{"gene":"CBY3","run_date":"2026-06-09T22:57:17","timeline":{"discoveries":[{"year":2024,"finding":"Cby3 forms a complex with ciBAR1 (Cby1-interacting BAR domain-containing 1) and both proteins colocalize to the sperm annulus near the curved membrane invagination at the flagellar pocket; loss of either gene in mice causes annulus mispositioning into the principal piece and kinked flagella, indicating that the Cby3/ciBAR1 complex regulates local periannular membrane properties to halt annulus migration at the midpiece/principal piece junction.","method":"Mouse knockout (ablation of Cby3 or ciBAR1), co-immunoprecipitation/interaction assay, colocalization imaging, ultrastructural membrane analysis","journal":"The Journal of cell biology","confidence":"High","confidence_rationale":"Tier 2 / Strong — reciprocal protein interaction confirmed, clean KO mouse with specific cellular/structural phenotype, colocalization, and membrane ultrastructure analysis; multiple orthogonal methods in a single focused study","pmids":["38197861"],"is_preprint":false}],"current_model":"CBY3 (Chibby3) forms a complex with the BAR-domain protein ciBAR1 at the sperm annulus, where together they regulate periannular membrane properties to correctly position the annulus at the midpiece/principal piece junction of the sperm flagellum, a process essential for male fertility."},"narrative":{"mechanistic_narrative":"CBY3 (Chibby3) is a regulator of sperm flagellum architecture that acts at the annulus to ensure correct positioning of the midpiece/principal piece junction [PMID:38197861]. CBY3 forms a complex with the BAR-domain protein ciBAR1, and the two proteins colocalize to the sperm annulus near the curved membrane invagination at the flagellar pocket; this complex regulates local periannular membrane properties to halt annulus migration at the midpiece/principal piece boundary [PMID:38197861]. Loss of CBY3 in mice causes the annulus to misposition into the principal piece and produces kinked flagella, linking CBY3 function to male fertility [PMID:38197861]. Beyond this single coherent study, no further mechanistic detail for CBY3 has been characterized in the available corpus.","teleology":[{"year":2024,"claim":"Established that CBY3 partners with ciBAR1 at the sperm annulus to control where the annulus stops migrating, defining a membrane-shaping mechanism required for normal flagellar architecture.","evidence":"Mouse knockout of Cby3 or ciBAR1 with co-immunoprecipitation, colocalization imaging, and ultrastructural membrane analysis","pmids":["38197861"],"confidence":"High","gaps":["The molecular basis by which the CBY3/ciBAR1 complex alters periannular membrane curvature or composition is not resolved","No structural model of the CBY3-ciBAR1 interface or of CBY3 domains is reported","Whether CBY3 has functions outside the sperm annulus is not addressed"]},{"year":null,"claim":"How the CBY3/ciBAR1 complex is recruited to the annulus and mechanistically halts annulus migration remains undefined.","evidence":"","pmids":[],"confidence":"High","gaps":["No upstream recruitment factor or post-translational regulation identified","Direct biochemical activity of CBY3 on membranes not demonstrated"]}],"mechanism_profile":{"molecular_activity":[],"localization":[{"term_id":"GO:0005929","term_label":"cilium","supporting_discovery_ids":[0]}],"pathway":[{"term_id":"R-HSA-1474165","term_label":"Reproduction","supporting_discovery_ids":[0]}],"complexes":[],"partners":["CIBAR1"],"other_free_text":[]}},"prefetch_data":{"uniprot":{"accession":"A6NI87","full_name":"Sperm annulus positioning complex subunit Chibby3","aliases":[],"length_aa":242,"mass_kda":27.3,"function":"Plays a key role in the correct positioning of the annulus, a septin-based ring structure in the sperm flagellum, serving both as a physical barrier and a membrane diffusion barrier that separates the midpiece (MP) from the principal piece (PP) (By similarity). This positioning is essential for proper sperm motility and function (By similarity). CBY3 interacts with CIBAR1 to form a complex which localizes to the curved membrane region of the flagellar pocket (By similarity). By doing so, may provide stability and rigidity to the periannular membrane to prevent membrane deformation (By similarity). This function is crucial for halting annulus migration at the proximal end of the fibrous sheath-containing PP (By similarity)","subcellular_location":"Cell projection, cilium, flagellum","url":"https://www.uniprot.org/uniprotkb/A6NI87/entry"},"depmap":{"release":"DepMap","has_data":true,"is_common_essential":false,"resolved_as":"","url":"https://depmap.org/portal/gene/CBY3","classification":"Not Classified","n_dependent_lines":3,"n_total_lines":1208,"dependency_fraction":0.0024834437086092716},"opencell":{"profiled":false,"resolved_as":"","ensg_id":"","cell_line_id":"","localizations":[],"interactors":[],"url":"https://opencell.sf.czbiohub.org/search/CBY3","total_profiled":1310},"omim":[{"mim_id":"620892","title":"CHIBBY FAMILY, MEMBER 3; CBY3","url":"https://www.omim.org/entry/620892"},{"mim_id":"617273","title":"CBY1-INTERACTING BAR DOMAIN-CONTAINING PROTEIN 1; CIBAR1","url":"https://www.omim.org/entry/617273"}],"hpa":{"profiled":true,"resolved_as":"","reliability":"Approved","locations":[{"location":"Nucleoplasm","reliability":"Approved"}],"tissue_specificity":"Tissue enriched","tissue_distribution":"Detected in single","driving_tissues":[{"tissue":"testis","ntpm":12.3}],"url":"https://www.proteinatlas.org/search/CBY3"},"hgnc":{"alias_symbol":[],"prev_symbol":[]},"alphafold":{"accession":"A6NI87","domains":[{"cath_id":"-","chopping":"105-151","consensus_level":"high","plddt":77.6679,"start":105,"end":151},{"cath_id":"1.20.5","chopping":"155-205","consensus_level":"medium","plddt":84.8269,"start":155,"end":205}],"viewer_url":"https://alphafold.ebi.ac.uk/entry/A6NI87","model_url":"https://alphafold.ebi.ac.uk/files/AF-A6NI87-F1-model_v6.cif","pae_url":"https://alphafold.ebi.ac.uk/files/AF-A6NI87-F1-predicted_aligned_error_v6.png","plddt_mean":67.56},"mouse_models":{"mgi_url":"https://www.informatics.jax.org/marker/summary?nomen=CBY3","jax_strain_url":"https://www.jax.org/strain/search?query=CBY3"},"sequence":{"accession":"A6NI87","fasta_url":"https://rest.uniprot.org/uniprotkb/A6NI87.fasta","uniprot_url":"https://www.uniprot.org/uniprotkb/A6NI87/entry","alphafold_viewer_url":"https://alphafold.ebi.ac.uk/entry/A6NI87"}},"corpus_meta":[{"pmid":"38197861","id":"PMC_38197861","title":"The Cby3/ciBAR1 complex positions the annulus along the sperm flagellum during spermiogenesis.","date":"2024","source":"The Journal of cell biology","url":"https://pubmed.ncbi.nlm.nih.gov/38197861","citation_count":9,"is_preprint":false},{"pmid":"41693862","id":"PMC_41693862","title":"Metagenomic and metatranscriptomic profiling of bronchoalveolar lavage fluid identifies microbial and host biomarkers of drug-resistant tuberculosis.","date":"2026","source":"Frontiers in cellular and infection microbiology","url":"https://pubmed.ncbi.nlm.nih.gov/41693862","citation_count":0,"is_preprint":false}],"cost":{"stage1":{"model":"claude-sonnet-4-6","input_tokens":3214,"output_tokens":379,"usd":0.007664,"stage1_stop_reason":"end_turn"},"stage2":{"model":"claude-opus-4-8","input_tokens":6635,"output_tokens":905,"usd":0.0279,"stage2_stop_reason":"end_turn"},"total_usd":0.035564,"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\": 2024,\n      \"finding\": \"Cby3 forms a complex with ciBAR1 (Cby1-interacting BAR domain-containing 1) and both proteins colocalize to the sperm annulus near the curved membrane invagination at the flagellar pocket; loss of either gene in mice causes annulus mispositioning into the principal piece and kinked flagella, indicating that the Cby3/ciBAR1 complex regulates local periannular membrane properties to halt annulus migration at the midpiece/principal piece junction.\",\n      \"method\": \"Mouse knockout (ablation of Cby3 or ciBAR1), co-immunoprecipitation/interaction assay, colocalization imaging, ultrastructural membrane analysis\",\n      \"journal\": \"The Journal of cell biology\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — reciprocal protein interaction confirmed, clean KO mouse with specific cellular/structural phenotype, colocalization, and membrane ultrastructure analysis; multiple orthogonal methods in a single focused study\",\n      \"pmids\": [\"38197861\"],\n      \"is_preprint\": false\n    }\n  ],\n  \"current_model\": \"CBY3 (Chibby3) forms a complex with the BAR-domain protein ciBAR1 at the sperm annulus, where together they regulate periannular membrane properties to correctly position the annulus at the midpiece/principal piece junction of the sperm flagellum, a process essential for male fertility.\"\n}\n```","stage2_raw":"{\n  \"mechanistic_narrative\": \"CBY3 (Chibby3) is a regulator of sperm flagellum architecture that acts at the annulus to ensure correct positioning of the midpiece/principal piece junction [#0]. CBY3 forms a complex with the BAR-domain protein ciBAR1, and the two proteins colocalize to the sperm annulus near the curved membrane invagination at the flagellar pocket; this complex regulates local periannular membrane properties to halt annulus migration at the midpiece/principal piece boundary [#0]. Loss of CBY3 in mice causes the annulus to misposition into the principal piece and produces kinked flagella, linking CBY3 function to male fertility [#0]. Beyond this single coherent study, no further mechanistic detail for CBY3 has been characterized in the available corpus.\",\n  \"teleology\": [\n    {\n      \"year\": 2024,\n      \"claim\": \"Established that CBY3 partners with ciBAR1 at the sperm annulus to control where the annulus stops migrating, defining a membrane-shaping mechanism required for normal flagellar architecture.\",\n      \"evidence\": \"Mouse knockout of Cby3 or ciBAR1 with co-immunoprecipitation, colocalization imaging, and ultrastructural membrane analysis\",\n      \"pmids\": [\"38197861\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\n        \"The molecular basis by which the CBY3/ciBAR1 complex alters periannular membrane curvature or composition is not resolved\",\n        \"No structural model of the CBY3-ciBAR1 interface or of CBY3 domains is reported\",\n        \"Whether CBY3 has functions outside the sperm annulus is not addressed\"\n      ]\n    },\n    {\n      \"year\": null,\n      \"claim\": \"How the CBY3/ciBAR1 complex is recruited to the annulus and mechanistically halts annulus migration remains undefined.\",\n      \"evidence\": \"\",\n      \"pmids\": [],\n      \"confidence\": \"High\",\n      \"gaps\": [\n        \"No upstream recruitment factor or post-translational regulation identified\",\n        \"Direct biochemical activity of CBY3 on membranes not demonstrated\"\n      ]\n    }\n  ],\n  \"mechanism_profile\": {\n    \"molecular_activity\": [],\n    \"localization\": [\n      {\"term_id\": \"GO:0005929\", \"supporting_discovery_ids\": [0]}\n    ],\n    \"pathway\": [\n      {\"term_id\": \"R-HSA-1474165\", \"supporting_discovery_ids\": [0]}\n    ],\n    \"complexes\": [],\n    \"partners\": [\"CIBAR1\"],\n    \"other_free_text\": []\n  }\n}","audit_flag":null,"evaluation":{"pairwise":"win","faith_supported":3,"faith_total":3,"faith_pct":100.0}}