IBA57 (Iron-sulfur cluster assembly factor IBA57, mitochondrial) is a nuclear-encoded mitochondrial protein that functions as a late-acting assembly factor in the mitochondrial iron-sulfur cluster (ISC) biogenesis pathway. IBA57 operates in cooperation with ISCA1 and ISCA2 to convert 2Fe-2S clusters into 4Fe-4S clusters. Specifically, IBA57 forms a heterodimeric complex with ISCA2 that contains a bridging 2Fe-2S cluster, which serves as an intermediate in the reductive coupling mechanism that generates 4Fe-4S clusters. The protein is essential for maturation of mitochondrial 4Fe-4S-containing enzymes including respiratory complexes I and II, aconitase, and lipoic acid synthase (LIAS). Pathogenic variants in IBA57 cause multiple mitochondrial dysfunctions syndrome 3 (MMDS3) and spastic paraplegia 74 (SPG74), characterized by defects in respiratory chain complexes and impaired lipoylation of pyruvate dehydrogenase and alpha-ketoglutarate dehydrogenase. The deep research review (IBA57-deep-research-falcon.md) confirms IBA57 functions downstream with ISCA1-ISCA2 during the late step that converts two GLRX5-derived 2Fe-2S clusters into a 4Fe-4S cluster.
| GO Term | Evidence | Action | Reason |
|---|---|---|---|
| GO:0005759 mitochondrial matrix | IBA GO_REF:0000033 | ACCEPT | Summary: IBA57 is localized to the mitochondrial matrix where it functions in the late-stage ISC machinery. This is well-supported by multiple lines of evidence including immunofluorescence microscopy (PMID:22323289) and the known mitochondrial targeting sequence (residues 1-39 per UniProt). The IBA phylogenetic inference is consistent with experimental data. The deep research (IBA57-deep-research-falcon.md) confirms mitochondrial matrix localization. Reason: The mitochondrial matrix localization is strongly supported by experimental evidence. PMID:22323289 demonstrated mitochondrial localization using immunofluorescence, and the UniProt entry confirms a mitochondrial transit peptide. The IBA annotation from phylogenetic inference is concordant with experimental data. Supporting Evidence: PMID:22323289 ISCA1, ISCA2, and IBA57 are localized to mitochondria file:human/IBA57/IBA57-deep-research-falcon.md model: Edison Scientific Literature |
| GO:0005739 mitochondrion | IEA GO_REF:0000044 | ACCEPT | Summary: IEA annotation based on UniProt subcellular location mapping. While correct, this is less specific than the IBA annotation to mitochondrial matrix (GO:0005759). Reason: This annotation is correct but less specific than the mitochondrial matrix annotation. Both annotations can be retained as they are both accurate - mitochondrion is a parent term of mitochondrial matrix. |
| GO:0006783 heme biosynthetic process | IEA GO_REF:0000043 | REMOVE | Summary: This annotation is inferred from UniProt keyword mapping. While there is indirect connection between iron-sulfur cluster assembly and heme biosynthesis (ferrochelatase is an Fe-S protein), IBA57 is not directly involved in heme biosynthesis. The primary role of IBA57 is in 4Fe-4S cluster assembly, not heme biosynthesis. Reason: This appears to be an over-annotation. IBA57 is specifically involved in 4Fe-4S cluster assembly, not heme biosynthesis. The UniProt keyword association is likely too broad. The literature consistently describes IBA57 as an Fe-S cluster assembly factor with no direct evidence for a role in heme biosynthesis. The primary pathway affected by IBA57 deficiency is Fe-S cluster biogenesis, not heme synthesis (PMID:22323289, PMID:23462291). Supporting Evidence: PMID:22323289 our data suggest that ISCA1, ISCA2, and IBA57 are specifically involved in the maturation of mitochondrial [4Fe-4S] proteins functioning late in the ISC assembly pathway |
| GO:0005515 protein binding | IPI PMID:31831856 Structural properties of [2Fe-2S] ISCA2-IBA57: a complex of ... | MODIFY | Summary: IBA57 interacts with ISCA2 to form a 2Fe-2S-bridged heterocomplex. The study (PMID:31831856) characterized the structural properties of this complex using SAXS and biophysical methods. The R146A mutation abolishes this interaction. Reason: While the protein-protein interaction is experimentally validated, protein binding is too generic. The interaction is specifically with ISCA2 and is mediated by a 2Fe-2S cluster. A more informative annotation would capture this functional aspect, such as 2 iron, 2 sulfur cluster binding (GO:0051537) given the cluster-mediated nature of the complex. Proposed replacements: 2 iron, 2 sulfur cluster binding Supporting Evidence: PMID:31831856 Specifically, the latter complex is formed in two steps: first, the [2Fe-2S] cluster is transferred from [2Fe-2S] GLRX5 to apo ISCA2 and then IBA57 interacts with [2Fe-2S] ISCA2 forming the heterodimeric [2Fe-2S] ISCA2-IBA57 complex |
| GO:0005515 protein binding | IPI PMID:33961781 Dual proteome-scale networks reveal cell-specific remodeling... | MARK AS OVER ANNOTATED | Summary: This annotation is from a large-scale interactome study. While IBA57 does engage in protein-protein interactions, this generic term provides little functional insight. Reason: Large-scale proteomics study. The protein binding term is not informative for IBA57s specific function in Fe-S cluster assembly. The interaction with ISCA2 is already captured by more specific annotations. Supporting Evidence: PMID:33961781 2021 May 6. Dual proteome-scale networks reveal cell-specific remodeling of the human interactome. |
| GO:0005515 protein binding | IPI PMID:39408793 Defects in the Maturation of Mitochondrial Iron-Sulfur Prote... | MODIFY | Summary: This annotation relates to the characterization of the MMDS3-causing G104C variant of IBA57 and its interaction with ISCA2. The study examined how this pathogenic mutation affects complex formation. Reason: The specific interaction characterized is with ISCA2 and involves 2Fe-2S cluster binding. This should be annotated more specifically rather than using the generic protein binding term. Proposed replacements: 2 iron, 2 sulfur cluster binding Supporting Evidence: PMID:39408793 the protein-protein interaction in the G104C-IBA57-[2Fe-2S]-ISCA2 heterocomplex involves less residues than in the WT-IBA57-[2Fe-2S]-ISCA2 heterocomplex, possibly weakening the complex of the mutant, which indeed appears less tight than the complex formed by the wild-type IBA57 |
| GO:0005515 protein binding | IPI PMID:40205054 Multimodal cell maps as a foundation for structural and func... | MARK AS OVER ANNOTATED | Summary: This annotation is from a multimodal cell mapping study. Generic protein binding annotation from high-throughput data. Reason: High-throughput study providing generic protein binding annotation. Not informative for the specific molecular function of IBA57 in Fe-S cluster assembly. Supporting Evidence: PMID:40205054 Apr 9. Multimodal cell maps as a foundation for structural and functional genomics. |
| GO:0005739 mitochondrion | IDA GO_REF:0000052 | ACCEPT | Summary: IDA annotation based on curation of immunofluorescence data from the Human Protein Atlas. This is direct experimental evidence for mitochondrial localization. Reason: Valid experimental evidence for mitochondrial localization from immunofluorescence studies curated by HPA. |
| GO:0005739 mitochondrion | IDA PMID:22323289 The human mitochondrial ISCA1, ISCA2, and IBA57 proteins are... | ACCEPT | Summary: The key paper from Sheftel et al. demonstrating that ISCA1, ISCA2, and IBA57 are required for 4Fe-4S protein maturation includes direct evidence for mitochondrial localization via immunofluorescence microscopy. Reason: Primary literature with direct experimental evidence for mitochondrial localization. The paper demonstrated mitochondrial localization using immunofluorescence microscopy and digitonin fractionation. Supporting Evidence: PMID:22323289 ISCA1, ISCA2, and IBA57 are localized to mitochondria |
| GO:0051604 protein maturation | NAS PMID:31831856 Structural properties of [2Fe-2S] ISCA2-IBA57: a complex of ... | MODIFY | Summary: IBA57 is involved in maturation of 4Fe-4S-containing proteins. The term protein maturation is correct but could be more specific. Reason: While IBA57 is indeed involved in protein maturation (specifically of Fe-S proteins), a more specific term would be 4Fe-4S cluster assembly (GO:0044572), which captures the precise biochemical role of IBA57 in the ISC pathway. The protein maturation term is too broad. Proposed replacements: [4Fe-4S] cluster assembly Supporting Evidence: PMID:22323289 our data suggest that ISCA1, ISCA2, and IBA57 are specifically involved in the maturation of mitochondrial [4Fe-4S] proteins functioning late in the ISC assembly pathway PMID:31831856 Structural properties of [2Fe-2S] ISCA2-IBA57: a complex of the mitochondrial iron-sulfur cluster assembly machinery. |
| GO:0005739 mitochondrion | HTP PMID:34800366 Quantitative high-confidence human mitochondrial proteome an... | ACCEPT | Summary: High-throughput proteomics study confirming mitochondrial localization as part of the high-confidence human mitochondrial proteome. Reason: While HTP evidence, this is consistent with multiple other lines of evidence confirming mitochondrial localization. Acceptable as supporting evidence. Supporting Evidence: PMID:34800366 Epub 2021 Nov 19. Quantitative high-confidence human mitochondrial proteome and its dynamics in cellular context. |
| GO:0003723 RNA binding | HDA PMID:22681889 The mRNA-bound proteome and its global occupancy profile on ... | REMOVE | Summary: This annotation comes from a high-throughput mRNA-bound proteome study that identified nearly 800 proteins in HEK293 cells. The study explicitly states that about one-third of identified proteins were not previously annotated as RNA binding. IBA57s primary established function is in Fe-S cluster assembly, with no other literature supporting an RNA binding function. Reason: This annotation is likely a false positive from high-throughput data. The Baltz et al. (2012) study was a large-scale mRNA-bound proteome analysis that identified many proteins not previously known to bind RNA. IBA57 has no known or predicted RNA-binding domain, and its well-established function is in mitochondrial 4Fe-4S cluster assembly with ISCA1/ISCA2. There is no corroborating evidence from any other study for RNA binding activity of IBA57. The domain structure (GcvT family, CAF17/IBA57 subfamily) is not consistent with RNA binding function. Supporting Evidence: PMID:22681889 nearly one-third were not previously annotated as RNA binding, and about 15% were not predictable by computational methods to interact with RNA |
| GO:0044572 [4Fe-4S] cluster assembly | IMP PMID:22323289 The human mitochondrial ISCA1, ISCA2, and IBA57 proteins are... | NEW | Summary: IBA57 specifically functions in 4Fe-4S cluster assembly as part of the late ISC machinery. This more specific term accurately captures IBA57s biochemical function. Reason: This annotation should be added based on primary literature. PMID:22323289 demonstrated that depletion of IBA57 specifically affects 4Fe-4S proteins (aconitase, complex I, lipoic acid synthase) but not 2Fe-2S proteins like ferrochelatase. The ISCA1-ISCA2-IBA57 system converts 2Fe-2S clusters to 4Fe-4S clusters. Supporting Evidence: PMID:22323289 The activities of mitochondrial [4Fe-4S] proteins, including aconitase, respiratory complex I, and lipoic acid synthase, were diminished following depletion of the three proteins |
| GO:0051537 2 iron, 2 sulfur cluster binding | IDA PMID:30269484 IBA57 Recruits ISCA2 to Form a [2Fe-2S] Cluster-Mediated Com... | NEW | Summary: IBA57 binds a 2Fe-2S cluster as part of the ISCA2-IBA57 heterocomplex. The crystal structure and biophysical studies show that Cys259 of IBA57 participates in coordinating the bridging 2Fe-2S cluster. Reason: PMID:30269484 demonstrated that IBA57 forms a 2Fe-2S-bridged complex with ISCA2, where Cys259 of IBA57 is required for cluster coordination. This is a core molecular function of IBA57. Supporting Evidence: PMID:30269484 IBA57 forms a heterodimeric complex with ISCA2 by bridging a [2Fe-2S] cluster, that [2Fe-2S] cluster binding is absolutely required to promote the complex formation |
| GO:0120510 mitochondrial [4Fe-4S] assembly complex | IDA PMID:31831856 Structural properties of [2Fe-2S] ISCA2-IBA57: a complex of ... | NEW | Summary: IBA57 is a component of the mitochondrial 4Fe-4S assembly complex along with ISCA1 and ISCA2. Complex Portal entry CPX-2503 documents the ISCA2-IBA57 complex. Reason: IBA57 functions as part of the mitochondrial 4Fe-4S assembly machinery. While the Complex Portal annotates CPX-2503 as ISCA2-IBA57 complex, IBA57 also functions with ISCA1-ISCA2 in the broader assembly context. This CC term appropriately captures IBA57s participation in this functional complex. Supporting Evidence: PMID:31831856 ISCAs and IBA57 proteins are required for the maturation of mitochondrial [4Fe-4S] proteins |
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Download this section (compressed HTML)Q: What is the precise mechanism by which the ISCA1-ISCA2-IBA57 complex converts two 2Fe-2S clusters into a 4Fe-4S cluster?
Q: Does IBA57 have additional roles beyond its function with ISCA proteins in 4Fe-4S cluster maturation?
Experiment: Structural characterization of the complete ISCA1-ISCA2-IBA57 complex to understand the reductive coupling mechanism
Experiment: Identification of direct client proteins that receive 4Fe-4S clusters from the ISCA-IBA57 machinery
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