{"gene":"CIBAR1","run_date":"2026-06-09T22:57:18","timeline":{"discoveries":[{"year":2018,"finding":"FAM92A1 (CIBAR1) is a BAR domain protein that localizes to the matrix side of the mitochondrial inner membrane (MIM) and is required for mitochondrial ultrastructure and function; loss of FAM92A1 causes severe disruption of mitochondrial morphology and impairs organelle bioenergetics; purified FAM92A1 displays membrane-remodeling activity in vitro, inducing high membrane curvature.","method":"Subcellular fractionation, fluorescence microscopy, electron microscopy, in vitro membrane-tubulation assay, loss-of-function cell lines","journal":"The Journal of cell biology","confidence":"High","confidence_rationale":"Tier 1–2 / Moderate — in vitro membrane-remodeling reconstitution combined with organelle fractionation/localization and KO phenotype, single lab but multiple orthogonal methods","pmids":["30404948"],"is_preprint":false},{"year":2018,"finding":"A nonsense variant in FAM92A (CIBAR1) disrupts the FAM92A/Chibby1 (CBY1) protein complex, abolishes FAM92A recruitment to and colocalization with CBY1 at the base of cilia, and impairs ciliogenesis; FAM92A localizes to cilia in the developing mouse limb, implicating the FAM92A–CBY1 complex as critical for ciliogenesis.","method":"Co-immunoprecipitation, immunofluorescence colocalization, Fam92a−/− mouse model, Sanger/exome sequencing for segregation","journal":"Journal of bone and mineral research","confidence":"High","confidence_rationale":"Tier 2 / Moderate — reciprocal Co-IP plus colocalization and KO mouse phenotype, replicated in human genetics and mouse model","pmids":["30395363"],"is_preprint":false},{"year":2024,"finding":"FAM92A1 (CIBAR1) BAR domain crystal structure (resolved at the same time as a second study) reveals an antiparallel crescent-shaped homodimer; the concave surface bears positively charged clusters critical for phosphoinositide- and cardiolipin-containing membrane binding; FAM92A1 induces lipid clustering and membrane curvature as shown by atomistic molecular dynamics simulations and biochemical assays.","method":"Crystal structure determination, atomistic molecular dynamics simulations, biochemical membrane-binding assays, FAM92A1-KO mouse model with cognitive and neuronal morphology phenotyping","journal":"Nature communications","confidence":"High","confidence_rationale":"Tier 1 / Moderate — crystal structure combined with MD simulations, biochemical lipid-binding assays, and in vivo KO phenotype in single rigorous study","pmids":["39043703"],"is_preprint":false},{"year":2025,"finding":"Crystal structure (2.2 Å) of the mouse FAM92A BAR domain reveals an antiparallel crescent-shaped homodimer; structure-guided mutagenesis identifies positively charged residues on the concave surface as critical for lipid binding and separate residues essential for dimerization; FAM92A BAR domain directly binds the N-terminal region of CBY1, and the dimerizations of both proteins synergistically enhance their mutual affinity.","method":"X-ray crystallography (2.2 Å), structure-guided mutagenesis, in vitro binding assays (lipid-binding and protein–protein interaction), dimerization assays","journal":"The Journal of biological chemistry","confidence":"High","confidence_rationale":"Tier 1 / Moderate — crystal structure plus mutagenesis plus in vitro binding assays in single rigorous study","pmids":["40484380"],"is_preprint":false},{"year":2024,"finding":"ciBAR1 (CIBAR1) forms a complex with Chibby3 (Cby3) at the sperm flagellar annulus; Cby3 and ciBAR1 colocalize to the annulus near the curved membrane invagination at the flagellar pocket; ablation of either gene in mice mispositions the annulus into the principal piece and causes male infertility with kinked flagella; the Cby3/ciBAR1 complex regulates local membrane properties to position the annulus at the midpiece/principal-piece junction.","method":"Cby3-KO and ciBAR1-KO mouse models, immunofluorescence colocalization, Co-immunoprecipitation, electron microscopy of flagellar ultrastructure, fertility assays","journal":"The Journal of cell biology","confidence":"High","confidence_rationale":"Tier 2 / Moderate — reciprocal Co-IP, colocalization, and independent KO mouse models with defined morphological and fertility phenotypes","pmids":["38197861"],"is_preprint":false},{"year":2024,"finding":"ciBAR1-KO mice exhibit randomized left-right asymmetry (~28% embryonic lethality), exocrine pancreatic lesions, impaired glucose tolerance, and reduced cilia number and length in ductal and islet cells; ciBAR1-KO MEFs also display ciliary defects, establishing that ciBAR1 plays a critical cell-type-dependent role in ciliogenesis in vivo.","method":"ciBAR1-KO mouse model, histological assessment, glucose tolerance testing, immunofluorescence quantification of cilia number and length, MEF ciliary assays","journal":"Life science alliance","confidence":"High","confidence_rationale":"Tier 2 / Moderate — KO mouse model with multiple defined phenotypic readouts plus MEF ciliary rescue experiments, single lab","pmids":["39622622"],"is_preprint":false},{"year":2025,"finding":"The BAR domain protein ciBAR1 (CIBAR1) can support membrane recruitment of the Fuzzy-Inturned RabGEF complex, as demonstrated by reconstitution experiments.","method":"In vitro reconstitution, protein-lipid interaction studies","journal":"bioRxiv","confidence":"Medium","confidence_rationale":"Tier 1 / Weak — reconstitution experiment but preprint, single lab, limited detail on ciBAR1-specific mechanism in abstract","pmids":["bio_10.1101_2025.03.27.645700"],"is_preprint":true},{"year":2021,"finding":"FAM92A1 (CIBAR1) exists as a dimer and binds the mitochondrial inner membrane as a peripheral membrane protein; the NT* spidroin tag stabilizes FAM92A1 as a dimer and the resulting fusion protein retains membrane-bending activity, confirming that the dimer is the functional unit for membrane remodeling.","method":"Recombinant protein expression and purification, size-exclusion chromatography (dimerization), in vitro liposome membrane-bending assay","journal":"Protein expression and purification","confidence":"Medium","confidence_rationale":"Tier 2 / Weak — in vitro membrane-bending assay with dimerization confirmation, single lab, single study","pmids":["34648955"],"is_preprint":false},{"year":2016,"finding":"FAM92A1-289 (a splice variant of CIBAR1) co-immunoprecipitates with PCNA, suggesting a physical interaction; overexpression promotes cell migration, proliferation, and tumor growth in cervical carcinoma cells.","method":"Co-immunoprecipitation (pulldown with anti-PCNA antibody), scratch assay, MTT assay, colony formation, xenograft","journal":"Anticancer research","confidence":"Low","confidence_rationale":"Tier 3 / Weak — single Co-IP with no reciprocal validation, single lab, tumor-biology context with no mechanistic pathway placement","pmids":["27798880"],"is_preprint":false}],"current_model":"CIBAR1 (FAM92A1) is a homodimeric BAR domain protein whose crescent-shaped concave surface binds phosphoinositide- and cardiolipin-containing membranes to induce membrane curvature; it localizes to the mitochondrial inner membrane matrix side to maintain cristae ultrastructure and bioenergetics, to the ciliary base where it forms a complex with CBY1 (and CBY3 in sperm) to drive ciliogenesis and annulus positioning, and in neurons it shapes mitochondrial, myelin, and synaptic membranes to support synaptic plasticity and cognition."},"narrative":{"mechanistic_narrative":"CIBAR1 (FAM92A1) is a homodimeric BAR domain protein that sculpts cellular membranes to support mitochondrial architecture and ciliogenesis [PMID:30404948, PMID:39043703]. Its crystal structure reveals an antiparallel crescent-shaped homodimer whose concave surface carries positively charged residue clusters that bind phosphoinositide- and cardiolipin-containing membranes, drive lipid clustering, and induce high membrane curvature in vitro [PMID:39043703, PMID:40484380]; dimerization is the functional prerequisite for this membrane-bending activity [PMID:34648955]. At the mitochondrial inner membrane, CIBAR1 acts as a peripheral protein on the matrix side and is required for normal cristae ultrastructure and organelle bioenergetics [PMID:30404948, PMID:34648955]. At the base of cilia, CIBAR1 binds the N-terminal region of CBY1 — an interaction in which the dimerization of both partners synergistically enhances mutual affinity — and this complex is required for ciliogenesis; a nonsense FAM92A variant that disrupts the complex abolishes CIBAR1 recruitment to CBY1 and impairs cilium formation [PMID:30395363, PMID:40484380]. In vivo loss of CIBAR1 produces cell-type-dependent ciliary defects with randomized left-right asymmetry, exocrine pancreatic lesions, and impaired glucose tolerance [PMID:39622622]. In sperm, CIBAR1 partners with CBY3 at the flagellar annulus to position it at the midpiece/principal-piece junction, with loss causing kinked flagella and male infertility [PMID:38197861]. CIBAR1 can also support membrane recruitment of the Fuzzy-Inturned RabGEF complex [PMID:bio_10.1101_2025.03.27.645700].","teleology":[{"year":2016,"claim":"An early association placed a CIBAR1 splice variant in a proliferative/tumor context, raising the question of whether the protein had a nuclear or cell-cycle role.","evidence":"Co-immunoprecipitation with PCNA plus migration, proliferation, colony formation, and xenograft assays in cervical carcinoma cells","pmids":["27798880"],"confidence":"Low","gaps":["Single Co-IP without reciprocal validation","No mechanistic pathway linking CIBAR1 to PCNA function","Splice-variant-specific; not reconciled with later membrane-remodeling biology"]},{"year":2018,"claim":"Established CIBAR1 as a membrane-remodeling BAR protein at the mitochondrial inner membrane, defining its core biochemical activity and an organelle role.","evidence":"Subcellular fractionation, EM, in vitro membrane-tubulation assay, and loss-of-function cell lines","pmids":["30404948"],"confidence":"High","gaps":["Molecular trigger for matrix-side recruitment not defined","Relationship between mitochondrial and ciliary pools unresolved"]},{"year":2018,"claim":"Identified the CIBAR1–CBY1 complex at the ciliary base as essential for ciliogenesis, extending the protein's role beyond mitochondria.","evidence":"Reciprocal Co-IP, immunofluorescence colocalization, Fam92a-KO mouse, and human variant segregation","pmids":["30395363"],"confidence":"High","gaps":["Did not resolve the structural basis of the CBY1 interaction","Mechanism connecting CBY1 binding to curvature generation unknown"]},{"year":2021,"claim":"Confirmed that the dimer, not the monomer, is the functional unit for membrane bending, clarifying the quaternary requirement for activity.","evidence":"Recombinant expression, size-exclusion chromatography, and liposome membrane-bending assays using an NT* spidroin dimerization tag","pmids":["34648955"],"confidence":"Medium","gaps":["In vitro only; physiological dimer regulation not addressed","Single lab"]},{"year":2024,"claim":"Solved the BAR domain structure and defined the concave-surface residues mediating phosphoinositide/cardiolipin binding, providing the physical basis for curvature induction and linking the protein to neuronal function.","evidence":"Crystal structure, atomistic MD simulations, biochemical membrane-binding assays, and FAM92A1-KO mouse cognitive/neuronal phenotyping","pmids":["39043703"],"confidence":"High","gaps":["How specific lipid recognition is tuned across mitochondrial vs ciliary membranes not resolved","Neuronal phenotype mechanism not traced to a specific membrane substrate"]},{"year":2024,"claim":"Showed CIBAR1 partners with CBY3 at the sperm flagellar annulus, demonstrating a tissue-specific paralog complex controlling annulus positioning and fertility.","evidence":"Cby3-KO and ciBAR1-KO mouse models, colocalization, Co-IP, EM, and fertility assays","pmids":["38197861"],"confidence":"High","gaps":["Determinants selecting CBY1 vs CBY3 partnership not defined","Molecular mechanism of annulus membrane positioning incomplete"]},{"year":2024,"claim":"Defined the in vivo consequences of CIBAR1 loss across tissues, establishing a cell-type-dependent ciliogenesis role with developmental and metabolic outcomes.","evidence":"ciBAR1-KO mouse histology, glucose tolerance testing, cilia quantification, and MEF ciliary assays","pmids":["39622622"],"confidence":"High","gaps":["Basis of cell-type-dependent ciliary requirement unexplained","Link between ciliary defect and glucose intolerance mechanism not established"]},{"year":2025,"claim":"Resolved the structural basis of the CIBAR1–CBY1 interaction, showing the BAR domain binds the CBY1 N-terminus and that mutual dimerization synergistically strengthens affinity.","evidence":"2.2 Å crystal structure, structure-guided mutagenesis, and in vitro lipid- and protein-binding/dimerization assays","pmids":["40484380"],"confidence":"High","gaps":["Does not show how complex formation is coupled to membrane curvature at the ciliary base in vivo","Regulation of complex assembly timing unknown"]},{"year":2025,"claim":"Connected CIBAR1's membrane-binding activity to downstream ciliary signaling machinery by showing it can recruit a RabGEF complex to membranes.","evidence":"In vitro reconstitution and protein-lipid interaction studies (preprint)","pmids":["bio_10.1101_2025.03.27.645700"],"confidence":"Medium","gaps":["Preprint, single lab","ciBAR1-specific recruitment mechanism not detailed","Not validated in cells/in vivo"]},{"year":null,"claim":"How CIBAR1 is partitioned and regulated between its mitochondrial, ciliary-base, and flagellar pools — and what selects its lipid and protein partners in each context — remains unresolved.","evidence":"","pmids":[],"confidence":"High","gaps":["No mechanism for targeting to distinct membrane compartments","No upstream regulator of CIBAR1 recruitment identified","Functional integration of mitochondrial vs ciliary roles unknown"]}],"mechanism_profile":{"molecular_activity":[{"term_id":"GO:0008289","term_label":"lipid binding","supporting_discovery_ids":[2,3]},{"term_id":"GO:0005198","term_label":"structural molecule activity","supporting_discovery_ids":[0,2,7]},{"term_id":"GO:0060090","term_label":"molecular adaptor activity","supporting_discovery_ids":[1,3]}],"localization":[{"term_id":"GO:0005739","term_label":"mitochondrion","supporting_discovery_ids":[0,7]},{"term_id":"GO:0005929","term_label":"cilium","supporting_discovery_ids":[1,5]},{"term_id":"GO:0005815","term_label":"microtubule organizing center","supporting_discovery_ids":[1,4]}],"pathway":[{"term_id":"R-HSA-1852241","term_label":"Organelle biogenesis and maintenance","supporting_discovery_ids":[1,5]},{"term_id":"R-HSA-1266738","term_label":"Developmental Biology","supporting_discovery_ids":[4,5]}],"complexes":["CIBAR1–CBY1 complex","CIBAR1–CBY3 complex"],"partners":["CBY1","CBY3"],"other_free_text":[]}},"prefetch_data":{"uniprot":{"accession":"A1XBS5","full_name":"CBY1-interacting BAR domain-containing protein 1","aliases":[],"length_aa":289,"mass_kda":33.4,"function":"Plays a critical role in regulating mitochondrial ultrastructure and function by maintaining the integrity of mitochondrial morphology, particularly the organization of cristae (PubMed:30404948). Preferentially binds to negatively charged phospholipids like cardiolipin and phosphatidylinositol 4,5-bisphosphate enhancing its interaction with mitochondrial membranes (PubMed:30404948). Induces membrane curvature and tubulation, which are critical for maintaining mitochondrial ultrastructure and the organization of cristae (PubMed:30404948). Plays a crucial role in ciliogenesis (PubMed:27528616, PubMed:30395363). May play a role in limb development through its role in ciliogenesis (PubMed:30395363). 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). Interacts with CBY3 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":"Nucleus","url":"https://www.uniprot.org/uniprotkb/A1XBS5/entry"},"depmap":{"release":"DepMap","has_data":true,"is_common_essential":false,"resolved_as":"","url":"https://depmap.org/portal/gene/CIBAR1","classification":"Not Classified","n_dependent_lines":2,"n_total_lines":1208,"dependency_fraction":0.0016556291390728477},"opencell":{"profiled":false,"resolved_as":"","ensg_id":"","cell_line_id":"","localizations":[],"interactors":[{"gene":"COPB2","stoichiometry":0.2}],"url":"https://opencell.sf.czbiohub.org/search/CIBAR1","total_profiled":1310},"omim":[{"mim_id":"620892","title":"CHIBBY FAMILY, MEMBER 3; CBY3","url":"https://www.omim.org/entry/620892"},{"mim_id":"620107","title":"OROFACIODIGITAL SYNDROME XIX; OFD19","url":"https://www.omim.org/entry/620107"},{"mim_id":"617274","title":"CBY1-INTERACTING BAR DOMAIN-CONTAINING PROTEIN 2; CIBAR2","url":"https://www.omim.org/entry/617274"},{"mim_id":"617273","title":"CBY1-INTERACTING BAR DOMAIN-CONTAINING PROTEIN 1; CIBAR1","url":"https://www.omim.org/entry/617273"},{"mim_id":"608095","title":"SODIUM CHANNEL MODIFIER 1; SCNM1","url":"https://www.omim.org/entry/608095"}],"hpa":{"profiled":true,"resolved_as":"","reliability":"Supported","locations":[{"location":"Mitochondria","reliability":"Supported"}],"tissue_specificity":"Tissue enhanced","tissue_distribution":"Detected in all","driving_tissues":[{"tissue":"testis","ntpm":102.1}],"url":"https://www.proteinatlas.org/search/CIBAR1"},"hgnc":{"alias_symbol":["FLJ38979","BARMR1"],"prev_symbol":["FAM92A1","FAM92A"]},"alphafold":{"accession":"A1XBS5","domains":[{"cath_id":"1.20.1270.60","chopping":"2-8_27-216","consensus_level":"medium","plddt":95.9619,"start":2,"end":216}],"viewer_url":"https://alphafold.ebi.ac.uk/entry/A1XBS5","model_url":"https://alphafold.ebi.ac.uk/files/AF-A1XBS5-F1-model_v6.cif","pae_url":"https://alphafold.ebi.ac.uk/files/AF-A1XBS5-F1-predicted_aligned_error_v6.png","plddt_mean":85.12},"mouse_models":{"mgi_url":"https://www.informatics.jax.org/marker/summary?nomen=CIBAR1","jax_strain_url":"https://www.jax.org/strain/search?query=CIBAR1"},"sequence":{"accession":"A1XBS5","fasta_url":"https://rest.uniprot.org/uniprotkb/A1XBS5.fasta","uniprot_url":"https://www.uniprot.org/uniprotkb/A1XBS5/entry","alphafold_viewer_url":"https://alphafold.ebi.ac.uk/entry/A1XBS5"}},"corpus_meta":[{"pmid":"30395363","id":"PMC_30395363","title":"FAM92A Underlies Nonsyndromic Postaxial Polydactyly in Humans and an Abnormal Limb and Digit Skeletal Phenotype in Mice.","date":"2018","source":"Journal of bone and mineral research : the official journal of the American Society for Bone and Mineral Research","url":"https://pubmed.ncbi.nlm.nih.gov/30395363","citation_count":35,"is_preprint":false},{"pmid":"30404948","id":"PMC_30404948","title":"FAM92A1 is a BAR domain protein required for mitochondrial ultrastructure and function.","date":"2018","source":"The Journal of cell biology","url":"https://pubmed.ncbi.nlm.nih.gov/30404948","citation_count":29,"is_preprint":false},{"pmid":"19059705","id":"PMC_19059705","title":"Prokaryotic expression, purification of a new tumor-relative protein FAM92A1-289 and its characterization in renal cell carcinoma.","date":"2008","source":"Cancer letters","url":"https://pubmed.ncbi.nlm.nih.gov/19059705","citation_count":15,"is_preprint":false},{"pmid":"39043703","id":"PMC_39043703","title":"Membrane remodeling by FAM92A1 during brain development regulates neuronal morphology, synaptic function, and cognition.","date":"2024","source":"Nature communications","url":"https://pubmed.ncbi.nlm.nih.gov/39043703","citation_count":9,"is_preprint":false},{"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":"17646714","id":"PMC_17646714","title":"Identification and characterization of two novel variants of the DUF1208 protein FAM92A1.","date":"2007","source":"Molecules and cells","url":"https://pubmed.ncbi.nlm.nih.gov/17646714","citation_count":6,"is_preprint":false},{"pmid":"34648955","id":"PMC_34648955","title":"Optimizing purification of the peripheral membrane protein FAM92A1 fused to a modified spidroin tag.","date":"2021","source":"Protein expression and purification","url":"https://pubmed.ncbi.nlm.nih.gov/34648955","citation_count":5,"is_preprint":false},{"pmid":"27798880","id":"PMC_27798880","title":"The Tumor-promoting Effects of FAM92A1-289 in Cervical Carcinoma Cells.","date":"2016","source":"Anticancer research","url":"https://pubmed.ncbi.nlm.nih.gov/27798880","citation_count":5,"is_preprint":false},{"pmid":"32891772","id":"PMC_32891772","title":"BARMR1/FAM92A1, a novel gene encoding BAR domain protein with multi-functions.","date":"2020","source":"Gene","url":"https://pubmed.ncbi.nlm.nih.gov/32891772","citation_count":3,"is_preprint":false},{"pmid":"38853702","id":"PMC_38853702","title":"A novel homozygous FAM92A gene (CIBAR1) variant further confirms its association with non-syndromic postaxial polydactyly type A9 (PAPA9).","date":"2024","source":"Clinical genetics","url":"https://pubmed.ncbi.nlm.nih.gov/38853702","citation_count":3,"is_preprint":false},{"pmid":"39622622","id":"PMC_39622622","title":"ciBAR1 loss in mice causes laterality defects, pancreatic degeneration, and altered glucose tolerance.","date":"2024","source":"Life science alliance","url":"https://pubmed.ncbi.nlm.nih.gov/39622622","citation_count":1,"is_preprint":false},{"pmid":"40484380","id":"PMC_40484380","title":"Dimerization of the BAR domain-containing protein FAM92A modulates lipid binding and interaction with CBY1.","date":"2025","source":"The Journal of biological chemistry","url":"https://pubmed.ncbi.nlm.nih.gov/40484380","citation_count":0,"is_preprint":false},{"pmid":"41568362","id":"PMC_41568362","title":"Identification of the HMGA2::CIBAR1-DT fusion transcript in two lipomas with chromosomal rearrangements involving chromosomes 8 and 12.","date":"2026","source":"Frontiers in oncology","url":"https://pubmed.ncbi.nlm.nih.gov/41568362","citation_count":0,"is_preprint":false},{"pmid":null,"id":"bio_10.1101_2025.03.27.645700","title":"Mechanistic Plasticity of the RabGEFs Mon1-Ccz1 and Fuzzy-Inturned","date":"2025-03-28","source":"bioRxiv","url":"https://doi.org/10.1101/2025.03.27.645700","citation_count":0,"is_preprint":true}],"cost":{"stage1":{"model":"claude-sonnet-4-6","input_tokens":7807,"output_tokens":2338,"usd":0.029246,"stage1_stop_reason":"end_turn"},"stage2":{"model":"claude-opus-4-8","input_tokens":9481,"output_tokens":3185,"usd":0.063515,"stage2_stop_reason":"end_turn"},"total_usd":0.092761,"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\": \"FAM92A1 (CIBAR1) is a BAR domain protein that localizes to the matrix side of the mitochondrial inner membrane (MIM) and is required for mitochondrial ultrastructure and function; loss of FAM92A1 causes severe disruption of mitochondrial morphology and impairs organelle bioenergetics; purified FAM92A1 displays membrane-remodeling activity in vitro, inducing high membrane curvature.\",\n      \"method\": \"Subcellular fractionation, fluorescence microscopy, electron microscopy, in vitro membrane-tubulation assay, loss-of-function cell lines\",\n      \"journal\": \"The Journal of cell biology\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1–2 / Moderate — in vitro membrane-remodeling reconstitution combined with organelle fractionation/localization and KO phenotype, single lab but multiple orthogonal methods\",\n      \"pmids\": [\"30404948\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2018,\n      \"finding\": \"A nonsense variant in FAM92A (CIBAR1) disrupts the FAM92A/Chibby1 (CBY1) protein complex, abolishes FAM92A recruitment to and colocalization with CBY1 at the base of cilia, and impairs ciliogenesis; FAM92A localizes to cilia in the developing mouse limb, implicating the FAM92A–CBY1 complex as critical for ciliogenesis.\",\n      \"method\": \"Co-immunoprecipitation, immunofluorescence colocalization, Fam92a−/− mouse model, Sanger/exome sequencing for segregation\",\n      \"journal\": \"Journal of bone and mineral research\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — reciprocal Co-IP plus colocalization and KO mouse phenotype, replicated in human genetics and mouse model\",\n      \"pmids\": [\"30395363\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2024,\n      \"finding\": \"FAM92A1 (CIBAR1) BAR domain crystal structure (resolved at the same time as a second study) reveals an antiparallel crescent-shaped homodimer; the concave surface bears positively charged clusters critical for phosphoinositide- and cardiolipin-containing membrane binding; FAM92A1 induces lipid clustering and membrane curvature as shown by atomistic molecular dynamics simulations and biochemical assays.\",\n      \"method\": \"Crystal structure determination, atomistic molecular dynamics simulations, biochemical membrane-binding assays, FAM92A1-KO mouse model with cognitive and neuronal morphology phenotyping\",\n      \"journal\": \"Nature communications\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 / Moderate — crystal structure combined with MD simulations, biochemical lipid-binding assays, and in vivo KO phenotype in single rigorous study\",\n      \"pmids\": [\"39043703\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2025,\n      \"finding\": \"Crystal structure (2.2 Å) of the mouse FAM92A BAR domain reveals an antiparallel crescent-shaped homodimer; structure-guided mutagenesis identifies positively charged residues on the concave surface as critical for lipid binding and separate residues essential for dimerization; FAM92A BAR domain directly binds the N-terminal region of CBY1, and the dimerizations of both proteins synergistically enhance their mutual affinity.\",\n      \"method\": \"X-ray crystallography (2.2 Å), structure-guided mutagenesis, in vitro binding assays (lipid-binding and protein–protein interaction), dimerization assays\",\n      \"journal\": \"The Journal of biological chemistry\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 / Moderate — crystal structure plus mutagenesis plus in vitro binding assays in single rigorous study\",\n      \"pmids\": [\"40484380\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2024,\n      \"finding\": \"ciBAR1 (CIBAR1) forms a complex with Chibby3 (Cby3) at the sperm flagellar annulus; Cby3 and ciBAR1 colocalize to the annulus near the curved membrane invagination at the flagellar pocket; ablation of either gene in mice mispositions the annulus into the principal piece and causes male infertility with kinked flagella; the Cby3/ciBAR1 complex regulates local membrane properties to position the annulus at the midpiece/principal-piece junction.\",\n      \"method\": \"Cby3-KO and ciBAR1-KO mouse models, immunofluorescence colocalization, Co-immunoprecipitation, electron microscopy of flagellar ultrastructure, fertility assays\",\n      \"journal\": \"The Journal of cell biology\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — reciprocal Co-IP, colocalization, and independent KO mouse models with defined morphological and fertility phenotypes\",\n      \"pmids\": [\"38197861\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2024,\n      \"finding\": \"ciBAR1-KO mice exhibit randomized left-right asymmetry (~28% embryonic lethality), exocrine pancreatic lesions, impaired glucose tolerance, and reduced cilia number and length in ductal and islet cells; ciBAR1-KO MEFs also display ciliary defects, establishing that ciBAR1 plays a critical cell-type-dependent role in ciliogenesis in vivo.\",\n      \"method\": \"ciBAR1-KO mouse model, histological assessment, glucose tolerance testing, immunofluorescence quantification of cilia number and length, MEF ciliary assays\",\n      \"journal\": \"Life science alliance\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — KO mouse model with multiple defined phenotypic readouts plus MEF ciliary rescue experiments, single lab\",\n      \"pmids\": [\"39622622\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2025,\n      \"finding\": \"The BAR domain protein ciBAR1 (CIBAR1) can support membrane recruitment of the Fuzzy-Inturned RabGEF complex, as demonstrated by reconstitution experiments.\",\n      \"method\": \"In vitro reconstitution, protein-lipid interaction studies\",\n      \"journal\": \"bioRxiv\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 1 / Weak — reconstitution experiment but preprint, single lab, limited detail on ciBAR1-specific mechanism in abstract\",\n      \"pmids\": [\"bio_10.1101_2025.03.27.645700\"],\n      \"is_preprint\": true\n    },\n    {\n      \"year\": 2021,\n      \"finding\": \"FAM92A1 (CIBAR1) exists as a dimer and binds the mitochondrial inner membrane as a peripheral membrane protein; the NT* spidroin tag stabilizes FAM92A1 as a dimer and the resulting fusion protein retains membrane-bending activity, confirming that the dimer is the functional unit for membrane remodeling.\",\n      \"method\": \"Recombinant protein expression and purification, size-exclusion chromatography (dimerization), in vitro liposome membrane-bending assay\",\n      \"journal\": \"Protein expression and purification\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Weak — in vitro membrane-bending assay with dimerization confirmation, single lab, single study\",\n      \"pmids\": [\"34648955\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2016,\n      \"finding\": \"FAM92A1-289 (a splice variant of CIBAR1) co-immunoprecipitates with PCNA, suggesting a physical interaction; overexpression promotes cell migration, proliferation, and tumor growth in cervical carcinoma cells.\",\n      \"method\": \"Co-immunoprecipitation (pulldown with anti-PCNA antibody), scratch assay, MTT assay, colony formation, xenograft\",\n      \"journal\": \"Anticancer research\",\n      \"confidence\": \"Low\",\n      \"confidence_rationale\": \"Tier 3 / Weak — single Co-IP with no reciprocal validation, single lab, tumor-biology context with no mechanistic pathway placement\",\n      \"pmids\": [\"27798880\"],\n      \"is_preprint\": false\n    }\n  ],\n  \"current_model\": \"CIBAR1 (FAM92A1) is a homodimeric BAR domain protein whose crescent-shaped concave surface binds phosphoinositide- and cardiolipin-containing membranes to induce membrane curvature; it localizes to the mitochondrial inner membrane matrix side to maintain cristae ultrastructure and bioenergetics, to the ciliary base where it forms a complex with CBY1 (and CBY3 in sperm) to drive ciliogenesis and annulus positioning, and in neurons it shapes mitochondrial, myelin, and synaptic membranes to support synaptic plasticity and cognition.\"\n}\n```","stage2_raw":"{\n  \"mechanistic_narrative\": \"CIBAR1 (FAM92A1) is a homodimeric BAR domain protein that sculpts cellular membranes to support mitochondrial architecture and ciliogenesis [#0, #2]. Its crystal structure reveals an antiparallel crescent-shaped homodimer whose concave surface carries positively charged residue clusters that bind phosphoinositide- and cardiolipin-containing membranes, drive lipid clustering, and induce high membrane curvature in vitro [#2, #3]; dimerization is the functional prerequisite for this membrane-bending activity [#7]. At the mitochondrial inner membrane, CIBAR1 acts as a peripheral protein on the matrix side and is required for normal cristae ultrastructure and organelle bioenergetics [#0, #7]. At the base of cilia, CIBAR1 binds the N-terminal region of CBY1 — an interaction in which the dimerization of both partners synergistically enhances mutual affinity — and this complex is required for ciliogenesis; a nonsense FAM92A variant that disrupts the complex abolishes CIBAR1 recruitment to CBY1 and impairs cilium formation [#1, #3]. In vivo loss of CIBAR1 produces cell-type-dependent ciliary defects with randomized left-right asymmetry, exocrine pancreatic lesions, and impaired glucose tolerance [#5]. In sperm, CIBAR1 partners with CBY3 at the flagellar annulus to position it at the midpiece/principal-piece junction, with loss causing kinked flagella and male infertility [#4]. CIBAR1 can also support membrane recruitment of the Fuzzy-Inturned RabGEF complex [#6].\",\n  \"teleology\": [\n    {\n      \"year\": 2016,\n      \"claim\": \"An early association placed a CIBAR1 splice variant in a proliferative/tumor context, raising the question of whether the protein had a nuclear or cell-cycle role.\",\n      \"evidence\": \"Co-immunoprecipitation with PCNA plus migration, proliferation, colony formation, and xenograft assays in cervical carcinoma cells\",\n      \"pmids\": [\"27798880\"],\n      \"confidence\": \"Low\",\n      \"gaps\": [\"Single Co-IP without reciprocal validation\", \"No mechanistic pathway linking CIBAR1 to PCNA function\", \"Splice-variant-specific; not reconciled with later membrane-remodeling biology\"]\n    },\n    {\n      \"year\": 2018,\n      \"claim\": \"Established CIBAR1 as a membrane-remodeling BAR protein at the mitochondrial inner membrane, defining its core biochemical activity and an organelle role.\",\n      \"evidence\": \"Subcellular fractionation, EM, in vitro membrane-tubulation assay, and loss-of-function cell lines\",\n      \"pmids\": [\"30404948\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Molecular trigger for matrix-side recruitment not defined\", \"Relationship between mitochondrial and ciliary pools unresolved\"]\n    },\n    {\n      \"year\": 2018,\n      \"claim\": \"Identified the CIBAR1–CBY1 complex at the ciliary base as essential for ciliogenesis, extending the protein's role beyond mitochondria.\",\n      \"evidence\": \"Reciprocal Co-IP, immunofluorescence colocalization, Fam92a-KO mouse, and human variant segregation\",\n      \"pmids\": [\"30395363\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Did not resolve the structural basis of the CBY1 interaction\", \"Mechanism connecting CBY1 binding to curvature generation unknown\"]\n    },\n    {\n      \"year\": 2021,\n      \"claim\": \"Confirmed that the dimer, not the monomer, is the functional unit for membrane bending, clarifying the quaternary requirement for activity.\",\n      \"evidence\": \"Recombinant expression, size-exclusion chromatography, and liposome membrane-bending assays using an NT* spidroin dimerization tag\",\n      \"pmids\": [\"34648955\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"In vitro only; physiological dimer regulation not addressed\", \"Single lab\"]\n    },\n    {\n      \"year\": 2024,\n      \"claim\": \"Solved the BAR domain structure and defined the concave-surface residues mediating phosphoinositide/cardiolipin binding, providing the physical basis for curvature induction and linking the protein to neuronal function.\",\n      \"evidence\": \"Crystal structure, atomistic MD simulations, biochemical membrane-binding assays, and FAM92A1-KO mouse cognitive/neuronal phenotyping\",\n      \"pmids\": [\"39043703\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"How specific lipid recognition is tuned across mitochondrial vs ciliary membranes not resolved\", \"Neuronal phenotype mechanism not traced to a specific membrane substrate\"]\n    },\n    {\n      \"year\": 2024,\n      \"claim\": \"Showed CIBAR1 partners with CBY3 at the sperm flagellar annulus, demonstrating a tissue-specific paralog complex controlling annulus positioning and fertility.\",\n      \"evidence\": \"Cby3-KO and ciBAR1-KO mouse models, colocalization, Co-IP, EM, and fertility assays\",\n      \"pmids\": [\"38197861\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Determinants selecting CBY1 vs CBY3 partnership not defined\", \"Molecular mechanism of annulus membrane positioning incomplete\"]\n    },\n    {\n      \"year\": 2024,\n      \"claim\": \"Defined the in vivo consequences of CIBAR1 loss across tissues, establishing a cell-type-dependent ciliogenesis role with developmental and metabolic outcomes.\",\n      \"evidence\": \"ciBAR1-KO mouse histology, glucose tolerance testing, cilia quantification, and MEF ciliary assays\",\n      \"pmids\": [\"39622622\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Basis of cell-type-dependent ciliary requirement unexplained\", \"Link between ciliary defect and glucose intolerance mechanism not established\"]\n    },\n    {\n      \"year\": 2025,\n      \"claim\": \"Resolved the structural basis of the CIBAR1–CBY1 interaction, showing the BAR domain binds the CBY1 N-terminus and that mutual dimerization synergistically strengthens affinity.\",\n      \"evidence\": \"2.2 Å crystal structure, structure-guided mutagenesis, and in vitro lipid- and protein-binding/dimerization assays\",\n      \"pmids\": [\"40484380\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Does not show how complex formation is coupled to membrane curvature at the ciliary base in vivo\", \"Regulation of complex assembly timing unknown\"]\n    },\n    {\n      \"year\": 2025,\n      \"claim\": \"Connected CIBAR1's membrane-binding activity to downstream ciliary signaling machinery by showing it can recruit a RabGEF complex to membranes.\",\n      \"evidence\": \"In vitro reconstitution and protein-lipid interaction studies (preprint)\",\n      \"pmids\": [\"bio_10.1101_2025.03.27.645700\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Preprint, single lab\", \"ciBAR1-specific recruitment mechanism not detailed\", \"Not validated in cells/in vivo\"]\n    },\n    {\n      \"year\": null,\n      \"claim\": \"How CIBAR1 is partitioned and regulated between its mitochondrial, ciliary-base, and flagellar pools — and what selects its lipid and protein partners in each context — remains unresolved.\",\n      \"evidence\": \"\",\n      \"pmids\": [],\n      \"confidence\": \"High\",\n      \"gaps\": [\"No mechanism for targeting to distinct membrane compartments\", \"No upstream regulator of CIBAR1 recruitment identified\", \"Functional integration of mitochondrial vs ciliary roles unknown\"]\n    }\n  ],\n  \"mechanism_profile\": {\n    \"molecular_activity\": [\n      {\"term_id\": \"GO:0008289\", \"supporting_discovery_ids\": [2, 3]},\n      {\"term_id\": \"GO:0005198\", \"supporting_discovery_ids\": [0, 2, 7]},\n      {\"term_id\": \"GO:0060090\", \"supporting_discovery_ids\": [1, 3]}\n    ],\n    \"localization\": [\n      {\"term_id\": \"GO:0005739\", \"supporting_discovery_ids\": [0, 7]},\n      {\"term_id\": \"GO:0005929\", \"supporting_discovery_ids\": [1, 5]},\n      {\"term_id\": \"GO:0005815\", \"supporting_discovery_ids\": [1, 4]}\n    ],\n    \"pathway\": [\n      {\"term_id\": \"R-HSA-1852241\", \"supporting_discovery_ids\": [1, 5]},\n      {\"term_id\": \"R-HSA-1266738\", \"supporting_discovery_ids\": [4, 5]}\n    ],\n    \"complexes\": [\"CIBAR1–CBY1 complex\", \"CIBAR1–CBY3 complex\"],\n    \"partners\": [\"CBY1\", \"CBY3\"],\n    \"other_free_text\": []\n  }\n}","audit_flag":null,"evaluation":{"pairwise":"win","faith_supported":6,"faith_total":6,"faith_pct":100.0}}