{"gene":"CZIB","run_date":"2026-06-09T22:57:19","timeline":{"discoveries":[{"year":2018,"finding":"C1orf123 (CZIB) binds a Zn2+ ion in tetrahedral coordination via four thiolate groups from two conserved CxxC motifs, as revealed by X-ray crystallography. The protein specifically interacts with the HMA domain of the copper chaperone for superoxide dismutase (CCS domain I; CCSdI), and this interaction requires the CxxC motifs in both C1orf123 and CCSdI, implying a metal-mediated interaction. C1orf123 did not interact with several other HMA-domain-containing proteins, indicating high specificity for CCSdI.","method":"Yeast two-hybrid screening, X-ray crystallography, site-directed mutagenesis of CxxC motifs","journal":"PloS one","confidence":"High","confidence_rationale":"Tier 1 / Strong — X-ray crystal structure combined with yeast two-hybrid interaction assay and CxxC mutagenesis validating the interaction mechanism in a single rigorous study","pmids":["30260988"],"is_preprint":false},{"year":2018,"finding":"The crystal structure of recombinant human C1ORF123 reveals a monomeric protein with 2-fold internal symmetry, two mirrored halves with distinct electrostatic potential, and an N-terminal zinc-binding domain near a potential ligand-binding cavity. Functional studies of C1ORF123 and its fission yeast homologue SpEss1 implicate the DUF866 family protein in mitochondrial oxidative phosphorylation.","method":"X-ray crystallography (crystal structure determination), functional studies of yeast homologue SpEss1 in mitochondrial oxidative phosphorylation","journal":"PeerJ","confidence":"Medium","confidence_rationale":"Tier 1 / Weak — crystal structure is rigorous but the functional link to mitochondrial oxidative phosphorylation is from a single study relying partly on the yeast homologue with limited mechanistic detail in the abstract","pmids":["30280012"],"is_preprint":false},{"year":2016,"finding":"Recombinant human C1ORF123 was successfully overexpressed, purified, and crystallized, diffracting to 1.9 Å resolution in an orthorhombic space group, with two molecules per asymmetric unit; identity confirmed by mass spectrometry and Western blot with anti-C1ORF123 antibodies.","method":"Recombinant protein expression and purification, mass spectrometry, Western blot, X-ray crystallography","journal":"Acta crystallographica. Section F, Structural biology communications","confidence":"Medium","confidence_rationale":"Tier 1 / Weak — crystal structure determination reported (structural paper) but no functional/mechanistic conclusions drawn beyond confirming protein identity and crystal parameters","pmids":["26919524"],"is_preprint":false}],"current_model":"CZIB (C1orf123) is a eukaryote-conserved DUF866-family zinc-binding protein whose crystal structure reveals two CxxC motifs that tetrahedrally coordinate a Zn2+ ion; it specifically interacts with the HMA domain of the copper chaperone CCS in a metal-mediated, CxxC-dependent manner, and functional studies in yeast implicate it in mitochondrial oxidative phosphorylation."},"narrative":{"mechanistic_narrative":"CZIB (C1orf123) is a eukaryote-conserved DUF866-family zinc-binding protein implicated in copper metalloregulation and mitochondrial energy metabolism [PMID:30260988, PMID:30280012]. X-ray crystallography establishes that it coordinates a single Zn2+ ion in tetrahedral geometry through four thiolate groups contributed by two conserved CxxC motifs, defining a monomeric protein with 2-fold internal symmetry and an N-terminal zinc-binding domain adjacent to a potential ligand-binding cavity [PMID:30260988, PMID:30280012]. Through these CxxC motifs it engages the HMA domain (domain I) of the copper chaperone for superoxide dismutase (CCS) in a metal-mediated, CxxC-dependent manner, and it discriminates against other HMA-domain proteins, indicating a specific partnership with CCSdI [PMID:30260988]. Functional analysis of the human protein and its fission yeast homologue SpEss1 links this DUF866 family to mitochondrial oxidative phosphorylation [PMID:30280012]. Beyond the CCS interaction and the OXPHOS association, the downstream biochemical role of CZIB has not been characterized in the available corpus.","teleology":[{"year":2016,"claim":"Before any structural data existed, it was unknown whether human C1ORF123 could be obtained in a form suitable for atomic-resolution study; establishing a diffracting crystal opened the protein to mechanistic interrogation.","evidence":"Recombinant expression, purification, mass-spectrometry/Western-blot identity confirmation, and crystallization diffracting to 1.9 Å","pmids":["26919524"],"confidence":"Medium","gaps":["No functional or mechanistic conclusion drawn","Metal content and binding partners not yet defined"]},{"year":2018,"claim":"The question of what CZIB binds and how was answered by showing it tetrahedrally coordinates Zn2+ via two CxxC motifs and uses those motifs to engage the HMA domain of the copper chaperone CCS, establishing a metal-mediated, partner-specific interaction.","evidence":"Yeast two-hybrid screening, X-ray crystallography, and site-directed mutagenesis of CxxC motifs","pmids":["30260988"],"confidence":"High","gaps":["Functional consequence of the CZIB–CCSdI interaction not defined","Whether the bound metal is exchanged or transferred to CCS not resolved","Cellular context and stoichiometry of the complex unknown"]},{"year":2018,"claim":"Building on the structure, the architecture (monomeric, 2-fold internal symmetry, N-terminal zinc-binding domain near a ligand cavity) was defined and the DUF866 family was functionally linked to mitochondrial oxidative phosphorylation via the human protein and its fission yeast homologue.","evidence":"X-ray crystallography plus functional studies of fission yeast homologue SpEss1 in mitochondrial oxidative phosphorylation","pmids":["30280012"],"confidence":"Medium","gaps":["Mechanism connecting CZIB to OXPHOS not established","Reliance partly on yeast homologue; human relevance not fully demonstrated","Identity of the ligand for the predicted cavity unknown"]},{"year":null,"claim":"The downstream biochemical function of CZIB and how its CCS interaction and zinc binding feed into mitochondrial oxidative phosphorylation remain unresolved.","evidence":"","pmids":[],"confidence":"Medium","gaps":["No enzymatic activity assigned","No demonstrated copper/zinc transfer reaction","Pathway linking CCS binding to OXPHOS not mapped"]}],"mechanism_profile":{"molecular_activity":[{"term_id":"GO:0140110","term_label":"transcription regulator activity","supporting_discovery_ids":[0]}],"localization":[],"pathway":[],"complexes":[],"partners":["CCS"],"other_free_text":[]}},"prefetch_data":{"uniprot":{"accession":"Q9NWV4","full_name":"CXXC motif containing zinc binding protein","aliases":["UPF0587 protein C1orf123"],"length_aa":160,"mass_kda":18.0,"function":"","subcellular_location":"","url":"https://www.uniprot.org/uniprotkb/Q9NWV4/entry"},"depmap":{"release":"DepMap","has_data":true,"is_common_essential":false,"resolved_as":"","url":"https://depmap.org/portal/gene/CZIB","classification":"Not Classified","n_dependent_lines":23,"n_total_lines":1208,"dependency_fraction":0.01903973509933775},"opencell":{"profiled":true,"resolved_as":"","ensg_id":"ENSG00000162384","cell_line_id":"CID000383","localizations":[{"compartment":"cytoplasmic","grade":3},{"compartment":"nucleoplasm","grade":3}],"interactors":[{"gene":"SFPQ","stoichiometry":0.2}],"url":"https://opencell.sf.czbiohub.org/target/CID000383","total_profiled":1310},"omim":[],"hpa":{"profiled":true,"resolved_as":"","reliability":"Approved","locations":[{"location":"Cytosol","reliability":"Approved"},{"location":"Vesicles","reliability":"Additional"},{"location":"Mitotic spindle","reliability":"Additional"}],"tissue_specificity":"Low tissue specificity","tissue_distribution":"Detected in all","driving_tissues":[],"url":"https://www.proteinatlas.org/search/CZIB"},"hgnc":{"alias_symbol":["FLJ20580"],"prev_symbol":["C1orf123"]},"alphafold":{"accession":"Q9NWV4","domains":[{"cath_id":"-","chopping":"1-158","consensus_level":"medium","plddt":96.9644,"start":1,"end":158}],"viewer_url":"https://alphafold.ebi.ac.uk/entry/Q9NWV4","model_url":"https://alphafold.ebi.ac.uk/files/AF-Q9NWV4-F1-model_v6.cif","pae_url":"https://alphafold.ebi.ac.uk/files/AF-Q9NWV4-F1-predicted_aligned_error_v6.png","plddt_mean":97.0},"mouse_models":{"mgi_url":"https://www.informatics.jax.org/marker/summary?nomen=CZIB","jax_strain_url":"https://www.jax.org/strain/search?query=CZIB"},"sequence":{"accession":"Q9NWV4","fasta_url":"https://rest.uniprot.org/uniprotkb/Q9NWV4.fasta","uniprot_url":"https://www.uniprot.org/uniprotkb/Q9NWV4/entry","alphafold_viewer_url":"https://alphafold.ebi.ac.uk/entry/Q9NWV4"}},"corpus_meta":[{"pmid":"35008858","id":"PMC_35008858","title":"New Proteins Contributing to Immune Cell Infiltration and Pannus Formation of Synovial Membrane from Arthritis Diseases.","date":"2021","source":"International journal of molecular sciences","url":"https://pubmed.ncbi.nlm.nih.gov/35008858","citation_count":25,"is_preprint":false},{"pmid":"30260988","id":"PMC_30260988","title":"Identification of a novel zinc-binding protein, C1orf123, as an interactor with a heavy metal-associated domain.","date":"2018","source":"PloS one","url":"https://pubmed.ncbi.nlm.nih.gov/30260988","citation_count":13,"is_preprint":false},{"pmid":"21798097","id":"PMC_21798097","title":"Integrated genomics and proteomics of the Torpedo californica electric organ: concordance with the mammalian neuromuscular junction.","date":"2011","source":"Skeletal muscle","url":"https://pubmed.ncbi.nlm.nih.gov/21798097","citation_count":12,"is_preprint":false},{"pmid":"33977573","id":"PMC_33977573","title":"TMT based deep proteome analysis of buffalo mammary epithelial cells and identification of novel protein signatures during lactogenic differentiation.","date":"2021","source":"FASEB journal : official publication of the Federation of American Societies for Experimental Biology","url":"https://pubmed.ncbi.nlm.nih.gov/33977573","citation_count":8,"is_preprint":false},{"pmid":"38154582","id":"PMC_38154582","title":"Genetic correlation, shared loci, but no causality between bipolar disorder and inflammatory bowel disease: A genome-wide pleiotropic analysis.","date":"2023","source":"Journal of affective disorders","url":"https://pubmed.ncbi.nlm.nih.gov/38154582","citation_count":7,"is_preprint":false},{"pmid":"30280012","id":"PMC_30280012","title":"Crystal structure and functional analysis of human C1ORF123.","date":"2018","source":"PeerJ","url":"https://pubmed.ncbi.nlm.nih.gov/30280012","citation_count":5,"is_preprint":false},{"pmid":"26919524","id":"PMC_26919524","title":"Cloning, expression, purification, crystallization and X-ray crystallographic analysis of recombinant human C1ORF123 protein.","date":"2016","source":"Acta crystallographica. Section F, Structural biology communications","url":"https://pubmed.ncbi.nlm.nih.gov/26919524","citation_count":1,"is_preprint":false}],"cost":{"stage1":{"model":"claude-sonnet-4-6","input_tokens":5649,"output_tokens":919,"usd":0.015366,"stage1_stop_reason":"end_turn"},"stage2":{"model":"claude-opus-4-8","input_tokens":7397,"output_tokens":1496,"usd":0.037193,"stage2_stop_reason":"end_turn"},"total_usd":0.052559,"stage1_batch_id":"msgbatch_01ACAxJQabDsht39JXeWG22d","stage2_batch_id":"msgbatch_01QEU22A9U5sbPTgsMzTmvSf","note":"batch pricing = 50% of standard"},"stage1_raw":"```json\n{\n  \"discoveries\": [\n    {\n      \"year\": 2018,\n      \"finding\": \"C1orf123 (CZIB) binds a Zn2+ ion in tetrahedral coordination via four thiolate groups from two conserved CxxC motifs, as revealed by X-ray crystallography. The protein specifically interacts with the HMA domain of the copper chaperone for superoxide dismutase (CCS domain I; CCSdI), and this interaction requires the CxxC motifs in both C1orf123 and CCSdI, implying a metal-mediated interaction. C1orf123 did not interact with several other HMA-domain-containing proteins, indicating high specificity for CCSdI.\",\n      \"method\": \"Yeast two-hybrid screening, X-ray crystallography, site-directed mutagenesis of CxxC motifs\",\n      \"journal\": \"PloS one\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 / Strong — X-ray crystal structure combined with yeast two-hybrid interaction assay and CxxC mutagenesis validating the interaction mechanism in a single rigorous study\",\n      \"pmids\": [\"30260988\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2018,\n      \"finding\": \"The crystal structure of recombinant human C1ORF123 reveals a monomeric protein with 2-fold internal symmetry, two mirrored halves with distinct electrostatic potential, and an N-terminal zinc-binding domain near a potential ligand-binding cavity. Functional studies of C1ORF123 and its fission yeast homologue SpEss1 implicate the DUF866 family protein in mitochondrial oxidative phosphorylation.\",\n      \"method\": \"X-ray crystallography (crystal structure determination), functional studies of yeast homologue SpEss1 in mitochondrial oxidative phosphorylation\",\n      \"journal\": \"PeerJ\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 1 / Weak — crystal structure is rigorous but the functional link to mitochondrial oxidative phosphorylation is from a single study relying partly on the yeast homologue with limited mechanistic detail in the abstract\",\n      \"pmids\": [\"30280012\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2016,\n      \"finding\": \"Recombinant human C1ORF123 was successfully overexpressed, purified, and crystallized, diffracting to 1.9 Å resolution in an orthorhombic space group, with two molecules per asymmetric unit; identity confirmed by mass spectrometry and Western blot with anti-C1ORF123 antibodies.\",\n      \"method\": \"Recombinant protein expression and purification, mass spectrometry, Western blot, X-ray crystallography\",\n      \"journal\": \"Acta crystallographica. Section F, Structural biology communications\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 1 / Weak — crystal structure determination reported (structural paper) but no functional/mechanistic conclusions drawn beyond confirming protein identity and crystal parameters\",\n      \"pmids\": [\"26919524\"],\n      \"is_preprint\": false\n    }\n  ],\n  \"current_model\": \"CZIB (C1orf123) is a eukaryote-conserved DUF866-family zinc-binding protein whose crystal structure reveals two CxxC motifs that tetrahedrally coordinate a Zn2+ ion; it specifically interacts with the HMA domain of the copper chaperone CCS in a metal-mediated, CxxC-dependent manner, and functional studies in yeast implicate it in mitochondrial oxidative phosphorylation.\"\n}\n```","stage2_raw":"{\n  \"mechanistic_narrative\": \"CZIB (C1orf123) is a eukaryote-conserved DUF866-family zinc-binding protein implicated in copper metalloregulation and mitochondrial energy metabolism [#0, #1]. X-ray crystallography establishes that it coordinates a single Zn2+ ion in tetrahedral geometry through four thiolate groups contributed by two conserved CxxC motifs, defining a monomeric protein with 2-fold internal symmetry and an N-terminal zinc-binding domain adjacent to a potential ligand-binding cavity [#0, #1]. Through these CxxC motifs it engages the HMA domain (domain I) of the copper chaperone for superoxide dismutase (CCS) in a metal-mediated, CxxC-dependent manner, and it discriminates against other HMA-domain proteins, indicating a specific partnership with CCSdI [#0]. Functional analysis of the human protein and its fission yeast homologue SpEss1 links this DUF866 family to mitochondrial oxidative phosphorylation [#1]. Beyond the CCS interaction and the OXPHOS association, the downstream biochemical role of CZIB has not been characterized in the available corpus.\",\n  \"teleology\": [\n    {\n      \"year\": 2016,\n      \"claim\": \"Before any structural data existed, it was unknown whether human C1ORF123 could be obtained in a form suitable for atomic-resolution study; establishing a diffracting crystal opened the protein to mechanistic interrogation.\",\n      \"evidence\": \"Recombinant expression, purification, mass-spectrometry/Western-blot identity confirmation, and crystallization diffracting to 1.9 Å\",\n      \"pmids\": [\"26919524\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"No functional or mechanistic conclusion drawn\", \"Metal content and binding partners not yet defined\"]\n    },\n    {\n      \"year\": 2018,\n      \"claim\": \"The question of what CZIB binds and how was answered by showing it tetrahedrally coordinates Zn2+ via two CxxC motifs and uses those motifs to engage the HMA domain of the copper chaperone CCS, establishing a metal-mediated, partner-specific interaction.\",\n      \"evidence\": \"Yeast two-hybrid screening, X-ray crystallography, and site-directed mutagenesis of CxxC motifs\",\n      \"pmids\": [\"30260988\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Functional consequence of the CZIB–CCSdI interaction not defined\", \"Whether the bound metal is exchanged or transferred to CCS not resolved\", \"Cellular context and stoichiometry of the complex unknown\"]\n    },\n    {\n      \"year\": 2018,\n      \"claim\": \"Building on the structure, the architecture (monomeric, 2-fold internal symmetry, N-terminal zinc-binding domain near a ligand cavity) was defined and the DUF866 family was functionally linked to mitochondrial oxidative phosphorylation via the human protein and its fission yeast homologue.\",\n      \"evidence\": \"X-ray crystallography plus functional studies of fission yeast homologue SpEss1 in mitochondrial oxidative phosphorylation\",\n      \"pmids\": [\"30280012\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Mechanism connecting CZIB to OXPHOS not established\", \"Reliance partly on yeast homologue; human relevance not fully demonstrated\", \"Identity of the ligand for the predicted cavity unknown\"]\n    },\n    {\n      \"year\": null,\n      \"claim\": \"The downstream biochemical function of CZIB and how its CCS interaction and zinc binding feed into mitochondrial oxidative phosphorylation remain unresolved.\",\n      \"evidence\": \"\",\n      \"pmids\": [],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"No enzymatic activity assigned\", \"No demonstrated copper/zinc transfer reaction\", \"Pathway linking CCS binding to OXPHOS not mapped\"]\n    }\n  ],\n  \"mechanism_profile\": {\n    \"molecular_activity\": [\n      {\"term_id\": \"GO:0140110\", \"supporting_discovery_ids\": [0]}\n    ],\n    \"localization\": [],\n    \"pathway\": [],\n    \"complexes\": [],\n    \"partners\": [\"CCS\"],\n    \"other_free_text\": []\n  }\n}","audit_flag":null,"evaluation":{"faith_supported":4,"faith_total":4,"faith_pct":100.0}}