Existing Annotations Review

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

Core Functions

IBA57 forms a 2Fe-2S-bridged heterocomplex with ISCA2. Structural and biophysical studies demonstrate that Cys259 of IBA57 coordinates the bridging 2Fe-2S cluster (PMID:30269484). The C259A mutation abolishes complex formation. The 2Fe-2S cluster serves as an intermediate in 4Fe-4S cluster assembly through a reductive coupling mechanism with ISCA1 and ISCA2.

Molecular Function:

2 iron, 2 sulfur cluster binding

Directly Involved In:

[4Fe-4S] cluster assembly

Cellular Locations:

mitochondrial matrix

In Complex:

mitochondrial [4Fe-4S] assembly complex

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:30269484
[2Fe-2S] cluster binding is absolutely required to promote the complex formation
PMID:31831856
a structural organization of dimer of dimers for the [2Fe-2S]2+ ISCA2-IBA57 complex

References

GO_REF:0000033

Annotation inferences using phylogenetic trees

GO_REF:0000043

Gene Ontology annotation based on UniProtKB/Swiss-Prot keyword mapping

GO_REF:0000044

Gene Ontology annotation based on UniProtKB/Swiss-Prot Subcellular Location vocabulary mapping

GO_REF:0000052

Gene Ontology annotation based on curation of immunofluorescence data

PMID:22323289

The human mitochondrial ISCA1, ISCA2, and IBA57 proteins are required for [4Fe-4S] protein maturation.

IBA57 localizes to mitochondria

"ISCA1, ISCA2, and IBA57 are localized to mitochondria"
Depletion of IBA57 specifically affects mitochondrial 4Fe-4S proteins

"The activities of mitochondrial [4Fe-4S] proteins, including aconitase, respiratory complex I, and lipoic acid synthase, were diminished following depletion of the three proteins"
Affected proteins include aconitase, respiratory complex I, and lipoic acid synthase

"The activities of mitochondrial [4Fe-4S] proteins, including aconitase, respiratory complex I, and lipoic acid synthase, were diminished following depletion of the three proteins"
Ferrochelatase (a 2Fe-2S protein) is not affected by IBA57 depletion

"the mitochondrial [2Fe-2S] enzyme ferrochelatase and cellular heme content were unaffected"

PMID:22681889

The mRNA-bound proteome and its global occupancy profile on protein-coding transcripts.

High-throughput screen identified many proteins not previously known to bind RNA

"nearly one-third were not previously annotated as RNA binding"
Many hits may not represent physiological RNA-binding functions

"about 15% were not predictable by computational methods to interact with RNA"

PMID:23462291

Mutation of the iron-sulfur cluster assembly gene IBA57 causes severe myopathy and encephalopathy.

IBA57 mutations cause MMDS3
Patients show deficiency of respiratory chain complexes and lipoylation defects

PMID:30269484

IBA57 Recruits ISCA2 to Form a [2Fe-2S] Cluster-Mediated Complex.

IBA57 forms a 2Fe-2S-bridged complex with ISCA2

"IBA57 forms a heterodimeric complex with ISCA2 by bridging a [2Fe-2S] cluster"
Cys259 of IBA57 is required for cluster coordination

"the cysteine of the conserved motif characterizing IBA57 protein family and the three conserved cysteines of the ISCA protein family act as cluster ligands"
Crystal structure at 1.55 A resolution

PMID:31831856

Structural properties of [2Fe-2S] ISCA2-IBA57: a complex of the mitochondrial iron-sulfur cluster assembly machinery.

ISCA2-IBA57 forms a dimer of dimers structure

"a structural organization of dimer of dimers for the [2Fe-2S]2+ ISCA2-IBA57 complex with ISCA2 providing the homodimerization core interface"
R146 of IBA57 is critical for interaction with ISCA2

"the pathogenic mutation Arg146Trp in IBA57"
The 2Fe-2S cluster is shared between ISCA2 and IBA57

"The [2Fe-2S] cluster is out of the ISCA2 core while being shared with IBA57"

PMID:33961781

Dual proteome-scale networks reveal cell-specific remodeling of the human interactome.

PMID:34800366

Quantitative high-confidence human mitochondrial proteome and its dynamics in cellular context.

IBA57 confirmed as part of high-confidence mitochondrial proteome

PMID:39408793

Defects in the Maturation of Mitochondrial Iron-Sulfur Proteins: Biophysical Investigation of the MMDS3 Causing Gly104Cys Variant of IBA57.

G104C pathogenic variant destabilizes ISCA2-IBA57 complex

"the G104C-IBA57 mutant has a lower conformational stability than WT-IBA57"
Does not completely abolish complex formation

"G104C Mutation of IBA57 Does Not Impair the Interaction with ISCA2 upon [2Fe-2S] Cluster Binding"

PMID:40205054

Multimodal cell maps as a foundation for structural and functional genomics.

file:human/IBA57/IBA57-deep-research-falcon.md

Deep research report on IBA57

Suggested Experiments

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

📚 Additional Documentation

Deep Research Falcon

(IBA57-deep-research-falcon.md)

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gene_id: IBA57
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AltName: Full=Iron-sulfur cluster assembly factor homolog; Flags: Precursor;'
gene_info: Name=IBA57; Synonyms=C1orf69;
organism_full: Homo sapiens (Human).
protein_family: Belongs to the GcvT family. CAF17/IBA57 subfamily.
protein_domains: TrmE/GcvT_dom1. (IPR027266); YgfZ/GcvT. (IPR045179); YgfZ/GcvT_CS.
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Question

Gene Research for Functional Annotation

⚠️ CRITICAL: Gene/Protein Identification Context

BEFORE YOU BEGIN RESEARCH: You MUST verify you are researching the CORRECT gene/protein. Gene symbols can be ambiguous, especially for less well-characterized genes from non-model organisms.

Target Gene/Protein Identity (from UniProt):

UniProt Accession: Q5T440
Protein Description: RecName: Full=Iron-sulfur cluster assembly factor IBA57, mitochondrial; AltName: Full=Iron-sulfur cluster assembly factor homolog; Flags: Precursor;
Gene Information: Name=IBA57; Synonyms=C1orf69;
Organism (full): Homo sapiens (Human).
Protein Family: Belongs to the GcvT family. CAF17/IBA57 subfamily.
Key Domains: TrmE/GcvT_dom1. (IPR027266); YgfZ/GcvT. (IPR045179); YgfZ/GcvT_CS. (IPR017703); Beta-barrel_CAF17_C (PF25455)

MANDATORY VERIFICATION STEPS:

Check if the gene symbol "IBA57" matches the protein description above
Verify the organism is correct: Homo sapiens (Human).
Check if protein family/domains align with what you find in literature
If you find literature for a DIFFERENT gene with the same or similar symbol, STOP

If Gene Symbol is Ambiguous or You Cannot Find Relevant Literature:

DO NOT PROCEED WITH RESEARCH ON A DIFFERENT GENE. Instead:
- State clearly: "The gene symbol 'IBA57' is ambiguous or literature is limited for this specific protein"
- Explain what you found (e.g., "Found extensive literature on a different gene with the same symbol in a different organism")
- Describe the protein based ONLY on the UniProt information provided above
- Suggest that the protein function can be inferred from domain/family information

Research Target:

Please provide a comprehensive research report on the gene IBA57 (gene ID: IBA57, UniProt: Q5T440) in human.

The research report should be a detailed narrative explaining the function, biological processes, and localization of the gene product. Citations should be given for all claims.

You should prioritize authoritative reviews and primary scientific literature when conducting research. You can supplement
this with annotations you find in gene/protein databases, but these can be outdated or inaccurate.

We are specifically interested in the primary function of the gene - for enzymes, what reaction is catalyzed, and what is the substrate specificity? For transporters, what is the substrate? For structural proteins or adapters, what is the broader structural role? For signaling molecules, what is the role in the pathway.

We are interested in where in or outside the cell the gene product carries out its function.

We are also interested in the signaling or biochemical pathways in which the gene functions. We are less interested in broad pleiotropic effects, except where these elucidate the precise role.

Include evidence where possible. We are interested in both experimental evidence as well as inference from structure, evolution, or bioinformatic analysis. Precise studies should be prioritized over high-throughput, where available.

Output

Question: You are an expert researcher providing comprehensive, well-cited information.

Provide detailed information focusing on:
1. Key concepts and definitions with current understanding
2. Recent developments and latest research (prioritize 2023-2024 sources)
3. Current applications and real-world implementations
4. Expert opinions and analysis from authoritative sources
5. Relevant statistics and data from recent studies

Format as a comprehensive research report with proper citations. Include URLs and publication dates where available.
Always prioritize recent, authoritative sources and provide specific citations for all major claims.

Gene Research for Functional Annotation

⚠️ CRITICAL: Gene/Protein Identification Context

BEFORE YOU BEGIN RESEARCH: You MUST verify you are researching the CORRECT gene/protein. Gene symbols can be ambiguous, especially for less well-characterized genes from non-model organisms.

Target Gene/Protein Identity (from UniProt):

UniProt Accession: Q5T440
Protein Description: RecName: Full=Iron-sulfur cluster assembly factor IBA57, mitochondrial; AltName: Full=Iron-sulfur cluster assembly factor homolog; Flags: Precursor;
Gene Information: Name=IBA57; Synonyms=C1orf69;
Organism (full): Homo sapiens (Human).
Protein Family: Belongs to the GcvT family. CAF17/IBA57 subfamily.
Key Domains: TrmE/GcvT_dom1. (IPR027266); YgfZ/GcvT. (IPR045179); YgfZ/GcvT_CS. (IPR017703); Beta-barrel_CAF17_C (PF25455)

MANDATORY VERIFICATION STEPS:

Check if the gene symbol "IBA57" matches the protein description above
Verify the organism is correct: Homo sapiens (Human).
Check if protein family/domains align with what you find in literature
If you find literature for a DIFFERENT gene with the same or similar symbol, STOP

If Gene Symbol is Ambiguous or You Cannot Find Relevant Literature:

Research Target:

Please provide a comprehensive research report on the gene IBA57 (gene ID: IBA57, UniProt: Q5T440) in human.

The research report should be a detailed narrative explaining the function, biological processes, and localization of the gene product. Citations should be given for all claims.

We are interested in where in or outside the cell the gene product carries out its function.

We are also interested in the signaling or biochemical pathways in which the gene functions. We are less interested in broad pleiotropic effects, except where these elucidate the precise role.

Plan and verification
- We verified the target as human IBA57, mitochondrial iron–sulfur cluster assembly factor (UniProt Q5T440), a nuclear-encoded mitochondrial protein functioning in the ISC pathway. Literature confirms its mitochondrial localization and role as a late-acting assembly factor for [4Fe-4S] protein maturation, consistent with the user-provided identity and domains context (CAF17/IBA57 subfamily) (bargagna2024molecularpathwaysfora pages 70-71, bargagna2024molecularpathwaysfora pages 16-20).

Key concepts and definitions
- Primary function and biochemical role: IBA57 is a late-acting mitochondrial iron–sulfur (Fe–S) cluster assembly factor required for maturation of mitochondrial [4Fe-4S] proteins; it is not a classical enzyme but acts within a protein network that converts [2Fe-2S] to [4Fe-4S] clusters (assembly factor rather than catalyst) (Bargagna 2024, Int. J. Mol. Sci., 28 Sep 2024, DOI: 10.3390/ijms251910466) (bargagna2024molecularpathwaysfora pages 70-71, bargagna2024molecularpathwaysfora pages 16-20).
- Pathway positioning: In the human mitochondrial ISC pathway, de novo [2Fe-2S] is formed upstream (ISCU2/NFS1/ISD11/ACP1/FXN) and transferred by GLRX5. IBA57 functions downstream with ISCA1–ISCA2 during the late step that converts two GLRX5-derived [2Fe-2S] clusters into a [4Fe-4S] cluster; electron input is provided by the mitochondrial ferredoxin system (FDX2–FDXR) (bargagna2024molecularpathwaysfora pages 70-71, bargagna2024molecularpathwaysfor pages 70-71, bargagna2024molecularpathwaysfora pages 76-77).
- Interaction partners and complex: (i) ISCA1–ISCA2 heterocomplex forms the scaffold for [4Fe-4S] assembly; (ii) IBA57 interacts directly with ISCA2 to form a heterocomplex bearing a [2Fe-2S] intermediate, supporting a reductive coupling mechanism; (iii) GLRX5 donates [2Fe-2S] to the ISCA scaffold; (iv) FDX2–FDXR supplies electrons. These relationships place IBA57 specifically at the late ISC conversion step (bargagna2024molecularpathwaysfora pages 63-70, bargagna2024molecularpathwaysfora pages 70-71, bargagna2024molecularpathwaysfor pages 70-71, bargagna2024molecularpathwaysfora pages 76-77).
- Subcellular localization: Mitochondria (matrix/inner compartment), functioning within the mitochondrial ISC machinery (bargagna2024molecularpathwaysfora pages 70-71, bargagna2024molecularpathwaysfora pages 16-20).

Mechanistic models and structural/biophysical insights
- Reductive coupling on ISCA1–ISCA2–IBA57: Biophysical data (NMR, SEC, CD) show IBA57 partners with ISCA2 in a [2Fe-2S]–ISCA2–IBA57 heterocomplex, consistent with handling of [2Fe-2S] intermediates en route to [4Fe-4S] assembly on ISCA1–ISCA2. Pathogenic IBA57 G104C does not abolish complex formation but weakens and destabilizes interactions, rationalizing loss of function (Bargagna 2024; DOI: 10.3390/ijms251910466) (bargagna2024molecularpathwaysfora pages 63-70, bargagna2024molecularpathwaysfor pages 76-77, bargagna2024molecularpathwaysfora pages 76-77).
- Specific residue context: Gly104 lies in a solvent-exposed loop of the IBA57 B-domain and is near Cys259 implicated in ligation within the [2Fe-2S]–ISCA2–IBA57 complex; substitution by Cys perturbs local interactions and reduces complex tightness despite preserving the overall fold (bargagna2024molecularpathwaysfora pages 63-70, bargagna2024molecularpathwaysfor pages 76-77, bargagna2024molecularpathwaysfora pages 76-77).

Downstream targets and cellular phenotypes of IBA57 deficiency
- IBA57 depletion or pathogenic variants diminish activities of mitochondrial [4Fe-4S]–dependent proteins: respiratory chain complexes I and II, mitochondrial aconitase, and succinate dehydrogenase; they also impair lipoic acid synthase (LIAS), causing reduced lipoylation of PDH, KGDH, and GCSH (Bargagna 2024; Mandigers 2023, Front. Genet., 12 Jul 2023, DOI: 10.3389/fgene.2023.1190222) (bargagna2024molecularpathwaysfora pages 70-71, bargagna2024molecularpathwaysfora pages 16-20, mandigers2023anoveliba57 pages 1-2).

Disease links and recent clinical data (2023–2024 priority)
- Multiple mitochondrial dysfunctions syndrome 3 (MMDS3; OMIM 615330): Autosomal recessive disorder due to biallelic IBA57 variants, characterized by a range of neurodevelopmental phenotypes and leukoencephalopathy, biochemical deficits in complex I/II and lipoylation, and impaired [4Fe-4S] maturation; ≈36 pathogenic IBA57 variants reported through 2024 (Bargagna 2024; DOI: 10.3390/ijms251910466) (bargagna2024molecularpathwaysfora pages 16-20, bargagna2024molecularpathwaysfora pages 70-71).
- 2023–2025 cohort update: A 2025 cohort analysis aggregating literature and 11 Chinese patients (total ~61 patients) identified c.286T>C as a hotspot in Chinese patients (≈85.2% in that subgroup) and reported >90% 5‑year survival in this subgroup, indicating genotype–phenotype variability and relatively stable natural history for that allele (Jiang 2025; database search up to Dec 2023) (jiang2025phenotypicspectrumofa pages 1-5).
- Comparative in vivo evidence: A canine IBA57 missense variant (R147W) underlies necrotizing myelopathy; humanized complementation assays showed only partial rescue of mitochondrial [4Fe-4S] protein defects with this variant, supporting pathogenic impairment of the late ISC step and reinforcing cross-species functional conservation (Front. Genet., 12 Jul 2023, DOI: 10.3389/fgene.2023.1190222) (mandigers2023anoveliba57 pages 1-2).

Current applications and implementations
- Diagnostics: Recognition of the IBA57 late-ISC role and its characteristic biochemical signature (complex I/II deficiency, decreased aconitase, hypo-lipoylation of PDH/KGDH) guides molecular testing panels for leukoencephalopathy/MMDS, variant interpretation (e.g., G104C), and prognosis stratification where genotype–phenotype data (e.g., c.286T>C hotspot) are available (bargagna2024molecularpathwaysfora pages 70-71, bargagna2024molecularpathwaysfora pages 16-20, jiang2025phenotypicspectrumofa pages 1-5).
- Functional validation: Cell-based complementation in IBA57-depleted human cells is used to assess variant pathogenicity (e.g., partial rescue by R147W), linking genotype to mitochondrial [4Fe-4S] target activities (mandigers2023anoveliba57 pages 1-2).

Expert opinions and authoritative reviews
- Comprehensive review (2024): Bargagna et al. synthesize human mitochondrial/cytosolic Fe–S maturation, positioning IBA57 with ISCA1/2 in the late [4Fe-4S] assembly step, summarizing interaction evidence, variant effects, and disease phenotypes (Int. J. Mol. Sci., 28 Sep 2024, DOI: 10.3390/ijms251910466) (bargagna2024molecularpathwaysfora pages 70-71, bargagna2024molecularpathwaysfor pages 70-71, bargagna2024molecularpathwaysfora pages 63-70, bargagna2024molecularpathwaysfora pages 16-20, bargagna2024molecularpathwaysfora pages 76-77).

Relevant statistics and data from recent studies
- Variant catalog: ≈36 pathogenic IBA57 variants (as of 2024) (bargagna2024molecularpathwaysfora pages 16-20).
- Cohort genetics: In a Chinese cohort, c.286T>C represented ~85.2% of IBA57 variants; aggregated patient count ~61; subgroup 5‑year survival >90% (data compiled up to Dec 2023) (jiang2025phenotypicspectrumofa pages 1-5).
- Functional impact: IBA57 deficiency reduces activities of complex I/II, aconitase, and lipoylation-dependent enzymes in human cells and models (bargagna2024molecularpathwaysfora pages 70-71, mandigers2023anoveliba57 pages 1-2, bargagna2024molecularpathwaysfora pages 16-20).

Identity, localization, function, interactions, disease summary (concise)
| Aspect | Summary | Key details/data | Recent sources (year, URL/DOI) | Citations (IDs) |
|---|---|---|---|---|
| Identity verification | Human IBA57 (UniProt Q5T440) — nuclear-encoded mitochondrial protein, also known as C1orf69. | Matches UniProt entry and literature descriptions as the human IBA57 mitochondrial Fe–S assembly factor. | Bargagna et al., 2024 (Int. J. Mol. Sci.; DOI: 10.3390/ijms251910466; published 28 Sep 2024) | (bargagna2024molecularpathwaysfora pages 70-71) |
| Subcellular localization | Mitochondrial matrix / inner mitochondrial compartment. | Localizes to mitochondria and functions within mitochondrial ISC machinery. | Bargagna et al., 2024 (DOI: 10.3390/ijms251910466) | (bargagna2024molecularpathwaysfora pages 70-71, bargagna2024molecularpathwaysfora pages 16-20) |
| Molecular function | Assembly factor (non-enzymatic) for maturation of [4Fe-4S] proteins. | Acts as a late-acting Fe–S cluster assembly factor (not a classical enzyme); required for [4Fe-4S] protein maturation. | Bargagna et al., 2024 (DOI: 10.3390/ijms251910466) | (bargagna2024molecularpathwaysfora pages 70-71, bargagna2024molecularpathwaysfora pages 16-20) |
| Pathway position in ISC | Late-stage mitochondrial ISC pathway: conversion/reductive coupling of [2Fe-2S] → [4Fe-4S]. | Receives GLRX5-derived [2Fe-2S] intermediates and cooperates with ISCA1/ISCA2 to generate [4Fe-4S] clusters; electron input provided by FDX2–FDXR system upstream. | Bargagna et al., 2024 (DOI: 10.3390/ijms251910466); Steinhilper et al. structural context (2024/2025) | (bargagna2024molecularpathwaysfora pages 70-71, bargagna2024molecularpathwaysfora pages 76-77) |
| Key interaction partners | ISCA2 (direct evidence), ISCA1 (functional/complex context), GLRX5 (donor), FDX2/FDXR (electron supply); NFU1/BOLA3 noted in late-ISC network. | Biophysical and complex-formation data show ISCA2–IBA57 heterocomplex with [2Fe-2S] intermediate; ISCA1–ISCA2 act as [4Fe-4S] assembler; NFU1/BOLA3 operate in adjacent late-ISC nodes. | Bargagna et al., 2024 (DOI: 10.3390/ijms251910466); Mandigers et al., 2023 (Front. Genet.; DOI: 10.3389/fgene.2023.1190222) | (bargagna2024molecularpathwaysfora pages 63-70, mandigers2023anoveliba57 pages 1-2) |
| Mechanistic model | Reductive coupling on ISCA1–ISCA2–IBA57 scaffold: ISCA proteins accept two [2Fe-2S] from GLRX5, IBA57 (with ISCA2) participates in handling the intermediate; FDX2–FDXR provides electrons for reductive fusion → [4Fe-4S]. | NMR/SEC and CD support formation of a [2Fe-2S]–ISCA2–IBA57 heterocomplex; pathogenic Gly104Cys perturbs this interaction and destabilizes IBA57, impairing cluster maturation. | Bargagna et al., 2024 (DOI: 10.3390/ijms251910466) | (bargagna2024molecularpathwaysfora pages 63-70, bargagna2024molecularpathwaysfor pages 76-77, bargagna2024molecularpathwaysfora pages 76-77) |
| Affected mitochondrial targets when deficient | Decreased activities of mitochondrial [4Fe-4S]-dependent proteins and lipoylation pathway enzymes. | Reduced complex I & II activities, decreased aconitase and succinate dehydrogenase activity, impaired lipoic acid synthase (LIAS) leading to hypo-lipoylation of PDH/KGDH/GCSH. | Bargagna et al., 2024; Mandigers et al., 2023 | (bargagna2024molecularpathwaysfora pages 70-71, mandigers2023anoveliba57 pages 1-2, bargagna2024molecularpathwaysfora pages 16-20) |
| Human disease links | Multiple mitochondrial dysfunctions syndrome 3 (MMDS3); overlapping phenotypes including leukoencephalopathy and spastic paraplegia (SPG74 reported in literature). | MMDS3: autosomal recessive, pediatric leukoencephalopathy, respiratory-chain defects; pathogenic variants (~36 reported) linked to loss of [4Fe-4S] maturation. | Bargagna et al., 2024 (DOI: 10.3390/ijms251910466) | (bargagna2024molecularpathwaysfora pages 16-20, bargagna2024molecularpathwaysfora pages 70-71) |
| Recent cohort data / variant statistics | Reported pathogenic variant count ≈36; Chinese cohort reports c.286T>C hotspot (~85.2% in that cohort) with favorable 5-year survival >90% in subgroup. | Jiang et al., 2025 aggregated cohort (11 Chinese patients + literature → total ~61 patients); c.286T>C identified as a hotspot (85.2% in the Chinese subgroup); overall variable severity and survival by genotype. | Jiang et al., 2025 (cohort analysis; no DOI in provided excerpt) | (jiang2025phenotypicspectrumofa pages 1-5) |
| Key recent sources (representative) | Primary mechanistic/biophysical and comparative in vivo evidence and cohort data. | Bargagna B., Int. J. Mol. Sci., 2024 (DOI: 10.3390/ijms251910466); Mandigers P.J.J. et al., Front. Genet., 2023 (DOI: 10.3389/fgene.2023.1190222); Jiang H. et al., 2025 (cohort paper). | Bargagna 2024 (DOI: 10.3390/ijms251910466); Mandigers 2023 (DOI: 10.3389/fgene.2023.1190222); Jiang 2025 (cohort) | (bargagna2024molecularpathwaysfora pages 70-71, mandigers2023anoveliba57 pages 1-2, jiang2025phenotypicspectrumofa pages 1-5) |

Table: Concise, literature-backed summary of human IBA57 (Q5T440) covering identity, localization, molecular role in mitochondrial Fe–S cluster assembly, partners/mechanism, functional consequences of deficiency, disease links, and key recent sources; citations map claims to gathered evidence IDs.

Notes on nomenclature and family/domains
- The literature consistently refers to human IBA57 as a mitochondrial late-ISC assembly factor that partners with ISCA1/2 for [4Fe-4S] maturation. Structural/biophysical analyses emphasize the ISCA2–IBA57 heterocomplex and pathogenic destabilization by G104C. While UniProt classifies IBA57 within the CAF17/IBA57 subfamily and notes homology to bacterial YgfZ/GcvT-like proteins, the gathered 2023–2024 sources above focus primarily on its mitochondrial ISC role; domain-specific assertions beyond these mechanistic data are therefore limited to avoid overreach (bargagna2024molecularpathwaysfora pages 70-71, bargagna2024molecularpathwaysfora pages 63-70, bargagna2024molecularpathwaysfora pages 76-77).

Full source details with URLs and dates
- Bargagna B. Molecular pathways for the maturation of mitochondrial and cytosolic human Fe–S proteins. International Journal of Molecular Sciences. Published 28 Sep 2024. DOI: 10.3390/ijms251910466. URL: https://doi.org/10.3390/ijms251910466 (bargagna2024molecularpathwaysfora pages 70-71, bargagna2024molecularpathwaysfor pages 70-71, bargagna2024molecularpathwaysfora pages 63-70, bargagna2024molecularpathwaysfor pages 76-77, bargagna2024molecularpathwaysfora pages 16-20, bargagna2024molecularpathwaysfora pages 76-77).
- Mandigers PJJ, Stehling O, Vos-Loohuis M, van Steenbeek FG, Lill R, Leegwater PA. A novel IBA57 variant is associated with mitochondrial iron–sulfur protein deficiency and necrotizing myelopathy in dogs. Frontiers in Genetics. Published 12 Jul 2023. DOI: 10.3389/fgene.2023.1190222. URL: https://doi.org/10.3389/fgene.2023.1190222 (mandigers2023anoveliba57 pages 1-2).
- Jiang H, Xu C, Duan R, Liu Z, Ren X, Li J. Phenotypic spectrum of iron–sulfur cluster assembly gene IBA57 mutations: c.286T>C identified as a hotspot mutation in Chinese patients with a stable natural history. Literature aggregated up to Dec 2023; published 2025. URL/DOI not provided in the excerpt (jiang2025phenotypicspectrumofa pages 1-5).

Conclusion
Human IBA57 (Q5T440) is a mitochondrial late-acting Fe–S assembly factor that collaborates with ISCA1/2 to convert GLRX5-delivered [2Fe-2S] into [4Fe-4S] clusters, with FDX2–FDXR supplying electrons. Direct ISCA2–IBA57 complex formation underlies a mechanistic model of reductive coupling; pathogenic variants (e.g., G104C) destabilize this process. Deficiency impairs respiratory complexes I/II, aconitase, and lipoic acid synthesis, producing MMDS3 and related phenotypes. Recent reviews and studies (2023–2024) consolidate these insights and provide expanding variant catalogs and cohort statistics that inform diagnosis and prognosis (bargagna2024molecularpathwaysfora pages 70-71, bargagna2024molecularpathwaysfora pages 63-70, bargagna2024molecularpathwaysfor pages 76-77, bargagna2024molecularpathwaysfora pages 16-20, mandigers2023anoveliba57 pages 1-2, jiang2025phenotypicspectrumofa pages 1-5).

References

(bargagna2024molecularpathwaysfora pages 70-71): B Bargagna. Molecular pathways for the maturation of mitochondrial and cytosolic human fe-s proteins. Unknown journal, 2024.
(bargagna2024molecularpathwaysfora pages 16-20): B Bargagna. Molecular pathways for the maturation of mitochondrial and cytosolic human fe-s proteins. Unknown journal, 2024.
(bargagna2024molecularpathwaysfor pages 70-71): B Bargagna. Molecular pathways for the maturation of mitochondrial and cytosolic human fe-s proteins. Unknown journal, 2024.
(bargagna2024molecularpathwaysfora pages 76-77): B Bargagna. Molecular pathways for the maturation of mitochondrial and cytosolic human fe-s proteins. Unknown journal, 2024.
(bargagna2024molecularpathwaysfora pages 63-70): B Bargagna. Molecular pathways for the maturation of mitochondrial and cytosolic human fe-s proteins. Unknown journal, 2024.
(bargagna2024molecularpathwaysfor pages 76-77): B Bargagna. Molecular pathways for the maturation of mitochondrial and cytosolic human fe-s proteins. Unknown journal, 2024.
(mandigers2023anoveliba57 pages 1-2): Paul J. J. Mandigers, Oliver Stehling, Manon Vos-Loohuis, Frank G. Van Steenbeek, Roland Lill, and Peter A. Leegwater. A novel iba57 variant is associated with mitochondrial iron–sulfur protein deficiency and necrotizing myelopathy in dogs. Frontiers in Genetics, Jul 2023. URL: https://doi.org/10.3389/fgene.2023.1190222, doi:10.3389/fgene.2023.1190222. This article has 9 citations and is from a peer-reviewed journal.
(jiang2025phenotypicspectrumofa pages 1-5): H Jiang, C Xu, R Duan, Z Liu, X Ren, and J Li. Phenotypic spectrum of iron-sulfur cluster assembly gene iba57 mutations: c. 286 t> c identified as a hotspot mutation in chinese patients with a stable natural …. Unknown journal, 2025.

Citations

jiang2025phenotypicspectrumofa pages 1-5
bargagna2024molecularpathwaysfora pages 16-20
bargagna2024molecularpathwaysfora pages 70-71
bargagna2024molecularpathwaysfor pages 70-71
bargagna2024molecularpathwaysfora pages 76-77
bargagna2024molecularpathwaysfora pages 63-70
bargagna2024molecularpathwaysfor pages 76-77
4Fe-4S
2Fe-2S
https://doi.org/10.3390/ijms251910466
https://doi.org/10.3389/fgene.2023.1190222
https://doi.org/10.3389/fgene.2023.1190222,

📄 View Raw YAML

id: Q5T440
gene_symbol: IBA57
product_type: PROTEIN
status: COMPLETE
taxon:
  id: NCBITaxon:9606
  label: Homo sapiens
description: 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.
existing_annotations:
  - term:
      id: GO:0005759
      label: mitochondrial matrix
    evidence_type: IBA
    original_reference_id: GO_REF:0000033
    review:
      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.
      action: ACCEPT
      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.
      supported_by:
        - reference_id: PMID:22323289
          supporting_text: ISCA1, ISCA2, and IBA57 are localized to mitochondria
        - reference_id: file:human/IBA57/IBA57-deep-research-falcon.md
          supporting_text: 'model: Edison Scientific Literature'
  - term:
      id: GO:0005739
      label: mitochondrion
    evidence_type: IEA
    original_reference_id: GO_REF:0000044
    review:
      summary: IEA annotation based on UniProt subcellular location mapping. 
        While correct, this is less specific than the IBA annotation to 
        mitochondrial matrix (GO:0005759).
      action: ACCEPT
      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.
  - term:
      id: GO:0006783
      label: heme biosynthetic process
    evidence_type: IEA
    original_reference_id: GO_REF:0000043
    review:
      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.
      action: REMOVE
      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).
      supported_by:
        - reference_id: PMID:22323289
          supporting_text: 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
  - term:
      id: GO:0005515
      label: protein binding
    evidence_type: IPI
    original_reference_id: PMID:31831856
    review:
      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.
      action: MODIFY
      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_replacement_terms:
        - id: GO:0051537
          label: 2 iron, 2 sulfur cluster binding
      supported_by:
        - reference_id: PMID:31831856
          supporting_text: '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'
  - term:
      id: GO:0005515
      label: protein binding
    evidence_type: IPI
    original_reference_id: PMID:33961781
    review:
      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.
      action: MARK_AS_OVER_ANNOTATED
      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.
      supported_by:
        - reference_id: PMID:33961781
          supporting_text: 2021 May 6. Dual proteome-scale networks reveal 
            cell-specific remodeling of the human interactome.
  - term:
      id: GO:0005515
      label: protein binding
    evidence_type: IPI
    original_reference_id: PMID:39408793
    review:
      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.
      action: MODIFY
      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_replacement_terms:
        - id: GO:0051537
          label: 2 iron, 2 sulfur cluster binding
      supported_by:
        - reference_id: PMID:39408793
          supporting_text: 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
  - term:
      id: GO:0005515
      label: protein binding
    evidence_type: IPI
    original_reference_id: PMID:40205054
    review:
      summary: This annotation is from a multimodal cell mapping study. Generic 
        protein binding annotation from high-throughput data.
      action: MARK_AS_OVER_ANNOTATED
      reason: High-throughput study providing generic protein binding 
        annotation. Not informative for the specific molecular function of IBA57
        in Fe-S cluster assembly.
      supported_by:
        - reference_id: PMID:40205054
          supporting_text: Apr 9. Multimodal cell maps as a foundation for 
            structural and functional genomics.
  - term:
      id: GO:0005739
      label: mitochondrion
    evidence_type: IDA
    original_reference_id: GO_REF:0000052
    review:
      summary: IDA annotation based on curation of immunofluorescence data from 
        the Human Protein Atlas. This is direct experimental evidence for 
        mitochondrial localization.
      action: ACCEPT
      reason: Valid experimental evidence for mitochondrial localization from 
        immunofluorescence studies curated by HPA.
  - term:
      id: GO:0005739
      label: mitochondrion
    evidence_type: IDA
    original_reference_id: PMID:22323289
    review:
      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.
      action: ACCEPT
      reason: Primary literature with direct experimental evidence for 
        mitochondrial localization. The paper demonstrated mitochondrial 
        localization using immunofluorescence microscopy and digitonin 
        fractionation.
      supported_by:
        - reference_id: PMID:22323289
          supporting_text: ISCA1, ISCA2, and IBA57 are localized to mitochondria
  - term:
      id: GO:0051604
      label: protein maturation
    evidence_type: NAS
    original_reference_id: PMID:31831856
    review:
      summary: IBA57 is involved in maturation of 4Fe-4S-containing proteins. 
        The term protein maturation is correct but could be more specific.
      action: MODIFY
      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_replacement_terms:
        - id: GO:0044572
          label: '[4Fe-4S] cluster assembly'
      supported_by:
        - reference_id: PMID:22323289
          supporting_text: 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
        - reference_id: PMID:31831856
          supporting_text: 'Structural properties of [2Fe-2S] ISCA2-IBA57: a complex
            of the mitochondrial iron-sulfur cluster assembly machinery.'
  - term:
      id: GO:0005739
      label: mitochondrion
    evidence_type: HTP
    original_reference_id: PMID:34800366
    review:
      summary: High-throughput proteomics study confirming mitochondrial 
        localization as part of the high-confidence human mitochondrial 
        proteome.
      action: ACCEPT
      reason: While HTP evidence, this is consistent with multiple other lines 
        of evidence confirming mitochondrial localization. Acceptable as 
        supporting evidence.
      supported_by:
        - reference_id: PMID:34800366
          supporting_text: Epub 2021 Nov 19. Quantitative high-confidence human 
            mitochondrial proteome and its dynamics in cellular context.
  - term:
      id: GO:0003723
      label: RNA binding
    evidence_type: HDA
    original_reference_id: PMID:22681889
    review:
      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.
      action: REMOVE
      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.
      supported_by:
        - reference_id: PMID:22681889
          supporting_text: nearly one-third were not previously annotated as RNA
            binding, and about 15% were not predictable by computational methods
            to interact with RNA
  - term:
      id: GO:0044572
      label: '[4Fe-4S] cluster assembly'
    evidence_type: IMP
    original_reference_id: PMID:22323289
    review:
      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.
      action: NEW
      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.
      supported_by:
        - reference_id: PMID:22323289
          supporting_text: The activities of mitochondrial [4Fe-4S] proteins, 
            including aconitase, respiratory complex I, and lipoic acid 
            synthase, were diminished following depletion of the three proteins
  - term:
      id: GO:0051537
      label: 2 iron, 2 sulfur cluster binding
    evidence_type: IDA
    original_reference_id: PMID:30269484
    review:
      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.
      action: NEW
      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.
      supported_by:
        - reference_id: PMID:30269484
          supporting_text: 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
  - term:
      id: GO:0120510
      label: mitochondrial [4Fe-4S] assembly complex
    evidence_type: IDA
    original_reference_id: PMID:31831856
    review:
      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.
      action: NEW
      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.
      supported_by:
        - reference_id: PMID:31831856
          supporting_text: ISCAs and IBA57 proteins are required for the 
            maturation of mitochondrial [4Fe-4S] proteins
references:
  - id: GO_REF:0000033
    title: Annotation inferences using phylogenetic trees
    findings: []
  - id: GO_REF:0000043
    title: Gene Ontology annotation based on UniProtKB/Swiss-Prot keyword 
      mapping
    findings: []
  - id: GO_REF:0000044
    title: Gene Ontology annotation based on UniProtKB/Swiss-Prot Subcellular 
      Location vocabulary mapping
    findings: []
  - id: GO_REF:0000052
    title: Gene Ontology annotation based on curation of immunofluorescence data
    findings: []
  - id: PMID:22323289
    title: The human mitochondrial ISCA1, ISCA2, and IBA57 proteins are required
      for [4Fe-4S] protein maturation.
    findings:
      - statement: IBA57 localizes to mitochondria
        supporting_text: ISCA1, ISCA2, and IBA57 are localized to mitochondria
      - statement: Depletion of IBA57 specifically affects mitochondrial 4Fe-4S 
          proteins
        supporting_text: The activities of mitochondrial [4Fe-4S] proteins, 
          including aconitase, respiratory complex I, and lipoic acid synthase, 
          were diminished following depletion of the three proteins
      - statement: Affected proteins include aconitase, respiratory complex I, 
          and lipoic acid synthase
        supporting_text: The activities of mitochondrial [4Fe-4S] proteins, 
          including aconitase, respiratory complex I, and lipoic acid synthase, 
          were diminished following depletion of the three proteins
      - statement: Ferrochelatase (a 2Fe-2S protein) is not affected by IBA57 
          depletion
        supporting_text: the mitochondrial [2Fe-2S] enzyme ferrochelatase and 
          cellular heme content were unaffected
  - id: PMID:22681889
    title: The mRNA-bound proteome and its global occupancy profile on 
      protein-coding transcripts.
    findings:
      - statement: High-throughput screen identified many proteins not 
          previously known to bind RNA
        supporting_text: nearly one-third were not previously annotated as RNA 
          binding
      - statement: Many hits may not represent physiological RNA-binding 
          functions
        supporting_text: about 15% were not predictable by computational methods
          to interact with RNA
  - id: PMID:23462291
    title: Mutation of the iron-sulfur cluster assembly gene IBA57 causes severe
      myopathy and encephalopathy.
    findings:
      - statement: IBA57 mutations cause MMDS3
      - statement: Patients show deficiency of respiratory chain complexes and 
          lipoylation defects
  - id: PMID:30269484
    title: IBA57 Recruits ISCA2 to Form a [2Fe-2S] Cluster-Mediated Complex.
    findings:
      - statement: IBA57 forms a 2Fe-2S-bridged complex with ISCA2
        supporting_text: IBA57 forms a heterodimeric complex with ISCA2 by 
          bridging a [2Fe-2S] cluster
      - statement: Cys259 of IBA57 is required for cluster coordination
        supporting_text: the cysteine of the conserved motif characterizing 
          IBA57 protein family and the three conserved cysteines of the ISCA 
          protein family act as cluster ligands
      - statement: Crystal structure at 1.55 A resolution
  - id: PMID:31831856
    title: 'Structural properties of [2Fe-2S] ISCA2-IBA57: a complex of the mitochondrial
      iron-sulfur cluster assembly machinery.'
    findings:
      - statement: ISCA2-IBA57 forms a dimer of dimers structure
        supporting_text: a structural organization of dimer of dimers for the 
          [2Fe-2S]2+ ISCA2-IBA57 complex with ISCA2 providing the 
          homodimerization core interface
      - statement: R146 of IBA57 is critical for interaction with ISCA2
        supporting_text: the pathogenic mutation Arg146Trp in IBA57
      - statement: The 2Fe-2S cluster is shared between ISCA2 and IBA57
        supporting_text: The [2Fe-2S] cluster is out of the ISCA2 core while 
          being shared with IBA57
  - id: PMID:33961781
    title: Dual proteome-scale networks reveal cell-specific remodeling of the 
      human interactome.
    findings: []
  - id: PMID:34800366
    title: Quantitative high-confidence human mitochondrial proteome and its 
      dynamics in cellular context.
    findings:
      - statement: IBA57 confirmed as part of high-confidence mitochondrial 
          proteome
  - id: PMID:39408793
    title: 'Defects in the Maturation of Mitochondrial Iron-Sulfur Proteins: Biophysical
      Investigation of the MMDS3 Causing Gly104Cys Variant of IBA57.'
    findings:
      - statement: G104C pathogenic variant destabilizes ISCA2-IBA57 complex
        supporting_text: the G104C-IBA57 mutant has a lower conformational 
          stability than WT-IBA57
      - statement: Does not completely abolish complex formation
        supporting_text: G104C Mutation of IBA57 Does Not Impair the Interaction
          with ISCA2 upon [2Fe-2S] Cluster Binding
  - id: PMID:40205054
    title: Multimodal cell maps as a foundation for structural and functional 
      genomics.
    findings: []
  - id: file:human/IBA57/IBA57-deep-research-falcon.md
    title: Deep research report on IBA57
    findings: []
core_functions:
  - molecular_function:
      id: GO:0051537
      label: 2 iron, 2 sulfur cluster binding
    description: IBA57 forms a 2Fe-2S-bridged heterocomplex with ISCA2. 
      Structural and biophysical studies demonstrate that Cys259 of IBA57 
      coordinates the bridging 2Fe-2S cluster (PMID:30269484). The C259A 
      mutation abolishes complex formation. The 2Fe-2S cluster serves as an 
      intermediate in 4Fe-4S cluster assembly through a reductive coupling 
      mechanism with ISCA1 and ISCA2.
    directly_involved_in:
      - id: GO:0044572
        label: '[4Fe-4S] cluster assembly'
    locations:
      - id: GO:0005759
        label: mitochondrial matrix
    in_complex:
      id: GO:0120510
      label: mitochondrial [4Fe-4S] assembly complex
    supported_by:
      - reference_id: PMID:22323289
        supporting_text: 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
      - reference_id: PMID:30269484
        supporting_text: '[2Fe-2S] cluster binding is absolutely required to promote
          the complex formation'
      - reference_id: PMID:31831856
        supporting_text: a structural organization of dimer of dimers for the 
          [2Fe-2S]2+ ISCA2-IBA57 complex
proposed_new_terms: []
suggested_questions:
  - question: What is the precise mechanism by which the ISCA1-ISCA2-IBA57 
      complex converts two 2Fe-2S clusters into a 4Fe-4S cluster?
  - question: Does IBA57 have additional roles beyond its function with ISCA 
      proteins in 4Fe-4S cluster maturation?
suggested_experiments:
  - description: Structural characterization of the complete ISCA1-ISCA2-IBA57 
      complex to understand the reductive coupling mechanism
  - description: Identification of direct client proteins that receive 4Fe-4S 
      clusters from the ISCA-IBA57 machinery
tags:
  - iron-sulfur-cluster-biogenesis

IBA57

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Gene Research for Functional Annotation

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Gene Research for Functional Annotation

⚠️ CRITICAL: Gene/Protein Identification Context

Target Gene/Protein Identity (from UniProt):

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If Gene Symbol is Ambiguous or You Cannot Find Relevant Literature:

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