Affinage

CIAO1

Probable cytosolic iron-sulfur protein assembly protein CIAO1 · UniProt O76071

Length
339 aa
Mass
37.8 kDa
Annotated
2026-06-09
19 papers in source corpus 11 papers cited in narrative 11 extracted findings
Cross-family judge vs UniProt: Affinage preferred faithfulness: 5/5 claims corpus-supported (100%)

Mechanistic narrative

Synthesis pass · prose summary of the discoveries below

CIAO1 is an essential WD40 β-propeller protein that acts in a late step of the cytosolic iron-sulfur cluster assembly (CIA) pathway, functioning downstream of the scaffold proteins Nbp35 and Nar1 to deliver Fe-S clusters specifically to cytosolic and nuclear, but not mitochondrial, target proteins (PMID:16314508). Its seven-bladed WD40 fold presents a conserved top surface required for cytosolic Fe-S protein biogenesis, and the protein is functionally conserved between yeast and humans (PMID:17937914). As a subunit of the CIA targeting complex together with FAM96B and MMS19, CIAO1 recruits apo-Fe-S client proteins—including DNA polymerase ε catalytic subunit POLE1 and DNA helicases—and the Cia1-Cia2 interface recognizes a C-terminal TCR motif present in a large fraction of CIA clients, an interaction that occurs even without the Fe-S cluster and that also engages the carrier protein Nar1 (PMID:27235625, PMID:40924805). The de novo cytosolic Fe-S biosynthesis machinery (ISCU1/NFS1) is bridged to this targeting complex via cytosolic HSC20, integrating cluster synthesis with delivery (PMID:29309586), and the holo CIA2A-CIAO1 complex coordinates a [4Fe-4S] cluster that it transfers to apo-IRP1/cytosolic aconitase (PMID:29842905). Biallelic loss-of-function CIAO1 variants cause a human neuromuscular disorder: disease-associated variants fail to recruit Fe-S recipient proteins and compromise the activities of CIA-dependent helicases, polymerases, and repair enzymes, with lentiviral restoration reversing patient cellular defects (PMID:38950322).

Mechanistic history

Synthesis pass · year-by-year structured walk · 10 steps
  1. 2005 High

    Established where CIAO1's ortholog acts within the iron-sulfur assembly machinery, distinguishing it from earlier scaffold steps and from mitochondrial Fe-S biogenesis.

    Evidence Genetic epistasis, conditional depletion, and reciprocal Co-IP in yeast

    PMID:16314508

    Open questions at the time
    • Did not resolve the structural basis of client or partner recognition
    • Mechanism of cluster handoff from Nar1 to clients unaddressed
  2. 2007 High

    Defined the molecular architecture as a seven-bladed WD40 β-propeller and identified a functionally critical top-surface residue, while demonstrating yeast-to-human functional conservation.

    Evidence 1.7 Å X-ray crystallography, site-directed mutagenesis, and cross-species complementation

    PMID:17937914

    Open questions at the time
    • Did not identify which surface engages clients versus partner subunits
    • No structure of CIAO1 within an assembled targeting complex
  3. 2016 Medium

    Showed CIAO1 directly engages a specific client, POLE1, and that this engagement uses a recognition mode distinct from MMS19's phosphorylation-dependent binding.

    Evidence Co-IP and POLE1 S1940 phosphosite mutagenesis in human cells

    PMID:27235625

    Open questions at the time
    • Did not map the CIAO1 surface contacting POLE1
    • Generality of phosphorylation-independent recruitment across clients untested
  4. 2018 High

    Demonstrated that CIAO1-containing subcomplexes can bind and transfer an actual [4Fe-4S] cluster to a physiological recipient, providing biochemical proof of cluster-delivery activity.

    Evidence NMR, UV-vis, EPR spectroscopy and in vitro cluster transfer to apo-IRP1 with the CIA2A-CIAO1 trimer

    PMID:29842905

    Open questions at the time
    • Cysteine ligand contributed by CIAO1 itself not defined
    • Did not address transfer to nuclear genome-maintenance clients
  5. 2018 Medium

    Connected upstream de novo Fe-S biosynthesis to the CIA targeting complex, explaining how synthesized clusters reach CIAO1-dependent delivery.

    Evidence Co-IP, interaction mapping, and Fe-S delivery assays in human cells

    PMID:29309586

    Open questions at the time
    • Single-lab interaction data without orthogonal structural confirmation
    • Stoichiometry and dynamics of the bridged assembly unresolved
  6. 2020 Medium

    Placed CIAO1 within a cell-growth and survival circuit in an animal model, linking its Fe-S target Xpd to CyclinE/Diap1-dependent control of apoptosis.

    Evidence Co-IP, RNAi, clonal imaginal-disc analysis, and epistasis/rescue in Drosophila

    PMID:32404863

    Open questions at the time
    • Whether growth effects are wholly attributable to Fe-S client maturation not fully isolated
    • Relevance of Crumbs-domain interaction to CIA function unclear
  7. 2024 High

    Established CIAO1 as the cause of a human disease and linked the molecular defect (failed client recruitment) to functional loss of genome-maintenance Fe-S enzymes, with causal rescue.

    Evidence Patient variant characterization, recruitment and enzymatic activity assays, and lentiviral rescue in patient-derived cells

    PMID:38950322

    Open questions at the time
    • Genotype-phenotype relationships across variants not delineated
    • Tissue-specific vulnerability of neuromuscular system not mechanistically explained
  8. 2024 Medium

    Mapped the system-wide cellular consequences of CIAO1 loss and extended its role to antiviral host defense via Fe-S protein maturation.

    Evidence Genome sequencing, multi-omics of patient fibroblasts, and zebrafish loss-of-function models

    PMID:38411040

    Open questions at the time
    • Specific Fe-S clients driving the antiviral phenotype not identified
    • Causality from omic correlations to individual client failures incomplete
  9. 2025 High

    Resolved the molecular logic of client selection, showing a TCR peptide docks at the Cia1-Cia2 interface independent of the cluster, and that the disease-linked R65W variant disrupts this recruitment.

    Evidence Computational docking, biochemical TCR peptide-binding and interface mutagenesis including a disease variant

    PMID:40924805

    Open questions at the time
    • High-resolution experimental structure of the docked complex not reported
    • Determinants of TCR-motif specificity across the >30 clients not exhaustively defined
  10. 2025 Medium

    Extended the TCR-interface recognition model to the CIAO2A-CIAO1 complex, indicating CIAO2A participates in maturing TCR-bearing clients beyond IRP1.

    Evidence Computational, biochemical, and biophysical TCR peptide binding and mutagenesis (preprint)

    PMID:40196589

    Open questions at the time
    • Preprint, not yet peer reviewed and largely overlapping with the JACS study
    • Physiological client repertoire of CIAO2A-CIAO1 versus FAM96B-CIAO1 untested

Open questions

Synthesis pass · forward-looking unresolved questions
  • How CIAO1 coordinates timed cluster handoff from Nar1 to specific apo-clients, and what determines tissue-specific disease vulnerability, remain unresolved.
  • No experimental structure of an intact CIAO1-bound targeting complex with a client
  • Order and kinetics of cluster transfer versus client docking undefined

Mechanism profile

Synthesis pass · controlled-vocabulary classification · explore literature graph →
Molecular activity
GO:0008092 cytoskeletal protein binding 2 GO:0060090 molecular adaptor activity 2 GO:0140096 catalytic activity, acting on a protein 2
Localization
GO:0005634 nucleus 1 GO:0005829 cytosol 1
Pathway
R-HSA-1430728 Metabolism 2 R-HSA-73894 DNA Repair 1
Partners
CIA2AFAM96BHSC20ISCU1MMS19NAR1POLE1XPD
Complex memberships
CIA targeting complex (CIAO1-MMS19-FAM96B)CIA2A-CIAO1 complex

Evidence

Reading pass · 11 per-paper findings extracted from the source corpus
Year Finding Method Journal Conf PMIDs
2005 Yeast Cia1 (ortholog of human CIAO1) is an essential WD40 repeat protein required for Fe/S cluster assembly on cytosolic and nuclear, but not mitochondrial, Fe/S proteins. Genetic epistasis showed that Nbp35 and Nar1 can assemble their own Fe/S clusters in the absence of Cia1, placing Cia1 in a late step of the CIA pathway, after Nbp35 and Nar1. Co-immunoprecipitation demonstrated a specific physical interaction between Cia1 and Nar1. Genetic epistasis (conditional depletion), coimmunoprecipitation, in vivo Fe/S assembly assays Molecular and cellular biology High 16314508
2007 Crystal structure of yeast Cia1 (ortholog of human CIAO1) resolved to 1.7 Å reveals a seven-bladed beta-propeller WD40 fold. Site-directed mutagenesis identified conserved top-surface residue R127 as functionally critical; R127 mutant cells grew slowly and were impaired in cytosolic Fe/S protein assembly. Human CIAO1 was shown to functionally replace yeast Cia1 and support cytosolic Fe/S protein biogenesis, confirming structural and functional conservation. X-ray crystallography (1.7 Å), site-directed mutagenesis, in vivo complementation assay Structure High 17937914
2018 The human CIA2A-CIAO1 heterotrimeric complex (two CIA2A molecules + one CIAO1) binds one [4Fe-4S] cluster, with Cys90 of CIA2A serving as a cluster ligand. The holo trimeric complex can transfer the [4Fe-4S] cluster to apo-IRP1 (cytosolic aconitase) to generate the active form of aconitase. NMR spectroscopy, UV-vis absorption, EPR spectroscopy, in vitro Fe/S cluster transfer assay Biochimica et biophysica acta. General subjects High 29842905
2018 Cytosolic HSC20 (C-HSC20) mediates complex formation between components of the cytosolic Fe-S biogenesis pathway (primary scaffold ISCU1 and cysteine desulfurase NFS1) and the CIA targeting complex (CIAO1, FAM96B, MMS19), thereby integrating de novo Fe-S biosynthesis with the CIA-mediated transfer of Fe-S clusters to cytoplasmic and nuclear recipient proteins. Co-immunoprecipitation, interaction mapping, functional Fe-S cluster delivery assays in human cells Human molecular genetics Medium 29309586
2016 Human CIAO1 physically interacts with POLE1 (the catalytic subunit of DNA polymerase ε) as a CIA complex component, facilitating Fe-S cluster acquisition by POLE1. The interaction between POLE1 and CIAO1 does not require POLE1 serine-1940 (in contrast to MMS19, which does require S1940 phosphorylation). Co-immunoprecipitation, mutagenesis of POLE1 S1940 DNA repair Medium 27235625
2024 Patients with biallelic loss-of-function CIAO1 variants develop a neuromuscular disorder; functional assays showed that disease-associated CIAO1 variants fail to recruit Fe-S recipient proteins to the CIA complex, resulting in compromised activities of CIA-dependent DNA helicases, polymerases, and repair enzymes. Lentivirus-mediated restoration of CIAO1 expression reversed all patient-derived cellular abnormalities, establishing CIAO1 as essential for CIA targeting complex function in vivo. Mutational stability analysis, functional recruitment assays, enzymatic activity assays, lentiviral rescue in patient-derived cells The Journal of clinical investigation High 38950322
2024 Loss of CIAO1 in patient-derived fibroblasts caused profound alterations in proteome, metabolome, and lipidome, consistent with general failure of cytosolic and nuclear iron-sulfur protein maturation. Zebrafish ciao1-deficiency models confirmed the detrimental effects, implicating CIAO1 in antiviral host defense through Fe-S protein maturation. Genome sequencing, proteomics/metabolomics/lipidomics of patient fibroblasts, zebrafish loss-of-function models Genetics in medicine Medium 38411040
2020 In Drosophila, Ciao1 physically interacts with Crumbs intracellular domain (Crbintra), Galla, and Xpd (DNA helicase/CIA target). Loss of Ciao1 reduces Cyclin E and Diap1 levels in imaginal discs and increases apoptotic cell death. Genetic epistasis placed Ciao1 and Xpd in the same growth-regulatory pathway; CycE overexpression rescued Ciao1 RNAi phenotypes, and reduced CycE in Ciao1 mutants was shown to be secondary to loss of Diap1. Co-immunoprecipitation, RNAi knockdown, clonal analysis in imaginal discs, epistasis rescue experiments, CycE/Diap1 overexpression Cell death & disease Medium 32404863
2025 The TCR (targeting complex recognition) peptide found in up to 25% of CIA client proteins docks at the conserved interface between Cia1 and Cia2 subunits of the CIA targeting complex, even in the absence of the Fe-S cluster. The same Cia1-Cia2 interface also mediates binding of apo-Nar1 (proposed Fe-S carrier). Mutations disrupting this interface, including the disease-linked R65W Cia1 variant, impair TCR-dependent client recruitment. In vitro evidence supports Nar1's role as a cluster trafficking protein in the CIA pathway. Computational docking, biochemical interaction assays, mutagenesis of Cia1-Cia2 interface, in vitro TCR peptide binding assays Journal of the American Chemical Society High 40924805
2025 The Cia1-Cia2 interface mediates recognition of apo-Fe-S client proteins bearing a C-terminal TCR motif; mutations destabilizing this interface disrupt TCR-based client identification. Human CIAO2A (Cia2a paralog) in complex with CIAO1 can also recruit TCR-motif-bearing clients, suggesting a broader role for CIAO2A in Fe-S protein maturation beyond IRP1. Computational, biochemical, and biophysical approaches; in vitro TCR peptide binding; mutagenesis bioRxivpreprint Medium 40196589
2021 A heterozygous CIAO1 variant (Val67Ile) increases the physical interaction of CIAO1 protein with immature (but not mature or soluble) amyloid-β protein precursor (AβPP), suggesting CIAO1 involvement in AβPP processing. Biochemical interaction assay (co-immunoprecipitation/pull-down) comparing WT and Val67Ile CIAO1 with AβPP forms Journal of Alzheimer's disease Low 34569959

Source papers

Stage 0 corpus · 19 papers · ranked by NIH iCite citations
Year Title Journal Citations PMID
2005 The essential WD40 protein Cia1 is involved in a late step of cytosolic and nuclear iron-sulfur protein assembly. Molecular and cellular biology 114 16314508
2001 Cell death with predominant apoptotic features in Saccharomyces cerevisiae mediated by deletion of the histone chaperone ASF1/CIA1. Genes to cells : devoted to molecular & cellular mechanisms 82 11737265
2007 Structure of the yeast WD40 domain protein Cia1, a component acting late in iron-sulfur protein biogenesis. Structure (London, England : 1993) 63 17937914
2002 Polyanionic stretch-deleted histone chaperone cia1/Asf1p is functional both in vivo and in vitro. Genes to cells : devoted to molecular & cellular mechanisms 57 11856374
2018 Cytosolic HSC20 integrates de novo iron-sulfur cluster biogenesis with the CIAO1-mediated transfer to recipients. Human molecular genetics 39 29309586
1993 Depletion of CD4+ and CD8+ T lymphocyte subpopulations by CIA-1, a chicken infectious anemia virus. Avian diseases 27 8363513
2011 Characterization of CIA-1, an Ambler class A extended-spectrum β-lactamase from Chryseobacterium indologenes. Antimicrobial agents and chemotherapy 23 22083470
2018 Investigating the role of the human CIA2A-CIAO1 complex in the maturation of aconitase. Biochimica et biophysica acta. General subjects 18 29842905
2024 CIAO1 loss of function causes a neuromuscular disorder with compromise of nucleocytoplasmic Fe-S enzymes. The Journal of clinical investigation 13 38950322
2024 CIAO1 and MMS19 deficiency: A lethal neurodegenerative phenotype caused by cytosolic Fe-S cluster protein assembly disorders. Genetics in medicine : official journal of the American College of Medical Genetics 9 38411040
2007 Genetic regulation of T regulatory, CD4, and CD8 cell numbers by the arthritis severity loci Cia5a, Cia5d, and the MHC/Cia1 in the rat. Molecular medicine (Cambridge, Mass.) 8 17673937
2020 Ciao1 interacts with Crumbs and Xpd to regulate organ growth in Drosophila. Cell death & disease 5 32404863
2016 Human DNA polymerase ε is phosphorylated at serine-1940 after DNA damage and interacts with the iron-sulfur complex chaperones CIAO1 and MMS19. DNA repair 5 27235625
2025 A Conserved Cia1-Cia2 Interface Mediates Client Recruitment in the Cytosolic Iron-Sulfur Cluster Assembly Pathway. Journal of the American Chemical Society 4 40924805
2023 Loss of Function of the Cytoplasmic Fe-S Assembly Protein CIAO1 Causes a Neuromuscular Disorder with Compromise of Nucleocytoplasmic Fe-S Enzymes. medRxiv : the preprint server for health sciences 2 38196629
2021 A Novel Heterozygous Missense Variant in the CIAO1 Gene in a Family with Alzheimer's Disease: The Val67Ile Variant Promotes the Interaction of CIAO1 and Amyloid-β Protein Precursor. Journal of Alzheimer's disease : JAD 2 34569959
2005 Purification, crystallization and preliminary X-ray diffraction analysis of the histone chaperone cia1 from fission yeast. Acta crystallographica. Section F, Structural biology and crystallization communications 2 16511210
2025 CIAO1 as a crucial signature gene of cuproptosis in gastric cancer. Oncology letters 1 40697348
2025 The Cia1 and Cia2 subunits of the CTC mediate recognition of apo-FeS proteins with a C-terminal targeting complex recognition motif. bioRxiv : the preprint server for biology 0 40196589

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