id: MODULE:cytosolic_iron_sulfur_assembly title: Cytosolic iron-sulfur protein assembly (CIA) in human cells description: >- The cytosolic iron-sulfur protein assembly (CIA) machinery builds [4Fe-4S] clusters in the cytosol and inserts them into cytosolic and nuclear apoproteins, including enzymes of DNA replication and repair, purine metabolism and iron regulation (IRP1). It depends on the mitochondrial iron-sulfur cluster (ISC) machinery, which produces a still-unidentified sulfur-containing compound that the inner-membrane ABC transporter ABCB7 exports to the cytosol. In the cytosol, the NADPH-dependent diflavin reductase NDOR1 passes electrons to the [2Fe-2S] cluster of anamorsin (CIAPIN1). A heterotetrameric scaffold of the P-loop NTPases NUBP1 and NUBP2 assembles [4Fe-4S] clusters. CIAO3 (NARFL) and the CIA targeting complex then transfer the clusters to recipient apoproteins. The targeting complex has a core of the WD40 protein CIAO1, the MIP18-family protein CIAO2B and the HEAT-repeat adaptor MMS19, which binds most client apoproteins. CIAO1 paired with the paralog CIAO2A instead matures IRP1. The client apoproteins are substrates of the pathway, not parts of the machinery. status: DRAFT scope: CONCRETE evidence: - source_id: PW:0002636 title: cytosolic iron-sulfur cluster protein assembly pathway statement: >- The module boundary follows the RGD Pathway Ontology term and its diagram. The diagram draws Nubp1 associated with Nubp2, Ciapin1 associated with Ndor1 and Ndor1 positively affecting Ciapin1, Nubp1 and Nubp2 positively affecting cytosolic and nuclear recipients, Narfl, and a labelled "CIA targeting complex" containing Ciao1, Fam96a (CIAO2A), Fam96b (CIAO2B) and Mms19. Its record text places the mitochondrial ISC and export pathways upstream and describes CIA2A as dedicated to IRP1 maturation. Derived through projects/RGD_PATHWAY_ONTOLOGY (pathways/PW_0002636.yaml). - source_id: GO:0016226 title: iron-sulfur cluster assembly statement: >- The only GO mapping the project records for PW:0002636, as a broad match (go_mappings_not_for_matching in the module seeds). GO release 2026-07-26 has no process term specific to the cytosolic machinery; the module concept is the narrower GO:0044572 [4Fe-4S] cluster assembly, and the cytosolic location is carried by context. - source_id: GO:0044572 title: '[4Fe-4S] cluster assembly' statement: >- The process term used for the module node: the CIA scaffold assembles [4Fe-4S] clusters, and the same term is used for the CIA scaffold and targeting-complex activities in the Drosophila and fission yeast iron-sulfur GO-CAMs. notes: >- Derived from RGD PW:0002636 (cytosolic iron-sulfur cluster protein assembly pathway), whose nine RGD-curated human genes are CIAO1, CIAO2A, CIAO2B, CIAO3, CIAPIN1, MMS19, NDOR1, NUBP1 and NUBP2; all nine are parts here. GO term check: GO release 2026-07-26 has no process term for the cytosolic machinery as such (no "cytosolic iron-sulfur cluster assembly" or CIA pathway term; the former maturation term GO:0097428 is obsolete). It does have the two CIA complexes as cellular components (GO:1904564 scaffold, GO:0097361 targeting complex), which are used as node concepts. The project maps PW:0002636 to GO:0016226 iron-sulfur cluster assembly only as a broad match; the module concept is its child GO:0044572 [4Fe-4S] cluster assembly with cytosol as context, matching how the fly and fission yeast GO-CAMs type their CIA activities. Boundary decisions. (1) Upstream: the mitochondrial ISC core is included by module_ref to mitochondrial_iron_sulfur_cluster_assembly, and ABCB7 export is written as its own optional step because that module does not model export (its notes list ABCB7 as not yet modelled). Both are optional parts so this module's satisfiability rests on the cytosolic steps; the RGD export pathway (PW:0002637, which adds glutathione and GFER) and the mitochondrial biogenesis pathway (PW:0002635) are separate RGD terms and are not claimed as evidence here. (2) Downstream: client apoproteins (DNA polymerases, helicases, primase, PPAT, IRP1/ACO1, CIAO3 itself possibly) are substrates and are named only as function targets, not parts; by the substrate-versus-participant rule they do not carry the process. IRP2 stabilization by CIAO2A is iron regulation, not cluster assembly, and is described only in prose. (3) GLRX3-BOLA2 [2Fe-2S] delivery to NUBP1 and the CIAO3-independent routes proposed in some systems are not modelled; GLRX3 is not in the RGD gene set. (4) The NUBP1-NUBP2 scaffold is given the cluster-binding function that NUBP1 carries by IDA, not the ATP-dependent FeS chaperone function used in the fission yeast model, because no human annotation supports ATP-dependent transfer. (5) CIAO2B and CIAO3 have no molecular function asserted (GOA has only protein binding); CIAPIN1 electron transfer activity is asserted from the cached electron-transfer experiments although GOA has it only by IEA. (6) CIAO2A is modelled as an optional single-client branch rather than as an alternative to CIAO2B, since cells need both. GO-CAM links point to the Drosophila iron-sulfur model (gomodel:6796b94c00000657, behind modules/dmel_iron_sulfur_cluster_assembly, the fly counterpart of this module and of the mitochondrial ISC module) and the fission yeast model (gomodel:6690711d00000331); no human GO-CAM in gocams/index.tsv contains a CIA member, and the seed recorded no best GO-CAM. The two orthologous models type the targeting complex differently (chaperone in fly, iron-sulfur transferase in fission yeast). module: id: cytosolic_iron_sulfur_assembly label: Cytosolic iron-sulfur protein assembly (CIA) module_type: BIOLOGICAL_PROCESS concepts: - preferred_term: '[4Fe-4S] cluster assembly' term: id: GO:0044572 label: '[4Fe-4S] cluster assembly' context: taxa: - preferred_term: Homo sapiens term: id: NCBITaxon:9606 label: Homo sapiens cellular_components: - preferred_term: cytosol term: id: GO:0005829 label: cytosol parts: - order: 1 role: upstream mitochondrial ISC machinery (supply of the exported sulfur compound) optional: true node: id: upstream_mitochondrial_isc label: Mitochondrial ISC core machinery (upstream) description: >- Included by reference to the mitochondrial ISC core module. CIA depends on it, but it is a separate process in another compartment; the part is optional so that this module's own steps are evaluated on their own. module_ref: mitochondrial_iron_sulfur_cluster_assembly evidence: - source_id: PMID:18573874 statement: Cytosolic Fe/S protein maturation in human cells requires the mitochondrial ISC and export machineries. supporting_text: The maturation of cytosolic iron-sulfur (Fe/S) proteins in mammalian cells requires components of the mitochondrial iron-sulfur cluster assembly and export machineries. - order: 2 role: export of the ISC-derived sulfur compound to the cytosol (upstream interface) optional: true node: id: mitochondrial_export label: ABCB7 export from the mitochondrial matrix module_type: TRANSPORT_STEP description: >- ABCB7 in the inner mitochondrial membrane exports the sulfur-containing product of the ISC machinery. The mitochondrial ISC module does not yet model this step, so it is written here as an optional interface; the wider export pathway (glutathione and the intermembrane-space sulfhydryl oxidase GFER/ALR) is RGD's separate export pathway. annotons: - id: abcb7_export label: ABCB7 iron-sulfur cluster export participant: selector_type: GENE_PRODUCT gene_product: preferred_term: ABCB7 term: id: UniProtKB:O75027 label: Iron-sulfur clusters transporter ABCB7, mitochondrial function: preferred_term: ABC-type iron-sulfur cluster transporter activity term: id: GO:0140481 label: ABC-type iron-sulfur cluster transporter activity processes: - preferred_term: iron-sulfur cluster export from the mitochondrion term: id: GO:0140466 label: iron-sulfur cluster export from the mitochondrion locations: - preferred_term: mitochondrial inner membrane term: id: GO:0005743 label: mitochondrial inner membrane role_description: Exports the ISC-derived compound that the CIA scaffold needs; its chemical identity is unresolved. evidence: - source_id: file:genes/human/ABCB7/ABCB7-ai-review.yaml statement: 'Reviewed core function of human ABCB7: ABC-type iron-sulfur cluster transporter activity, in the mitochondrial inner membrane.' gocam_associations: - model: gomodel:6796b94c00000657 activity: gomodel:6796b94c00000657/6796b94c00002766 title: Drosophila ABCB7 ABC-type iron-sulfur cluster transporter activity (GO:0140481) in iron-sulfur cluster export from the mitochondrion description: Orthologous fly model; no human GO-CAM contains a CIA or export member. - model: gomodel:6690711d00000331 activity: gomodel:6690711d00000331/6690711d00000461 title: Fission yeast atm1 ABC-type iron-sulfur cluster transporter activity (GO:0140481) description: Orthologous S. pombe model. - order: 3 role: NADPH-dependent electron supply node: id: cia_electron_supply label: NDOR1-anamorsin (CIAPIN1) electron transfer chain module_type: MOLECULAR_FUNCTION description: >- NDOR1 and anamorsin form a stable complex. Electrons flow from NADPH through the FAD and FMN of NDOR1 to the [2Fe-2S] cluster of anamorsin's C-terminal CIAPIN1 domain, which supplies the reducing equivalents needed for [4Fe-4S] assembly on the scaffold. annotons: - id: ndor1_reductase label: NDOR1 NADPH-dependent diflavin reductase participant: selector_type: GENE_PRODUCT gene_product: preferred_term: NDOR1 term: id: UniProtKB:Q9UHB4 label: NADPH-dependent diflavin oxidoreductase 1 function: preferred_term: NADPH-iron-sulfur [2Fe-2S] protein oxidoreductase activity term: id: GO:0160246 label: NADPH-iron-sulfur [2Fe-2S] protein oxidoreductase activity substrates: - preferred_term: NADPH - preferred_term: oxidized [2Fe-2S]-anamorsin products: - preferred_term: reduced [2Fe-2S]-anamorsin locations: - preferred_term: cytosol term: id: GO:0005829 label: cytosol role_description: Reduces the [2Fe-2S] cluster of anamorsin with electrons from NADPH. The function is the activity human NDOR1 carries by IDA in GOA. evidence: - source_id: PMID:23596212 statement: Human NDOR1 and anamorsin form a stable complex in which one electron passes from the reduced FMN of NDOR1 to the [2Fe-2S] cluster of anamorsin. supporting_text: We showed that the two proteins form a stable complex where one electron is transferred from the hydroquinone state of the FMN moiety of Ndor1 to the oxidized [2Fe-2S] cluster of anamorsin. gocam_associations: - model: gomodel:6796b94c00000657 activity: gomodel:6796b94c00000657/6796b94c00004121 title: Drosophila CG13667 (NDOR1 ortholog) NADPH-iron-sulfur [2Fe-2S] protein oxidoreductase activity (GO:0160246) description: Orthologous fly model. - model: gomodel:6690711d00000331 activity: gomodel:6690711d00000331/6a2b236300000148 title: Fission yeast tah18 NADPH-iron-sulfur [2Fe-2S] protein oxidoreductase activity (GO:0160246) description: Orthologous S. pombe model. - id: ciapin1_electron_carrier label: Anamorsin (CIAPIN1) [2Fe-2S] electron carrier participant: selector_type: GENE_PRODUCT gene_product: preferred_term: CIAPIN1 (anamorsin) term: id: UniProtKB:Q6FI81 label: Anamorsin function: preferred_term: electron transfer activity term: id: GO:0009055 label: electron transfer activity locations: - preferred_term: cytosol term: id: GO:0005829 label: cytosol role_description: Accepts electrons from NDOR1 on its [2Fe-2S] cluster and passes them on for cluster assembly. GOA gives human anamorsin this function only by IEA; the activity is supported here by the electron-transfer experiments with NDOR1 and matches the activity curated for the fly and fission yeast orthologs in their GO-CAMs. evidence: - source_id: PMID:23596212 statement: Reduced NDOR1 FMN transfers electrons stoichiometrically to the [2Fe-2S] cluster of anamorsin. supporting_text: electrons were stoichiometrically transferred from FMN to [2Fe-2S], producing the reduced state of the [2Fe-2S] cluster gocam_associations: - model: gomodel:6796b94c00000657 activity: gomodel:6796b94c00000657/6796b94c00004169 title: Drosophila CIAPIN1 electron transfer activity (GO:0009055) description: Orthologous fly model. - model: gomodel:6690711d00000331 activity: gomodel:6690711d00000331/6690711d00000484 title: Fission yeast dre2 electron transfer activity (GO:0009055) description: Orthologous S. pombe model. - order: 4 role: '[4Fe-4S] cluster assembly on the cytosolic scaffold' node: id: cia_scaffold label: NUBP1-NUBP2 cytosolic [4Fe-4S] assembly scaffold module_type: PROTEIN_COMPLEX concepts: - preferred_term: cytosolic [4Fe-4S] assembly scaffold complex term: id: GO:1904564 label: cytosolic [4Fe-4S] assembly scaffold complex description: >- The P-loop NTPases NUBP1 and NUBP2 form a heterotetramer that assembles [4Fe-4S] clusters. NUBP1 carries a tightly bound cluster at an N-terminal ferredoxin-like motif and a labile, transferable cluster at a conserved C-terminal motif. annotons: - id: nubp_scaffold_complex label: NUBP1-NUBP2 scaffold complex participant: selector_type: PROTEIN_COMPLEX protein_complex: preferred_term: NUBP1-NUBP2 heterotetramer term: id: GO:1904564 label: cytosolic [4Fe-4S] assembly scaffold complex active_units: - id: nubp1_unit label: NUBP1 role: Fe/S-binding scaffold subunit; carries the transferable [4Fe-4S] cluster. participant: selector_type: GENE_PRODUCT gene_product: preferred_term: NUBP1 term: id: UniProtKB:P53384 label: Cytosolic Fe-S cluster assembly factor NUBP1 function: preferred_term: 4 iron, 4 sulfur cluster binding term: id: GO:0051539 label: 4 iron, 4 sulfur cluster binding - id: nubp2_unit label: NUBP2 role: Partner P-loop NTPase of the heterotetramer. participant: selector_type: GENE_PRODUCT gene_product: preferred_term: NUBP2 term: id: UniProtKB:Q9Y5Y2 label: Cytosolic Fe-S cluster assembly factor NUBP2 function: preferred_term: 4 iron, 4 sulfur cluster binding term: id: GO:0051539 label: 4 iron, 4 sulfur cluster binding processes: - preferred_term: '[4Fe-4S] cluster assembly' term: id: GO:0044572 label: '[4Fe-4S] cluster assembly' locations: - preferred_term: cytosol term: id: GO:0005829 label: cytosol role_description: Assembles [4Fe-4S] clusters for transfer onward. The function is cluster binding, as NUBP1 carries by IDA in GOA; GO has no scaffold-specific activity term that GOA uses for the human proteins. evidence: - source_id: PMID:18573874 statement: Human NUBP1 is an Fe/S protein required for maturation of cytosolic but not mitochondrial Fe/S proteins, and forms a complex with NUBP2 in vivo. supporting_text: huNbp35 formed a complex with its close homologue huCfd1 (also known as Nubp2) in vivo, suggesting the existence of a heteromeric P-loop NTPase complex that is required for both cytosolic Fe/S protein assembly and cellular iron homeostasis. - source_id: PMID:18573874 statement: NUBP1 depletion impairs maturation of cytosolic Fe/S proteins and IRP1 but leaves mitochondrial Fe/S proteins intact. supporting_text: Consequently, huNbp35 is specifically involved in the formation of extramitochondrial Fe/S proteins. gocam_associations: - model: gomodel:6796b94c00000657 activity: gomodel:6796b94c00000657/6796b94c00004196 title: Drosophila cytosolic [4Fe-4S] assembly scaffold complex, 4 iron, 4 sulfur cluster binding (GO:0051539) in [4Fe-4S] cluster assembly description: Orthologous fly model; same function and process as asserted here. - model: gomodel:6690711d00000331 activity: gomodel:6690711d00000331/6796b94c00003526 title: Fission yeast cytosolic [4Fe-4S] assembly scaffold complex, ATP-dependent FeS chaperone activity (GO:0140663) description: Orthologous S. pombe model; it types the scaffold as an ATP-dependent FeS chaperone, a stronger claim than the human GOA annotations support. - order: 5 role: transfer of the scaffold-built cluster toward the targeting complex node: id: cia_ciao3_transfer label: CIAO3 (NARFL) cluster transfer module_type: BIOLOGICAL_PROCESS description: >- CIAO3, a homolog of iron-only hydrogenases that binds [4Fe-4S] clusters, acts between the NUBP scaffold and the targeting complex. It is an external, more loosely bound component of the targeting complex. Whether it passes clusters on or is itself matured by the complex is not settled. annotons: - id: ciao3_transfer label: CIAO3 (NARFL) late-acting CIA factor participant: selector_type: GENE_PRODUCT gene_product: preferred_term: CIAO3 (NARFL, IOP1) term: id: UniProtKB:Q9H6Q4 label: Cytosolic iron-sulfur assembly component 3 processes: - preferred_term: iron-sulfur cluster assembly term: id: GO:0016226 label: iron-sulfur cluster assembly locations: - preferred_term: cytosol term: id: GO:0005829 label: cytosol role_description: Required for maturation of cytosolic Fe/S proteins and associated with the targeting complex. No molecular function is asserted, because GOA has no experimental function for human CIAO3 other than protein binding and its activity in the transfer step is unresolved. evidence: - source_id: PMID:18270200 statement: IOP1 (CIAO3) knockdown lowers cytosolic but not mitochondrial aconitase activity and lowers xanthine oxidase activity, and is rescued by an siRNA-resistant IOP1. supporting_text: Taken together, these results provide evidence that IOP1 is involved in mammalian cytosolic Fe-S protein maturation. - source_id: PMID:23585563 statement: CIAO3 binds the MMS19-CIAO2B-CIAO1 core complex as an external component and may itself behave like a target of the CIA reaction. supporting_text: IOP1 behaves like a target protein in the CIA reaction, like other Fe-S helicases, and the core complex may participate in the maturation process of IOP1. - order: 6 role: insertion of [4Fe-4S] clusters into most cytosolic and nuclear apoproteins node: id: cia_targeting_complex label: CIAO1-CIAO2B-MMS19 CIA targeting complex module_type: PROTEIN_COMPLEX concepts: - preferred_term: cytosolic [4Fe-4S] assembly targeting complex term: id: GO:0097361 label: cytosolic [4Fe-4S] assembly targeting complex description: >- CIAO1, CIAO2B and MMS19 form a tight core complex. MMS19 binds client apoproteins, including enzymes of DNA replication and repair, and CIAO2B bridges MMS19 to CIAO1. The complex transfers the [4Fe-4S] cluster to the apoprotein. annotons: - id: ctc_core label: CIA targeting complex cluster delivery participant: selector_type: PROTEIN_COMPLEX protein_complex: preferred_term: CIAO1-CIAO2B-MMS19 core complex term: id: GO:0097361 label: cytosolic [4Fe-4S] assembly targeting complex active_units: - id: ctc_ciao1 label: CIAO1 role: WD40 subunit that binds CIAO2B (or CIAO2A) and CIAO3. participant: selector_type: GENE_PRODUCT gene_product: preferred_term: CIAO1 term: id: UniProtKB:O76071 label: Probable cytosolic iron-sulfur protein assembly protein CIAO1 function: preferred_term: iron-sulfur cluster chaperone activity term: id: GO:0140132 label: iron-sulfur cluster chaperone activity - id: ctc_ciao2b label: CIAO2B (FAM96B, MIP18) role: MIP18-family subunit that bridges MMS19 and CIAO1. participant: selector_type: GENE_PRODUCT gene_product: preferred_term: CIAO2B term: id: UniProtKB:Q9Y3D0 label: Cytosolic iron-sulfur assembly component 2B - id: ctc_mms19 label: MMS19 role: HEAT-repeat adaptor that binds client apoproteins. participant: selector_type: GENE_PRODUCT gene_product: preferred_term: MMS19 term: id: UniProtKB:Q96T76 label: MMS19 nucleotide excision repair protein homolog function: preferred_term: protein-macromolecule adaptor activity term: id: GO:0030674 label: protein-macromolecule adaptor activity function: preferred_term: iron-sulfur cluster chaperone activity term: id: GO:0140132 label: iron-sulfur cluster chaperone activity targets: - preferred_term: cytosolic and nuclear [4Fe-4S] apoproteins (for example DNA polymerases, DNA helicases, primase, glutamine PRPP amidotransferase) processes: - preferred_term: protein maturation term: id: GO:0051604 label: protein maturation locations: - preferred_term: cytosol term: id: GO:0005829 label: cytosol role_description: Delivers [4Fe-4S] clusters to most cytosolic and nuclear client apoproteins. The subunit functions follow the reviewed core functions of CIAO1 (iron-sulfur cluster chaperone activity) and MMS19 (protein-macromolecule adaptor activity, bridging CIA components and client apoproteins); CIAO2B has no experimental molecular function in GOA and none is asserted. evidence: - source_id: PMID:23891004 statement: CIAO1 associates with CIAO2B and MMS19, and this complex binds and matures most cytosolic-nuclear Fe/S proteins. supporting_text: The CIA2B-CIA1-MMS19 complex binds to and facilitates assembly of most cytosolic-nuclear Fe/S proteins. - source_id: PMID:22678362 statement: MMS19 is the adapter between early-acting CIA components and client apoproteins. supporting_text: MMS19 thus serves as an adapter between early-acting CIA components and a subset of cellular iron-sulfur proteins. - source_id: PMID:22678361 statement: MMS19 forms a complex with CIAO1, CIAO3 and MIP18 (CIAO2B) and binds nuclear Fe-S proteins of DNA metabolism. supporting_text: MMS19 forms a complex with the cytoplasmic Fe-S assembly (CIA) proteins CIAO1, IOP1, and MIP18. - source_id: PMID:23585563 statement: MMS19, MIP18 (CIAO2B) and CIAO1 form a tight core complex. supporting_text: MMS19, MIP18, and CIAO1 form a tight "core" complex and that IOP1 is an "external" component of this complex. - source_id: file:genes/human/CIAO1/CIAO1-ai-review.yaml statement: 'Reviewed core function of human CIAO1: iron-sulfur cluster chaperone activity, in the cytosolic [4Fe-4S] assembly targeting complex.' - source_id: file:genes/human/MMS19/MMS19-ai-review.yaml statement: 'Reviewed core function of human MMS19: protein-macromolecule adaptor activity, in the cytosolic [4Fe-4S] assembly targeting complex.' gocam_associations: - model: gomodel:6796b94c00000657 activity: gomodel:6796b94c00000657/6796b94c00004207 title: Drosophila cytosolic [4Fe-4S] assembly targeting complex, iron-sulfur cluster chaperone activity (GO:0140132) in [4Fe-4S] cluster assembly description: Orthologous fly model; same function as asserted here. - model: gomodel:6690711d00000331 activity: gomodel:6690711d00000331/6796b94c00004124 title: Fission yeast cytosolic [4Fe-4S] assembly targeting complex, iron-sulfur transferase activity (GO:0036455) in protein maturation description: Orthologous S. pombe model; it types the complex with the catalytic iron-sulfur transferase term rather than the chaperone term used here and in the fly model. - order: 7 role: dedicated maturation of IRP1 (ACO1) optional: true node: id: cia_irp1_branch label: CIAO1-CIAO2A branch for IRP1 maturation module_type: PROTEIN_COMPLEX description: >- CIAO1 paired with the CIAO2B paralog CIAO2A, without MMS19, matures the cytosolic aconitase/iron regulatory protein 1 (ACO1/IRP1). CIAO2A binding also stabilizes IRP2, which has no Fe/S cluster. The branch links CIA to post-transcriptional control of iron homeostasis. It is optional because it serves one client. annotons: - id: ctc_ciao2a_irp1 label: CIAO1-CIAO2A IRP1 maturation participant: selector_type: PROTEIN_COMPLEX protein_complex: preferred_term: CIAO1-CIAO2A complex term: id: GO:0097361 label: cytosolic [4Fe-4S] assembly targeting complex active_units: - id: irp1_branch_ciao1 label: CIAO1 role: WD40 subunit shared with the general targeting complex. participant: selector_type: GENE_PRODUCT gene_product: preferred_term: CIAO1 term: id: UniProtKB:O76071 label: Probable cytosolic iron-sulfur protein assembly protein CIAO1 function: preferred_term: iron-sulfur cluster chaperone activity term: id: GO:0140132 label: iron-sulfur cluster chaperone activity - id: irp1_branch_ciao2a label: CIAO2A (FAM96A) role: MIP18-family subunit that directs the complex to IRP1. participant: selector_type: GENE_PRODUCT gene_product: preferred_term: CIAO2A term: id: UniProtKB:Q9H5X1 label: Cytosolic iron-sulfur assembly component 2A function: preferred_term: iron-sulfur cluster chaperone activity term: id: GO:0140132 label: iron-sulfur cluster chaperone activity targets: - preferred_term: iron regulatory protein 1 (ACO1/IRP1) apoprotein processes: - preferred_term: protein maturation term: id: GO:0051604 label: protein maturation locations: - preferred_term: cytosol term: id: GO:0005829 label: cytosol role_description: Inserts the [4Fe-4S] cluster that converts IRP1 into cytosolic aconitase. evidence: - source_id: PMID:23891004 statement: CIAO2A specifically matures IRP1, while CIAO2B-CIAO1-MMS19 serves most other clients. supporting_text: In contrast, CIA2A specifically matures iron regulatory protein 1 (IRP1), which is critical for cellular iron homeostasis. - source_id: PMID:32222833 statement: CIAO3 forms a stable [4Fe-4S]-bound ternary complex with the CIAO2A-CIAO1 heterodimer. supporting_text: the formation of a stable, [4Fe-4S]-bound, complex, composed by CIAO3 and the hetero-CIA2A-CIAO1 complex. connections: - source: upstream_mitochondrial_isc target: mitochondrial_export connection_type: PRECEDES description: The mitochondrial ISC machinery produces the sulfur-containing compound that ABCB7 exports. - source: mitochondrial_export target: cia_scaffold connection_type: PROVIDES_INPUT_FOR description: The exported compound is required for [4Fe-4S] assembly on the NUBP1-NUBP2 scaffold. - source: cia_electron_supply target: cia_scaffold connection_type: PROVIDES_INPUT_FOR description: NDOR1 and anamorsin supply electrons for [4Fe-4S] assembly on the scaffold. - source: cia_scaffold target: cia_ciao3_transfer connection_type: PRECEDES description: The cluster built on NUBP1 is released toward CIAO3 and the targeting complex. - source: cia_ciao3_transfer target: cia_targeting_complex connection_type: PRECEDES description: CIAO3 acts with the targeting complex, which inserts the cluster into client apoproteins. - source: cia_ciao3_transfer target: cia_irp1_branch connection_type: PRECEDES description: CIAO3 also associates with the CIAO1-CIAO2A complex that matures IRP1. knowledge_gaps: - gap_statement: >- The chemical identity of the sulfur-containing compound that ABCB7 exports from mitochondria for cytosolic Fe-S cluster assembly is not known, and it is not known how it reaches the NUBP1-NUBP2 scaffold. boundary: Mitochondrial export step linking ISC and CIA. gap_kind: - BIOLOGY - gap_statement: >- Whether CIAO3 passes [4Fe-4S] clusters from the NUBP scaffold to the targeting complex, or is itself a client matured by the complex, is not resolved. boundary: CIAO3 step between scaffold and targeting complex. gap_kind: - BIOLOGY