 is an integral membrane ATP-dependent floppase, followed by extracellular acceptor-mediated extraction. Replace the soluble-transfer mechanism with its directly established PC floppase activity. Proposed replacements: phosphatidylcholine floppase activity |
| GO:0120014 phospholipid transfer activity | TAS Reactome:R-HSA-5678749 | MODIFY | Summary: The Reactome PC-export event is executed by a membrane floppase. Reason: Reactome R-HSA-5678749 describes defective PC export by ABCB4 variants. GO:0120014 specifically describes extracting a phospholipid and shielding it during transfer through an aqueous phase. ABCB4 is an integral membrane ATP-dependent floppase, followed by extracellular acceptor-mediated extraction. Replace the soluble-transfer mechanism with its directly established PC floppase activity. Proposed replacements: phosphatidylcholine floppase activity |
| GO:0140326 ATPase-coupled intramembrane lipid carrier activity | IEA GO_REF:0000003 | ACCEPT | Summary: The EC-derived intramembrane lipid-transport activity is correct. Reason: EC:7.6.2.1 describes ATP-dependent phospholipid translocation. ABCB4 directly performs this activity, with PC specificity separately captured in the existing annotations. The broad EC mapping does not imply transport of every phospholipid class. Propagation Review Root cause: NO FAILURE CORE Sources checked: EC:7.6.2.1 SUPPORTS TRANSFER EC:7.6.2.1 mapping describes the experimentally established ATP-dependent phospholipid translocation reaction. |
| GO:0140326 ATPase-coupled intramembrane lipid carrier activity | ISS GO_REF:0000024 | ACCEPT | Summary: The mouse ortholog directly demonstrates ATP-dependent intramembrane lipid transport. Reason: Mouse Abcb4/P21440 carries experimental support from PMID:7912658, which measures ATP- and Mg-dependent PC redistribution in secretory vesicles. Human ABCB4 transport assays independently corroborate conservation, so this transfer is not based only on sequence similarity. Propagation Review Root cause: NO FAILURE CORE Sources checked: UniProtKB:P21440 SUPPORTS TRANSFER Mouse Abcb4/P21440 has direct EXP evidence from PMID:7912658; human PMID:8898203 corroborates the transfer. |
| GO:0140359 ABC-type transporter activity | IEA GO_REF:0000002 | ACCEPT | Summary: ABCB4 is an active ABC transporter. Reason: IPR011527 identifies the relevant ABC transporter family. Human structure and ATP-dependent PC transport establish that the target retains this activity; the PC-specific function is separately represented. Propagation Review Root cause: NO FAILURE CORE Sources checked: InterPro:IPR011527 SUPPORTS TRANSFER ABCB family classification corroborated by structure and transport assays on human ABCB4. |
| GO:1901557 response to fenofibrate | IEA GO_REF:0000107 | KEEP AS NON CORE | Summary: Fenofibrate induces ABCB4 expression as part of a lipid-secretion response. Reason: The mouse donor has IDA evidence from PMID:8615769, which reports increased mdr2 expression after fenofibrate. Human primary hepatocytes also upregulate ABCB4 after fenofibrate in PMID:24122873, supporting conservation. Retain the drug-response context without treating ABCB4 as a fenofibrate transporter, receptor or upstream transcription factor. Propagation Review Root cause: NO FAILURE NON CORE Sources checked: UniProtKB:P21440 SUPPORTS TRANSFER Mouse Abcb4 fenofibrate-response IDA traces to PMID:8615769, with independent human induction in PMID:24122873. ensembl:ENSMUSP00000003717 SUPPORTS TRANSFER Mouse Abcb4 fenofibrate-response IDA traces to PMID:8615769, with independent human induction in PMID:24122873. |
| GO:1901557 response to fenofibrate | ISS GO_REF:0000024 | KEEP AS NON CORE | Summary: Fenofibrate induces ABCB4 expression as part of a lipid-secretion response. Reason: The mouse donor has IDA evidence from PMID:8615769, which reports increased mdr2 expression after fenofibrate. Human primary hepatocytes also upregulate ABCB4 after fenofibrate in PMID:24122873, supporting conservation. Retain the drug-response context without treating ABCB4 as a fenofibrate transporter, receptor or upstream transcription factor. Propagation Review Root cause: NO FAILURE NON CORE Sources checked: UniProtKB:P21440 SUPPORTS TRANSFER Mouse Abcb4 induction by fenofibrate in PMID:8615769 is conserved in primary human hepatocytes (PMID:24122873). |
| GO:1903413 cellular response to bile acid | IDA PMID:17523162 Bile salt-dependent efflux of cellular phospholipids mediate... | KEEP AS NON CORE | Summary: Bile salts enhance ABCB4-dependent extracellular lipid output. Reason: PMID:17523162 shows that taurocholate promotes phospholipid efflux from ABCB4-expressing cells. This is a cellular response mediated through PC transport and acceptor-dependent extraction, not evidence that ABCB4 transports the bile acid or serves as its receptor. |
| GO:2001140 positive regulation of phospholipid transport | IDA PMID:8898203 MDR1 P-glycoprotein is a lipid translocase of broad specific... | MODIFY | Summary: The original study measures direct PC translocation. Reason: PMID:8898203 uses low-temperature epithelial assays to separate membrane translocation from vesicular secretion. ABCB4 executes the lipid-moving step; a positive-regulation term obscures that direct role. Preserve the measured process as phospholipid translocation. Proposed replacements: phospholipid translocation |
| GO:2001140 positive regulation of phospholipid transport | IMP PMID:24045840 Two ABCB4 point mutations of strategic NBD-motifs do not pre... | MODIFY | Summary: Wild-type ABCB4 directly transports PC; mutations impair this step. Reason: PMID:24045840 compares PC secretion by wild-type and NBD-variant ABCB4 with similar expression/localization. This supports phospholipid translocation by the transporter, not an additional regulatory activity over another transporter. Proposed replacements: phospholipid translocation |
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Download this section (compressed HTML)Q: Does a direct oriented-transport experiment test free ceramide, beyond the negative SM/GlcCer analog panel in PMID:8898203, sufficiently to support the two existing NOT ceramide annotations?
Q: Which ABCB4 peptides underlie the exosome assignment in PMID:23533145, and is the detected protein an intact functional transporter?
Q: Can the UniProt PE and sphingomyelin catalytic-reaction statements attributed to PMID:8898203 be reconciled with that paper's MDR1/MDR3 substrate contrast? The cached source record is preserved unchanged.
Q: How do PC acyl-chain composition and bile-salt acceptors affect direct ABCB4 flux versus secondary cholesterol and other phospholipid efflux?
Q: Which ABCB4 drug interactions correspond to direct transport under physiological conditions rather than binding, ATPase modulation or inhibition?
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