ABCB6 is a homodimeric half-type ATP-binding cassette transporter of the ABCB subfamily that couples ATP binding and hydrolysis to the translocation of porphyrins across membranes. Each subunit carries an accessory N-terminal transmembrane domain (TMD0, residues 1-205) that is dispensable for catalysis but directs the protein to the endolysosomal system, followed by the canonical ABC transmembrane domain and nucleotide-binding domain (Walker A lysine K629). The protein is N-glycosylated, is inserted co-translationally into the endoplasmic reticulum, matures through the Golgi, reaches the plasma membrane and is then internalised to multivesicular bodies, lysosomes and melanosomes; in erythroid cells it remains in the plasma membrane of mature red cells, where it carries the Langereis (Lan) blood group antigen, and is partly shed in exosomes. Purified, liposome-reconstituted ABCB6 transports hemin, coproporphyrin III, protoporphyrin IX and pheophorbide a, and its ATPase is stimulated by porphyrins, with glutathione acting as a cofactor for metal-centred porphyrins; cryo-EM structures show hemin and coproporphyrin III bound in a slit-like central cavity. Physiologically, plasma membrane ABCB6 exports porphyrins from red cells and modifies the severity of hereditary porphyrias, while the endolysosomal pool sequesters heavy-metal species and is required for PMEL amyloid matrix formation in early melanosomes. Human ABCB6 loss of function is well tolerated: Lan(-) individuals are healthy, and missense alleles instead cause dyschromatosis universalis hereditaria, ocular coloboma and familial pseudohyperkalemia. Whether ABCB6 also resides in the mitochondrial outer membrane and imports porphyrin precursors for heme synthesis remains contested.
Definition: Catalysis of the reaction: ATP + H2O + porphyrin(in) = ADP + phosphate + porphyrin(out), covering metal-free porphyrins such as coproporphyrin III, protoporphyrin IX and the uroporphyrins as well as metallated ones.
Justification: GO's only ABC-type tetrapyrrole transport term is GO:0015439 ABC-type heme transporter activity, which covers metallated heme only. The demonstrated and curated substrate range of ABCB6 includes coproporphyrin III, coproporphyrin I, protoporphyrin IX, uroporphyrin I, uroporphyrin III, coproporphyrinogen III and pheophorbide a, none of which is heme; UniProt records a separate Rhea reaction for each. Reviewers are currently forced either to use the heme term for metal-free porphyrin transport or to fall back on the uninformative parent GO:0140359. A sibling of GO:0015439 at the porphyrin level would let both be stated accurately.
Parent term: ABC-type transporter activity
Supporting Evidence:
| GO Term | Evidence | Action | Reason |
|---|---|---|---|
| GO:0000139 Golgi membrane | EXP PMID:18279659 Human ABC transporter isoform B6 (ABCB6) localizes primarily... | KEEP AS NON CORE | Summary: ABCB6 is detected in Golgi membranes of transfected cells, consistent with its maturation through the secretory pathway. Reason: ABCB6 is an N-glycosylated multipass membrane protein inserted co-translationally into the ER by an N-terminal signal-anchor and matured through the Golgi before delivery to the plasma membrane and the endolysosomal system. The Golgi signal is real but reflects biosynthetic transit (accentuated by overexpression), not the compartment in which ABCB6 performs transport. Supporting Evidence: PMID:18279659 it localized in the ER-derived and brefeldin A-sensitive perinuclear compartments, mainly in the Golgi apparatus |
| GO:0000139 Golgi membrane | EXP PMID:21199866 Conserved intramolecular disulfide bond is critical to traff... | KEEP AS NON CORE | Summary: Glycan-maturation and brefeldin A experiments place ABCB6 in the Golgi during biosynthesis. Reason: Endoglycosidase sensitivity and brefeldin A block show that ABCB6 traffics ER to Golgi as part of its maturation. Correct, but a transit compartment rather than a site of function. Supporting Evidence: PMID:21199866 indicating that ABCB6 is modified by N -glycans and traffics through the ER to the Golgi |
| GO:0000139 Golgi membrane | EXP PMID:22226084 ABCB6 mutations cause ocular coloboma. | KEEP AS NON CORE | Summary: Myc-tagged ABCB6 co-localizes with the Golgi marker GM130 in retinal pigment epithelial cells. Reason: Confirms Golgi localization of transfected ABCB6 in RPE cells, a biosynthetic compartment for this protein rather than its functional site. Supporting Evidence: PMID:22226084 showed that it localized to the endoplasmic reticulum and Golgi apparatus of RPE cells |
| GO:0000139 Golgi membrane | IEA GO_REF:0000044 | KEEP AS NON CORE | Summary: UniProt subcellular-location mapping to Golgi membrane, concordant with the experimental rows. Reason: The SubCell-derived term agrees with the experimental Golgi observations and is kept for the same reason - a maturation compartment, not the site of transport. Supporting Evidence: PMID:21199866 indicating that ABCB6 is modified by N -glycans and traffics through the ER to the Golgi |
| GO:0005524 ATP binding | IDA PMID:10837493 MTABC3, a novel mitochondrial ATP-binding cassette protein i... | ACCEPT | Summary: ABCB6 binds ATP through its canonical C-terminal nucleotide-binding domain. Reason: Nucleotide binding is directly demonstrated for human ABCB6 - high-affinity MgATP binding by the purified protein, ATP/ADP-bound NBD crystal structures, and loss of ATP-agarose binding in Walker A mutants. ATP binding is intrinsic to the transport cycle and belongs to the core function. Supporting Evidence: PMID:23792964 Mutagenesis of the conserved lysine to alanine (K629A) in the Walker A motif abolished ATP hydrolysis and substrate transport |
| GO:0005524 ATP binding | IDA PMID:27507172 The severity of hereditary porphyria is modulated by the por... | ACCEPT | Summary: ATP-agarose binding by ABCB6 is abolished in the Walker A K629G mutant. Reason: A direct, internally controlled demonstration of ATP binding by human ABCB6, with the Walker A mutant as the negative control. Supporting Evidence: PMID:27507172 ABCB6 R192Q-bound ATP-agarose normally, while the A492T-substituted protein displayed markedly impaired ATP binding and as expected the positive control K629G did not bind ATP |
| GO:0005524 ATP binding | IEA GO_REF:0000002 | ACCEPT | Summary: InterPro ABC-transporter nucleotide-binding signatures imply ATP binding. Reason: The signature-based call matches the experimentally demonstrated nucleotide binding of ABCB6 and the presence of a canonical ABC transporter ATP-binding domain. Supporting Evidence: file:human/ABCB6/ABCB6-uniprot.txt DR InterPro; IPR003439; ABC_transporter-like_ATP-bd. PMID:27507172 as expected the positive control K629G did not bind ATP |
| GO:0005576 extracellular region | IEA GO_REF:0000044 | MODIFY | Summary: UniProt "Secreted, extracellular exosome" mapped to the generic extracellular region term. Reason: ABCB6 reaches the extracellular space only as a membrane protein of released exosomes; the generic parent term is correct but less precise than the evidence supports. Replace with extracellular exosome (GO:0070062, part of extracellular region), which this gene already carries by IDA and HDA. Proposed replacements: extracellular exosome Supporting Evidence: PMID:22655043 Here we show that ABCB6 is a glycoprotein present in the membrane of mature erythrocytes and in exosomes released from reticulocytes during the final steps of erythroid maturation |
| GO:0005739 mitochondrion | HTP PMID:34800366 Quantitative high-confidence human mitochondrial proteome an... | UNDECIDED | Summary: High-throughput mitochondrial proteome study lists ABCB6 among mitochondrial proteins. Reason: Mitochondrial residence of ABCB6 is genuinely contested (see the other mitochondrion rows). This is an HTP call whose underlying data are in supplementary tables that are not in the cached record, so the specific evidence for ABCB6 could not be inspected, and co-purification of an endolysosomal protein with mitochondria is a known confounder. |
| GO:0005739 mitochondrion | IDA PMID:10837493 MTABC3, a novel mitochondrial ATP-binding cassette protein i... | UNDECIDED | Summary: Immunoblot and confocal analysis of CHO cells stably expressing MTABC3 placed the protein in mitochondria. Reason: The original assignment rests on heterologous overexpression of tagged MTABC3 in CHO cells. Imaging of the endogenous human protein in several cell lines later found ABCB6 in endolysosomes and absent from mitochondria, and ABCB6 is N-glycosylated and enters the ER co-translationally, which is difficult to reconcile with outer-membrane insertion. The conflict is unresolved, so no action is taken on either side. Supporting Evidence: PMID:10837493 MTABC3 protein is shown to be present in the mitochondria, as assessed by immunoblot analysis and confocal microscopic analysis of subcellular fractions of Chinese hamster ovary cells stably expressing MTABC3 |
| GO:0005739 mitochondrion | IDA NOT PMID:18279659 Human ABC transporter isoform B6 (ABCB6) localizes primarily... | UNDECIDED | Summary: NOT mitochondrion - tagged ABCB6 did not co-localize with mitochondrial staining. Reason: This negative call is part of the unresolved localization dispute. It is supported by the ER/Golgi targeting determinants of ABCB6 but is contradicted by fractionation and digitonin studies that detect a mitochondrial pool. Both polarities are left undecided rather than one being asserted over the other. Supporting Evidence: PMID:18279659 Laser scanning microscopic observation revealed that ABCB6 did not co-localize with mitochondrial staining |
| GO:0005739 mitochondrion | IDA NOT PMID:22655043 Shifting the paradigm: the putative mitochondrial protein AB... | UNDECIDED | Summary: NOT mitochondrion - endogenous ABCB6 is absent from purified mitochondria and resides in endolysosomes. Reason: The strongest negative evidence, obtained on the endogenous protein in three cell lines with validated antibodies and with ABCB7/ABCB8/ABCB10 as positive mitochondrial controls. It nonetheless conflicts with several independent reports of a mitochondrial ABCB6 pool, so the dispute is recorded rather than resolved here. Supporting Evidence: PMID:22655043 endogenous ABCB6 is localized to the endo/lysosomal compartment, and is absent from the mitochondria of cells |
| GO:0005739 mitochondrion | IMP PMID:23792964 Efficient purification and reconstitution of ATP binding cas... | UNDECIDED | Summary: ABCB6 was purified from the mitochondrial membrane fraction of overexpressing HEK293 cells. Reason: The protein used for the in vitro transport work was solubilized from a mitochondrial membrane preparation of overexpressing cells, which supports a mitochondrial pool only as strongly as the purity of that fraction allows. Part of the unresolved localization dispute. Supporting Evidence: PMID:23792964 ABCB6 overexpressed in HEK293 cells was solubilized from mitochondrial membranes and purified to homogeneity |
| GO:0005740 mitochondrial envelope | IDA PMID:10837493 MTABC3, a novel mitochondrial ATP-binding cassette protein i... | UNDECIDED | Summary: Mitochondrial envelope localization of overexpressed MTABC3. Reason: Same evidence and same dispute as the mitochondrion row from this reference; the envelope refinement inherits the uncertainty. Supporting Evidence: PMID:10837493 MTABC3 protein is shown to be present in the mitochondria, as assessed by immunoblot analysis and confocal microscopic analysis of subcellular fractions of Chinese hamster ovary cells stably expressing MTABC3 |
| GO:0005741 mitochondrial outer membrane | IDA PMID:17006453 Identification of a mammalian mitochondrial porphyrin transp... | UNDECIDED | Summary: ABCB6 reported to reside uniquely in the outer mitochondrial membrane, where it mediates porphyrin uptake. Reason: This is the origin of the mitochondrial porphyrin-importer model. Subsequent work on the endogenous protein places ABCB6 in the endolysosomal system and finds no mitochondrial pool, and UniProt flags the localization as a matter of debate. The claim is left undecided rather than removed, since the full text of the supporting work is not available here. Supporting Evidence: PMID:17006453 Here we demonstrate that ABCB6 is uniquely located in the outer mitochondrial membrane and is required for mitochondrial porphyrin uptake |
| GO:0005741 mitochondrial outer membrane | IDA PMID:17661442 Human ABCB6 localizes to both the outer mitochondrial membra... | UNDECIDED | Summary: Digitonin solubilization places a lower-molecular-weight ABCB6 form in the outer mitochondrial membrane, with the NBD facing the cytoplasm. Reason: Independent biochemical support for a mitochondrial outer-membrane pool, from the same study that establishes the plasma membrane pool. It remains in conflict with the endogenous-protein imaging studies, so the row is left undecided. Supporting Evidence: PMID:17661442 Digitonin solubilization of mitochondria demonstrated that ABCB6 is present in the outer mitochondrial membrane |
| GO:0005741 mitochondrial outer membrane | TAS Reactome:R-HSA-1369065 | UNDECIDED | Summary: Reactome models ABCB6 as an outer mitochondrial membrane porphyrin importer. Reason: The Reactome reaction is a traceable restatement of the 2000/2006 mitochondrial model and carries the same uncertainty; it does not add independent evidence. Supporting Evidence: Reactome:R-HSA-1369065 It plays a crucial role in heme synthesis by mediating porphyrin uptake into mitochondria |
| GO:0005741 mitochondrial outer membrane | TAS Reactome:R-HSA-5683355 | UNDECIDED | Summary: Reactome disease reaction placing defective ABCB6 in the outer mitochondrial membrane. Reason: Same model, same unresolved localization question as the corresponding normal reaction; the disease variant reaction adds no independent localization evidence. |
| GO:0005765 lysosomal membrane | IDA PMID:22655043 Shifting the paradigm: the putative mitochondrial protein AB... | ACCEPT | Summary: Endogenous ABCB6 localizes to the endo/lysosomal compartment. Reason: Imaging of the endogenous protein with validated antibodies in three human cell lines places ABCB6 on lysosomes. This is the compartment that is conserved across the clade - PAINT placed vacuolar membrane at opisthokont node PTN008609345 with human ABCB6, rat Abcb6, C. elegans HMT-1 and Drosophila HMT-1 as seeds - and it is a core location. Supporting Evidence: PMID:22655043 endogenous ABCB6 is localized to the endo/lysosomal compartment, and is absent from the mitochondria of cells |
| GO:0005765 lysosomal membrane | IDA PMID:25627919 Role of the N-terminal transmembrane domain in the endo-lyso... | ACCEPT | Summary: ABCB6 is internalized from the plasma membrane to multivesicular bodies and lysosomes; the N-terminal TMD0 is the lysosomal targeting determinant. Reason: Confocal and electron microscopy, plus domain dissection showing that TMD0 alone is targeted to lysosomes while the TMD0-less core is retained at the plasma membrane, establish the lysosomal membrane as a genuine steady-state location. Supporting Evidence: PMID:25627919 we confirm the endo-lysosomal localization of ABCB6 and show that the protein is internalized from the plasma membrane through endocytosis, to be distributed to multivesicular bodies and lysosomes |
| GO:0005765 lysosomal membrane | IDA PMID:29940187 ABCB6 Resides in Melanosomes and Regulates Early Steps of Me... | ACCEPT | Summary: ABCB6 is present on lysosomes and early melanosomes of MNT-1 melanocytic cells. Reason: Independent confirmation of lysosomal membrane localization in a pigment cell line, in the study that also shows a catalysis-dependent melanosomal function. Supporting Evidence: PMID:29940187 We show that ABCB6 localizes to the membrane of early melanosomes and lysosomes of the human melanocytic cell line MNT-1 |
| GO:0005765 lysosomal membrane | IDA PMID:31053883 The human ABCB6 protein is the functional homologue of HMT-1... | ACCEPT | Summary: Endogenous ABCB6 co-localizes with LAMP1 in glioblastoma cells. Reason: A fourth independent demonstration of lysosomal localization, in the study linking endolysosomal ABCB6 to cadmium sequestration. Supporting Evidence: PMID:31053883 confirmed the localization of the endogenous ABCB6 protein in the lysosomal compartment (labeled by LAMP1), and its absence in mitochondria (labeled by AIF) |
| GO:0005765 lysosomal membrane | IEA GO_REF:0000120 | ACCEPT | Summary: Combined automated annotation of lysosomal membrane, concordant with the human experimental data. Reason: The electronic call agrees with four independent experimental demonstrations in human cells and with the rat ortholog data from which it is partly derived. Supporting Evidence: PMID:25627919 we confirm the endo-lysosomal localization of ABCB6 and show that the protein is internalized from the plasma membrane through endocytosis, to be distributed to multivesicular bodies and lysosomes |
| GO:0005768 endosome | IEA GO_REF:0000107 | MODIFY | Summary: Endosome localization transferred from mouse Abcb6 by Ensembl Compara. Reason: Correct but less precise than the human evidence supports. ABCB6 is an integral membrane protein of the endosomal limiting membrane, so endosome membrane (GO:0010008, a part_of descendant that this gene already carries by EXP) is the appropriate term. Proposed replacements: endosome membrane Supporting Evidence: PMID:25627919 we confirm the endo-lysosomal localization of ABCB6 and show that the protein is internalized from the plasma membrane through endocytosis, to be distributed to multivesicular bodies and lysosomes |
| GO:0005768 endosome | ISS GO_REF:0000024 | MODIFY | Summary: ISS transfer of endosome localization from mouse Abcb6. Reason: Same refinement as the Compara row - ABCB6 is a limiting-membrane protein, so endosome membrane (GO:0010008), supported in human by EXP evidence, is the precise term. Proposed replacements: endosome membrane Supporting Evidence: PMID:25627919 we confirm the endo-lysosomal localization of ABCB6 and show that the protein is internalized from the plasma membrane through endocytosis, to be distributed to multivesicular bodies and lysosomes |
| GO:0005774 vacuolar membrane | IBA GO_REF:0000033 | MODIFY | Summary: IBA for vacuolar membrane from opisthokont node PTN008609345, seeded by human ABCB6, rat Abcb6, C. elegans HMT-1 and Drosophila HMT-1. Reason: The phylogenetic judgment is sound - the vacuolar/lysosomal limiting membrane is the conserved compartment of the HMT-1/ABCB6 clade, and human ABCB6 is itself one of the descendants whose experimental data seeded the node, which is expected rather than circular. For a human protein the supported descendant is lysosomal membrane (GO:0005765, is_a vacuolar membrane via lytic vacuole membrane), which this gene carries by IDA from four studies, so the general term should be refined rather than kept. Propagation Review Root cause: TERM SCOPING PROBLEM Failure modes: GRANULARITY MISMATCH Sources checked: PANTHER:PTN008609345 · Opisthokont node of PTHR24221 annotated vacuolar membrane by IBD SUPPORTS TRANSFER The node placement is sound: its seeds are human ABCB6, rat Abcb6, C. elegans HMT-1 and Drosophila HMT-1, all of which are documented on the vacuolar or lysosomal limiting membrane. Only the granularity of the term is at issue for a human protein. UniProtKB:Q9NP58 · Human ABCB6 (the target itself, one of the IBD seeds) SUPPORTS TRANSFER The target's own experimental lysosomal-membrane data are among the descendant evidences the PAINT curator used, which is expected for a seed rather than circular. Proposed replacements: lysosomal membrane Supporting Evidence: PMID:31053883 confirmed the localization of the endogenous ABCB6 protein in the lysosomal compartment (labeled by LAMP1), and its absence in mitochondria (labeled by AIF) file:human/ABCB6/ABCB6-uniprot.txt DR PANTHER; PTHR24221:SF654; ATP-BINDING CASSETTE SUB-FAMILY B MEMBER 6; 1. |
| GO:0005783 endoplasmic reticulum | IDA PMID:22226084 ABCB6 mutations cause ocular coloboma. | MODIFY | Summary: ABCB6 detected in the endoplasmic reticulum of retinal pigment epithelial cells. Reason: Correct but less precise than warranted: ABCB6 is a multipass integral membrane protein, so endoplasmic reticulum membrane (GO:0005789, a part_of descendant already carried by EXP/IDA in this gene) is the supported term. The ER pool itself reflects co-translational insertion and biosynthetic transit, not the site of transport. Proposed replacements: endoplasmic reticulum membrane Supporting Evidence: PMID:22226084 showed that it localized to the endoplasmic reticulum and Golgi apparatus of RPE cells |
| GO:0005789 endoplasmic reticulum membrane | EXP PMID:18279659 Human ABC transporter isoform B6 (ABCB6) localizes primarily... | KEEP AS NON CORE | Summary: The ABCB6 N-terminal hydrophobic region acts as a type I signal-anchor directing co-translational insertion into the ER membrane. Reason: Accurate and mechanistically grounded, but the ER is where ABCB6 is made and glycosylated rather than where it functions. Supporting Evidence: PMID:18279659 it localized in the ER-derived and brefeldin A-sensitive perinuclear compartments, mainly in the Golgi apparatus |
| GO:0005789 endoplasmic reticulum membrane | EXP PMID:22226084 ABCB6 mutations cause ocular coloboma. | KEEP AS NON CORE | Summary: Wild-type and coloboma-mutant ABCB6 localize to the ER membrane in RPE cells. Reason: Correct localization of transfected protein in a disease-relevant cell type, but a biosynthetic compartment rather than a functional site. Supporting Evidence: PMID:22226084 showed that it localized to the endoplasmic reticulum and Golgi apparatus of RPE cells |
| GO:0005789 endoplasmic reticulum membrane | IDA PMID:21199866 Conserved intramolecular disulfide bond is critical to traff... | KEEP AS NON CORE | Summary: Glycan analysis shows ABCB6 passes through the ER on its way to the Golgi. Reason: The glycosylation and brefeldin A data establish ER transit; retained as a non-core location for the same reason as the other secretory-pathway rows. Supporting Evidence: PMID:21199866 indicating that ABCB6 is modified by N -glycans and traffics through the ER to the Golgi |
| GO:0005789 endoplasmic reticulum membrane | IEA GO_REF:0000044 | KEEP AS NON CORE | Summary: UniProt subcellular-location mapping to ER membrane. Reason: Concordant with the experimental ER rows and kept on the same basis. Supporting Evidence: PMID:21199866 indicating that ABCB6 is modified by N -glycans and traffics through the ER to the Golgi |
| GO:0005794 Golgi apparatus | IDA GO_REF:0000052 | MODIFY | Summary: Immunofluorescence (HPA) places ABCB6 in the Golgi apparatus. Reason: ABCB6 is an integral membrane protein, so the supported descendant is Golgi membrane (GO:0000139), which this gene already carries by EXP. The Golgi pool is a maturation compartment rather than a site of transport. Proposed replacements: Golgi membrane Supporting Evidence: PMID:18279659 it localized in the ER-derived and brefeldin A-sensitive perinuclear compartments, mainly in the Golgi apparatus |
| GO:0005794 Golgi apparatus | IDA PMID:18279659 Human ABC transporter isoform B6 (ABCB6) localizes primarily... | MODIFY | Summary: Tagged ABCB6 accumulates mainly in the Golgi apparatus. Reason: Refine to Golgi membrane (GO:0000139) for an integral membrane protein; already supported by EXP evidence in this gene. Proposed replacements: Golgi membrane Supporting Evidence: PMID:18279659 it localized in the ER-derived and brefeldin A-sensitive perinuclear compartments, mainly in the Golgi apparatus |
| GO:0005794 Golgi apparatus | IDA PMID:21199866 Conserved intramolecular disulfide bond is critical to traff... | MODIFY | Summary: Glycan maturation and brefeldin A sensitivity place ABCB6 in the Golgi. Reason: Refine to Golgi membrane (GO:0000139); ABCB6 is inserted in the membrane of the compartment it traverses. Proposed replacements: Golgi membrane Supporting Evidence: PMID:21199866 indicating that ABCB6 is modified by N -glycans and traffics through the ER to the Golgi |
| GO:0005794 Golgi apparatus | IDA PMID:22226084 ABCB6 mutations cause ocular coloboma. | MODIFY | Summary: ABCB6 co-localizes with GM130 in the Golgi of RPE cells. Reason: Refine to Golgi membrane (GO:0000139), the term supported for a multipass membrane protein and already carried by this gene. Proposed replacements: Golgi membrane Supporting Evidence: PMID:22226084 showed that it localized to the endoplasmic reticulum and Golgi apparatus of RPE cells |
| GO:0005886 plasma membrane | EXP PMID:22246506 ABCB6 is dispensable for erythropoiesis and specifies the ne... | ACCEPT | Summary: ABCB6 is the Langereis (Lan) blood group antigen carried on the red cell plasma membrane. Reason: Genetic and serological identification of ABCB6 as the Lan antigen establishes a bona fide plasma membrane pool in erythrocytes and in hepatocellular carcinoma cells. Together with porphyrin export from red cells this is a core location for human ABCB6. Supporting Evidence: PMID:22246506 We identified ABCB6 as the genetic basis of the Lan blood group antigen expressed on red blood cells but also at the plasma membrane of hepatocellular carcinoma (HCC) cells |
| GO:0005886 plasma membrane | EXP PMID:23180570 Missense mutations in the ABCB6 transporter cause dominant f... | ACCEPT | Summary: ABCB6 protein localization in mature erythrocyte membranes was assessed in the familial pseudohyperkalemia study. Reason: Independent confirmation of erythrocyte plasma membrane localization, in the work linking codon 375 variants to the red cell potassium leak phenotype. Supporting Evidence: PMID:23180570 a porphyrin transporter that, in erythrocyte membranes, bears the Langereis blood group antigen system |
| GO:0005886 plasma membrane | IDA GO_REF:0000052 | ACCEPT | Summary: Immunofluorescence curation (HPA) reports plasma membrane localization. Reason: Concordant with multiple experimental demonstrations of a plasma membrane pool. Supporting Evidence: PMID:22246506 We identified ABCB6 as the genetic basis of the Lan blood group antigen expressed on red blood cells but also at the plasma membrane of hepatocellular carcinoma (HCC) cells |
| GO:0005886 plasma membrane | IDA PMID:17661442 Human ABCB6 localizes to both the outer mitochondrial membra... | ACCEPT | Summary: Confocal microscopy and differential centrifugation detect a plasma membrane form of ABCB6 that is functionally relevant there. Reason: This study established the plasma membrane pool and showed it is functional, with ABCB6 expression preventing intracellular accumulation of specific porphyrins. Supporting Evidence: PMID:17661442 Preliminary studies indicate that ABCB6 is functionally relevant in the plasma membrane, where its expression prevents the accumulation of specific porphyrins in the cell |
| GO:0005886 plasma membrane | IDA PMID:22655043 Shifting the paradigm: the putative mitochondrial protein AB... | ACCEPT | Summary: Endogenous ABCB6 is abundant in the membrane of mature erythrocytes. Reason: Mature erythrocytes have no internal membranes, so detection of full-length glycosylated ABCB6 in red cell ghosts is unambiguous plasma membrane localization. Supporting Evidence: PMID:22655043 Here we show that ABCB6 is a glycoprotein present in the membrane of mature erythrocytes and in exosomes released from reticulocytes during the final steps of erythroid maturation |
| GO:0005886 plasma membrane | IDA PMID:25627919 Role of the N-terminal transmembrane domain in the endo-lyso... | ACCEPT | Summary: ABCB6 reaches the plasma membrane before being endocytosed to the endolysosomal system. Reason: Domain dissection shows the transporter core is delivered to and retained at the plasma membrane; the full-length protein transits it en route to lysosomes. Supporting Evidence: PMID:25627919 we confirm the endo-lysosomal localization of ABCB6 and show that the protein is internalized from the plasma membrane through endocytosis, to be distributed to multivesicular bodies and lysosomes |
| GO:0005886 plasma membrane | IDA PMID:27507172 The severity of hereditary porphyria is modulated by the por... | ACCEPT | Summary: Plasma membrane ABCB6 exports porphyrins from red cells. Reason: The functional study of porphyria modifier alleles both localizes ABCB6 to the red cell plasma membrane and shows that it exports porphyrins there. Supporting Evidence: PMID:27507172 Plasma membrane ABCB6 exports a variety of disease-related porphyrins PMID:27507172 We also demonstrate that ABCB6 mediates the plasma membrane export of porphyrins in red cells |
| GO:0005886 plasma membrane | IEA GO_REF:0000044 | ACCEPT | Summary: UniProt subcellular-location mapping to plasma membrane. Reason: Agrees with several independent experimental demonstrations of the plasma membrane pool. Supporting Evidence: PMID:22246506 We identified ABCB6 as the genetic basis of the Lan blood group antigen expressed on red blood cells but also at the plasma membrane of hepatocellular carcinoma (HCC) cells |
| GO:0006778 porphyrin-containing compound metabolic process | IDA PMID:27507172 The severity of hereditary porphyria is modulated by the por... | MODIFY | Summary: ABCB6 exports disease-related porphyrins and its loss worsens porphyrin accumulation in a mouse porphyria model. Reason: ABCB6 acts on porphyrins but catalyses none of the chemistry of porphyrin metabolism; it moves them across a membrane. The evidence cited (plasma membrane export of porphyrins, increased porphyrin accumulation and liver injury when Abcb6 is deleted in Fech mutant mice) is transport evidence, so the accurate term is heme transmembrane transport (GO:0035351), whose GO classification covers transmembrane movement of iron-coordinated and related porphyrin species and which ABCB6 already carries by IDA. Proposed replacements: heme transmembrane transport Supporting Evidence: PMID:27507172 Plasma membrane ABCB6 exports a variety of disease-related porphyrins PMID:27507172 homozygous disruption of the Abcb6 gene in mice exacerbates porphyria phenotypes |
| GO:0006778 porphyrin-containing compound metabolic process | IEA GO_REF:0000107 | MODIFY | Summary: Porphyrin metabolic process transferred from mouse Abcb6 by Ensembl Compara. Reason: Same correction as the human experimental row: the mouse evidence is also transport and modifier evidence, not participation in porphyrin chemistry. Replace with heme transmembrane transport (GO:0035351). Proposed replacements: heme transmembrane transport Supporting Evidence: PMID:27507172 homozygous disruption of the Abcb6 gene in mice exacerbates porphyria phenotypes |
| GO:0006778 porphyrin-containing compound metabolic process | IMP PMID:33007128 Cryo-electron microscopy structure of human ABCB6 transporte... | MODIFY | Summary: Porphyrin-stimulated ATPase activity of ABCB6 in the cryo-EM study. Reason: Substrate-stimulated ATPase activity demonstrates that porphyrins are transport substrates, not that ABCB6 performs a step of porphyrin metabolism. Replace with heme transmembrane transport (GO:0035351), which the same study supports by IDA. Proposed replacements: heme transmembrane transport Supporting Evidence: PMID:33007128 the ATPase activity of ABCB6 stimulated with a variety of porphyrin substrates showed different profiles in the presence of glutathione (GSH) |
| GO:0006779 porphyrin-containing compound biosynthetic process | IDA PMID:17006453 Identification of a mammalian mitochondrial porphyrin transp... | UNDECIDED | Summary: Mitochondrial porphyrin uptake by ABCB6 was reported to activate de novo porphyrin biosynthesis. Reason: A transporter that delivered a biosynthetic intermediate into the organelle where the pathway runs could reasonably be said to participate in it, but the premise is contested on two counts - the mitochondrial pool of ABCB6 is disputed, and knockdown in differentiating K562 cells does not affect de novo heme synthesis while ABCB6-null (Lan-negative) people are healthy. The full text of the supporting study is not available here, so the row is left undecided rather than removed. Supporting Evidence: PMID:17006453 After ABCB6 is upregulated in response to increased intracellular porphyrin, mitochondrial porphyrin uptake activates de novo porphyrin biosynthesis PMID:22655043 Knock-down studies demonstrate that ABCB6 function is not required for de novo heme biosynthesis in differentiating K562 cells |
| GO:0006785 heme B biosynthetic process | IMP NOT PMID:22655043 Shifting the paradigm: the putative mitochondrial protein AB... | ACCEPT | Summary: NOT heme B biosynthetic process - ABCB6 knockdown does not impair de novo heme synthesis in differentiating K562 cells. Reason: The negative claim is well supported and independently corroborated. Inducible shRNA silencing did not change baseline or induced protoporphyrin IX levels nor prevent differentiation-induced hemoglobin production, and humans homozygous for ABCB6 null alleles (Lan-negative) have normal erythropoiesis and no clinical phenotype. ABCB6 is therefore not a required participant in heme B biosynthesis, whatever residual role it has in porphyrin handling. Supporting Evidence: PMID:22655043 Knock-down studies demonstrate that ABCB6 function is not required for de novo heme biosynthesis in differentiating K562 cells PMID:22246506 Lan(-) (ABCB6(-/-)) individuals do not suffer any clinical consequences |
| GO:0006878 intracellular copper ion homeostasis | IEA GO_REF:0000107 | KEEP AS NON CORE | Summary: Intracellular copper ion homeostasis transferred from rat Abcb6 by Ensembl Compara. Reason: The claim comes from the rat ortholog rather than from human experiments, and the only human-side data are in vitro - copper inhibits the ATPase of purified ABCB6 and glutathione reverses that inhibition, which shows modulation rather than a homeostatic role. A metal-handling role for an endolysosomal HMT-1-family transporter is plausible and is not contradicted, so the term is kept but not treated as core for human ABCB6. Supporting Evidence: PMID:33007128 the ATPase activity of ABCB6 stimulated with a variety of porphyrin substrates showed different profiles in the presence of glutathione (GSH) |
| GO:0006878 intracellular copper ion homeostasis | ISS GO_REF:0000024 | KEEP AS NON CORE | Summary: ISS transfer of intracellular copper ion homeostasis from rat Abcb6. Reason: Same basis as the Compara row - curator-judged sequence-similarity transfer from the rat ortholog, plausible for a metal-sequestering endolysosomal transporter but without direct human evidence, so retained as non-core. |
| GO:0006879 intracellular iron ion homeostasis | NAS PMID:11977179 ABCB6 (MTABC3) excluded as the causative gene for the growth... | REMOVE | Summary: Non-traceable author statement that ABCB6/MTABC3 functions in intracellular iron homeostasis. Reason: The iron link traces to complementation of the yeast atm1-1 mutant by overexpressed MTABC3, but ATM1's human ortholog is ABCB7, not ABCB6, so heterologous rescue by an overexpressed relative is not evidence that ABCB6 handles iron. The cited paper is itself an exclusion study and argues the opposite for human disease. No iron phenotype has been reported for ABCB6-null humans, who are clinically normal, and the demonstrated substrates are intact porphyrins rather than iron ions. Supporting Evidence: PMID:11977179 Based on these data, ABCB6 is not the causative gene for GRACILE syndrome. PMID:22246506 Lan(-) (ABCB6(-/-)) individuals do not suffer any clinical consequences |
| GO:0007420 brain development | IMP PMID:22100072 Recessive mutations in ELOVL4 cause ichthyosis, intellectual... | REMOVE | Summary: IMP for brain development citing a paper about ELOVL4. Reason: The cited reference reports recessive ELOVL4 mutations causing ichthyosis, intellectual disability and spastic quadriplegia; its cached full text does not mention ABCB6 at all and its stated conclusion concerns ELOVL4 and very-long-chain fatty acids. No experiment in that paper perturbs ABCB6. This looks like an ELOVL4 annotation attached to the wrong gene product. Supporting Evidence: PMID:22100072 Our findings highlight the critical role of ELOVL4 and VLCFAs in early brain development and in the integrity of the epidermal water barrier. |
| GO:0010008 endosome membrane | EXP PMID:25627919 Role of the N-terminal transmembrane domain in the endo-lyso... | ACCEPT | Summary: ABCB6 is present in Rab5-positive endosome membranes after internalization from the cell surface. Reason: Experimental demonstration of ABCB6 on endosomal limiting membranes as part of the endolysosomal continuum in which the protein resides and acts. Supporting Evidence: PMID:25627919 we confirm the endo-lysosomal localization of ABCB6 and show that the protein is internalized from the plasma membrane through endocytosis, to be distributed to multivesicular bodies and lysosomes |
| GO:0010008 endosome membrane | IEA GO_REF:0000120 | ACCEPT | Summary: Automated annotation of endosome membrane. Reason: Concordant with the human EXP evidence for endosomal membrane localization. Supporting Evidence: PMID:25627919 we confirm the endo-lysosomal localization of ABCB6 and show that the protein is internalized from the plasma membrane through endocytosis, to be distributed to multivesicular bodies and lysosomes |
| GO:0015232 heme transmembrane transporter activity | IEA GO_REF:0000117 | MODIFY | Summary: ARBA rule-based heme transmembrane transporter activity. Reason: Correct but less precise than the evidence supports: ABCB6 is a primary active transporter that couples ATP hydrolysis to heme translocation, with EC 7.6.2.5 assigned from direct assays. Replace with the descendant ABC-type heme transporter activity (GO:0015439), which this gene already carries by EXP, IMP and IBA. Proposed replacements: ABC-type heme transporter activity Supporting Evidence: PMID:23792964 Mutagenesis of the conserved lysine to alanine (K629A) in the Walker A motif abolished ATP hydrolysis and substrate transport |
| GO:0015439 ABC-type heme transporter activity | EXP PMID:17661442 Human ABCB6 localizes to both the outer mitochondrial membra... | ACCEPT | Summary: Plasma membrane ABCB6 prevents cellular accumulation of specific porphyrins, consistent with ATP-driven heme/porphyrin transport. Reason: One of the two experimental anchors for the EC 7.6.2.5 assignment in UniProt. ATP-dependent translocation of hemin and related porphyrins is the core molecular function of ABCB6. Supporting Evidence: PMID:17661442 Preliminary studies indicate that ABCB6 is functionally relevant in the plasma membrane, where its expression prevents the accumulation of specific porphyrins in the cell |
| GO:0015439 ABC-type heme transporter activity | EXP PMID:23792964 Efficient purification and reconstitution of ATP binding cas... | ACCEPT | Summary: Purified, liposome-reconstituted ABCB6 transports porphyrin substrates in an ATP-dependent, Walker A-dependent manner. Reason: The strongest direct evidence for the core activity: pure protein in a defined system, substrate-stimulated ATPase, measured transport kinetics, and loss of both activities in the K629A Walker A mutant. Supporting Evidence: PMID:23792964 Mutagenesis of the conserved lysine to alanine (K629A) in the Walker A motif abolished ATP hydrolysis and substrate transport PMID:23792964 These results suggest a direct interaction between mitochondrial ABCB6 and its transport substrates that is critical for the activity of the transporter |
| GO:0015439 ABC-type heme transporter activity | IBA GO_REF:0000033 | ACCEPT | Summary: IBA from eumetazoan node PTN001199916, whose IBD was seeded by human ABCB6 itself. Reason: The PAINT curator placed heme transporter activity at a eumetazoan node of PTHR24221 on the basis of the human ABCB6 experimental data; ABCB6 appearing in its own WITH/FROM marks that experimental grounding rather than circularity, and the IBA additionally asserts that the activity is inherited rather than human-specific. The node placement is consistent with ABCB6 and its invertebrate relatives sharing the ABCB6/HMT-1 subfamily PTHR24221:SF654 architecture. Supporting Evidence: PMID:23792964 Mutagenesis of the conserved lysine to alanine (K629A) in the Walker A motif abolished ATP hydrolysis and substrate transport file:human/ABCB6/ABCB6-uniprot.txt DR PANTHER; PTHR24221:SF654; ATP-BINDING CASSETTE SUB-FAMILY B MEMBER 6; 1. |
| GO:0015439 ABC-type heme transporter activity | IEA GO_REF:0000003 | ACCEPT | Summary: EC 7.6.2.5 mapped to ABC-type heme transporter activity. Reason: The EC assignment itself rests on experimental work in human ABCB6 (ECO:0000269 on PubMed:17006453 and PubMed:17661442 in the UniProt catalytic activity block), so the mapped GO term restates a demonstrated activity. Supporting Evidence: PMID:17661442 Preliminary studies indicate that ABCB6 is functionally relevant in the plasma membrane, where its expression prevents the accumulation of specific porphyrins in the cell |
| GO:0015439 ABC-type heme transporter activity | IMP PMID:17006453 Identification of a mammalian mitochondrial porphyrin transp... | ACCEPT | Summary: Silencing ABCB6 blocks porphyrin uptake into mitochondria, used to infer heme transporter activity. Reason: The compartment in which this assay places ABCB6 is disputed, but the activity it measures - ATP-dependent movement of porphyrins across a membrane by ABCB6 - is independently confirmed with purified protein and in plasma membrane assays, so the molecular function call stands on its own. Supporting Evidence: PMID:17006453 Here we demonstrate that ABCB6 is uniquely located in the outer mitochondrial membrane and is required for mitochondrial porphyrin uptake |
| GO:0015439 ABC-type heme transporter activity | TAS Reactome:R-HSA-5683355 | ACCEPT | Summary: Reactome traceable statement of ABCB6 heme/porphyrin transporter activity. Reason: The activity is correct even though the Reactome reaction's compartment assignment follows the contested mitochondrial model. Supporting Evidence: Reactome:R-HSA-1369065 It plays a crucial role in heme synthesis by mediating porphyrin uptake into mitochondria |
| GO:0015562 efflux transmembrane transporter activity | IDA PMID:17661442 Human ABCB6 localizes to both the outer mitochondrial membra... | ACCEPT | Summary: ABCB6 at the plasma membrane effluxes porphyrins out of the cell. Reason: Efflux transmembrane transporter activity records the direction of transport, which the substrate-specific term ABC-type heme transporter activity does not entail, and the directionality is directly supported - expression of plasma membrane ABCB6 prevents intracellular porphyrin accumulation, and later work shows export of porphyrins from red cells. The term is therefore complementary rather than redundant. Supporting Evidence: PMID:17661442 Preliminary studies indicate that ABCB6 is functionally relevant in the plasma membrane, where its expression prevents the accumulation of specific porphyrins in the cell PMID:27507172 We also demonstrate that ABCB6 mediates the plasma membrane export of porphyrins in red cells |
| GO:0015886 heme transport | IBA GO_REF:0000033 | ACCEPT | Summary: IBA for heme transport from eumetazoan node PTN001199916, seeded by human ABCB6. Reason: The process counterpart of the heme transporter activity IBA from the same node. The inference is sound and the human protein has direct experimental support for heme translocation. Supporting Evidence: PMID:33007128 the ATPase activity of ABCB6 stimulated with a variety of porphyrin substrates showed different profiles in the presence of glutathione (GSH) |
| GO:0015886 heme transport | IDA PMID:17661442 Human ABCB6 localizes to both the outer mitochondrial membra... | ACCEPT | Summary: ABCB6 expression at the plasma membrane changes cellular porphyrin content. Reason: Direct cellular evidence that ABCB6 moves porphyrins, including heme precursors, across a membrane. Supporting Evidence: PMID:17661442 Preliminary studies indicate that ABCB6 is functionally relevant in the plasma membrane, where its expression prevents the accumulation of specific porphyrins in the cell |
| GO:0015886 heme transport | IMP PMID:17006453 Identification of a mammalian mitochondrial porphyrin transp... | ACCEPT | Summary: ABCB6 silencing blocks porphyrin movement into mitochondria. Reason: Whatever the membrane involved, the perturbation shows ABCB6-dependent translocation of porphyrins, a claim corroborated by the reconstituted system and by red cell export studies. Supporting Evidence: PMID:17006453 Here we demonstrate that ABCB6 is uniquely located in the outer mitochondrial membrane and is required for mitochondrial porphyrin uptake |
| GO:0016020 membrane | IEA GO_REF:0000002 | MODIFY | Summary: InterPro-based generic membrane localization. Reason: True but uninformative on its own; the specific supported membranes are known from direct evidence. Replace with the plasma membrane and lysosomal membrane, the two locations where ABCB6 is shown to act, both already carried by this gene with experimental evidence. Proposed replacements: plasma membrane lysosomal membrane Supporting Evidence: PMID:22246506 We identified ABCB6 as the genetic basis of the Lan blood group antigen expressed on red blood cells but also at the plasma membrane of hepatocellular carcinoma (HCC) cells PMID:31053883 confirmed the localization of the endogenous ABCB6 protein in the lysosomal compartment (labeled by LAMP1), and its absence in mitochondria (labeled by AIF) |
| GO:0016887 ATP hydrolysis activity | IDA PMID:33007128 Cryo-electron microscopy structure of human ABCB6 transporte... | ACCEPT | Summary: ABCB6 hydrolyses ATP, with activity stimulated by porphyrin substrates and glutathione. Reason: ATPase activity of purified ABCB6 is measured directly in several studies, with substrate stimulation and kinetic constants, and is abolished by Walker A substitutions. It is a distinct, demonstrated molecular function that powers the transport cycle. Supporting Evidence: PMID:33007128 the ATPase activity of ABCB6 stimulated with a variety of porphyrin substrates showed different profiles in the presence of glutathione (GSH) PMID:23792964 Mutagenesis of the conserved lysine to alanine (K629A) in the Walker A motif abolished ATP hydrolysis and substrate transport |
| GO:0016887 ATP hydrolysis activity | IEA GO_REF:0000002 | ACCEPT | Summary: InterPro ABC signatures imply ATP hydrolysis activity. Reason: Matches the directly measured ATPase activity of the purified human protein. Supporting Evidence: PMID:23792964 Mutagenesis of the conserved lysine to alanine (K629A) in the Walker A motif abolished ATP hydrolysis and substrate transport |
| GO:0020037 heme binding | IBA GO_REF:0000033 | ACCEPT | Summary: IBA for heme binding from eumetazoan node PTN001199916, seeded by human ABCB6. Reason: Heme binding is demonstrated directly in human ABCB6 (hemin-agarose pull-down; hemin-bound cryo-EM structure) and the PAINT curator placed the capability at a node from which this gene descends. Supporting Evidence: PMID:35950458 Here we report the cryo-electron microscopy (cryo-EM) structures of human ABCB6 with its substrates, coproporphyrin III (CPIII) and hemin |
| GO:0020037 heme binding | IDA PMID:17006453 Identification of a mammalian mitochondrial porphyrin transp... | ACCEPT | Summary: ABCB6 interacts directly with hemin. Reason: Direct binding of hemin by ABCB6 underpins its transport activity and is corroborated by structures of the hemin-bound transporter and by hemin-stimulated ATPase with sub-micromolar KM. Supporting Evidence: PMID:35950458 when ABCB6 binds a metal-centered porphyrin hemin in complex with two glutathione molecules |
| GO:0020037 heme binding | IDA PMID:33007128 Cryo-electron microscopy structure of human ABCB6 transporte... | ACCEPT | Summary: Hemin binding to ABCB6 shown in the cryo-EM and ATPase study. Reason: Heme binding with measured affinity in the presence of glutathione, in the study that also resolves the substrate cavity. Supporting Evidence: PMID:33007128 A slit-like substrate binding pocket of ABCB6 may accommodate the planar shape of porphyrins |
| GO:0031901 early endosome membrane | IEA GO_REF:0000120 | KEEP AS NON CORE | Summary: Early endosome membrane transferred from rat Abcb6 by combined automated methods. Reason: Consistent with the human data showing ABCB6 in Rab5-positive early endosomes after internalization. Accurate at this level of detail, but an itinerary compartment rather than the main site of action. Supporting Evidence: PMID:25627919 we confirm the endo-lysosomal localization of ABCB6 and show that the protein is internalized from the plasma membrane through endocytosis, to be distributed to multivesicular bodies and lysosomes |
| GO:0031901 early endosome membrane | ISS GO_REF:0000024 | KEEP AS NON CORE | Summary: ISS transfer of early endosome membrane from rat Abcb6. Reason: Same basis as the automated row; supported by human endocytosis data and kept as a non-core location. Supporting Evidence: PMID:25627919 we confirm the endo-lysosomal localization of ABCB6 and show that the protein is internalized from the plasma membrane through endocytosis, to be distributed to multivesicular bodies and lysosomes |
| GO:0031902 late endosome membrane | IEA GO_REF:0000120 | KEEP AS NON CORE | Summary: Late endosome membrane transferred from rat Abcb6. Reason: Part of the endolysosomal route taken by human ABCB6 and consistent with its multivesicular body localization; retained as non-core relative to the lysosomal pool. Supporting Evidence: PMID:25627919 we confirm the endo-lysosomal localization of ABCB6 and show that the protein is internalized from the plasma membrane through endocytosis, to be distributed to multivesicular bodies and lysosomes |
| GO:0031902 late endosome membrane | ISS GO_REF:0000024 | KEEP AS NON CORE | Summary: ISS transfer of late endosome membrane from rat Abcb6. Reason: Same basis as the automated late endosome row. Supporting Evidence: PMID:25627919 we confirm the endo-lysosomal localization of ABCB6 and show that the protein is internalized from the plasma membrane through endocytosis, to be distributed to multivesicular bodies and lysosomes |
| GO:0032585 multivesicular body membrane | IDA PMID:25627919 Role of the N-terminal transmembrane domain in the endo-lyso... | KEEP AS NON CORE | Summary: Electron microscopy places ABCB6 on the limiting membrane of multivesicular bodies. Reason: Directly observed and consistent with the release of ABCB6 in exosomes during reticulocyte maturation. A real location on the route to lysosomes rather than the principal functional compartment. Supporting Evidence: PMID:25627919 we confirm the endo-lysosomal localization of ABCB6 and show that the protein is internalized from the plasma membrane through endocytosis, to be distributed to multivesicular bodies and lysosomes |
| GO:0032585 multivesicular body membrane | IEA GO_REF:0000044 | KEEP AS NON CORE | Summary: UniProt subcellular-location mapping to multivesicular body membrane. Reason: Concordant with the electron microscopy evidence; kept on the same basis. Supporting Evidence: PMID:25627919 we confirm the endo-lysosomal localization of ABCB6 and show that the protein is internalized from the plasma membrane through endocytosis, to be distributed to multivesicular bodies and lysosomes |
| GO:0033013 tetrapyrrole metabolic process | IMP PMID:23792964 Efficient purification and reconstitution of ATP binding cas... | MODIFY | Summary: Transport of the tetrapyrrole coproporphyrin III by reconstituted ABCB6 annotated as tetrapyrrole metabolic process. Reason: The experiment measures transport of a tetrapyrrole into proteoliposomes; ABCB6 performs no chemical step of tetrapyrrole metabolism. Replace with heme transmembrane transport (GO:0035351), the transport process this gene carries by IDA, which covers the ATP-driven membrane translocation of porphyrin substrates demonstrated here. Proposed replacements: heme transmembrane transport Supporting Evidence: PMID:23792964 transport kinetics of its proposed endogenous substrate coproporphyrinogen III |
| GO:0033162 melanosome membrane | IDA PMID:29940187 ABCB6 Resides in Melanosomes and Regulates Early Steps of Me... | ACCEPT | Summary: ABCB6 is present on the limiting membrane of early melanosomes in melanocytic cells. Reason: Direct imaging in MNT-1 cells, in the study that also shows the melanosomal function depends on ABCB6 catalytic activity. Melanosomes are lysosome-related organelles, so this is a specialised instance of the conserved endolysosomal localization. Supporting Evidence: PMID:29940187 We show that ABCB6 localizes to the membrane of early melanosomes and lysosomes of the human melanocytic cell line MNT-1 |
| GO:0033162 melanosome membrane | IEA GO_REF:0000044 | ACCEPT | Summary: UniProt subcellular-location mapping to melanosome membrane. Reason: Concordant with the experimental demonstration in melanocytic cells. Supporting Evidence: PMID:29940187 We show that ABCB6 localizes to the membrane of early melanosomes and lysosomes of the human melanocytic cell line MNT-1 |
| GO:0034755 iron ion transmembrane transport | IEA GO_REF:0000117 | TOO GENERAL | Summary: ARBA rule-based annotation of iron ion transmembrane transport. Reason: Not false - in GO, heme transmembrane transport is classified beneath iron coordination entity transport and iron ion transmembrane transport, so this term is entailed by the heme transmembrane transport annotation asserted elsewhere in this review. It conveys nothing beyond that and would misleadingly suggest free iron ion transport, for which there is no evidence; ABCB6 moves intact iron-porphyrin complexes. Supporting Evidence: PMID:33007128 A slit-like substrate binding pocket of ABCB6 may accommodate the planar shape of porphyrins |
| GO:0035351 heme transmembrane transport | IDA PMID:33007128 Cryo-electron microscopy structure of human ABCB6 transporte... | ACCEPT | Summary: ABCB6 translocates heme across a membrane in an ATP-dependent manner. Reason: The core biological process. Supported by hemin transport and hemin-stimulated ATPase of purified protein, hemin-bound structures, and porphyrin export at the plasma membrane of red cells. Supporting Evidence: PMID:33007128 the ATPase activity of ABCB6 stimulated with a variety of porphyrin substrates showed different profiles in the presence of glutathione (GSH) PMID:27507172 We also demonstrate that ABCB6 mediates the plasma membrane export of porphyrins in red cells |
| GO:0036020 endolysosome membrane | IDA PMID:25627919 Role of the N-terminal transmembrane domain in the endo-lyso... | ACCEPT | Summary: ABCB6 is present on endolysosome membranes. Reason: Directly observed in the domain-dissection study; part of the conserved endolysosomal compartment in which ABCB6 functions. Supporting Evidence: PMID:25627919 we confirm the endo-lysosomal localization of ABCB6 and show that the protein is internalized from the plasma membrane through endocytosis, to be distributed to multivesicular bodies and lysosomes |
| GO:0036020 endolysosome membrane | IDA PMID:31053883 The human ABCB6 protein is the functional homologue of HMT-1... | ACCEPT | Summary: Endogenous ABCB6 occupies the endolysosomal compartment of glioblastoma cells. Reason: Independent confirmation in the study linking the endolysosomal pool of ABCB6 to cadmium sequestration. Supporting Evidence: PMID:31053883 confirmed the localization of the endogenous ABCB6 protein in the lysosomal compartment (labeled by LAMP1), and its absence in mitochondria (labeled by AIF) |
| GO:0036020 endolysosome membrane | IEA GO_REF:0000107 | ACCEPT | Summary: Endolysosome membrane transferred from rat Abcb6 by Ensembl Compara. Reason: The ortholog-based call agrees with direct human evidence for the same compartment. Supporting Evidence: PMID:31053883 confirmed the localization of the endogenous ABCB6 protein in the lysosomal compartment (labeled by LAMP1), and its absence in mitochondria (labeled by AIF) |
| GO:0042168 heme metabolic process | IDA PMID:33007128 Cryo-electron microscopy structure of human ABCB6 transporte... | MODIFY | Summary: Heme-stimulated ATPase and hemin binding annotated as heme metabolic process. Reason: ABCB6 binds and translocates heme but catalyses no step of heme synthesis or degradation, so the metabolic process term misstates what the experiment shows. Replace with heme transmembrane transport (GO:0035351), which the same study supports and which this gene already carries by IDA. Proposed replacements: heme transmembrane transport Supporting Evidence: PMID:33007128 the ATPase activity of ABCB6 stimulated with a variety of porphyrin substrates showed different profiles in the presence of glutathione (GSH) |
| GO:0043190 ATP-binding cassette (ABC) transporter complex | NAS PMID:11955620 Isolation of a genomic clone containing the promoter region ... | ACCEPT | Summary: ABCB6 forms an ABC transporter complex. Reason: The cited reference is a promoter-cloning paper and provides no direct evidence, but the claim is independently established: ABCB6 is a half transporter that assembles into a disulfide-linked homodimer, giving the four-domain architecture of GO's ABC transporter complex, as shown by purification, cross-linking and cryo-EM of the dimeric transporter. Supporting Evidence: file:human/ABCB6/ABCB6-uniprot.txt CC -!- SUBUNIT: Homodimer. {ECO:0000269|PubMed:16791740, PMID:25627919 We find that the folding, dimerization, membrane insertion and ATP binding/hydrolysis of the core-ABCB6 complex devoid of TMD0 are preserved |
| GO:0043588 skin development | IMP PMID:22100072 Recessive mutations in ELOVL4 cause ichthyosis, intellectual... | REMOVE | Summary: IMP for skin development citing a paper about ELOVL4. Reason: As for the companion brain development row, the cited reference studies recessive ELOVL4 mutations causing ichthyosis with intellectual disability and spastic quadriplegia and does not mention ABCB6; the epidermal phenotype it reports belongs to ELOVL4 and very-long-chain fatty acid synthesis. ABCB6 does have pigmentary skin disease alleles (dyschromatosis universalis hereditaria), but that is a different claim resting on different papers, and it is a disease association rather than participation in skin development. Supporting Evidence: PMID:22100072 Our findings highlight the critical role of ELOVL4 and VLCFAs in early brain development and in the integrity of the epidermal water barrier. |
| GO:0046906 tetrapyrrole binding | IDA PMID:17006453 Identification of a mammalian mitochondrial porphyrin transp... | ACCEPT | Summary: ABCB6 binds tetrapyrroles, demonstrated with hemin. Reason: Tetrapyrrole binding is the precise term for the demonstrated ligand range, which includes both metal-free porphyrins (coproporphyrin III, protoporphyrin IX) and metallated ones (hemin); it is not merely a general stand-in for heme binding. Supporting Evidence: PMID:35950458 Here we report the cryo-electron microscopy (cryo-EM) structures of human ABCB6 with its substrates, coproporphyrin III (CPIII) and hemin |
| GO:0046906 tetrapyrrole binding | IDA PMID:23792964 Efficient purification and reconstitution of ATP binding cas... | ACCEPT | Summary: Purified ABCB6 binds and transports the tetrapyrrole coproporphyrin III. Reason: Direct binding and transport of a metal-free tetrapyrrole by the purified protein, with measured kinetics, supports the tetrapyrrole-level term rather than only the heme-level one. Supporting Evidence: PMID:23792964 transport kinetics of its proposed endogenous substrate coproporphyrinogen III |
| GO:0055085 transmembrane transport | IBA GO_REF:0000033 | TOO GENERAL | Summary: IBA for transmembrane transport from the deep ABCB node PTN000657189. Reason: True of ABCB6, and the node placement across the ABCB family is sound, but the claim is entailed by the specific heme transmembrane transport annotation asserted in this review. No new information is added at this level of generality. Supporting Evidence: PMID:33007128 the ATPase activity of ABCB6 stimulated with a variety of porphyrin substrates showed different profiles in the presence of glutathione (GSH) |
| GO:0055085 transmembrane transport | IEA GO_REF:0000002 | TOO GENERAL | Summary: InterPro-based transmembrane transport annotation. Reason: Entailed by the specific transport process already asserted for this gene; retained in GOA it adds nothing beyond heme transmembrane transport. Supporting Evidence: PMID:27507172 We also demonstrate that ABCB6 mediates the plasma membrane export of porphyrins in red cells |
| GO:0070062 extracellular exosome | HDA PMID:19056867 Large-scale proteomics and phosphoproteomics of urinary exos... | KEEP AS NON CORE | Summary: ABCB6 detected in urinary exosomes by large-scale proteomics. Reason: Consistent with the targeted demonstration that ABCB6 is released in exosomes from maturing reticulocytes, which follows from its multivesicular body localization. A real but peripheral location. Supporting Evidence: PMID:19056867 we used LC-MS/MS to profile the proteome of human urinary exosomes |
| GO:0070062 extracellular exosome | IDA PMID:22655043 Shifting the paradigm: the putative mitochondrial protein AB... | KEEP AS NON CORE | Summary: ABCB6 is present in exosomes released from reticulocytes. Reason: Directly demonstrated and mechanistically explained by sorting into intraluminal vesicles of multivesicular bodies; peripheral to the transport function. Supporting Evidence: PMID:22655043 Here we show that ABCB6 is a glycoprotein present in the membrane of mature erythrocytes and in exosomes released from reticulocytes during the final steps of erythroid maturation |
| GO:0070062 extracellular exosome | IEA GO_REF:0000107 | KEEP AS NON CORE | Summary: Extracellular exosome transferred from mouse Abcb6. Reason: Agrees with two independent human datasets; kept as a non-core location. Supporting Evidence: PMID:22655043 Here we show that ABCB6 is a glycoprotein present in the membrane of mature erythrocytes and in exosomes released from reticulocytes during the final steps of erythroid maturation |
| GO:0098849 cellular detoxification of cadmium ion | IDA PMID:31053883 The human ABCB6 protein is the functional homologue of HMT-1... | ACCEPT | Summary: ABCB6 sequesters cadmium in acidic vesicles and confers cadmium tolerance, functionally replacing HMT-1 proteins. Reason: Strong, multi-system experimental evidence that ABCB6 itself performs the detoxifying step - human ABCB6 rescues the cadmium hypersensitivity of S. pombe and C. elegans hmt-1 mutants, restores vacuolar cadmium content, requires an intact Walker A motif to do so, and changes cadmium sensitivity of human glioblastoma cells when its level is manipulated. Sequestration into an acidic compartment is explicitly within the scope of the GO term. Note that PAINT has not propagated this term anywhere in PTHR24221, which is consistent with the transported species differing between clade members - Drosophila HMT-1 confers cadmium tolerance without transporting cadmium-phytochelatin complexes. Supporting Evidence: PMID:31053883 the cadmium-sensitive phenotype of Schizosaccharomyces pombe and Caenorhabditis elegans strains defective for HMT-1 is rescued by the human ABCB6 protein PMID:31053883 Inactivating mutations of ABCB6 abolished vacuolar sequestration of cadmium, effectively suppressing the cadmium tolerance phenotype PMID:31053883 Modulation of ABCB6 expression levels in human glioblastoma cells resulted in a concomitant change in cadmium sensitivity |
| GO:0140359 ABC-type transporter activity | IDA PMID:27507172 The severity of hereditary porphyria is modulated by the por... | ACCEPT | Summary: ABCB6 is an ATP-binding cassette transporter, shown by ATP binding and transport assays on variants. Reason: Kept at this level deliberately rather than refined to the heme-specific child. ABCB6's demonstrated substrate range extends beyond heme to metal-free porphyrins and, in the cadmium work, to a metal species whose identity is unknown, and GO has no ABC-type porphyrin transporter term. The generic term therefore covers claims the heme-specific one does not. Supporting Evidence: PMID:27507172 ABCB6 R192Q-bound ATP-agarose normally, while the A492T-substituted protein displayed markedly impaired ATP binding and as expected the positive control K629G did not bind ATP |
| GO:0140359 ABC-type transporter activity | IEA GO_REF:0000120 | ACCEPT | Summary: Combined automated annotation of ABC-type transporter activity. Reason: Matches the demonstrated architecture and activity of the protein, and covers the non-heme substrates for which no specific GO term exists. Supporting Evidence: file:human/ABCB6/ABCB6-uniprot.txt DR InterPro; IPR011527; ABC1_TM_dom. |
| GO:0140359 ABC-type transporter activity | IMP PMID:23792964 Efficient purification and reconstitution of ATP binding cas... | ACCEPT | Summary: ATP-dependent substrate transport by purified, reconstituted ABCB6, abolished by a Walker A mutation. Reason: The cleanest demonstration that ABCB6 is a primary active ABC transporter, and the assay measured several chemically distinct substrates, which the generic term accommodates. Supporting Evidence: PMID:23792964 Mutagenesis of the conserved lysine to alanine (K629A) in the Walker A motif abolished ATP hydrolysis and substrate transport |
| GO:0140359 ABC-type transporter activity | ISS GO_REF:0000024 | ACCEPT | Summary: ISS transfer of ABC-type transporter activity from mouse Abcb6. Reason: Concordant with the direct human biochemical evidence. Supporting Evidence: PMID:23792964 Mutagenesis of the conserved lysine to alanine (K629A) in the Walker A motif abolished ATP hydrolysis and substrate transport |
| GO:1903232 melanosome assembly | IDA PMID:29940187 ABCB6 Resides in Melanosomes and Regulates Early Steps of Me... | ACCEPT | Summary: ABCB6 transport activity is required for PMEL amyloid matrix formation and normal maturation of early melanosomes. Reason: ABCB6 does work in this process rather than merely being required for it: it sits in the limiting membrane of the early melanosome, its depletion blocks PMEL fibril formation and causes aberrant multilamellar aggregates, and rescue requires a catalytically competent transporter - the K629M Walker A mutant and the disease allele G579E both fail. Transport across the melanosomal membrane is therefore a step the organelle's maturation depends on, performed by ABCB6 itself. Mouse knockout retinal pigment epithelium has fewer melanosomes, corroborating the cellular result. Supporting Evidence: PMID:29940187 PMEL fibril formation and normal maturation of pigmented melanosomes could be restored by the overexpression of wild-type ABCB6 but not by variants containing an inactivating catalytic mutation (K629M) or the G579E DUH mutation PMID:29940187 We show that ABCB6 localizes to the membrane of early melanosomes and lysosomes of the human melanocytic cell line MNT-1 |
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Download this section (compressed HTML)Q: Does human ABCB6 occupy the mitochondrial outer membrane at all? Overexpression and fractionation studies report a mitochondrial pool while imaging of the endogenous protein does not, and the question determines whether the porphyrin import model for heme synthesis can be retained.
Q: Which chemical species does ABCB6 carry during heavy-metal detoxification in human cells, given the absence of phytochelatins and the finding that Drosophila HMT-1 does not transport cadmium-phytochelatin complexes?
Q: What is the direction of transport at the lysosomal and melanosomal membrane? The nucleotide-binding domains face the cytosol, predicting import into the lumen, while at the plasma membrane the same protein exports porphyrins.
Q: Why do missense alleles of ABCB6 cause dyschromatosis universalis hereditaria, ocular coloboma and pseudohyperkalemia while complete loss of the protein in Lan-negative individuals is clinically silent? Are the disease alleles acting by a dominant-negative or gain-of-function mechanism?
Experiment: Reconstitute purified ABCB6 into proteoliposomes and screen candidate melanosomal metabolites, including glutathione conjugates and melanin precursors, for substrate-stimulated ATPase and for transport; test the hits in ABCB6-depleted MNT-1 cells for rescue of PMEL fibril formation.
Hypothesis: The ABCB6-dependent step in melanosome maturation is the transport of a glutathione-conjugated or porphyrin-like species into the early melanosome lumen.
Type: in vitro transport assay
Experiment: Apply split-fluorophore or proximity-labelling reporters to endogenously tagged ABCB6 in cells that also carry validated outer mitochondrial membrane and lysosomal baits, and quantify the two pools at native expression levels; combine with immuno-electron microscopy on untransfected cells.
Hypothesis: The contested mitochondrial pool of ABCB6 is an artefact of overexpression and of endolysosome-mitochondrion co-fractionation.
Type: subcellular localization
Experiment: Measure ATP-dependent uptake of cadmium with and without glutathione into ABCB6 proteoliposomes by inductively coupled plasma mass spectrometry, with the K629A Walker A mutant as the negative control, and compare with Schizosaccharomyces pombe HMT-1 run in parallel.
Hypothesis: ABCB6 transports a cadmium-glutathione complex into the lysosomal lumen.
Type: in vitro transport assay
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