CIAO1 Human
Description
CIAO1 is essential for Fe-S cluster transfer to nucleocytoplasmic enzymes, including:
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DNA Replication/Repair Proteins: DNA polymerases, helicases (e.g., DNA2), and primases .
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tRNA Modification Enzymes: Required for proper translation fidelity .
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Metabolic Enzymes: Involved in purine/pyrimidine metabolism .
Functional assays demonstrate that CIAO1 collaborates with FAM96B, HSC20, and ISCU to assemble Fe-S clusters . Loss of CIAO1 disrupts Fe-S enzyme activity, leading to genomic instability and metabolic defects .
Clinical Implications
Biallelic CIAO1 mutations cause a multisystem neuromuscular disorder characterized by:
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Musculoskeletal: Progressive proximal/axial muscle weakness, respiratory insufficiency, elevated creatine kinase .
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Neurological: Learning difficulties, neurobehavioral comorbidities, iron deposition in deep brain nuclei .
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Hematologic/Gastrointestinal: Macrocytic anemia, gastrointestinal dysmotility .
Key Pathogenic Variants
Experimental Models and Functional Studies
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Patient-Derived Cells: Fibroblasts with CIAO1 mutations show defective DNA helicase/polymerase activities, reversed by lentiviral CIAO1 restoration .
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Biochemical Assays: Mutant CIAO1 fails to stabilize Fe-S recipient proteins (e.g., XPD, DNA2) .
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Structural Insights: Cryo-EM reveals CTC’s bipartite client recognition mode, with CIAO1 positioning Fe-S clusters ~70 Å from reactive cysteines .
Research Findings and Therapeutic Insights
Recent studies highlight:
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Mechanistic Flexibility: The CTC adapts conformationally to accommodate diverse Fe-S client proteins .
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Tissue-Specific Vulnerability: Muscle and neurons are disproportionately affected due to high Fe-S enzyme demand .
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Therapeutic Potential: Gene therapy or small-molecule stabilizers of mutant CIAO1 could ameliorate symptoms .
Key Research Studies
Product Specs
Product Science Overview
Cytosolic Iron-Sulfur Protein Assembly 1 (CIAO1) is a crucial component in the biogenesis of iron-sulfur (Fe-S) clusters, which are essential cofactors for a variety of cellular processes. These clusters are involved in electron transfer, enzyme catalysis, and regulation of gene expression. The human recombinant form of CIAO1 is used in research to study its function and role in cellular metabolism.
CIAO1 is encoded by the CIAO1 gene, which is located on chromosome 2 in humans . The protein is also known by other names such as WD Repeat-Containing Protein 39 (WDR39) and Probable Cytosolic Iron-Sulfur Protein Assembly Protein CIAO1 . It is a protein-coding gene associated with several pathways, including metabolism and cytosolic iron-sulfur cluster assembly .
CIAO1 is a key component of the cytosolic iron-sulfur protein assembly (CIA) complex. This multiprotein complex mediates the incorporation of iron-sulfur clusters into extramitochondrial Fe-S proteins . The CIA complex includes other components such as CIAO2A, CIAO2B, and MMS19, which interact with CIAO1 to facilitate the assembly and maturation of various Fe-S proteins .
CIAO1 is ubiquitously expressed in various tissues, reflecting its fundamental role in cellular metabolism. It is primarily located in the cytoplasm and is part of the CIA complex and the mitotic spindle-associated MMXD complex . The protein’s widespread expression underscores its importance in maintaining cellular function and homeostasis.
The primary function of CIAO1 is to assist in the assembly and maturation of Fe-S clusters in cytosolic and nuclear proteins . These clusters are vital for the proper functioning of numerous enzymes and proteins involved in critical cellular processes. CIAO1, in conjunction with other CIA components, ensures the correct incorporation of Fe-S clusters into target proteins, thereby maintaining cellular health and function .
The activity of CIAO1 is regulated through its interactions with other components of the CIA complex. For instance, the CIAO1:CIAO2B:MMS19 complex is responsible for the assembly of most cytosolic-nuclear Fe-S proteins, while the CIAO1:CIAO2A complex specifically matures ACO1 and stabilizes IREB2 . These interactions highlight the intricate regulatory mechanisms that govern Fe-S cluster biogenesis.
Mutations or dysfunctions in the CIAO1 gene can lead to various diseases, including Autism Spectrum Disorder and Deafness, Autosomal Recessive 48 . Understanding the role of CIAO1 in Fe-S cluster assembly can provide insights into the molecular basis of these conditions and potentially lead to the development of therapeutic interventions.
