ABCB7

Existing Annotations Review

GO Term	Evidence	Action	Reason
GO:0042626 ATPase-coupled transmembrane transporter activity	IBA GO_REF:0000033	ACCEPT	Summary: ABCB7 is an ABC transporter that couples ATP hydrolysis to transmembrane transport. The phylogenetically-derived IBA annotation is accurate and represents a core molecular function of this protein (ABCB7-deep-research-falcon.md). Reason: ABCB7 belongs to the ABC transporter superfamily and its ATPase activity has been directly demonstrated. The deep research file confirms that ABCB7 shows ATPase stimulation by glutathione and [2Fe-2S](GS)4 in proteoliposomes (PMID:33157103). The IBA annotation based on phylogenetic inference is sound. Supporting Evidence: PMID:33157103 a functional comparison of native human protein, versus a disease-causing mutant, demonstrates a key role for residue E433 in promoting cluster transport file:human/ABCB7/ABCB7-deep-research-falcon.md Human ABCB7 reconstituted in proteoliposomes shows ATPase stimulation by glutathione and [2Fe-2S](GS)4
GO:0055085 transmembrane transport	IBA GO_REF:0000033	ACCEPT	Summary: ABCB7 is involved in transmembrane transport of Fe-S cluster intermediates across the inner mitochondrial membrane. This is a core biological process. Reason: ABCB7 exports glutathione-coordinated [2Fe-2S] clusters from mitochondria to cytosol, which is a transmembrane transport process. The IBA annotation is accurate. Supporting Evidence: PMID:33157103 Iron-sulfur cofactors are assembled primarily in mitochondria and are then exported to the cytosol by use of an ABCB7 transporter
GO:0006879 intracellular iron ion homeostasis	IBA GO_REF:0000033	ACCEPT	Summary: ABCB7 plays a critical role in intracellular iron homeostasis by exporting Fe-S cluster precursors from mitochondria. ABCB7 deficiency causes mitochondrial iron accumulation and cytosolic iron deficiency. Reason: Multiple studies demonstrate ABCB7's role in iron homeostasis. ABCB7 knockdown causes mitochondrial iron overload with cytosolic iron deficiency phenotype (PMID:17192393, PMID:30765471). Supporting Evidence: PMID:17192393 The phenotype of the ABCB7-deficient cells was characterized by a strong reduction in proliferation rate that was not rescued by iron supplementation, by evident signs of iron deficiency, and by a large approximately 6-fold increase of iron accumulation in the mitochondria PMID:30765471 In erythroid cells, loss of ABCB7 altered cellular iron distribution and caused mitochondrial iron overload
GO:0005743 mitochondrial inner membrane	IBA GO_REF:0000033	ACCEPT	Summary: ABCB7 is localized to the mitochondrial inner membrane with its nucleotide-binding domain facing the matrix. This is well-established by multiple lines of evidence. Reason: Localization to the mitochondrial inner membrane is confirmed by direct experimental evidence and is consistent with its function as an exporter of Fe-S clusters from the mitochondrial matrix. Supporting Evidence: PMID:10196363 This gene, ABC7, is an ortholog of the yeast ATM1 gene whose product localizes to the mitochondrial inner membrane and is involved in iron homeostasis PMID:30765471 These members are ABCB7 (the human ortholog of yeast Atm1), ABCB10 and ABCB8
GO:0000166 nucleotide binding	IEA GO_REF:0000043	ACCEPT	Summary: ABCB7 contains a nucleotide-binding domain (NBD) that binds ATP. This is an accurate but general annotation. Reason: As an ABC transporter, ABCB7 contains an AAA+ ATPase/nucleotide-binding domain that binds and hydrolyzes ATP. The IEA annotation from UniProtKB keyword mapping is accurate. Supporting Evidence: PMID:9621516 The nucleotide sequence was highly homologous to the ATM1 gene in yeast, which encodes an ABC transporter
GO:0005524 ATP binding	IEA GO_REF:0000120	ACCEPT	Summary: ABCB7 binds ATP at its nucleotide-binding domain to power transport. Reason: ATP binding is essential for ABCB7 function. The deep research file confirms biochemical characterization of ATPase activity stimulated by substrates. Supporting Evidence: file:human/ABCB7/ABCB7-deep-research-falcon.md Human ABCB7 reconstituted in proteoliposomes shows ATPase stimulation by glutathione and [2Fe-2S](GS)4
GO:0005743 mitochondrial inner membrane	IEA GO_REF:0000044	ACCEPT	Summary: IEA annotation consistent with experimentally validated localization. Reason: Redundant with IBA annotation for same term. Mitochondrial inner membrane localization is well-established. Supporting Evidence: PMID:10196363 This gene, ABC7, is an ortholog of the yeast ATM1 gene whose product localizes to the mitochondrial inner membrane
GO:0006879 intracellular iron ion homeostasis	IEA GO_REF:0000117	ACCEPT	Summary: Machine learning-derived annotation consistent with established function. Reason: Redundant with IBA and IMP annotations. ABCB7's role in iron homeostasis is well-established experimentally. Supporting Evidence: PMID:17192393 a large approximately 6-fold increase of iron accumulation in the mitochondria
GO:0015232 heme transmembrane transporter activity	IEA GO_REF:0000117	REMOVE	Summary: This annotation is likely incorrect. ABCB7 does NOT transport heme. It transports glutathione-coordinated [2Fe-2S] clusters. Early literature speculated about heme transport based on analogy with yeast Atm1, but this has not been experimentally validated and is inconsistent with current understanding. Reason: ABCB7 is an Fe-S cluster transporter, not a heme transporter. The transported substrate has been biochemically characterized as [2Fe-2S](GS)4 (glutathione- coordinated iron-sulfur cluster) (PMID:33157103). ABCB7 affects heme biosynthesis indirectly through the FECH-ABCB7-ABCB10 complex and by providing Fe-S clusters for iron regulation, but it does not transport heme itself.
GO:0015886 heme transport	IEA GO_REF:0000108	REMOVE	Summary: This annotation is derived from the incorrect GO:0015232 (heme transmembrane transporter activity) annotation and should be removed. Reason: ABCB7 does not transport heme. This annotation is propagated from the incorrect molecular function annotation GO:0015232. The actual transported substrate is glutathione-coordinated [2Fe-2S] clusters as established by biochemical studies.
GO:0016020 membrane	IEA GO_REF:0000002	ACCEPT	Summary: Generic membrane annotation. More specific term (mitochondrial inner membrane) is available. Reason: While accurate, this is a very general term. GO:0005743 (mitochondrial inner membrane) is more appropriate and already annotated. Keeping as valid but non-core.
GO:0016887 ATP hydrolysis activity	IEA GO_REF:0000002	ACCEPT	Summary: ABCB7 has intrinsic ATPase activity that is stimulated by glutathione and its substrate [2Fe-2S](GS)4. Reason: ATP hydrolysis activity is experimentally validated. The E433K disease mutation impairs ATP hydrolysis stimulation and cluster transport. Supporting Evidence: PMID:33157103 a functional comparison of native human protein, versus a disease-causing mutant, demonstrates a key role for residue E433 in promoting cluster transport
GO:0034755 iron ion transmembrane transport	IEA GO_REF:0000117	MODIFY	Summary: ABCB7 transports iron as part of glutathione-coordinated [2Fe-2S] clusters, not free iron ions. This annotation is technically imprecise. Reason: ABCB7 does not transport free iron ions. It exports [2Fe-2S](GS)4, a glutathione-coordinated iron-sulfur cluster complex. The term GO:0140466 (iron-sulfur cluster export from the mitochondrion) is more accurate. Proposed replacements: iron-sulfur cluster export from the mitochondrion
GO:0055085 transmembrane transport	IEA GO_REF:0000002	ACCEPT	Summary: Redundant with IBA annotation for same term. Reason: Accurate general annotation. Already covered by more specific Fe-S cluster transport annotation.
GO:0140359 ABC-type transporter activity	IEA GO_REF:0000002	ACCEPT	Summary: ABCB7 is an ABC transporter. This is accurate. Reason: ABCB7 is a member of the ABC transporter superfamily, ABCB family. The annotation is accurate.
GO:0005515 protein binding	IPI PMID:30765471 Dimeric ferrochelatase bridges ABCB7 and ABCB10 homodimers i...	MODIFY	Summary: ABCB7 binds to ferrochelatase (FECH) as part of the FECH-ABCB7-ABCB10 complex. However, "protein binding" is too vague. Reason: The interaction with FECH (ferrochelatase) is experimentally validated by crosslinking/MS and co-immunoprecipitation (PMID:30765471). However, "protein binding" is uninformative. The homodimerization annotation (GO:0042802) is more informative for the self-interaction. Proposed replacements: identical protein binding Supporting Evidence: PMID:30765471 By combining chemical crosslinking, tandem mass spectrometry and mutational analyses, we characterized a complex formed of ferrochelatase, ABCB7 and ABCB10, and mapped the interfaces of interactions of its components
GO:0042802 identical protein binding	IPI PMID:30765471 Dimeric ferrochelatase bridges ABCB7 and ABCB10 homodimers i...	ACCEPT	Summary: ABCB7 functions as a homodimer. The identical protein binding annotation reflects this self-interaction. Reason: ABCB7 is a half-transporter that forms functional homodimers. The Maio et al. study demonstrated homodimerization by crosslinking/MS (PMID:30765471). Supporting Evidence: PMID:30765471 A dimeric ferrochelatase physically bridged ABCB7 and ABCB10 homodimers by binding near the nucleotide-binding domains of each ABC transporter
GO:0016226 iron-sulfur cluster assembly	IEA GO_REF:0000107	ACCEPT	Summary: ABCB7 is involved in iron-sulfur cluster assembly by exporting Fe-S cluster precursors from mitochondria to the cytosol, enabling maturation of cytosolic Fe-S proteins. Reason: ABCB7 is essential for cytosolic Fe-S cluster assembly. Knockdown of ABCB7 impairs cytosolic Fe-S enzymes like aconitase/IRP1 (PMID:17192393). Supporting Evidence: PMID:17192393 aconitase activity, particularly that of the cytosolic, IRP1 form, was reduced
GO:0070455 positive regulation of heme biosynthetic process	IEA GO_REF:0000107	ACCEPT	Summary: ABCB7 positively regulates heme biosynthesis by stabilizing ferrochelatase through the FECH-ABCB7-ABCB10 complex and by providing Fe-S clusters that regulate iron metabolism. Reason: Loss of ABCB7 causes profound hemoglobinization defects in erythroid cells due to ferrochelatase destabilization (PMID:30765471). The effect on heme biosynthesis is well-documented in XLSA/A and MDS-RS. Supporting Evidence: PMID:30765471 erythroid cells lacking ABCB7 showed a profound hemoglobinization defect
GO:1903331 positive regulation of iron-sulfur cluster assembly	IEA GO_REF:0000107	ACCEPT	Summary: ABCB7 positively regulates cytosolic/nuclear iron-sulfur cluster assembly by exporting the required precursor from mitochondria. Reason: ABCB7 exports the sulfur compound required for cytosolic Fe-S protein maturation. Without ABCB7, cytosolic Fe-S proteins cannot be assembled (PMID:17192393). Supporting Evidence: PMID:17192393 The results support the hypothesis that ABCB7 is involved in the transfer of iron from mitochondria to cytosol, and in the maturation of cytosolic Fe/S enzymes
GO:0006783 heme biosynthetic process	NAS PMID:30765471 Dimeric ferrochelatase bridges ABCB7 and ABCB10 homodimers i...	KEEP AS NON CORE	Summary: ABCB7 is required for heme biosynthesis in erythroid cells through its role in stabilizing ferrochelatase and providing Fe-S clusters for iron regulation. Reason: ABCB7's involvement in heme biosynthesis is indirect - it affects heme synthesis through the FECH-ABCB7-ABCB10 complex and by providing Fe-S clusters that regulate iron metabolism. The core function is Fe-S cluster export, with heme biosynthesis being a downstream effect primarily relevant in erythroid cells. Supporting Evidence: PMID:30765471 In ABCB7-depleted cells, defective heme biosynthesis resulted from translational repression of ALAS2 by iron regulatory proteins and from decreased stability of the terminal enzyme ferrochelatase
GO:0031966 mitochondrial membrane	IDA PMID:30765471 Dimeric ferrochelatase bridges ABCB7 and ABCB10 homodimers i...	ACCEPT	Summary: General localization annotation. More specific term GO:0005743 (mitochondrial inner membrane) is available and already annotated. Reason: Accurate but less specific than GO:0005743. The IDA evidence from Maio et al. supports mitochondrial localization. Supporting Evidence: PMID:30765471 Epub 2019 Feb 14. Dimeric ferrochelatase bridges ABCB7 and ABCB10 homodimers in an architecturally defined molecular complex required for heme biosynthesis.
GO:0005739 mitochondrion	HTP PMID:34800366 Quantitative high-confidence human mitochondrial proteome an...	ACCEPT	Summary: High-throughput proteomics confirms mitochondrial localization. Reason: Mitochondrial localization is well-established. This HTP annotation from the mitochondrial proteome study is consistent with other evidence. Supporting Evidence: PMID:34800366 Epub 2021 Nov 19. Quantitative high-confidence human mitochondrial proteome and its dynamics in cellular context.
GO:0042803 protein homodimerization activity	IDA PMID:30765471 Dimeric ferrochelatase bridges ABCB7 and ABCB10 homodimers i...	ACCEPT	Summary: ABCB7 forms functional homodimers. As a half-transporter, dimerization is essential for function. Reason: Homodimerization is experimentally demonstrated by crosslinking/MS in the Maio et al. study (PMID:30765471). ABCB7 is a half-transporter requiring homodimerization for transport activity. Supporting Evidence: PMID:30765471 A dimeric ferrochelatase physically bridged ABCB7 and ABCB10 homodimers by binding near the nucleotide-binding domains of each ABC transporter
GO:0006879 intracellular iron ion homeostasis	ISS GO_REF:0000024	ACCEPT	Summary: Sequence similarity-based transfer from mouse ortholog (Q61102). Consistent with experimentally validated function. Reason: Redundant with IBA and IMP annotations. Function is conserved between human and mouse.
GO:0016226 iron-sulfur cluster assembly	ISS GO_REF:0000024	ACCEPT	Summary: ISS annotation from mouse ortholog. Consistent with established function. Reason: Redundant with IEA annotation. Fe-S cluster assembly function is well-established.
GO:0070455 positive regulation of heme biosynthetic process	ISS GO_REF:0000024	ACCEPT	Summary: ISS annotation from mouse ortholog. Consistent with experimental data. Reason: Redundant with IEA and IMP annotations. Effect on heme biosynthesis is experimentally validated.
GO:0140466 iron-sulfur cluster export from the mitochondrion	IMP PMID:33157103 Evolution of the human mitochondrial ABCB7 [2Fe-2S](GS)(4) c...	ACCEPT	Summary: This is the core biological process of ABCB7 - exporting glutathione-coordinated [2Fe-2S] clusters from mitochondria. Reason: This is the most specific and accurate annotation for ABCB7's primary function. The Pearson and Cowan study (PMID:33157103) provides biochemical evidence for [2Fe-2S](GS)4 cluster export activity. Supporting Evidence: PMID:33157103 It has been shown that the yeast mitochondrial transporter Atm1 can export glutathione-coordinated iron-sulfur clusters, [2Fe-2S](SG)4, providing a source of cluster units for cytosolic iron-sulfur cluster assembly systems
GO:0140481 ABC-type iron-sulfur cluster transporter activity	IMP PMID:33157103 Evolution of the human mitochondrial ABCB7 [2Fe-2S](GS)(4) c...	ACCEPT	Summary: This is the core molecular function annotation for ABCB7. It accurately describes the ABC-type mechanism for Fe-S cluster transport. Reason: This term precisely captures ABCB7's function as an ABC transporter that transports iron-sulfur clusters. Experimental evidence from proteoliposome reconstitution studies supports this function (PMID:33157103). Supporting Evidence: PMID:33157103 a functional comparison of native human protein, versus a disease-causing mutant, demonstrates a key role for residue E433 in promoting cluster transport
GO:1903427 negative regulation of reactive oxygen species biosynthetic process	ISS GO_REF:0000024	KEEP AS NON CORE	Summary: ABCB7 deficiency leads to increased ROS and oxidative stress sensitivity. This is a downstream consequence of mitochondrial iron accumulation. Reason: ABCB7-deficient cells show higher sensitivity to H2O2 toxicity and reduced SOD2 activity (PMID:17192393). However, ROS regulation is an indirect effect of iron dyshomeostasis, not a core function of ABCB7. Supporting Evidence: PMID:17192393 The cells showed an increase of protoporphyrin IX, a higher sensitivity to H(2)O(2) toxicity, and a reduced activity of mitochondrial superoxide dismutase 2 (SOD2)
GO:0006879 intracellular iron ion homeostasis	IMP PMID:30765471 Dimeric ferrochelatase bridges ABCB7 and ABCB10 homodimers i...	ACCEPT	Summary: IMP annotation from the Maio et al. study. ABCB7 knockdown causes iron redistribution with mitochondrial accumulation. Reason: Direct experimental evidence from knockdown studies shows ABCB7 is required for proper iron distribution (PMID:30765471). Supporting Evidence: PMID:30765471 In erythroid cells, loss of ABCB7 altered cellular iron distribution and caused mitochondrial iron overload
GO:0070455 positive regulation of heme biosynthetic process	IMP PMID:30765471 Dimeric ferrochelatase bridges ABCB7 and ABCB10 homodimers i...	ACCEPT	Summary: IMP annotation from Maio et al. ABCB7 knockdown impairs heme synthesis through ferrochelatase destabilization. Reason: Experimental evidence shows ABCB7 is required for heme biosynthesis, primarily through the FECH-ABCB7-ABCB10 complex (PMID:30765471). Supporting Evidence: PMID:30765471 erythroid cells lacking ABCB7 showed a profound hemoglobinization defect
GO:0034755 iron ion transmembrane transport	IDA PMID:17192393 RNA silencing of the mitochondrial ABCB7 transporter in HeLa...	MODIFY	Summary: This annotation from Cavadini et al. (2007) is based on ABCB7 knockdown causing mitochondrial iron accumulation. However, ABCB7 transports [2Fe-2S](GS)4 clusters, not free iron ions. Reason: The Cavadini study showed ABCB7 is involved in iron transfer from mitochondria to cytosol, but the transported species is [2Fe-2S](GS)4, not free iron ions. GO:0140466 (iron-sulfur cluster export from the mitochondrion) is more accurate. Proposed replacements: iron-sulfur cluster export from the mitochondrion Supporting Evidence: PMID:17192393 The results support the hypothesis that ABCB7 is involved in the transfer of iron from mitochondria to cytosol
GO:1903331 positive regulation of iron-sulfur cluster assembly	ISS GO_REF:0000024	ACCEPT	Summary: ISS annotation from mouse ortholog. Consistent with established function. Reason: Redundant with IEA and IMP annotations. ABCB7's role in promoting cytosolic Fe-S cluster assembly is well-established.
GO:1903331 positive regulation of iron-sulfur cluster assembly	IMP PMID:17192393 RNA silencing of the mitochondrial ABCB7 transporter in HeLa...	ACCEPT	Summary: IMP annotation from Cavadini et al. ABCB7 knockdown impairs cytosolic Fe-S enzyme activity. Reason: ABCB7 knockdown causes reduced activity of cytosolic aconitase/IRP1, demonstrating its role in cytosolic Fe-S cluster assembly (PMID:17192393). Supporting Evidence: PMID:17192393 aconitase activity, particularly that of the cytosolic, IRP1 form, was reduced
GO:0005739 mitochondrion	IDA PMID:22655043 Shifting the paradigm: the putative mitochondrial protein AB...	ACCEPT	Summary: IDA annotation for mitochondrial localization. Reason: Mitochondrial localization is well-established by multiple studies. Supporting Evidence: PMID:22655043 Shifting the paradigm: the putative mitochondrial protein ABCB6 resides in the lysosomes of cells and in the plasma membrane of erythrocytes.
GO:0005515 protein binding	IPI PMID:25063848 PAAT, a novel ATPase and trans-regulator of mitochondrial AB...	KEEP AS NON CORE	Summary: ABCB7 interacts with PAAT (C10orf88/Q9H8K7), an ATPase that regulates mitochondrial ABC transporters. Reason: The interaction with PAAT is experimentally validated (PMID:25063848). However, "protein binding" is too general. PAAT regulates ABCB7 function but this interaction is not a core function of ABCB7 itself. Supporting Evidence: PMID:25063848 PAAT, a novel ATPase and trans-regulator of mitochondrial ABC transporters, is critically involved in the maintenance of mitochondrial homeostasis.
GO:0005743 mitochondrial inner membrane	TAS Reactome:R-HSA-382560	ACCEPT	Summary: TAS annotation from Reactome pathway. Note that the Reactome pathway name referring to heme transport is outdated - ABCB7 transports Fe-S clusters. Reason: The localization to mitochondrial inner membrane is correct, though the Reactome pathway description regarding heme transport is outdated.
GO:0005743 mitochondrial inner membrane	IDA PMID:17006453 Identification of a mammalian mitochondrial porphyrin transp...	ACCEPT	Summary: IDA annotation from Krishnamurthy et al. 2006 (a study primarily about ABCB6). Reason: Mitochondrial inner membrane localization is well-established. This study confirms the general localization of ABC transporters to mitochondria. Supporting Evidence: PMID:17006453 Identification of a mammalian mitochondrial porphyrin transporter.
GO:0005524 ATP binding	TAS PMID:9621516 Cloning and chromosomal mapping of a novel ABC transporter g...	ACCEPT	Summary: TAS annotation from the original cloning paper describing ABCB7's ATP-binding cassette domain. Reason: ATP binding is inherent to ABC transporters. The NBD domain was identified in the original cloning (PMID:9621516). Supporting Evidence: PMID:9621516 The nucleotide sequence was highly homologous to the ATM1 gene in yeast, which encodes an ABC transporter
GO:0042626 ATPase-coupled transmembrane transporter activity	TAS PMID:9621516 Cloning and chromosomal mapping of a novel ABC transporter g...	ACCEPT	Summary: TAS annotation from the original cloning paper. ABCB7 was identified as an ABC transporter orthologous to yeast Atm1. Reason: ABCB7's function as an ATPase-coupled transporter was predicted from sequence homology to Atm1 and later confirmed experimentally. Supporting Evidence: PMID:9621516 The nucleotide sequence was highly homologous to the ATM1 gene in yeast, which encodes an ABC transporter
GO:0005743 mitochondrial inner membrane	TAS PMID:10196363 Mutation of a putative mitochondrial iron transporter gene (...	ACCEPT	Summary: TAS annotation from Allikmets et al. 1999, the study that established ABCB7 mutations cause XLSA/A. Reason: This foundational paper established ABCB7's localization and function based on homology to yeast Atm1. Supporting Evidence: PMID:10196363 This gene, ABC7, is an ortholog of the yeast ATM1 gene whose product localizes to the mitochondrial inner membrane and is involved in iron homeostasis
GO:0015232 heme transmembrane transporter activity	TAS PMID:9621516 Cloning and chromosomal mapping of a novel ABC transporter g...	REMOVE	Summary: This annotation is based on early speculation that ABCB7/Atm1 might transport heme. This has been superseded by evidence that the transported substrate is [2Fe-2S](GS)4 clusters. Reason: The 1998 cloning paper (PMID:9621516) suggested heme transport based on yeast Atm1 function speculation. Current biochemical evidence firmly establishes that ABCB7 transports glutathione-coordinated [2Fe-2S] clusters, not heme. The paper states the product is "probably involved in heme transport" but this was speculative and has since been superseded. Supporting Evidence: PMID:9621516 Cloning and chromosomal mapping of a novel ABC transporter gene (hABC7), a candidate for X-linked sideroblastic anemia with spinocerebellar ataxia.

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