ABCG8 (sterolin-2) is an ABC-family half-transporter that forms an obligate functional heterodimer with ABCG5. At apical membranes of intestinal enterocytes and hepatocytes, the complex couples ATP hydrolysis to export of neutral sterols, including cholesterol and plant sterols, into the intestinal lumen or bile. This limits net dietary sterol absorption and supports elimination of sterols from the body. Each subunit contributes a transmembrane domain and elements of two asymmetric nucleotide-binding sites; ABCG8 supplies the signature region of the transport-essential catalytic site. Loss-of-function variants cause autosomal recessive sitosterolemia, with sterol accumulation and increased cardiovascular risk.
| GO Term | Evidence | Action | Reason |
|---|---|---|---|
| GO:0005515 protein binding | IPI PMID:16870176 Expression and functional characterization of ABCG1 splice v... | REMOVE | Summary: The ABCG5 interaction is retained by the specific heterodimerization assertion. Reason: PMID:16870176 Figure 7 supports the reported ABCG8–ABCG5 association. The existing GO:0046982 IPI annotation cites this same paper and the same partner UniProtKB:Q9H222, and is retained as ACCEPT. Human-pair purification and structure independently establish functional heterodimerization (PMID:16893193; PMID:27144356). Remove the uninformative generic protein-binding assertion while retaining that specific assembly function and all original interaction provenance; this does not reject the interaction. Supporting Evidence: PMID:16893193 Furthermore, ABCG5/G8 eluted as a dimer on gel filtration columns. The data suggest that the hetero-dimer is the catalytically active species, and likely the active species in vivo. PMID:27144356 To obtain diffraction-quality crystals, human G5 and G8 were coexpressed in Pichia pastoris12, and tandem affinity chromatography was used to purify stable, monodisperse G5G8 heterodimers that retained ATPase activity (Extended Data Fig. 1). |
| GO:0005515 protein binding | IPI PMID:32296183 A reference map of the human binary protein interactome. | REMOVE | Summary: The ABCG8–MESD interaction is retained as interaction context, without a specific molecular-function assignment. Reason: PMID:32296183 is the HuRI binary-interaction mapping study; the immutable UniProt record identifies MESD as the reported partner. The exact supplementary pair and native-cell mechanism were not independently resolved. Generic protein binding supplies no informative ABCG8 function, so remove this term under the binding policy without declaring the interaction false or inferring a chaperone/adaptor activity. Supporting Evidence: file:human/ABCG8/ABCG8-uniprot.txt Q9H221; Q14696: MESD; NbExp=3; IntAct=EBI-3908684, EBI-6165891; |
| GO:0005524 ATP binding | IDA PMID:16893193 Purification and ATP hydrolysis of the putative cholesterol ... | ACCEPT | Summary: ABCG8 contributes to nucleotide binding by the ABCG5–ABCG8 transporter. Reason: The source purified recombinant human G5/G8 from Pichia and measured nucleotide trapping with fluoroaluminate/fluoroberyllate. Its contribution-qualified assertion fits the composite nucleotide sites. Later structures establish strong asymmetry between those sites; ABCG8 contributes the signature region to the active site, so this is not a claim that isolated ABCG8 has the same ATP-binding properties as ABCG5. Supporting Evidence: PMID:16893193 AlFx and BeFx inhibited MgATP hydrolysis by specific trapping of nucleotides in the ABCG5/G8 proteins. PMID:27144356 The inactive G5 Signature motif (part of NBS1)21, which binds but does not hydrolyse ATP, is adjacent to the CnH/CpH/E-helix bundle of G5, whereas the active G8 Signature motif (part of NBS2) is near the three-helix bundle of G8 |
| GO:0005524 ATP binding | IEA GO_REF:0000002 | ACCEPT | Summary: The ABC nucleotide-binding domains support ATP interaction within the heterodimer. Reason: IPR003439 and IPR017871 occur in the human UniProt record. Purified human heterodimer nucleotide trapping and the composite-site structure independently support ATP binding. The domain mapping does not establish equal nucleotide affinity of both sites or autonomous ABCG8 ATPase activity. Propagation Review Root cause: NO FAILURE CORE Sources checked: InterPro:IPR003439 SUPPORTS TRANSFER The ABC ATP-binding domain/signature entries are present in human ABCG8; human heterodimer experiments corroborate nucleotide interaction, with asymmetric composite sites. InterPro:IPR017871 SUPPORTS TRANSFER The ABC ATP-binding domain/signature entries are present in human ABCG8; human heterodimer experiments corroborate nucleotide interaction, with asymmetric composite sites. Supporting Evidence: PMID:16893193 AlFx and BeFx inhibited MgATP hydrolysis by specific trapping of nucleotides in the ABCG5/G8 proteins. PMID:27144356 The inactive G5 Signature motif (part of NBS1)21, which binds but does not hydrolyse ATP, is adjacent to the CnH/CpH/E-helix bundle of G5, whereas the active G8 Signature motif (part of NBS2) is near the three-helix bundle of G8 |
| GO:0005886 plasma membrane | IBA GO_REF:0000033 | ACCEPT | Summary: ABCG8 acts at the plasma membrane as part of the sterol exporter. Reason: The PAINT plasma-membrane assertion agrees with cultured-cell trafficking and direct human ABCG8 localization in transgenic mouse liver in Figure 2 of PMID:14504269. The broader compartment is correct even though its apical specialization is represented separately. No target-specific loss of this inherited membrane role is indicated. Propagation Review Root cause: NO FAILURE CORE Sources checked: PANTHER:PTN000443664 UNRESOLVED Direct human ABCG8 trafficking and apical liver-membrane localization support the target plasma-membrane assertion. The exact ancestral IBD placement and complete alignment were not independently inspected. Target self-evidence among descendants is legitimate experimental grounding, not circularity. Supporting Evidence: PMID:14504269 Expression of both G5 and G8 is required for either protein to be transported to the plasma membrane of cultured cells. file:human/ABCG8/ABCG8-uniprot.txt Apical cell CC membrane {ECO:0000269|PubMed:14504269}; Multi-pass membrane protein CC {ECO:0000269|PubMed:27144356}. |
| GO:0005886 plasma membrane | IEA GO_REF:0000044 | ACCEPT | Summary: The UniProt plasma-membrane mapping matches ABCG8 localization. Reason: SL-0039 maps the curated cell-membrane location. Human ABCG8 is a multipass membrane subunit whose ABCG5-dependent trafficking delivers the functional exporter to the cell surface; the source-level broad compartment is appropriate. Propagation Review Root cause: NO FAILURE CORE Sources checked: UniProtKB-SubCell:SL-0039 SUPPORTS TRANSFER SL-0039 is the seeded cell-membrane vocabulary mapping and is corroborated by human trafficking/localization evidence. Supporting Evidence: PMID:14504269 Expression of both G5 and G8 is required for either protein to be transported to the plasma membrane of cultured cells. file:human/ABCG8/ABCG8-uniprot.txt Apical cell CC membrane {ECO:0000269|PubMed:14504269}; Multi-pass membrane protein CC {ECO:0000269|PubMed:27144356}. |
| GO:0005886 plasma membrane | ISS GO_REF:0000024 | ACCEPT | Summary: Mouse-to-human plasma-membrane transfer agrees with direct human localization. Reason: Q9DBM0 is mouse Abcg8. The conserved G5/G8 architecture and the cross-species maturation experiments in PMID:14504269 support transfer; Figure 2 also directly detects human ABCG8 on apical hepatic membranes in transgenic mice. The exact historical donor GO record was not separately reconstructed, but the human target location is independently supported. Propagation Review Root cause: NO FAILURE CORE Sources checked: UniProtKB:Q9DBM0 SUPPORTS TRANSFER Mouse Abcg8 identity and conserved partner-dependent trafficking are supported by the primary experiments; direct human localization independently supports transfer. Supporting Evidence: PMID:14504269 Expression of both G5 and G8 is required for either protein to be transported to the plasma membrane of cultured cells. file:human/ABCG8/ABCG8-uniprot.txt Apical cell CC membrane {ECO:0000269|PubMed:14504269}; Multi-pass membrane protein CC {ECO:0000269|PubMed:27144356}. |
| GO:0005886 plasma membrane | TAS Reactome:R-HSA-265783 | ACCEPT | Summary: The normal Reactome sterol-export reaction places ABCG8 in the plasma membrane. Reason: R-HSA-265783 explicitly locates the ABCG5:ABCG8 catalyst in the plasma membrane. This agrees with human trafficking and localization. Its historical note that human transport was incompletely characterized is supplemented by the later human structural and in vivo reconstitution study. Supporting Evidence: Reactome:R-HSA-265783 The complex of ATP-binding cassette sub-family G members 5 and 8 (ABCG5:ABCG8) in the plasma membrane mediates the ATP-dependent export of cytosolic sterols (cholesterol and phytosterols). PMID:14504269 Expression of both G5 and G8 is required for either protein to be transported to the plasma membrane of cultured cells. |
| GO:0005886 plasma membrane | TAS Reactome:R-HSA-5679101 | ACCEPT | Summary: The disease-pathway record retains the normal complex’s plasma-membrane compartment. Reason: R-HSA-5679101 describes defective ABCG8 in the shared transporter and states the normal complex localization. The plasma-membrane annotation is independently correct for wild-type human ABCG8. This does not imply that every pathogenic variant traffics normally or that a defective transport event is a positive wild-type activity assay. Supporting Evidence: Reactome:R-HSA-5679101 This complex translocates to the plasma membrane PMID:14504269 Expression of both G5 and G8 is required for either protein to be transported to the plasma membrane of cultured cells. |
| GO:0005886 plasma membrane | TAS Reactome:R-HSA-5679145 | ACCEPT | Summary: The disease-pathway record retains the normal complex’s plasma-membrane compartment. Reason: R-HSA-5679145 describes defective ABCG5 in the shared transporter and states the normal complex localization. The plasma-membrane annotation is independently correct for wild-type human ABCG8. This does not imply that every pathogenic variant traffics normally or that a defective transport event is a positive wild-type activity assay. Supporting Evidence: Reactome:R-HSA-5679145 This complex translocates to the plasma membrane PMID:14504269 Expression of both G5 and G8 is required for either protein to be transported to the plasma membrane of cultured cells. |
| GO:0005886 plasma membrane | TAS Reactome:R-HSA-9029591 | ACCEPT | Summary: The regulated-expression pathway correctly describes the location of the ABCG8 product. Reason: R-HSA-9029591 describes ABCG8 as an LXR-regulated gene product and explicitly places G5/G8 on enterocyte brush-border and hepatocyte canalicular membranes. This supports the source-level plasma-membrane location; it does not assign transcriptional regulation to ABCG8 itself. Supporting Evidence: Reactome:R-HSA-9029591 ABCG5 and ABCG8 are expressed almost exclusively on the brush border membranes of enterocytes and in the canalicular membranes of hepatocytes file:human/ABCG8/ABCG8-uniprot.txt Apical cell CC membrane {ECO:0000269|PubMed:14504269}; Multi-pass membrane protein CC {ECO:0000269|PubMed:27144356}. |
| GO:0006869 lipid transport | IEA GO_REF:0000117 | MODIFY | Summary: ABCG8 participates specifically in neutral-sterol transport. Reason: The ARBA lipid-transport assignment is compatible with ABCG8 but does not capture its established neutral-sterol cargo. Refine to sterol transport using human G5G8 biliary export and the curated cholesterol/sitosterol reaction, rather than assuming that the rule itself establishes substrate specificity. Propagation Review Root cause: TERM SCOPING PROBLEM Failure modes: GRANULARITY MISMATCH Sources checked: ARBA:ARBA00027046 UNRESOLVED The exact ARBA00027046 rule conditions were not recovered; independent human transport experiments justify the target-level sterol refinement. Proposed replacements: sterol transport Supporting Evidence: PMID:27144356 Expression of wild-type (WT) G5 together with WT G8 resulted in a ~30-fold increase in cholesterol transport into bile. Reactome:R-HSA-265783 The complex of ATP-binding cassette sub-family G members 5 and 8 (ABCG5:ABCG8) in the plasma membrane mediates the ATP-dependent export of cytosolic sterols (cholesterol and phytosterols). |
| GO:0007584 response to nutrient | IEA GO_REF:0000107 | UNDECIDED | Summary: The rat-derived response to nutrient assignment requires a resolved process-level transfer. Reason: The historical MGI comparative graph traces the rat IEP source to PMID:15710224. Its primary abstract reports dietary lipid loading with cell-type-specific induction of Abcg5/Abcg8 in rat liver, particularly Kupffer cells. Full source methods/results were not recovered; conservation of the specific response and ABCG8 participation beyond regulated abundance cannot be resolved from this evidence. Propagation Review Root cause: UNRESOLVED Sources checked: UniProtKB:P58428 UNRESOLVED Rat Abcg8 is the ortholog source (UniProt P58428 / ENSRNOP00000058587). MGI comparative graph snapshot 2023-03-10 identifies IEP evidence from PMID:15710224. Primary abstracts were read; full assay scope and human process-level transfer remain unresolved. ensembl:ENSRNOP00000058587 UNRESOLVED Rat Abcg8 is the ortholog source (UniProt P58428 / ENSRNOP00000058587). MGI comparative graph snapshot 2023-03-10 identifies IEP evidence from PMID:15710224. Primary abstracts were read; full assay scope and human process-level transfer remain unresolved. |
| GO:0009410 response to xenobiotic stimulus | IEA GO_REF:0000107 | UNDECIDED | Summary: The rat-derived response to xenobiotic stimulus assignment requires a resolved process-level transfer. Reason: The rat IEP chain resolves to PMID:17109865. The primary abstract reports higher hepatic Abcg5/Abcg8 mRNA after pioglitazone than insulin in diabetic Zucker rats. This is positive drug-responsive expression evidence, but the inaccessible full study and untested human response leave the role of ABCG8 as a response effector unresolved; it does not establish transport of the drug. Propagation Review Root cause: UNRESOLVED Sources checked: UniProtKB:P58428 UNRESOLVED Rat Abcg8 is the ortholog source (UniProt P58428 / ENSRNOP00000058587). MGI comparative graph snapshot 2023-03-10 identifies IEP evidence from PMID:17109865. Primary abstracts were read; full assay scope and human process-level transfer remain unresolved. ensembl:ENSRNOP00000058587 UNRESOLVED Rat Abcg8 is the ortholog source (UniProt P58428 / ENSRNOP00000058587). MGI comparative graph snapshot 2023-03-10 identifies IEP evidence from PMID:17109865. Primary abstracts were read; full assay scope and human process-level transfer remain unresolved. |
| GO:0010949 negative regulation of intestinal phytosterol absorption | IMP PMID:11099417 Accumulation of dietary cholesterol in sitosterolemia caused... | ACCEPT | Summary: ABCG8 limits intestinal retention and absorption of dietary phytosterols. Reason: The cited human study identifies ABCG8 mutations in sitosterolemia with increased dietary sterol absorption and reduced biliary elimination. This physiological interpretation is supported by the later G5/G8 export mechanism and mouse-donor sterol-reconstitution evidence. ABCG8 contributes the export machinery itself; this is not inferred from disease association alone. Supporting Evidence: PMID:11099417 six mutations in ABCG8 and one in ABCG5 PMID:11099417 These data suggest that ABCG5 and ABCG8 normally cooperate to limit intestinal absorption and to promote biliary excretion of sterols Reactome:R-HSA-265783 The complex of ATP-binding cassette sub-family G members 5 and 8 (ABCG5:ABCG8) in the plasma membrane mediates the ATP-dependent export of cytosolic sterols (cholesterol and phytosterols). |
| GO:0014850 response to muscle activity | IEA GO_REF:0000107 | UNDECIDED | Summary: The rat-derived response to muscle activity assignment requires a resolved process-level transfer. Reason: The rat IEP source is PMID:23117815, which reports increased intestinal Abcg8 transcripts with exercise training on standard diet, suppressed by an atherogenic diet. This physiological context is relevant, but full experimental detail and conservation of the response mechanism in humans remain unresolved. Neither the IEP code nor the absence of a direct human assay alone establishes that the response annotation is wrong. Propagation Review Root cause: UNRESOLVED Sources checked: UniProtKB:P58428 UNRESOLVED Rat Abcg8 is the ortholog source (UniProt P58428 / ENSRNOP00000058587). MGI comparative graph snapshot 2023-03-10 identifies IEP evidence from PMID:23117815. Primary abstracts were read; full assay scope and human process-level transfer remain unresolved. ensembl:ENSRNOP00000058587 UNRESOLVED Rat Abcg8 is the ortholog source (UniProt P58428 / ENSRNOP00000058587). MGI comparative graph snapshot 2023-03-10 identifies IEP evidence from PMID:23117815. Primary abstracts were read; full assay scope and human process-level transfer remain unresolved. |
| GO:0015918 sterol transport | ISS GO_REF:0000024 | ACCEPT | Summary: Conserved ABCG5–ABCG8 transport directly handles neutral sterols. Reason: The donor is mouse Abcg8 Q9DBM0. The MGI comparative graph identifies PMID:16867993, whose full PMC source uses mouse proteins in Sf9 vesicles and purified proteoliposomes to measure ATP-dependent cholesterol/sitosterol transfer. Human G5G8 reconstitution and structural evidence independently support the conserved transport role; the mouse assay is not relabeled as human. Propagation Review Root cause: NO FAILURE CORE Sources checked: UniProtKB:Q9DBM0 SUPPORTS TRANSFER Mouse Abcg8 donor sterol-transfer experiments were read in full PMC4527585; human complex structure and biliary export corroborate conservation. Supporting Evidence: PMID:27144356 Expression of wild-type (WT) G5 together with WT G8 resulted in a ~30-fold increase in cholesterol transport into bile. Reactome:R-HSA-265783 The complex of ATP-binding cassette sub-family G members 5 and 8 (ABCG5:ABCG8) in the plasma membrane mediates the ATP-dependent export of cytosolic sterols (cholesterol and phytosterols). |
| GO:0016020 membrane | IEA GO_REF:0000002 | ACCEPT | Summary: The ABC2 transmembrane domain places ABCG8 in membranes. Reason: IPR013525 is present in the human UniProt record, and the human G5G8 structure directly resolves a multipass transmembrane domain. The broad membrane compartment is a correct domain-level assertion; apical plasma-membrane annotations separately capture physiological localization. Propagation Review Root cause: NO FAILURE CORE Sources checked: InterPro:IPR013525 SUPPORTS TRANSFER The ABC2_TM domain is present and its membrane-spanning architecture is confirmed by human G5G8 structures. Supporting Evidence: PMID:27144356 To obtain diffraction-quality crystals, human G5 and G8 were coexpressed in Pichia pastoris12, and tandem affinity chromatography was used to purify stable, monodisperse G5G8 heterodimers that retained ATPase activity (Extended Data Fig. 1). file:human/ABCG8/ABCG8-uniprot.txt Apical cell CC membrane {ECO:0000269|PubMed:14504269}; Multi-pass membrane protein CC {ECO:0000269|PubMed:27144356}. |
| GO:0016324 apical plasma membrane | IEA GO_REF:0000044 | ACCEPT | Summary: ABCG8’s apical membrane location is captured by the UniProt mapping. Reason: SL-0015 maps the curated apical cell-membrane location. It agrees with the human ABCG8 immunofluorescence experiment in Figure 2 of PMID:14504269 and with the export direction of the functional transporter. Propagation Review Root cause: NO FAILURE CORE Sources checked: UniProtKB-SubCell:SL-0015 SUPPORTS TRANSFER The source vocabulary maps the experimentally supported apical membrane specialization. Supporting Evidence: file:human/ABCG8/ABCG8-uniprot.txt Apical cell CC membrane {ECO:0000269|PubMed:14504269}; Multi-pass membrane protein CC {ECO:0000269|PubMed:27144356}. |
| GO:0016324 apical plasma membrane | IMP PMID:14504269 ABCG5 and ABCG8 are obligate heterodimers for protein traffi... | ACCEPT | Summary: Human ABCG8 is localized on apical hepatic membranes in the cited study. Reason: The full author manuscript of PMID:14504269 includes human ABCG8 immunofluorescence in liver membrane sheets from human G5/G8 transgenic mice (Figure 2), compared with apical and basolateral markers. This directly supports the human protein location in a mouse host. Figure 1’s mouse G5 staining is a separate experiment and is not used as human G8 evidence. Supporting Evidence: file:human/ABCG8/ABCG8-uniprot.txt Apical cell CC membrane {ECO:0000269|PubMed:14504269}; Multi-pass membrane protein CC {ECO:0000269|PubMed:27144356}. PMID:14504269 Expression of both G5 and G8 is required for either protein to be transported to the plasma membrane of cultured cells. |
| GO:0016324 apical plasma membrane | ISS GO_REF:0000024 | ACCEPT | Summary: The mouse apical-membrane assignment transfers consistently to human ABCG8. Reason: The donor is mouse Abcg8 Q9DBM0. Conserved G5/G8 assembly and trafficking support this location, and human ABCG8 apical staining in the same primary study independently resolves the target. The exact historical donor localization record was not separately reconstructed. Propagation Review Root cause: NO FAILURE CORE Sources checked: UniProtKB:Q9DBM0 SUPPORTS TRANSFER Mouse Abcg8 identity and shared trafficking are established; human ABCG8 Figure 2 localization independently supports the target apical compartment. Supporting Evidence: file:human/ABCG8/ABCG8-uniprot.txt Apical cell CC membrane {ECO:0000269|PubMed:14504269}; Multi-pass membrane protein CC {ECO:0000269|PubMed:27144356}. PMID:14504269 Expression of both G5 and G8 is required for either protein to be transported to the plasma membrane of cultured cells. |
| GO:0016887 ATP hydrolysis activity | IDA PMID:16893193 Purification and ATP hydrolysis of the putative cholesterol ... | ACCEPT | Summary: ABCG8 contributes to ATP hydrolysis by the assembled heterodimer. Reason: PMID:16893193 directly measures purified recombinant human G5G8 ATPase activity and inhibitory nucleotide trapping. The contribution qualifier correctly scopes the assay to the pair. The later composite-site structure identifies the ABCG8 signature as part of the active nucleotide site; neither equal catalytic activity of both sites nor efficient isolated ABCG8 hydrolysis is claimed. Supporting Evidence: PMID:16893193 Copurified ABCG5/G8 displayed low but significant ATPase activity with a V(max) of approximately 15 nmol min(-)(1) mg(-)(1). PMID:27144356 The inactive G5 Signature motif (part of NBS1)21, which binds but does not hydrolyse ATP, is adjacent to the CnH/CpH/E-helix bundle of G5, whereas the active G8 Signature motif (part of NBS2) is near the three-helix bundle of G8 |
| GO:0016887 ATP hydrolysis activity | IEA GO_REF:0000002 | ACCEPT | Summary: ABCG8 supplies the signature component of the active composite ATPase site. Reason: Human G5/G8 purification and MgATP-hydrolysis assays establish catalytic activity of the assembled pair (PMID:16893193; PMID:27144356). NBS2 is formed by the G5 Walker motifs and the G8 signature; the opposite G8 Walker-containing NBS1 is degenerate. The recovered full PMID:34404721 additionally measures pair hydrolysis and its inhibition by a G8-binding Fab. ABCG8 therefore contributes physical catalytic machinery to the active site, beyond merely regulating a separate ATPase. Retain this core catalytic subactivity in its obligatory heterodimer context, with no claim of autonomous G8 hydrolysis or equal activity of the two sites. The InterPro domain mapping alone does not establish those stronger claims. Propagation Review Root cause: NO FAILURE CORE Sources checked: InterPro:IPR003439 SUPPORTS TRANSFER The ATPase-family features occur in ABCG8 and human heterodimer catalysis supports their functional context; this does not imply two equivalent ATP-hydrolyzing sites. InterPro:IPR017871 SUPPORTS TRANSFER The ATPase-family features occur in ABCG8 and human heterodimer catalysis supports their functional context; this does not imply two equivalent ATP-hydrolyzing sites. Supporting Evidence: PMID:16893193 Copurified ABCG5/G8 displayed low but significant ATPase activity with a V(max) of approximately 15 nmol min(-)(1) mg(-)(1). PMID:27144356 The inactive G5 Signature motif (part of NBS1)21, which binds but does not hydrolyse ATP, is adjacent to the CnH/CpH/E-helix bundle of G5, whereas the active G8 Signature motif (part of NBS2) is near the three-helix bundle of G8 PMID:34404721 Fab2C7 binds the nucleotide-binding domain (NBD) of G8 (SI Appendix, Fig. S2B) and restrains the conformational changes required for ATP hydrolysis. |
| GO:0030299 intestinal cholesterol absorption | IC PMID:12208868 Overexpression of ABCG5 and ABCG8 promotes biliary cholester... | MODIFY | Summary: Human G5/G8 transgene expression reduces fractional cholesterol absorption. Reason: GO:0030299 defines uptake from the intestine into blood. The full source instead measures reduced fractional absorption after expression of human ABCG5 and ABCG8 in mice. Its Discussion explicitly leaves intestinal efflux versus increased biliary cholesterol delivery unresolved. Negative regulation captures the measured direction without assigning an uptake step or a resolved tissue-specific mechanism to this experiment; the original IC source and GO:0120020 supporting entity are preserved. Propagation Review Root cause: TERM SCOPING PROBLEM Failure modes: ROLE CONFLATION Sources checked: GO:0120020 UNRESOLVED GO:0120020 is the seeded IC premise. Its current aqueous-carrier definition does not establish intestinal uptake; the measured transgene effect independently supports a negative-regulation refinement. Proposed replacements: negative regulation of intestinal cholesterol absorption Supporting Evidence: PMID:12208868 a P1 clone containing the human ABCG5 and ABCG8 genes was used to generate transgenic mice. PMID:12208868 The fractional absorption of dietary cholesterol was reduced by about 50%, and biliary cholesterol levels were increased more than fivefold. PMID:12208868 Alternatively, the reduction in cholesterol absorption in our transgenic mice may be secondary to the increased delivery of cholesterol to the intestinal lumen from the liver. |
| GO:0031667 response to nutrient levels | IEA GO_REF:0000107 | UNDECIDED | Summary: The rat-derived response to nutrient levels assignment requires a resolved process-level transfer. Reason: Historical rat IEP sources are PMID:23117815 and PMID:25263431. The first abstract explicitly reports diet- and exercise-dependent Abcg8 expression. The second describes ovariectomy/high-cholesterol effects on liver lipid accumulation and VLDL assembly without naming Abcg8; its specific Abcg8 connection is established by the donor annotation, not the abstract. Full source-specific mechanistic evidence was not recovered, so conserved participation in this response cannot be separated confidently from ABCG8 being transcriptionally regulated. Propagation Review Root cause: UNRESOLVED Sources checked: UniProtKB:P58428 UNRESOLVED Rat Abcg8 is the ortholog source (UniProt P58428 / ENSRNOP00000058587). MGI comparative graph snapshot 2023-03-10 identifies IEP evidence from PMID:23117815, PMID:25263431. Primary abstracts were read; full assay scope and human process-level transfer remain unresolved. ensembl:ENSRNOP00000058587 UNRESOLVED Rat Abcg8 is the ortholog source (UniProt P58428 / ENSRNOP00000058587). MGI comparative graph snapshot 2023-03-10 identifies IEP evidence from PMID:23117815, PMID:25263431. Primary abstracts were read; full assay scope and human process-level transfer remain unresolved. |
| GO:0033344 cholesterol efflux | IBA GO_REF:0000033 | ACCEPT | Summary: ABCG8 contributes directly to cholesterol export through the G5/G8 complex. Reason: The PAINT efflux assertion is supported independently by human G5/G8-mediated biliary cholesterol export. Human ABCG8 among the descendant evidence is legitimate grounding for the ancestral judgment, not circular support. Exact node placement was not independently reconstructed. Propagation Review Root cause: NO FAILURE CORE Sources checked: PANTHER:PTN002710463 UNRESOLVED The human target has direct heterodimer-dependent cholesterol-export evidence. The exact ancestral IBD placement and complete alignment were not independently inspected. Target self-evidence among descendants is legitimate experimental grounding, not circularity. Supporting Evidence: PMID:27144356 Expression of wild-type (WT) G5 together with WT G8 resulted in a ~30-fold increase in cholesterol transport into bile. |
| GO:0033344 cholesterol efflux | IGI PMID:14504269 ABCG5 and ABCG8 are obligate heterodimers for protein traffi... | ACCEPT | Summary: The human ABCG8 cholesterol-efflux assignment agrees with the established paired exporter. Reason: The full 2003 source includes human/mouse cross-species trafficking experiments, while its in vivo biliary rescue in Figure 5 uses mouse G5 and G8. Preserve the curated human IGI assignment with that boundary: later PMID:27144356 directly restores biliary efflux with human G5/G8. The mouse Q9DBM0 supporting entity is retained without treating it as evidence for an ABCG8–ABCG8 functional transport pair. Supporting Evidence: PMID:14504269 Expression of both G5 and G8 is required for either protein to be transported to the plasma membrane of cultured cells. PMID:27144356 Expression of wild-type (WT) G5 together with WT G8 resulted in a ~30-fold increase in cholesterol transport into bile. |
| GO:0033344 cholesterol efflux | IMP PMID:27144356 Crystal structure of the human sterol transporter ABCG5/ABCG... | ACCEPT | Summary: Human G5/G8 restores biliary cholesterol export in transporter-deficient mice. Reason: PMID:27144356 tests recombinant human G5 and G8 in G5G8-deficient mice and measures a large increase in biliary cholesterol after wild-type pair expression. Structure-guided mutants reduce transport despite mature protein expression. This is direct efflux by the human heterodimer in a mouse host, not activity of ABCG8 alone. Supporting Evidence: PMID:27144356 Expression of wild-type (WT) G5 together with WT G8 resulted in a ~30-fold increase in cholesterol transport into bile. PMID:27144356 To obtain diffraction-quality crystals, human G5 and G8 were coexpressed in Pichia pastoris12, and tandem affinity chromatography was used to purify stable, monodisperse G5G8 heterodimers that retained ATPase activity (Extended Data Fig. 1). |
| GO:0033344 cholesterol efflux | IMP PMID:27144356 Crystal structure of the human sterol transporter ABCG5/ABCG... | ACCEPT | Summary: Human G5/G8 restores biliary cholesterol export in transporter-deficient mice. Reason: PMID:27144356 tests recombinant human G5 and G8 in G5G8-deficient mice and measures a large increase in biliary cholesterol after wild-type pair expression. Structure-guided mutants reduce transport despite mature protein expression. This is direct efflux by the human heterodimer in a mouse host, not activity of ABCG8 alone. The ABCG5 supporting entity correctly records the partner dependence. Supporting Evidence: PMID:27144356 Expression of wild-type (WT) G5 together with WT G8 resulted in a ~30-fold increase in cholesterol transport into bile. PMID:27144356 To obtain diffraction-quality crystals, human G5 and G8 were coexpressed in Pichia pastoris12, and tandem affinity chromatography was used to purify stable, monodisperse G5G8 heterodimers that retained ATPase activity (Extended Data Fig. 1). |
| GO:0042626 ATPase-coupled transmembrane transporter activity | IBA GO_REF:0000033 | MODIFY | Summary: ABCG8 contributes to ATP-powered neutral-sterol export. Reason: The broad transporter term is correct, but GO:0034041 specifies the established ATP-driven sterol-export activity. Human structural, ATPase and biliary-export experiments support the refinement. Both halves form the transport machinery; the integrated core records contribution to the complex activity rather than autonomous transport by ABCG8. Propagation Review Root cause: TERM SCOPING PROBLEM Failure modes: GRANULARITY MISMATCH Sources checked: PANTHER:PTN008283605 UNRESOLVED The ancestral ABC-transporter role is compatible with the target; human transport assays supply the sterol-specific refinement. The exact ancestral IBD placement and complete alignment were not independently inspected. Target self-evidence among descendants is legitimate experimental grounding, not circularity. Proposed replacements: ABC-type sterol transporter activity Supporting Evidence: PMID:27144356 Expression of wild-type (WT) G5 together with WT G8 resulted in a ~30-fold increase in cholesterol transport into bile. PMID:27144356 To obtain diffraction-quality crystals, human G5 and G8 were coexpressed in Pichia pastoris12, and tandem affinity chromatography was used to purify stable, monodisperse G5G8 heterodimers that retained ATPase activity (Extended Data Fig. 1). PMID:16893193 Copurified ABCG5/G8 displayed low but significant ATPase activity with a V(max) of approximately 15 nmol min(-)(1) mg(-)(1). |
| GO:0042626 ATPase-coupled transmembrane transporter activity | IDA PMID:27144356 Crystal structure of the human sterol transporter ABCG5/ABCG... | MODIFY | Summary: ABCG8 contributes to ATP-powered neutral-sterol export. Reason: The broad transporter term is correct, but GO:0034041 specifies the established ATP-driven sterol-export activity. Human structural, ATPase and biliary-export experiments support the refinement. Both halves form the transport machinery; the integrated core records contribution to the complex activity rather than autonomous transport by ABCG8. Proposed replacements: ABC-type sterol transporter activity Supporting Evidence: PMID:27144356 Expression of wild-type (WT) G5 together with WT G8 resulted in a ~30-fold increase in cholesterol transport into bile. PMID:27144356 To obtain diffraction-quality crystals, human G5 and G8 were coexpressed in Pichia pastoris12, and tandem affinity chromatography was used to purify stable, monodisperse G5G8 heterodimers that retained ATPase activity (Extended Data Fig. 1). PMID:16893193 Copurified ABCG5/G8 displayed low but significant ATPase activity with a V(max) of approximately 15 nmol min(-)(1) mg(-)(1). |
| GO:0042632 cholesterol homeostasis | IBA GO_REF:0000033 | ACCEPT | Summary: The inherited cholesterol-homeostasis role is supported by direct sterol export. Reason: Human ABCG8 loss-of-function disrupts sterol balance, and human G5/G8 increases biliary cholesterol export in reconstituted mice. Those data identify a transport step that maintains cholesterol balance rather than only a correlated plasma phenotype. Propagation Review Root cause: NO FAILURE CORE Sources checked: PANTHER:PTN002710463 UNRESOLVED Human genetics and direct transport establish ABCG8’s cholesterol-homeostasis role independently of unresolved node reconstruction. The exact ancestral IBD placement and complete alignment were not independently inspected. Target self-evidence among descendants is legitimate experimental grounding, not circularity. Supporting Evidence: PMID:11099417 six mutations in ABCG8 and one in ABCG5 PMID:27144356 Expression of wild-type (WT) G5 together with WT G8 resulted in a ~30-fold increase in cholesterol transport into bile. |
| GO:0042632 cholesterol homeostasis | IEA GO_REF:0000120 | ACCEPT | Summary: The combined automated homeostasis assignment agrees with human ABCG8 function. Reason: The combined ARBA/rat-ortholog row is supported at target level by human genetics and direct G5/G8 sterol export. Its exact rule internals and rat term-specific donor chain were not independently resolved; they are not substituted for the positive human evidence. Propagation Review Root cause: NO FAILURE CORE Sources checked: ARBA:ARBA00086791 UNRESOLVED The source is a combined ARBA00086791 / rat Abcg8 transfer. Exact rule conditions or term-specific donor evidence were not recovered; independent human genetics and transport support the target assertion. UniProtKB:P58428 UNRESOLVED The source is a combined ARBA00086791 / rat Abcg8 transfer. Exact rule conditions or term-specific donor evidence were not recovered; independent human genetics and transport support the target assertion. ensembl:ENSRNOP00000058587 UNRESOLVED The source is a combined ARBA00086791 / rat Abcg8 transfer. Exact rule conditions or term-specific donor evidence were not recovered; independent human genetics and transport support the target assertion. Supporting Evidence: PMID:11099417 These data suggest that ABCG5 and ABCG8 normally cooperate to limit intestinal absorption and to promote biliary excretion of sterols PMID:27144356 Expression of wild-type (WT) G5 together with WT G8 resulted in a ~30-fold increase in cholesterol transport into bile. |
| GO:0042632 cholesterol homeostasis | IMP PMID:11099417 Accumulation of dietary cholesterol in sitosterolemia caused... | ACCEPT | Summary: Human ABCG8 variants connect loss of sterol export to disrupted cholesterol balance. Reason: PMID:11099417 identifies six ABCG8 mutations in affected patients and describes increased sterol absorption and reduced biliary excretion. Later human G5/G8 functional experiments independently establish the transport mechanism underlying this core homeostatic role. The source’s patient association is not recast as purified-protein enzymology. Supporting Evidence: PMID:11099417 six mutations in ABCG8 and one in ABCG5 PMID:11099417 These data suggest that ABCG5 and ABCG8 normally cooperate to limit intestinal absorption and to promote biliary excretion of sterols PMID:27144356 Expression of wild-type (WT) G5 together with WT G8 resulted in a ~30-fold increase in cholesterol transport into bile. |
| GO:0042632 cholesterol homeostasis | IMP PMID:27144356 Crystal structure of the human sterol transporter ABCG5/ABCG... | ACCEPT | Summary: Human G5/G8 directly executes a cholesterol-elimination step. Reason: The source tests human transporter expression and structure-guided variants in a mouse biliary-export assay. Restoration of cholesterol delivery to bile identifies direct work in cholesterol homeostasis; it is more specific evidence than a downstream disease phenotype. Supporting Evidence: PMID:27144356 Expression of wild-type (WT) G5 together with WT G8 resulted in a ~30-fold increase in cholesterol transport into bile. PMID:27144356 To obtain diffraction-quality crystals, human G5 and G8 were coexpressed in Pichia pastoris12, and tandem affinity chromatography was used to purify stable, monodisperse G5G8 heterodimers that retained ATPase activity (Extended Data Fig. 1). |
| GO:0043190 ATP-binding cassette (ABC) transporter complex | IDA PMID:16893193 Purification and ATP hydrolysis of the putative cholesterol ... | ACCEPT | Summary: Purified human ABCG5 and ABCG8 form the active ABC transporter complex. Reason: The source coexpresses human proteins in Pichia, copurifies them, measures ATPase activity and observes dimeric gel-filtration behavior. These complementary assays support heterodimeric ABC transporter membership without requiring an unrelated signaling-receptor interpretation. Supporting Evidence: PMID:16893193 Furthermore, ABCG5/G8 eluted as a dimer on gel filtration columns. The data suggest that the hetero-dimer is the catalytically active species, and likely the active species in vivo. PMID:16893193 Copurified ABCG5/G8 displayed low but significant ATPase activity with a V(max) of approximately 15 nmol min(-)(1) mg(-)(1). |
| GO:0043190 ATP-binding cassette (ABC) transporter complex | IDA PMID:27144356 Crystal structure of the human sterol transporter ABCG5/ABCG... | ACCEPT | Summary: The human G5/G8 structure directly establishes ABC-transporter complex membership. Reason: The crystallographic model resolves the two human half-transporters, and the purified complex retains ATPase activity. ABCG8 supplies one transmembrane domain and elements of both composite nucleotide sites. Supporting Evidence: PMID:27144356 To obtain diffraction-quality crystals, human G5 and G8 were coexpressed in Pichia pastoris12, and tandem affinity chromatography was used to purify stable, monodisperse G5G8 heterodimers that retained ATPase activity (Extended Data Fig. 1). PMID:27144356 The inactive G5 Signature motif (part of NBS1)21, which binds but does not hydrolyse ATP, is adjacent to the CnH/CpH/E-helix bundle of G5, whereas the active G8 Signature motif (part of NBS2) is near the three-helix bundle of G8 |
| GO:0043235 signaling receptor complex | IBA GO_REF:0000033 | MODIFY | Summary: The experimentally established assembly is an ABC sterol-transporter complex. Reason: GO:0043235 defines a ligand-responsive signaling receptor complex. Full PMID:14504269 instead tests G5/G8 assembly, trafficking and biliary export; human structural evidence establishes the ABC transporter complex. Replace with GO:0043190 to retain the demonstrated assembly without importing an unmeasured receptor-signaling mechanism. This is a term-role refinement, not a claim that an abstract omits ABCG8. Propagation Review Root cause: TERM SCOPING PROBLEM Failure modes: COMPARTMENT OR COMPLEX MISMATCH Sources checked: PANTHER:PTN002710463 UNRESOLVED The target complex has direct transport/assembly support, but the current signaling-receptor definition does not match that evidence. The exact ancestral IBD placement and complete alignment were not independently inspected. Target self-evidence among descendants is legitimate experimental grounding, not circularity. Proposed replacements: ATP-binding cassette (ABC) transporter complex Supporting Evidence: PMID:14504269 Expression of both G5 and G8 is required for either protein to be transported to the plasma membrane of cultured cells. PMID:27144356 To obtain diffraction-quality crystals, human G5 and G8 were coexpressed in Pichia pastoris12, and tandem affinity chromatography was used to purify stable, monodisperse G5G8 heterodimers that retained ATPase activity (Extended Data Fig. 1). |
| GO:0043235 signaling receptor complex | IDA PMID:14504269 ABCG5 and ABCG8 are obligate heterodimers for protein traffi... | MODIFY | Summary: The experimentally established assembly is an ABC sterol-transporter complex. Reason: GO:0043235 defines a ligand-responsive signaling receptor complex. Full PMID:14504269 instead tests G5/G8 assembly, trafficking and biliary export; human structural evidence establishes the ABC transporter complex. Replace with GO:0043190 to retain the demonstrated assembly without importing an unmeasured receptor-signaling mechanism. This is a term-role refinement, not a claim that an abstract omits ABCG8. Proposed replacements: ATP-binding cassette (ABC) transporter complex Supporting Evidence: PMID:14504269 Expression of both G5 and G8 is required for either protein to be transported to the plasma membrane of cultured cells. PMID:27144356 To obtain diffraction-quality crystals, human G5 and G8 were coexpressed in Pichia pastoris12, and tandem affinity chromatography was used to purify stable, monodisperse G5G8 heterodimers that retained ATPase activity (Extended Data Fig. 1). |
| GO:0045796 negative regulation of intestinal cholesterol absorption | IMP PMID:11099417 Accumulation of dietary cholesterol in sitosterolemia caused... | ACCEPT | Summary: ABCG8 limits net absorption of dietary cholesterol. Reason: The human genetic source associates ABCG8 defects with increased sterol absorption. Human G5/G8 transgenes independently reduce fractional cholesterol absorption in mice. Export is the protein’s direct molecular work; the transgenic study does not separate the relative enterocyte and biliary contributions to its measured absorption phenotype. Supporting Evidence: PMID:11099417 These data suggest that ABCG5 and ABCG8 normally cooperate to limit intestinal absorption and to promote biliary excretion of sterols PMID:12208868 The fractional absorption of dietary cholesterol was reduced by about 50%, and biliary cholesterol levels were increased more than fivefold. PMID:12208868 Alternatively, the reduction in cholesterol absorption in our transgenic mice may be secondary to the increased delivery of cholesterol to the intestinal lumen from the liver. |
| GO:0046982 protein heterodimerization activity | IPI PMID:16870176 Expression and functional characterization of ABCG1 splice v... | ACCEPT | Summary: ABCG8 heterodimerization with ABCG5 is an established component of transporter assembly. Reason: The publisher-indexed Results and Figure 7 of the ABCG1-focused source include G5/G8 co-immunoprecipitation. Independently, purified human G5/G8 and the human heterodimer structure establish the same assembly. The title’s focus on ABCG1 does not invalidate this experimental G5/G8 annotation. Supporting Evidence: PMID:16893193 Furthermore, ABCG5/G8 eluted as a dimer on gel filtration columns. The data suggest that the hetero-dimer is the catalytically active species, and likely the active species in vivo. PMID:27144356 To obtain diffraction-quality crystals, human G5 and G8 were coexpressed in Pichia pastoris12, and tandem affinity chromatography was used to purify stable, monodisperse G5G8 heterodimers that retained ATPase activity (Extended Data Fig. 1). |
| GO:0046983 protein dimerization activity | IEA GO_REF:0000117 | MODIFY | Summary: ABCG8’s physiological transport assembly is a heterodimer with ABCG5. Reason: The broad ARBA dimerization term can be refined to the well-established human G5/G8 heterodimerization activity. This refinement does not assert that homodimers or other associations can never occur under overexpression conditions; it identifies the partner-dependent physiological export assembly. Propagation Review Root cause: TERM SCOPING PROBLEM Failure modes: GRANULARITY MISMATCH Sources checked: ARBA:ARBA00027598 UNRESOLVED ARBA00027598 internal conditions were not recovered. Independent human biochemical and structural evidence supports the heterodimer-specific target refinement. Proposed replacements: protein heterodimerization activity Supporting Evidence: PMID:16893193 Furthermore, ABCG5/G8 eluted as a dimer on gel filtration columns. The data suggest that the hetero-dimer is the catalytically active species, and likely the active species in vivo. PMID:27144356 To obtain diffraction-quality crystals, human G5 and G8 were coexpressed in Pichia pastoris12, and tandem affinity chromatography was used to purify stable, monodisperse G5G8 heterodimers that retained ATPase activity (Extended Data Fig. 1). |
| GO:0055085 transmembrane transport | IBA GO_REF:0000033 | ACCEPT | Summary: ABCG8 performs transmembrane transport as part of the G5/G8 exporter. Reason: The conserved broad transmembrane-transport process is directly supported by the human ABC transporter architecture and biliary cholesterol export. This valid ancestral process is retained; separate activity refinements capture sterol specificity without claiming every member of the PAINT clade shares that cargo. Propagation Review Root cause: NO FAILURE CORE Sources checked: PANTHER:PTN008283605 UNRESOLVED The broad inherited transport process is corroborated directly by the human target; no claim is made that every descendant shares sterol specificity. The exact ancestral IBD placement and complete alignment were not independently inspected. Target self-evidence among descendants is legitimate experimental grounding, not circularity. Supporting Evidence: PMID:27144356 To obtain diffraction-quality crystals, human G5 and G8 were coexpressed in Pichia pastoris12, and tandem affinity chromatography was used to purify stable, monodisperse G5G8 heterodimers that retained ATPase activity (Extended Data Fig. 1). PMID:27144356 Expression of wild-type (WT) G5 together with WT G8 resulted in a ~30-fold increase in cholesterol transport into bile. |
| GO:0070328 triglyceride homeostasis | IEA GO_REF:0000107 | UNDECIDED | Summary: The rat-derived triglyceride homeostasis assignment requires a resolved process-level transfer. Reason: The historical rat IEP source is PMID:23117815. The abstract associates diet-induced liver triglyceride accumulation with several transcriptional changes, including lower Abcg8. ABCG8’s established transported substrates are neutral sterols; however, that does not exclude indirect triglyceride control. Without the full study, an ABCG8-dependent homeostatic contribution cannot be resolved from the reported expression/lipid correlation. Propagation Review Root cause: UNRESOLVED Sources checked: UniProtKB:P58428 UNRESOLVED Rat Abcg8 is the ortholog source (UniProt P58428 / ENSRNOP00000058587). MGI comparative graph snapshot 2023-03-10 identifies IEP evidence from PMID:23117815. Primary abstracts were read; full assay scope and human process-level transfer remain unresolved. ensembl:ENSRNOP00000058587 UNRESOLVED Rat Abcg8 is the ortholog source (UniProt P58428 / ENSRNOP00000058587). MGI comparative graph snapshot 2023-03-10 identifies IEP evidence from PMID:23117815. Primary abstracts were read; full assay scope and human process-level transfer remain unresolved. |
| GO:0120020 cholesterol transfer activity | IBA GO_REF:0000033 | MODIFY | Summary: ABCG8 contributes to ATP-driven sterol export rather than an aqueous cholesterol-carrier activity. Reason: Live GO:0120020 describes removal from a membrane, passage through an aqueous phase in a hydrophobic protein pocket, and delivery to an acceptor membrane or particle. G5/G8 is an integral ABC exporter. The full 2003 assembly study, mouse membrane-reconstitution study and human functional/structural experiments support GO:0034041. The mouse transfer assay does not by itself resolve flippase versus membrane-extraction mechanics, and the original contributes_to scope is preserved. Propagation Review Root cause: TERM SCOPING PROBLEM Failure modes: ROLE CONFLATION Sources checked: PANTHER:PTN002710463 UNRESOLVED The target has strong sterol-export evidence; the present aqueous-carrier definition is a different molecular role. The exact ancestral IBD placement and complete alignment were not independently inspected. Target self-evidence among descendants is legitimate experimental grounding, not circularity. Proposed replacements: ABC-type sterol transporter activity Supporting Evidence: Reactome:R-HSA-265783 The complex of ATP-binding cassette sub-family G members 5 and 8 (ABCG5:ABCG8) in the plasma membrane mediates the ATP-dependent export of cytosolic sterols (cholesterol and phytosterols). PMID:27144356 To obtain diffraction-quality crystals, human G5 and G8 were coexpressed in Pichia pastoris12, and tandem affinity chromatography was used to purify stable, monodisperse G5G8 heterodimers that retained ATPase activity (Extended Data Fig. 1). PMID:27144356 Expression of wild-type (WT) G5 together with WT G8 resulted in a ~30-fold increase in cholesterol transport into bile. |
| GO:0120020 cholesterol transfer activity | IGI PMID:14504269 ABCG5 and ABCG8 are obligate heterodimers for protein traffi... | MODIFY | Summary: ABCG8 contributes to ATP-driven sterol export rather than an aqueous cholesterol-carrier activity. Reason: Live GO:0120020 describes removal from a membrane, passage through an aqueous phase in a hydrophobic protein pocket, and delivery to an acceptor membrane or particle. G5/G8 is an integral ABC exporter. The full 2003 assembly study, mouse membrane-reconstitution study and human functional/structural experiments support GO:0034041. The mouse transfer assay does not by itself resolve flippase versus membrane-extraction mechanics, and the original contributes_to scope is preserved. Proposed replacements: ABC-type sterol transporter activity Supporting Evidence: Reactome:R-HSA-265783 The complex of ATP-binding cassette sub-family G members 5 and 8 (ABCG5:ABCG8) in the plasma membrane mediates the ATP-dependent export of cytosolic sterols (cholesterol and phytosterols). PMID:27144356 To obtain diffraction-quality crystals, human G5 and G8 were coexpressed in Pichia pastoris12, and tandem affinity chromatography was used to purify stable, monodisperse G5G8 heterodimers that retained ATPase activity (Extended Data Fig. 1). PMID:27144356 Expression of wild-type (WT) G5 together with WT G8 resulted in a ~30-fold increase in cholesterol transport into bile. |
| GO:0140359 ABC-type transporter activity | IEA GO_REF:0000002 | MODIFY | Summary: ABCG8 contributes to ATP-powered neutral-sterol export. Reason: The broad transporter term is correct, but GO:0034041 specifies the established ATP-driven sterol-export activity. Human structural, ATPase and biliary-export experiments support the refinement. Both halves form the transport machinery; the integrated core records contribution to the complex activity rather than autonomous transport by ABCG8. Propagation Review Root cause: TERM SCOPING PROBLEM Failure modes: GRANULARITY MISMATCH Sources checked: InterPro:IPR013525 SUPPORTS TRANSFER The ABC2 transmembrane and ABCG domains occur in human ABCG8. Direct human complex assays supply the substrate specificity missing from the domain mapping. InterPro:IPR043926 SUPPORTS TRANSFER The ABC2 transmembrane and ABCG domains occur in human ABCG8. Direct human complex assays supply the substrate specificity missing from the domain mapping. Proposed replacements: ABC-type sterol transporter activity Supporting Evidence: PMID:27144356 Expression of wild-type (WT) G5 together with WT G8 resulted in a ~30-fold increase in cholesterol transport into bile. PMID:27144356 To obtain diffraction-quality crystals, human G5 and G8 were coexpressed in Pichia pastoris12, and tandem affinity chromatography was used to purify stable, monodisperse G5G8 heterodimers that retained ATPase activity (Extended Data Fig. 1). PMID:16893193 Copurified ABCG5/G8 displayed low but significant ATPase activity with a V(max) of approximately 15 nmol min(-)(1) mg(-)(1). |
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Download this section (compressed HTML)Q: Which conserved effector steps, beyond changed Abcg8 transcript abundance, explain the rat nutrient, drug and exercise response annotations in human enterocytes or hepatocytes?
Q: How do the two ABCG8 isoforms differ in assembly, trafficking and transport? The seeded annotations are not isoform-resolved, so no isoform-specific function is inferred.
Q: What fraction of the reduced dietary-cholesterol absorption after human G5/G8 transgene expression arises from enterocyte efflux versus altered biliary sterol delivery? The 2002 experiment does not separate these contributions.
Experiment: Measure directional cholesterol and sitosterol transport in matched human polarized enterocyte and hepatocyte models with controlled ABCG5/ABCG8 expression, alongside surface localization and ATPase-coupling controls. Test diet- or drug-response conditions independently of transporter abundance.
Hypothesis: Changes in ABCG8 abundance and changes in intrinsic transport efficiency contribute differently to context-dependent sterol flux.
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