ABCG5 is an ATP-binding cassette half-transporter that forms an obligate heterodimer with ABCG8. The complex exports cholesterol and plant sterols across the apical membranes of hepatocytes and intestinal enterocytes, supporting biliary sterol secretion and limiting net intestinal sterol absorption. ABCG5 supplies one transmembrane domain and one nucleotide-binding domain; its Walker motifs combine with the ABCG8 signature motif at the catalytically active composite nucleotide-binding site. Assembly with ABCG8 permits maturation and export from the endoplasmic reticulum. Biallelic loss of ABCG5 causes sitosterolemia, in which defective sterol elimination produces accumulation of dietary plant sterols and cholesterol.
| GO Term | Evidence | Action | Reason |
|---|---|---|---|
| GO:0005515 protein binding | IPI PMID:16870176 Expression and functional characterization of ABCG1 splice v... | REMOVE | Summary: The ABCG8 interaction is retained by the specific heterodimerization assertion. Reason: PMID:16870176 Figure 7 supports the reported ABCG5–ABCG8 association. The existing GO:0046982 IPI annotation cites this same paper and the same partner UniProtKB:Q9H221, 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 We have expressed the recombinant human ABCG5 and ABCG8 genes in the yeast Pichia pastoris and purified the proteins to near homogeneity. PMID:16893193 Furthermore, ABCG5/G8 eluted as a dimer on gel filtration columns. |
| GO:0005515 protein binding | IPI PMID:17474147 Systematic identification of SH3 domain-mediated human prote... | REMOVE | Summary: Generic binding to the NCK1 screening partner does not identify a specific ABCG5 function. Reason: GOA assigns the NCK1 (P16333) interaction to the SH3-domain peptide-array screen in PMID:17474147. The cached abstract establishes that screening method and selected full-protein follow-up, but the exact ABCG5 pair record was not recovered. Retain the curator-reported interaction as source information; removing this generic protein-binding term for lack of functional information does not deny the interaction. Neither an adaptor activity nor a physiological NCK1-dependent transport mechanism follows from the available record. Supporting Evidence: PMID:17474147 By taking advantage of the modular nature of many regulatory proteins, we attempted to simplify protein-protein interactions to the corresponding domain-ligand recognition and employed peptide arrays to identify such binding events. |
| GO:0005524 ATP binding | IDA PMID:16893193 Purification and ATP hydrolysis of the putative cholesterol ... | ACCEPT | Summary: ABCG5 contributes to nucleotide binding by the heterodimer. Reason: The human proteins expressed in Pichia were copurified and assayed for nucleotide trapping and MgATP hydrolysis in PMID:16893193. The full source Figure 9 uses azido-ATP trapping, nucleotide competition and crosslinking of the pair. Preserve contributes_to: these assays do not resolve an independently functional ABCG5 monomer. The human structure places ABCG5 Walker motifs in the active composite site with the ABCG8 signature motif (PMID:27144356). Supporting Evidence: PMID:16893193 AlFx and BeFx inhibited MgATP hydrolysis by specific trapping of nucleotides in the ABCG5/G8 proteins. PMID:16893193 We have expressed the recombinant human ABCG5 and ABCG8 genes in the yeast Pichia pastoris and purified the proteins to near homogeneity. |
| GO:0005524 ATP binding | IEA GO_REF:0000002 | ACCEPT | Summary: The ABC nucleotide-binding domain binds ATP in the assembled transporter. Reason: The InterPro IPR003439 ATP-binding mapping agrees with nucleotide trapping of recombinant human G5/G8 and the composite nucleotide-binding-site architecture. It is not evidence that the isolated half-transporter completes transport (PMID:16893193; PMID:27144356). Propagation Review Root cause: NO FAILURE CORE Sources checked: InterPro:IPR003439 UNRESOLVED GOA identifies this domain/family mapping. Individual mapping predicates were not inspected; primary human structure and biochemical evidence independently establish the relevant transporter architecture/activity. Supporting Evidence: PMID:16893193 AlFx and BeFx inhibited MgATP hydrolysis by specific trapping of nucleotides in the ABCG5/G8 proteins. |
| GO:0005886 plasma membrane | IBA GO_REF:0000033 | ACCEPT | Summary: Inherited plasma-membrane function agrees with human sterol export. Reason: The PAINT assertion at PTN000443664 is consistent with obligate partner-dependent membrane trafficking and human G5/G8 functional reconstitution. Human Q9H222 among descendant evidence is legitimate grounding, not circularity. The actual IBD placement and alignment were not recovered, so no new evolutionary placement is asserted (PMID:14504269; PMID:27144356). Propagation Review Root cause: NO FAILURE CORE Sources checked: PANTHER:PTN000443664 UNRESOLVED GOA identifies this PAINT ancestral node. The original IBD/tree placement was not recovered; current annotation judgment is independently grounded in the human G5/G8 experiments described above. Extant source count and inclusion of human ABCG5 are not treated as defects. 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:0005886 plasma membrane | IEA GO_REF:0000120 | ACCEPT | Summary: The ortholog and subcellular-location mapping correctly place ABCG5 at the plasma membrane. Reason: The combined source names mouse Abcg5 Q99PE8/ENSMUSP00000069495 and UniProt SL-0039. Mouse trafficking evidence is positive, and human G5/G8 maturation, structural membrane domains and transport independently support the broad location (PMID:14504269; PMID:27144356). Broad plasma membrane remains accurate without requiring every source to resolve the apical subdomain. Propagation Review Root cause: NO FAILURE CORE Sources checked: UniProtKB:Q99PE8 SUPPORTS TRANSFER Mouse Abcg5 donor. Human and mouse G5/G8 experiments establish conserved assembly, membrane localization and sterol export (PMID:14504269; PMID:27144356). ensembl:ENSMUSP00000069495 SUPPORTS TRANSFER Mouse Abcg5 donor. Human and mouse G5/G8 experiments establish conserved assembly, membrane localization and sterol export (PMID:14504269; PMID:27144356). UniProtKB-SubCell:SL-0039 SUPPORTS TRANSFER The cached human UniProt record explicitly describes cell/apical membrane localization, consistent with primary partner-dependent trafficking 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/ABCG5/ABCG5-uniprot.txt SUBCELLULAR LOCATION: Cell membrane |
| GO:0005886 plasma membrane | ISS GO_REF:0000024 | ACCEPT | Summary: Mouse plasma-membrane localization transfers to the human transporter. Reason: Q99PE8 is mouse Abcg5. The historical comparative GO graph traces its trafficking evidence to PMID:12208867; human-pair experiments in PMID:14504269 and human functional reconstitution in PMID:27144356 independently corroborate this conserved location. The inference does not depend on treating a mouse localization assay as directly performed in human tissue. Propagation Review Root cause: NO FAILURE CORE Sources checked: UniProtKB:Q99PE8 SUPPORTS TRANSFER Mouse Abcg5 donor. Human and mouse G5/G8 experiments establish conserved assembly, membrane localization and sterol export (PMID:14504269; PMID:27144356). 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:0005886 plasma membrane | TAS Reactome:R-HSA-265783 | ACCEPT | Summary: The Reactome sterol-export event places the transporter in the plasma membrane. Reason: R-HSA-265783 describes ATP-dependent sterol export by the G5/G8 membrane complex. This location agrees with independent trafficking and human-pair functional studies. Its historical statement that human biochemistry was poorly characterized does not negate the later human experiments (PMID:14504269; PMID:27144356). 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. |
| GO:0005886 plasma membrane | TAS Reactome:R-HSA-5679101 | ACCEPT | Summary: The defective-ABCG8 event retains the normal complex membrane context. Reason: R-HSA-5679101 describes loss of sterol export when ABCG8 is defective and provides the wild-type ER-to-plasma-membrane trafficking background. It is not by itself a wild-type transport assay. The broad ABCG5 plasma-membrane location is independently established with the functional pair (PMID:14504269; PMID:27144356). 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. |
| GO:0005886 plasma membrane | TAS Reactome:R-HSA-5679145 | ACCEPT | Summary: The defective-ABCG5 event retains the normal complex membrane context. Reason: R-HSA-5679145 describes defective ABCG5-mediated export and the normal partner-dependent trafficking pathway. A loss-of-function event need not demonstrate activity of its mutant product; this annotation is retained for the independently supported wild-type plasma-membrane location (PMID:14504269; PMID:27144356). 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. |
| GO:0005886 plasma membrane | TAS Reactome:R-HSA-9029531 | ACCEPT | Summary: The expression event identifies ABCG5 as a plasma-membrane transporter product. Reason: R-HSA-9029531 concerns NR1H2/NR1H3 regulation of ABCG5 expression. The transcriptional regulators perform that regulatory step; the ABCG5 product is the membrane exporter. The supplied cellular-component assertion is consistent with the cached UniProt and trafficking evidence (PMID:14504269). 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/ABCG5/ABCG5-uniprot.txt SUBCELLULAR LOCATION: Cell membrane |
| GO:0007584 response to nutrient | IEA GO_REF:0000107 | UNDECIDED | Summary: The rat-derived nutrient assertion has unresolved human functional scope. Reason: The historical MGI comparative graph traces this rat IEP annotation to PMID:15710224. The primary abstract reports diet-dependent Abcg5/Abcg8 expression in rat liver parenchymal and Kupffer cells. It is positive evidence of a rat expression response; it does not by itself resolve the conserved human protein-level response in that cell and diet context. Preserve the original Ensembl transfer and defer final adjudication until the supporting experimental context can be inspected. Propagation Review Root cause: UNRESOLVED Sources checked: UniProtKB:Q99PE7 UNRESOLVED Rat Abcg5 donor, traced through the MGI comparative GO graph generated 2023-03-10. Term-specific IEP source: PMID:15710224. Full source context/human transfer remains unresolved. ensembl:ENSRNOP00000007174 UNRESOLVED Rat Abcg5 donor, traced through the MGI comparative GO graph generated 2023-03-10. Term-specific IEP source: PMID:15710224. Full source context/human transfer remains unresolved. |
| GO:0009410 response to xenobiotic stimulus | IEA GO_REF:0000107 | UNDECIDED | Summary: The rat-derived xenobiotic stimulus assertion has unresolved human functional scope. Reason: The rat IEP source is PMID:17109865, which compares pioglitazone and insulin in diabetic rats and measures hepatic/intestinal transporter transcripts. Abcg5/Abcg8 expression changes are positive source evidence, not evidence of drug transport by ABCG5. The full source and the human counterpart of this regulatory response remain unresolved. Preserve the original Ensembl transfer and defer final adjudication until the supporting experimental context can be inspected. Propagation Review Root cause: UNRESOLVED Sources checked: UniProtKB:Q99PE7 UNRESOLVED Rat Abcg5 donor, traced through the MGI comparative GO graph generated 2023-03-10. Term-specific IEP source: PMID:17109865. Full source context/human transfer remains unresolved. ensembl:ENSRNOP00000007174 UNRESOLVED Rat Abcg5 donor, traced through the MGI comparative GO graph generated 2023-03-10. Term-specific IEP source: PMID:17109865. Full source context/human transfer remains unresolved. |
| GO:0010212 response to ionizing radiation | IEA GO_REF:0000107 | UNDECIDED | Summary: The rat-derived ionizing radiation assertion has unresolved human functional scope. Reason: The rat IEP source is PMID:17132608: chronic 137cesium exposure decreased hepatic Abcg5 transcript abundance. The abstract reports no dysregulation of overall cholesterol homeostasis. An expression response can support the rat curator assertion without establishing which human ABCG5 activity participates in the radiation response; the full experimental scope was not recovered. Preserve the original Ensembl transfer and defer final adjudication until the supporting experimental context can be inspected. Propagation Review Root cause: UNRESOLVED Sources checked: UniProtKB:Q99PE7 UNRESOLVED Rat Abcg5 donor, traced through the MGI comparative GO graph generated 2023-03-10. Term-specific IEP source: PMID:17132608. Full source context/human transfer remains unresolved. ensembl:ENSRNOP00000007174 UNRESOLVED Rat Abcg5 donor, traced through the MGI comparative GO graph generated 2023-03-10. Term-specific IEP source: PMID:17132608. Full source context/human transfer remains unresolved. |
| GO:0010949 negative regulation of intestinal phytosterol absorption | IMP PMID:11099417 Accumulation of dietary cholesterol in sitosterolemia caused... | ACCEPT | Summary: The transporter restricts net uptake and accumulation of dietary plant sterols. Reason: Human ABCG5 loss-of-function in sitosterolemia supports the negative intestinal-absorption role in PMID:11099417. The protein itself performs sterol export as part of G5/G8, so this is more than a disease-necessity association. Human-transgene mice show reduced circulating plant sterols and altered sterol trafficking (PMID:12208868); mouse reconstitution additionally establishes sitosterol transport (PMID:16867993). Supporting Evidence: PMID:11099417 These data suggest that ABCG5 and ABCG8 normally cooperate to limit intestinal absorption and to promote biliary excretion of sterols, and that mutated forms of these transporters predispose to sterol accumulation and atherosclerosis. PMID:12208868 Expression of a human transgene encoding ABCG5 and ABCG8 increased biliary cholesterol concentrations more than fivefold but did not significantly affect the bile acid pool size or composition. |
| GO:0014850 response to muscle activity | IEA GO_REF:0000107 | UNDECIDED | Summary: The rat-derived muscle activity assertion has unresolved human functional scope. Reason: The rat IEP source PMID:23117815 reports endurance-training-associated intestinal Abcg5/Abcg8 expression changes under standard versus atherogenic diets. The available primary abstract does not establish a conserved human protein-level role in that exercise response. This is a source-context uncertainty, not a claim that an expression-based GO annotation is categorically invalid. Preserve the original Ensembl transfer and defer final adjudication until the supporting experimental context can be inspected. Propagation Review Root cause: UNRESOLVED Sources checked: UniProtKB:Q99PE7 UNRESOLVED Rat Abcg5 donor, traced through the MGI comparative GO graph generated 2023-03-10. Term-specific IEP source: PMID:23117815. Full source context/human transfer remains unresolved. ensembl:ENSRNOP00000007174 UNRESOLVED Rat Abcg5 donor, traced through the MGI comparative GO graph generated 2023-03-10. Term-specific IEP source: PMID:23117815. Full source context/human transfer remains unresolved. |
| GO:0015918 sterol transport | IEA GO_REF:0000107 | ACCEPT | Summary: ABCG5 directly participates in sterol transport. Reason: The source Q99PE8 is mouse Abcg5, with positive reconstituted sterol-transport evidence in PMID:16867993. Human G5/G8 functional reconstitution independently establishes cholesterol export (PMID:27144356). The broad sterol-transport process is a correct core assertion alongside the more mechanistic transmembrane activity; acceptance does not claim that all ABC-family proteins transport sterols. Propagation Review Root cause: NO FAILURE CORE Sources checked: UniProtKB:Q99PE8 SUPPORTS TRANSFER Mouse Abcg5 donor. Human and mouse G5/G8 experiments establish conserved assembly, membrane localization and sterol export (PMID:14504269; PMID:27144356). ensembl:ENSMUSP00000069495 SUPPORTS TRANSFER Mouse Abcg5 donor. Human and mouse G5/G8 experiments establish conserved assembly, membrane localization and sterol export (PMID:14504269; PMID:27144356). 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:0015918 sterol transport | ISS GO_REF:0000024 | ACCEPT | Summary: ABCG5 directly participates in sterol transport. Reason: The source Q99PE8 is mouse Abcg5, with positive reconstituted sterol-transport evidence in PMID:16867993. Human G5/G8 functional reconstitution independently establishes cholesterol export (PMID:27144356). The broad sterol-transport process is a correct core assertion alongside the more mechanistic transmembrane activity; acceptance does not claim that all ABC-family proteins transport sterols. Propagation Review Root cause: NO FAILURE CORE Sources checked: UniProtKB:Q99PE8 SUPPORTS TRANSFER Mouse Abcg5 donor. Human and mouse G5/G8 experiments establish conserved assembly, membrane localization and sterol export (PMID:14504269; PMID:27144356). 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:0016020 membrane | IEA GO_REF:0000120 | ACCEPT | Summary: ABCG5 is an integral membrane component of the exporter. Reason: The combined mouse ortholog/InterPro mapping is corroborated by the human structure, which contains six transmembrane helices in each half-transporter. The broad membrane term accurately describes these structural data without assigning a compartment more narrowly than this source mapping resolves (PMID:27144356). Propagation Review Root cause: NO FAILURE CORE Sources checked: UniProtKB:Q99PE8 SUPPORTS TRANSFER Mouse Abcg5 donor. Human and mouse G5/G8 experiments establish conserved assembly, membrane localization and sterol export (PMID:14504269; PMID:27144356). ensembl:ENSMUSP00000069495 SUPPORTS TRANSFER Mouse Abcg5 donor. Human and mouse G5/G8 experiments establish conserved assembly, membrane localization and sterol export (PMID:14504269; PMID:27144356). InterPro:IPR013525 UNRESOLVED GOA identifies this domain/family mapping. Individual mapping predicates were not inspected; primary human structure and biochemical evidence independently establish the relevant transporter architecture/activity. 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). |
| GO:0016324 apical plasma membrane | IBA GO_REF:0000033 | ACCEPT | Summary: Apical membrane localization is integral to the conserved sterol-export role. Reason: PTN002710457 is the PAINT ancestor in the seeded assertion. Mouse apical localization and human-pair trafficking/function support conservation; inclusion of human Q9H222 in the descendant evidence is expected. Native mouse staining in PMID:14504269 must be distinguished from its human G8 localization in human-G5/G8 transgenic mouse liver and the human-pair cell experiments. Propagation Review Root cause: NO FAILURE CORE Sources checked: PANTHER:PTN002710457 UNRESOLVED GOA identifies this PAINT ancestral node. The original IBD/tree placement was not recovered; current annotation judgment is independently grounded in the human G5/G8 experiments described above. Extant source count and inclusion of human ABCG5 are not treated as defects. Supporting Evidence: PMID:14504269 In this paper we used immunofluorescence microscopy to confirm, in vivo, that G5 is localized to the apical membranes of mouse enterocytes and hepatocytes. 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 | IEA GO_REF:0000120 | ACCEPT | Summary: The apical-membrane mapping is consistent with the assembled human transporter. Reason: Mouse Q99PE8/ENSMUSP00000069495 trafficking evidence and UniProt SL-0015 identify the apical membrane. Human G5/G8 coassembly, human G8 localization in transgenic liver, and later human functional reconstitution corroborate that inference. ER retention of unpaired precursor is an assembly intermediate, not contrary localization evidence (PMID:14504269; PMID:27144356). Propagation Review Root cause: NO FAILURE CORE Sources checked: UniProtKB:Q99PE8 SUPPORTS TRANSFER Mouse Abcg5 donor. Human and mouse G5/G8 experiments establish conserved assembly, membrane localization and sterol export (PMID:14504269; PMID:27144356). ensembl:ENSMUSP00000069495 SUPPORTS TRANSFER Mouse Abcg5 donor. Human and mouse G5/G8 experiments establish conserved assembly, membrane localization and sterol export (PMID:14504269; PMID:27144356). UniProtKB-SubCell:SL-0015 SUPPORTS TRANSFER The cached human UniProt record explicitly describes cell/apical membrane localization, consistent with primary partner-dependent trafficking evidence. Supporting Evidence: PMID:14504269 In this paper we used immunofluorescence microscopy to confirm, in vivo, that G5 is localized to the apical membranes of mouse enterocytes and hepatocytes. 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 | IMP PMID:14504269 ABCG5 and ABCG8 are obligate heterodimers for protein traffi... | ACCEPT | Summary: The cited trafficking study supports apical localization of functional G5/G8. Reason: PMID:14504269 Figure 1 detects native mouse G5 at apical enterocyte/hepatocyte membranes; Figure 2 detects human G8 in liver membranes of human-G5/G8 transgenic mice. Human G5/G8 constructs are tested for partner-dependent maturation in cultured cells. These source-specific observations, together with human functional reconstitution, support the human apical-location assignment; none is described as direct staining of endogenous human G5 in a human liver. Supporting Evidence: PMID:14504269 In this paper we used immunofluorescence microscopy to confirm, in vivo, that G5 is localized to the apical membranes of mouse enterocytes and hepatocytes. 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:0016324 apical plasma membrane | ISS GO_REF:0000024 | ACCEPT | Summary: Mouse apical localization is a sound ortholog inference. Reason: Mouse Abcg5 Q99PE8 supplies the ISS evidence. Partner-dependent apical targeting in PMID:12208867 and native mouse staining in PMID:14504269 agree with the membrane-export function of human G5/G8. Preserve the organism distinction while accepting the conserved location. Propagation Review Root cause: NO FAILURE CORE Sources checked: UniProtKB:Q99PE8 SUPPORTS TRANSFER Mouse Abcg5 donor. Human and mouse G5/G8 experiments establish conserved assembly, membrane localization and sterol export (PMID:14504269; PMID:27144356). Supporting Evidence: PMID:14504269 In this paper we used immunofluorescence microscopy to confirm, in vivo, that G5 is localized to the apical membranes of mouse enterocytes and hepatocytes. 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: ABCG5 contributes to ATP hydrolysis by the assembled heterodimer. Reason: PMID:16893193 measures MgATP hydrolysis in copurified human G5/G8 expressed in Pichia; individually purified subunits have much lower activity. The source supports the weaker contributes_to assertion, not independently sufficient monomer catalysis. The later structure resolves the active composite site formed by ABCG5 Walker motifs and the ABCG8 signature motif (PMID:27144356). 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:16893193 We have expressed the recombinant human ABCG5 and ABCG8 genes in the yeast Pichia pastoris and purified the proteins to near homogeneity. |
| GO:0016887 ATP hydrolysis activity | IEA GO_REF:0000002 | ACCEPT | Summary: The ABC domain participates directly in the transporter ATPase cycle. Reason: IPR003439 identifies an ABC nucleotide-binding domain. Human-pair hydrolysis assays and the composite-site architecture substantiate the biological activity beyond the family mapping. ABCG5 supplies the Walker motifs of the active site; catalysis occurs in the G5/G8 assembly, not as a demonstrated isolated-monomer transport reaction (PMID:16893193; PMID:27144356). Propagation Review Root cause: NO FAILURE CORE Sources checked: InterPro:IPR003439 UNRESOLVED GOA identifies this domain/family mapping. Individual mapping predicates were not inspected; primary human structure and biochemical evidence independently establish the relevant transporter architecture/activity. 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:16893193 We have expressed the recombinant human ABCG5 and ABCG8 genes in the yeast Pichia pastoris and purified the proteins to near homogeneity. |
| GO:0030299 intestinal cholesterol absorption | IC PMID:12208868 Overexpression of ABCG5 and ABCG8 promotes biliary cholester... | MODIFY | Summary: Human G5/G8 expression reduces fractional intestinal cholesterol absorption. Reason: GO:0030299 formally describes cholesterol uptake from the small intestine into blood. PMID:12208868 instead reports about 50% lower fractional absorption in mice carrying the human G5/G8 transgene, supporting the separately seeded negative-regulation term. Its Discussion explicitly leaves enterocyte efflux versus increased biliary delivery as contributors to this result. Refine the IC assertion to the measured regulatory direction without claiming that this experiment alone isolates the intestinal mechanism. Proposed replacements: negative regulation of intestinal cholesterol absorption Supporting Evidence: PMID:12208868 The intestinal absorption of cholesterol was reduced about 50% in both male and female transgenic animals compared with their wild-type counterparts (Figure 6 a). 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 nutrient levels assertion has unresolved human functional scope. Reason: The historical rat GO graph assigns this IEP term using PMID:23117815, PMID:25263431 and PMID:25612518. The accessible abstracts concern training/diet, ovariectomy/high-fat feeding, and high-fat regulation of nuclear-receptor target genes. PMID:25612518 explicitly reports increased hepatic Abcg5 mRNA. Full term-specific assays and transfer of these regulatory contexts to human ABCG5 remain unresolved. Preserve the original Ensembl transfer and defer final adjudication until the supporting experimental context can be inspected. Propagation Review Root cause: UNRESOLVED Sources checked: UniProtKB:Q99PE7 UNRESOLVED Rat Abcg5 donor, traced through the MGI comparative GO graph generated 2023-03-10. Term-specific IEP source: PMID:23117815, PMID:25263431, PMID:25612518. Full source context/human transfer remains unresolved. ensembl:ENSRNOP00000007174 UNRESOLVED Rat Abcg5 donor, traced through the MGI comparative GO graph generated 2023-03-10. Term-specific IEP source: PMID:23117815, PMID:25263431, PMID:25612518. Full source context/human transfer remains unresolved. |
| GO:0033344 cholesterol efflux | IBA GO_REF:0000033 | ACCEPT | Summary: Inherited cholesterol efflux agrees with direct human transporter function. Reason: The PTN001059486 PAINT assignment is supported by mouse and human descendant evidence and by human G5/G8 rescue of biliary cholesterol secretion (PMID:27144356). No lineage-specific loss is indicated. The exact ancestral placement was not independently reconstructed, and the human descendant is not treated as circular evidence. Propagation Review Root cause: NO FAILURE CORE Sources checked: PANTHER:PTN001059486 UNRESOLVED GOA identifies this PAINT ancestral node. The original IBD/tree placement was not recovered; current annotation judgment is independently grounded in the human G5/G8 experiments described above. Extant source count and inclusion of human ABCG5 are not treated as defects. 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 | IEA GO_REF:0000107 | ACCEPT | Summary: Mouse cholesterol efflux transfers to human G5/G8. Reason: The Q99PE8/ENSMUSP00000069495 source represents mouse Abcg5. Mouse coexpression and sterol-secretion experiments in PMID:14504269 support the source, while the human constructs in PMID:27144356 independently support the target. Efflux is performed by the heterodimer. Propagation Review Root cause: NO FAILURE CORE Sources checked: UniProtKB:Q99PE8 SUPPORTS TRANSFER Mouse Abcg5 donor. Human and mouse G5/G8 experiments establish conserved assembly, membrane localization and sterol export (PMID:14504269; PMID:27144356). ensembl:ENSMUSP00000069495 SUPPORTS TRANSFER Mouse Abcg5 donor. Human and mouse G5/G8 experiments establish conserved assembly, membrane localization and sterol export (PMID:14504269; PMID:27144356). Supporting Evidence: PMID:14504269 These experiments indicate that G5 and G8 function as obligate heterodimers to promote sterol excretion into bile. 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 genetic-interaction study supports cooperative cholesterol export. Reason: PMID:14504269 tests human and mouse partners in cultured cells, but its approximately tenfold biliary-cholesterol rescue uses the mouse pair in double-knockout mice. The supporting entity Q99PE8 is therefore meaningful source context. Later human G5/G8 rescue in the same general physiological system independently supports human efflux (PMID:27144356), without relabeling the earlier mouse assay as human. Supporting Evidence: PMID:14504269 These experiments indicate that G5 and G8 function as obligate heterodimers to promote sterol excretion into bile. 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 wild-type G5/G8 restores biliary cholesterol export. Reason: PMID:27144356 combines purified human-complex structure with adenoviral expression of human G5/G8 in G5/G8-deficient mice. Wild-type rescue and loss of rescue with G5 A540F or Y432A establish target-specific export function; proposed sterol-density assignments and molecular simulations are not the sole evidence. 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:0042626 ATPase-coupled transmembrane transporter activity | IBA GO_REF:0000033 | MODIFY | Summary: Resolve the broad transporter activity to ATP-coupled sterol transport. Reason: The PAINT PTN008283605 annotation captures the inherited ATP-coupled transport machinery. Human G5/G8 substrate-specific export supports GO:0034041, whose reaction couples ATP hydrolysis to sterol movement across the membrane (PMID:16893193; PMID:27144356). The activity belongs to the heterodimer, to which ABCG5 contributes; no independent complete transporter activity is assigned to one subunit. Propagation Review Root cause: TERM SCOPING PROBLEM Failure modes: GRANULARITY MISMATCH Sources checked: PANTHER:PTN008283605 UNRESOLVED GOA identifies this PAINT ancestral node. The original IBD/tree placement was not recovered; current annotation judgment is independently grounded in the human G5/G8 experiments described above. Extant source count and inclusion of human ABCG5 are not treated as defects. Proposed replacements: ABC-type sterol transporter activity 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 Expression of wild-type (WT) G5 together with WT G8 resulted in a ~30-fold increase in cholesterol transport into bile. |
| GO:0042626 ATPase-coupled transmembrane transporter activity | IDA PMID:27144356 Crystal structure of the human sterol transporter ABCG5/ABCG... | MODIFY | Summary: Resolve the broad transporter activity to ATP-coupled sterol transport. Reason: The cited human structure/function study includes both purified-complex ATPase and human-construct biliary-transport assays. Human G5/G8 substrate-specific export supports GO:0034041, whose reaction couples ATP hydrolysis to sterol movement across the membrane (PMID:16893193; PMID:27144356). The activity belongs to the heterodimer, to which ABCG5 contributes; no independent complete transporter activity is assigned to one subunit. Proposed replacements: ABC-type sterol transporter activity 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 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 | IBA GO_REF:0000033 | ACCEPT | Summary: The conserved exporter is a direct determinant of cholesterol balance. Reason: The PAINT PTN001059486 homeostasis assertion is independently supported by human disease genetics, human transgene physiology and human-pair export assays (PMID:11099417; PMID:12208868; PMID:27144356). Rat RGD:620298 and human Q9H222 are descendant sources, not a pairwise donor count or circular chain. Propagation Review Root cause: NO FAILURE CORE Sources checked: PANTHER:PTN001059486 UNRESOLVED GOA identifies this PAINT ancestral node. The original IBD/tree placement was not recovered; current annotation judgment is independently grounded in the human G5/G8 experiments described above. Extant source count and inclusion of human ABCG5 are not treated as defects. Supporting Evidence: PMID:11099417 These data suggest that ABCG5 and ABCG8 normally cooperate to limit intestinal absorption and to promote biliary excretion of sterols, and that mutated forms of these transporters predispose to sterol accumulation and atherosclerosis. PMID:12208868 Expression of a human transgene encoding ABCG5 and ABCG8 increased biliary cholesterol concentrations more than fivefold but did not significantly affect the bile acid pool size or composition. |
| GO:0042632 cholesterol homeostasis | IEA GO_REF:0000107 | ACCEPT | Summary: Cholesterol homeostasis is core even though this rat donor uses expression evidence. Reason: The rat Q99PE7/ENSRNOP00000007174 chain includes the diet/training IEP study PMID:23117815 in the historical comparative graph. That donor experiment is not itself a human flux assay. Independent human disease, transgene and transporter experiments establish direct ABCG5 participation in cholesterol balance, supporting acceptance of this broad core term (PMID:11099417; PMID:12208868; PMID:27144356). Propagation Review Root cause: NO FAILURE CORE Sources checked: UniProtKB:Q99PE7 UNRESOLVED Rat Abcg5 donor, traced through the MGI comparative GO graph generated 2023-03-10. The cholesterol-homeostasis donor has IEP support from PMID:23117815; the human conclusion is independently supported by disease/transgene/transport experiments. ensembl:ENSRNOP00000007174 UNRESOLVED Rat Abcg5 donor, traced through the MGI comparative GO graph generated 2023-03-10. The cholesterol-homeostasis donor has IEP support from PMID:23117815; the human conclusion is independently supported by disease/transgene/transport experiments. Supporting Evidence: PMID:11099417 These data suggest that ABCG5 and ABCG8 normally cooperate to limit intestinal absorption and to promote biliary excretion of sterols, and that mutated forms of these transporters predispose to sterol accumulation and atherosclerosis. PMID:12208868 Expression of a human transgene encoding ABCG5 and ABCG8 increased biliary cholesterol concentrations more than fivefold but did not significantly affect the bile acid pool size or composition. |
| GO:0042632 cholesterol homeostasis | IMP PMID:11099417 Accumulation of dietary cholesterol in sitosterolemia caused... | ACCEPT | Summary: Human ABCG5 loss links the exporter to cholesterol homeostasis. Reason: PMID:11099417 identifies one ABCG5 mutation among sitosterolemia patients and describes increased sterol absorption and reduced biliary elimination. Independent human-transgene and biochemical evidence establishes the transport mechanism behind that phenotype. This is a core physiological consequence of ABCG5 performing sterol export, not an unrelated downstream disease process. Supporting Evidence: PMID:11099417 These data suggest that ABCG5 and ABCG8 normally cooperate to limit intestinal absorption and to promote biliary excretion of sterols, and that mutated forms of these transporters predispose to sterol accumulation and atherosclerosis. PMID:12208868 Expression of a human transgene encoding ABCG5 and ABCG8 increased biliary cholesterol concentrations more than fivefold but did not significantly affect the bile acid pool size or composition. |
| GO:0042632 cholesterol homeostasis | IMP PMID:27144356 Crystal structure of the human sterol transporter ABCG5/ABCG... | ACCEPT | Summary: Human transporter activity directly supports cholesterol homeostasis. Reason: PMID:27144356 tests human wild-type and mutant G5/G8 in deficient mice and resolves the transporter architecture. Restored biliary cholesterol secretion and its loss with specific mature G5 variants demonstrate an active role in cholesterol handling, beyond merely observing cholesterol accumulation in disease. 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:0043190 ATP-binding cassette (ABC) transporter complex | IBA GO_REF:0000033 | ACCEPT | Summary: The inherited ABC-transporter-complex membership is directly corroborated in human protein. Reason: PAINT places complex membership at PTN001059486 with human Q9H222 descendant support. Purification, gel filtration and the human heterodimer structure satisfy GO:0043190, whose four core domains can be distributed across multiple polypeptides. Each G5/G8 subunit supplies an NBD and a membrane domain (PMID:16893193; PMID:27144356). Propagation Review Root cause: NO FAILURE CORE Sources checked: PANTHER:PTN001059486 UNRESOLVED GOA identifies this PAINT ancestral node. The original IBD/tree placement was not recovered; current annotation judgment is independently grounded in the human G5/G8 experiments described above. Extant source count and inclusion of human ABCG5 are not treated as defects. Supporting Evidence: PMID:16893193 Furthermore, ABCG5/G8 eluted as a dimer on gel filtration columns. 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 G5/G8 forms an ATPase-active dimer. Reason: PMID:16893193 copurifies the recombinant human pair from Pichia and shows dimer-sized gel-filtration behavior and MgATPase activity. These observations support the ABC transporter complex rather than an independently functioning G5 monomer. Supporting Evidence: PMID:16893193 Furthermore, ABCG5/G8 eluted as a dimer on gel filtration columns. 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 structure directly establishes the ABCG5–ABCG8 transporter assembly. Reason: The human pair was copurified, reconstituted into bicelles and crystallized in PMID:27144356. Its two membrane domains and two nucleotide-binding domains fit the formal ABC-transporter-complex definition; the functional unit is the heterodimer rather than the crystal asymmetric-unit packing of two heterodimers. 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). |
| GO:0043235 signaling receptor complex | IDA PMID:14504269 ABCG5 and ABCG8 are obligate heterodimers for protein traffi... | MODIFY | Summary: The supported assembly is an ABC transporter complex. Reason: The source PMID:14504269 assays partner-dependent trafficking and transporter assembly, including human G5/G8 constructs. GO:0043235 requires a signaling-receptor complex that binds a messenger to initiate a cellular response. The positively established G5/G8 assembly transports sterols; no signaling-receptor role is established by these experiments. Refine to GO:0043190 using the source assembly evidence and independent human structure, preserving the original assertion for provenance (PMID:27144356). Proposed replacements: ATP-binding cassette (ABC) transporter complex Supporting Evidence: PMID:14504269 These experiments indicate that G5 and G8 function as obligate heterodimers to promote sterol excretion 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:0043235 signaling receptor complex | IEA GO_REF:0000107 | MODIFY | Summary: The supported assembly is an ABC transporter complex. Reason: The mouse Q99PE8/ENSMUSP00000069495 source is traced in the historical comparative graph to the G5/G8 assembly study PMID:14504269. GO:0043235 requires a signaling-receptor complex that binds a messenger to initiate a cellular response. The positively established G5/G8 assembly transports sterols; no signaling-receptor role is established by these experiments. Refine to GO:0043190 using the source assembly evidence and independent human structure, preserving the original assertion for provenance (PMID:27144356). Propagation Review Root cause: TERM SCOPING PROBLEM Failure modes: COMPARTMENT OR COMPLEX MISMATCH Sources checked: UniProtKB:Q99PE8 UNRESOLVED Mouse Abcg5 donor. Human and mouse G5/G8 experiments establish conserved assembly, membrane localization and sterol export (PMID:14504269; PMID:27144356). The formal term scope is assessed separately from this positive biology. ensembl:ENSMUSP00000069495 UNRESOLVED Mouse Abcg5 donor. Human and mouse G5/G8 experiments establish conserved assembly, membrane localization and sterol export (PMID:14504269; PMID:27144356). The formal term scope is assessed separately from this positive biology. Proposed replacements: ATP-binding cassette (ABC) transporter complex Supporting Evidence: PMID:14504269 These experiments indicate that G5 and G8 function as obligate heterodimers to promote sterol excretion 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:0045177 apical part of cell | IEA GO_REF:0000107 | ACCEPT | Summary: ABCG5 functions in the apical region of polarized epithelial cells. Reason: The broad apical-part annotation transferred from mouse Q99PE8/ENSMUSP00000069495 is consistent with direct native mouse apical-membrane staining and partner-dependent human-pair trafficking in PMID:14504269. The exact experimental chain for this particular broad source row was not fully reconstructed; independent positive localization supports its biological content without requiring an unsupported compartment refinement. Propagation Review Root cause: NO FAILURE CORE Sources checked: UniProtKB:Q99PE8 UNRESOLVED Mouse Abcg5 donor. Human and mouse G5/G8 experiments establish conserved assembly, membrane localization and sterol export (PMID:14504269; PMID:27144356). The exact primary chain for this broad apical-part row was not reconstructed. ensembl:ENSMUSP00000069495 UNRESOLVED Mouse Abcg5 donor. Human and mouse G5/G8 experiments establish conserved assembly, membrane localization and sterol export (PMID:14504269; PMID:27144356). The exact primary chain for this broad apical-part row was not reconstructed. Supporting Evidence: PMID:14504269 In this paper we used immunofluorescence microscopy to confirm, in vivo, that G5 is localized to the apical membranes of mouse enterocytes and hepatocytes. PMID:14504269 Expression of both G5 and G8 is required for either protein to be transported to the plasma membrane of cultured cells. |
| GO:0045796 negative regulation of intestinal cholesterol absorption | IMP PMID:11099417 Accumulation of dietary cholesterol in sitosterolemia caused... | ACCEPT | Summary: ABCG5-containing transporters limit net intestinal cholesterol absorption. Reason: Human sitosterolemia in PMID:11099417 is characterized by increased absorption when the pathway is defective. Human G5/G8 transgenic mice independently show reduced fractional absorption (PMID:12208868). The latter source does not isolate enterocyte export from effects of increased biliary cholesterol, so its tissue-mechanism limitation is retained while accepting the regulatory direction. Supporting Evidence: PMID:11099417 These data suggest that ABCG5 and ABCG8 normally cooperate to limit intestinal absorption and to promote biliary excretion of sterols, and that mutated forms of these transporters predispose to sterol accumulation and atherosclerosis. PMID:12208868 The intestinal absorption of cholesterol was reduced about 50% in both male and female transgenic animals compared with their wild-type counterparts (Figure 6 a). 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 | IEA GO_REF:0000107 | ACCEPT | Summary: Heterodimerization with ABCG8 is conserved and functionally required. Reason: The mouse Q99PE8/ENSMUSP00000069495 source is consistent with mouse trafficking and reconstitution evidence. Human co-immunoprecipitation, purified-pair ATPase and the human structure independently establish the same assembly function (PMID:16870176; PMID:16893193; PMID:27144356). This does not infer functional G5 homodimers from ER-retained material. Propagation Review Root cause: NO FAILURE CORE Sources checked: UniProtKB:Q99PE8 SUPPORTS TRANSFER Mouse Abcg5 donor. Human and mouse G5/G8 experiments establish conserved assembly, membrane localization and sterol export (PMID:14504269; PMID:27144356). ensembl:ENSMUSP00000069495 SUPPORTS TRANSFER Mouse Abcg5 donor. Human and mouse G5/G8 experiments establish conserved assembly, membrane localization and sterol export (PMID:14504269; PMID:27144356). Supporting Evidence: PMID:16893193 We have expressed the recombinant human ABCG5 and ABCG8 genes in the yeast Pichia pastoris and purified the proteins to near homogeneity. PMID:16893193 Furthermore, ABCG5/G8 eluted as a dimer on gel filtration columns. |
| GO:0046982 protein heterodimerization activity | IPI PMID:16870176 Expression and functional characterization of ABCG1 splice v... | ACCEPT | Summary: The cited study contains a genuine G5–G8 heterodimerization control. Reason: PMID:16870176 Figure 7 includes EGFP-G5/EGFP-G8 and HA-tagged partners in HeLa co-immunoprecipitation experiments. Its ABCG1-focused title is not a misattribution. Human-pair purification and structure provide independent functional assembly evidence (PMID:16893193; PMID:27144356). Supporting Evidence: PMID:16893193 We have expressed the recombinant human ABCG5 and ABCG8 genes in the yeast Pichia pastoris and purified the proteins to near homogeneity. PMID:16893193 Furthermore, ABCG5/G8 eluted as a dimer on gel filtration columns. |
| GO:0046983 protein dimerization activity | IEA GO_REF:0000117 | MODIFY | Summary: Resolve generic dimerization to the established heterodimerization function. Reason: ARBA00027598 propagates generic protein dimerization; its rule internals were not inspected. Direct human G5/G8 purification and structure support the more informative heterodimerization term. This precision correction does not assert that all observed self-association or higher-order assembly is impossible (PMID:16893193; PMID:27144356). Propagation Review Root cause: TERM SCOPING PROBLEM Failure modes: GRANULARITY MISMATCH Sources checked: ARBA:ARBA00027598 UNRESOLVED GOA supplies this rule identifier. ARBA predicates were not inspected; human heterodimer experiments support the specific replacement independently. Proposed replacements: protein heterodimerization activity Supporting Evidence: PMID:16893193 Furthermore, ABCG5/G8 eluted as a dimer on gel filtration columns. 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 | MODIFY | Summary: Specify sterol transmembrane transport within the broad inherited process. Reason: The PAINT PTN008283605 assertion captures ATP-driven membrane transport. Human G5/G8 physiology and structural/functional experiments identify sterols as the transported substrate class. GO:0035382 is the verified child of both sterol transport and transmembrane transport; the refinement adds substrate precision without proposing an additional redundant NEW process (PMID:12208868; PMID:27144356). Propagation Review Root cause: TERM SCOPING PROBLEM Failure modes: GRANULARITY MISMATCH Sources checked: PANTHER:PTN008283605 UNRESOLVED GOA identifies this PAINT ancestral node. The original IBD/tree placement was not recovered; current annotation judgment is independently grounded in the human G5/G8 experiments described above. Extant source count and inclusion of human ABCG5 are not treated as defects. Proposed replacements: sterol transmembrane transport Supporting Evidence: PMID:12208868 Expression of a human transgene encoding ABCG5 and ABCG8 increased biliary cholesterol concentrations more than fivefold but did not significantly affect the bile acid pool size or composition. 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 assertion has unresolved human functional scope. Reason: The rat IEP donor traces to PMID:23117815, which measures diet-induced hepatic triglyceride accumulation together with altered FXR, MTP and transporter expression. The available abstract does not separate ABCG5-specific triglyceride control from concurrent changes in other lipid pathways. A direct human sterol-export mechanism does not by itself establish triglyceride homeostasis, and the unread full donor study prevents a stronger source-side judgment. Preserve the original Ensembl transfer and defer final adjudication until the supporting experimental context can be inspected. Propagation Review Root cause: UNRESOLVED Sources checked: UniProtKB:Q99PE7 UNRESOLVED Rat Abcg5 donor, traced through the MGI comparative GO graph generated 2023-03-10. Term-specific IEP source: PMID:23117815. Full source context/human transfer remains unresolved. ensembl:ENSRNOP00000007174 UNRESOLVED Rat Abcg5 donor, traced through the MGI comparative GO graph generated 2023-03-10. Term-specific IEP source: PMID:23117815. Full source context/human transfer remains unresolved. |
| GO:0120020 cholesterol transfer activity | IBA GO_REF:0000033 | MODIFY | Summary: Represent contribution to the membrane sterol exporter with the specific ABC-transporter activity. Reason: The IBA at PTN001059486 carries contributes_to and is grounded by mouse and human descendant evidence; that qualifier is preserved. The current GO:0120020 definition describes cholesterol carriage through an aqueous phase inside a protective hydrophobic pocket between membranes or particles. The established G5/G8 activity is ATP-driven membrane export, captured by GO:0034041; even the weaker contribution claim does not establish that soluble-carrier mechanism. This is a term-scope correction, not evidence of loss of cholesterol transport or invalid PAINT ancestry. Independent human functional reconstitution supports the replacement (PMID:27144356). Propagation Review Root cause: TERM SCOPING PROBLEM Failure modes: ROLE CONFLATION Sources checked: PANTHER:PTN001059486 UNRESOLVED GOA identifies this PAINT ancestral node. The original IBD/tree placement was not recovered; current annotation judgment is independently grounded in the human G5/G8 experiments described above. Extant source count and inclusion of human ABCG5 are not treated as defects. 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:16893193 Copurified ABCG5/G8 displayed low but significant ATPase activity with a V(max) of approximately 15 nmol min(-)(1) mg(-)(1). |
| GO:0120020 cholesterol transfer activity | IEA GO_REF:0000107 | MODIFY | Summary: Represent contribution to the membrane sterol exporter with the specific ABC-transporter activity. Reason: The mouse Q99PE8/ENSMUSP00000069495 inference carries contributes_to; that qualifier is preserved. The current GO:0120020 definition describes cholesterol carriage through an aqueous phase inside a protective hydrophobic pocket between membranes or particles. The established G5/G8 activity is ATP-driven membrane export, captured by GO:0034041; even the weaker contribution claim does not establish that soluble-carrier mechanism. This is a term-scope correction, not evidence of loss of cholesterol transport or invalid PAINT ancestry. Independent human functional reconstitution supports the replacement (PMID:27144356). Propagation Review Root cause: TERM SCOPING PROBLEM Failure modes: ROLE CONFLATION Sources checked: UniProtKB:Q99PE8 UNRESOLVED Mouse Abcg5 donor. Human and mouse G5/G8 experiments establish conserved assembly, membrane localization and sterol export (PMID:14504269; PMID:27144356). The formal term scope is assessed separately from this positive biology. ensembl:ENSMUSP00000069495 UNRESOLVED Mouse Abcg5 donor. Human and mouse G5/G8 experiments establish conserved assembly, membrane localization and sterol export (PMID:14504269; PMID:27144356). The formal term scope is assessed separately from this positive biology. 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:16893193 Copurified ABCG5/G8 displayed low but significant ATPase activity with a V(max) of approximately 15 nmol min(-)(1) mg(-)(1). |
| GO:0120020 cholesterol transfer activity | IGI PMID:14504269 ABCG5 and ABCG8 are obligate heterodimers for protein traffi... | MODIFY | Summary: Represent contribution to the membrane sterol exporter with the specific ABC-transporter activity. Reason: The PMID:14504269 genetic-interaction assertion carries contributes_to, with mouse Q99PE8 as its supporting entity. The full source separates human-pair trafficking from mouse-pair biliary-flux rescue. The current GO:0120020 definition describes cholesterol carriage through an aqueous phase inside a protective hydrophobic pocket between membranes or particles. The established G5/G8 activity is ATP-driven membrane export, captured by GO:0034041; even the weaker contribution claim does not establish that soluble-carrier mechanism. This is a term-scope correction, not evidence of loss of cholesterol transport or invalid PAINT ancestry. Independent human functional reconstitution supports the replacement (PMID:27144356). 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:16893193 Copurified ABCG5/G8 displayed low but significant ATPase activity with a V(max) of approximately 15 nmol min(-)(1) mg(-)(1). |
| GO:0140359 ABC-type transporter activity | IEA GO_REF:0000002 | MODIFY | Summary: Resolve the broad transporter activity to ATP-coupled sterol transport. Reason: InterPro IPR013525/IPR043926 identifies the ABC transporter machinery; the individual mapping predicates were not reconstructed. Human G5/G8 substrate-specific export supports GO:0034041, whose reaction couples ATP hydrolysis to sterol movement across the membrane (PMID:16893193; PMID:27144356). The activity belongs to the heterodimer, to which ABCG5 contributes; no independent complete transporter activity is assigned to one subunit. Propagation Review Root cause: TERM SCOPING PROBLEM Failure modes: GRANULARITY MISMATCH Sources checked: InterPro:IPR013525 UNRESOLVED GOA identifies this domain/family mapping. Individual mapping predicates were not inspected; primary human structure and biochemical evidence independently establish the relevant transporter architecture/activity. InterPro:IPR043926 UNRESOLVED GOA identifies this domain/family mapping. Individual mapping predicates were not inspected; primary human structure and biochemical evidence independently establish the relevant transporter architecture/activity. Proposed replacements: ABC-type sterol transporter activity 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 Expression of wild-type (WT) G5 together with WT G8 resulted in a ~30-fold increase in cholesterol transport into bile. |
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Download this section (compressed HTML)Q: Should historical ABCG5/ABCG8 GO:0120020 assertions be migrated to GO:0034041, given that the current cholesterol-transfer definition describes an aqueous-pocket carrier while the complex performs ATP-driven membrane export?
Q: Can the full rat IEP donor studies and comparable human experiments resolve the nutrient, drug, radiation, exercise and triglyceride-homeostasis transfers without equating expression response with a demonstrated conserved effector mechanism?
Q: Does the signaling-receptor-complex mapping in the mouse donor chain require correction to the experimentally established ABC transporter complex?
Q: What is the physiological significance of the reported NCK1 peptide-domain interaction, beyond the generic binding annotation?
Experiment: Use polarized human intestinal organoids and hepatocyte systems with matched ABCG5/ABCG8 expression to quantify apical isotope-labeled cholesterol and plant-sterol export and separate enterocyte efflux from altered biliary sterol delivery.
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