{"gene":"CABIN1","run_date":"2026-06-09T22:57:17","timeline":{"discoveries":[{"year":2000,"finding":"Cabin1 represses MEF2 transcriptional activity by two distinct mechanisms: (1) recruiting mSin3 and its associated histone deacetylases 1 and 2, and (2) competing with p300 for binding to MEF2, thereby controlling calcium-dependent Nur77 transcription and T cell apoptosis.","method":"Co-immunoprecipitation, transcriptional reporter assays, protein interaction studies","journal":"Immunity","confidence":"High","confidence_rationale":"Tier 2 / Strong — reciprocal Co-IP and functional reporter assays, replicated across multiple mechanistic angles in a focused study","pmids":["10933397"],"is_preprint":false},{"year":2002,"finding":"During apoptosis, calpain cleaves Cain/Cabin1 at its calcineurin-binding domain (C-terminus) to generate a 32 kDa fragment, preventing Cabin1 from binding calcineurin and thereby activating calcineurin to mediate calcium-triggered cell death. In vitro binding assays showed Cabin1 binds the Cn B-binding domain of calcineurin A.","method":"In vitro calpain cleavage assay, immunoprecipitation with deletion mutants, calpain inhibitor treatment, in vitro binding assays","journal":"Proceedings of the National Academy of Sciences of the United States of America","confidence":"High","confidence_rationale":"Tier 1 / Moderate — in vitro reconstitution (cleavage and binding assays) combined with mutagenesis (deletion mutants) and pharmacological inhibition, single lab but multiple orthogonal methods","pmids":["12114545"],"is_preprint":false},{"year":2003,"finding":"Crystal structure of the MADS-box/MEF2S domain of human MEF2B bound to a Cabin1 motif and DNA at 2.2 Å resolution revealed that Cabin1 adopts an amphipathic alpha-helix to bind a hydrophobic groove on the MEF2S domain, forming a triple-helical interaction that constitutes the general mechanism for MEF2 recruitment of Cabin1 and class II HDACs to specific DNA sites.","method":"X-ray crystallography at 2.2 Å resolution, structural analysis of ternary complex","journal":"Nature","confidence":"High","confidence_rationale":"Tier 1 / Strong — high-resolution crystal structure with functional validation, published in Nature","pmids":["12700764"],"is_preprint":false},{"year":2001,"finding":"Overexpression of Cabin1 inhibits thapsigargin-induced Nur77 expression and apoptosis in T cell hybridomas, placing Cabin1 as a negative regulator of the MEF2-Nur77 axis downstream of calcium signaling; Nur77 induction was calcineurin-dependent (sensitive to cyclosporin A).","method":"Overexpression in T cell hybridomas, pharmacological inhibition (cyclosporin A), apoptosis assay","journal":"European journal of immunology","confidence":"Medium","confidence_rationale":"Tier 3 / Moderate — functional overexpression with defined phenotypic readout, consistent with mechanistic framework from other papers","pmids":["11385620"],"is_preprint":false},{"year":2005,"finding":"CaMKIV directly phosphorylates Cabin1, creating a docking site for 14-3-3 proteins, which causes nuclear export of Cabin1 during T cell activation; CaMKIV knockdown abrogated TCR-mediated IL-2 transcription in human T cells.","method":"Lentivirus-mediated RNAi knockdown of CaMKIV, direct phosphorylation assay, 14-3-3 binding assay, nuclear export assay","journal":"The EMBO journal","confidence":"High","confidence_rationale":"Tier 2 / Moderate — direct kinase phosphorylation assay plus 14-3-3 interaction and nuclear export readout, multiple orthogonal methods in single study","pmids":["15902271"],"is_preprint":false},{"year":2006,"finding":"Cabin1 recruits the histone methyltransferase SUV39H1 via its 501–900 amino acid region (distinct from its HDAC-recruiting domain) to methylate histone H3, thereby repressing MEF2 transcriptional activity; both SUV39H1 and Cabin1 bind the MEF2 target promoter in a calcium-dependent manner.","method":"Co-immunoprecipitation, histone methyltransferase assay, Gal4-reporter assay, chromatin immunoprecipitation","journal":"The Journal of biological chemistry","confidence":"High","confidence_rationale":"Tier 2 / Moderate — enzymatic methyltransferase assay combined with ChIP and domain-mapping mutagenesis, multiple orthogonal methods","pmids":["17172641"],"is_preprint":false},{"year":2007,"finding":"Cabin1 contains an additional calcineurin-binding domain within residues 701–900 (beyond the previously identified C-terminal domain); this domain blocked calcineurin-mediated dephosphorylation and nuclear import of NFAT and inhibited IL-2 production, explaining why Cabin1ΔC mice show no significant defect in calcineurin signaling.","method":"In vitro dephosphorylation assay, NFAT nuclear import assay, IL-2 reporter assay, deletion mutagenesis","journal":"Biochemical and biophysical research communications","confidence":"Medium","confidence_rationale":"Tier 2 / Weak — functional in vitro and cellular assays with defined domain mutants, single lab single study","pmids":["17531200"],"is_preprint":false},{"year":2009,"finding":"Cabin1 physically interacts with p53 on target promoters and represses p53 transcriptional activity in the absence of genotoxic stress by regulating histone modification and p53 acetylation marks; Cabin1 knockdown induces activation of a subset of p53 target genes and promotes cell death after DNA damage in a p53-dependent manner.","method":"Chromatin immunoprecipitation, Co-immunoprecipitation, siRNA knockdown, reporter assays, histone modification analysis","journal":"Nature structural & molecular biology","confidence":"High","confidence_rationale":"Tier 2 / Moderate — ChIP, Co-IP, and functional knockdown with p53-dependent phenotypic rescue, multiple orthogonal methods","pmids":["19668210"],"is_preprint":false},{"year":2011,"finding":"CABIN1 is a functional member of the human HIRA/UBN1/CABIN1/ASF1a (HUCA) histone H3.3 chaperone quaternary complex; HIRA acts as a scaffold to bring together UBN1, ASF1a, and CABIN1. CABIN1 interacts with HIRA at endogenous levels, and CABIN1 is involved in heterochromatinization of the genome in senescent human cells. CABIN1 is likely the ortholog of yeast Hir3p.","method":"Co-immunoprecipitation (endogenous and ectopic), recombinant protein complex reconstitution, mutational analysis, senescence chromatin assays","journal":"Molecular and cellular biology","confidence":"High","confidence_rationale":"Tier 1 / Moderate — quaternary complex reconstituted from recombinant proteins, supported by endogenous Co-IP and functional senescence assay, multiple orthogonal methods","pmids":["21807893"],"is_preprint":false},{"year":2012,"finding":"The NHRD (residues 41–77) of UBN1 is essential for interaction with the HIRA WD repeat domain and for stability of the HUCA complex in vitro and in vivo; the UBN1 NHRD and HIRA WD repeats form a tight 1:1 complex with nanomolar dissociation constant, and key NHRD residues are required for chromatin organization in primary human cells.","method":"Analytical ultracentrifugation, mutational analysis, biochemical reconstitution, in vivo chromatin organization assays","journal":"Biochemistry","confidence":"Medium","confidence_rationale":"Tier 1 / Weak — biophysical binding measurements and mutagenesis defining the HUCA complex architecture, but focused on UBN1-HIRA interface with CABIN1 as complex context","pmids":["22401310"],"is_preprint":false},{"year":2013,"finding":"Upon DNA damage, ATM and CHK2 phosphorylate CABIN1, promoting its ubiquitin-dependent proteasomal degradation via the CRL4DDB2 ubiquitin ligase complex; this degradation releases p53 for transcriptional activation. Both phosphorylation and ubiquitination are required for controlling CABIN1 protein levels upon genotoxic stress.","method":"In vitro kinase assay, knockdown/overexpression of ATM and CHK2, ubiquitination assay, proteasome inhibition, identification of CRL4DDB2 as E3 ligase","journal":"Nucleic acids research","confidence":"High","confidence_rationale":"Tier 2 / Moderate — kinase assay, E3 ligase identification, and functional rescue experiments with multiple orthogonal methods in a single focused study","pmids":["23303793"],"is_preprint":false},{"year":2022,"finding":"A decameric CABIN1 peptide (residues 2146–2155) containing a 'PPTP' C-terminal sequence and 'PxIxIT' N-terminal motif is minimally required for binding to calcineurin; p38MAPK phosphorylates the threonine in the 'PPTP' sequence under physiological conditions, dramatically enhancing binding affinity to calcineurin and inhibiting the calcineurin-NFAT pathway without affecting calcineurin phosphatase activity.","method":"Peptide binding assay, mutagenesis, kinase phosphorylation assay, NFAT reporter assay, T cell activation assay","journal":"Experimental & molecular medicine","confidence":"Medium","confidence_rationale":"Tier 2 / Weak — peptide binding and kinase assay with functional NFAT/T cell readout, single lab single study","pmids":["35550603"],"is_preprint":false},{"year":2015,"finding":"In cultured podocytes, Cabin1 undergoes nuclear translocation upon AngII-induced injury; knockdown of Cabin1 by siRNA disrupts F-actin cytoskeleton and increases cytochrome c expression, indicating Cabin1 is required for cytoskeletal integrity and mitochondrial homeostasis in podocytes.","method":"siRNA knockdown, immunofluorescence, subcellular fractionation, western blot","journal":"International urology and nephrology / Renal failure","confidence":"Low","confidence_rationale":"Tier 3 / Weak — single lab siRNA knockdown with phenotypic readout, limited mechanistic pathway placement","pmids":["26275115","29368245"],"is_preprint":false},{"year":2020,"finding":"In AngII-treated renal tubular epithelial cells, Cabin1 knockdown further decreases SIRT1 levels and increases p53 and cytochrome c, placing Cabin1 upstream of a SIRT1/p53 pathway in mitochondrial dysfunction.","method":"siRNA knockdown, western blot, electron microscopy","journal":"Journal of receptor and signal transduction research","confidence":"Low","confidence_rationale":"Tier 3 / Weak — single lab, single siRNA knockdown method, limited mechanistic validation","pmids":["32000560"],"is_preprint":false}],"current_model":"CABIN1 is a multifunctional scaffold protein that represses MEF2-dependent transcription by recruiting mSin3/HDACs and the histone methyltransferase SUV39H1 to target promoters while competing with p300, represses p53 activity on chromatin in unstressed cells (with ATM/CHK2-mediated phosphorylation and CRL4DDB2-driven ubiquitination triggering its proteasomal degradation to release p53 upon DNA damage), inhibits calcineurin phosphatase activity through a C-terminal PxIxIT/PPTP motif (itself regulated by p38MAPK phosphorylation and calpain cleavage), undergoes CaMKIV-mediated phosphorylation creating a 14-3-3 docking site for nuclear export during T cell activation, and functions as an integral structural member of the HIRA/UBN1/CABIN1/ASF1a (HUCA) histone H3.3 chaperone complex involved in replication-independent chromatin assembly and heterochromatinization in senescent cells."},"narrative":{"mechanistic_narrative":"CABIN1 is a multifunctional nuclear scaffold and transcriptional corepressor that integrates calcium signaling with chromatin regulation in T cells and other contexts [PMID:10933397, PMID:17172641]. It represses MEF2-dependent transcription by two complementary routes: recruiting the mSin3 corepressor with associated histone deacetylases HDAC1/2 and competing with the p300 coactivator for MEF2 binding, thereby controlling calcium-dependent Nur77 induction and T cell apoptosis [PMID:10933397, PMID:11385620]. A distinct internal region (residues 501–900) additionally recruits the histone methyltransferase SUV39H1 to methylate histone H3 at MEF2 target promoters in a calcium-dependent manner [PMID:17172641], and a crystal structure of MEF2 bound to a CABIN1 motif showed CABIN1 engages a hydrophobic groove on the MEF2S domain via an amphipathic α-helix, defining the general mechanism for MEF2 recruitment of corepressors [PMID:12700764]. CABIN1 also restrains p53: it binds p53 on target promoters and represses its activity through histone-modification and p53-acetylation control in unstressed cells, and upon DNA damage ATM/CHK2 phosphorylation drives CRL4DDB2-dependent ubiquitination and proteasomal degradation of CABIN1 to release p53 for transcriptional activation [PMID:19668210, PMID:23303793]. Beyond chromatin, CABIN1 inhibits calcineurin through C-terminal and internal calcineurin-binding determinants, including a minimal PxIxIT/PPTP-containing peptide whose binding is enhanced by p38MAPK phosphorylation; calpain cleavage of this region during apoptosis liberates calcineurin to promote calcium-triggered cell death [PMID:12114545, PMID:35550603, PMID:17531200]. CABIN1 nucleocytoplasmic distribution is itself regulated, as CaMKIV phosphorylation creates a 14-3-3 docking site that exports CABIN1 during T cell activation [PMID:15902271]. Finally, CABIN1 is an integral structural subunit of the HIRA/UBN1/CABIN1/ASF1a (HUCA) histone H3.3 chaperone complex, interacting with HIRA at endogenous levels and contributing to heterochromatinization in senescent human cells [PMID:21807893].","teleology":[{"year":2000,"claim":"Established CABIN1 as a MEF2 corepressor, answering how MEF2-driven Nur77 transcription and T cell apoptosis are negatively controlled downstream of calcium signaling.","evidence":"Co-IP, transcriptional reporter and protein interaction assays defining mSin3/HDAC recruitment and p300 competition","pmids":["10933397"],"confidence":"High","gaps":["Did not resolve the structural basis of the MEF2-CABIN1 interaction","Calcium-dependent regulation of recruitment not defined at the chromatin level"]},{"year":2001,"claim":"Placed CABIN1 functionally within the calcium/calcineurin–MEF2–Nur77 apoptotic axis by showing overexpression blocks thapsigargin-induced Nur77 and apoptosis.","evidence":"Overexpression in T cell hybridomas with cyclosporin A inhibition and apoptosis readout","pmids":["11385620"],"confidence":"Medium","gaps":["Overexpression phenotype does not establish endogenous requirement","Did not separate calcineurin-inhibitory from MEF2-corepressor functions"]},{"year":2002,"claim":"Defined how CABIN1 inhibition of calcineurin is relieved during apoptosis, showing calpain cleaves the C-terminal calcineurin-binding domain to activate calcineurin for calcium-triggered death.","evidence":"In vitro calpain cleavage, binding assays with deletion mutants, and calpain inhibitor treatment","pmids":["12114545"],"confidence":"High","gaps":["In vivo relevance of the 32 kDa fragment not established","Did not address other calcineurin-binding determinants later found internally"]},{"year":2003,"claim":"Provided the structural mechanism of MEF2 corepressor recruitment by solving the MEF2B/CABIN1-peptide/DNA ternary complex.","evidence":"X-ray crystallography at 2.2 Å of the MADS-box/MEF2S domain bound to a CABIN1 motif and DNA","pmids":["12700764"],"confidence":"High","gaps":["Structure limited to a short CABIN1 motif, not full-length protein","Does not show how HDAC/SUV39H1 recruitment is coordinated on chromatin"]},{"year":2005,"claim":"Explained dynamic control of CABIN1 localization, showing CaMKIV phosphorylation creates a 14-3-3 docking site driving nuclear export during T cell activation.","evidence":"RNAi knockdown of CaMKIV, direct phosphorylation, 14-3-3 binding and nuclear export assays with IL-2 transcription readout","pmids":["15902271"],"confidence":"High","gaps":["Phosphorylation site(s) on CABIN1 not fully mapped in this account","Link between export and derepression of specific target genes not quantified"]},{"year":2006,"claim":"Identified a second corepressor arm, showing CABIN1 recruits SUV39H1 through a distinct internal region to methylate H3 and repress MEF2 at promoters.","evidence":"Co-IP, HMT assay, Gal4 reporter and ChIP with domain mapping","pmids":["17172641"],"confidence":"High","gaps":["Interplay between HDAC and SUV39H1 arms on the same promoter not resolved","Genome-wide targets not defined"]},{"year":2007,"claim":"Resolved why C-terminal deletion mice retain calcineurin signaling by identifying a second internal calcineurin-binding domain (residues 701–900).","evidence":"In vitro dephosphorylation, NFAT nuclear import, IL-2 reporter assays with deletion mutants","pmids":["17531200"],"confidence":"Medium","gaps":["Single-lab functional study without structural validation","Relative contribution of the two calcineurin-binding regions in vivo unclear"]},{"year":2009,"claim":"Extended CABIN1 corepressor function to p53, showing it binds p53 on promoters and restrains its activity in unstressed cells via histone and p53-acetylation marks.","evidence":"ChIP, Co-IP, siRNA knockdown and reporter assays with p53-dependent cell-death rescue","pmids":["19668210"],"confidence":"High","gaps":["Mechanism linking CABIN1 to specific acetyltransferases/deacetylases on p53 not defined","Did not address how stress relieves repression"]},{"year":2013,"claim":"Defined the switch that releases p53 upon DNA damage, showing ATM/CHK2 phosphorylation and CRL4DDB2-mediated ubiquitination drive CABIN1 degradation.","evidence":"In vitro kinase assay, ATM/CHK2 manipulation, ubiquitination and proteasome inhibition assays, CRL4DDB2 identification","pmids":["23303793"],"confidence":"High","gaps":["Precise phosphodegron and ubiquitination sites not fully mapped","Kinetics of CABIN1 loss relative to p53 target activation not quantified"]},{"year":2011,"claim":"Established CABIN1 as a stable structural subunit of the HUCA H3.3 chaperone complex, linking it to replication-independent chromatin assembly and senescence heterochromatin.","evidence":"Endogenous and ectopic Co-IP, recombinant complex reconstitution, mutational analysis and senescence chromatin assays","pmids":["21807893"],"confidence":"High","gaps":["Specific contribution of CABIN1 to H3.3 deposition activity not isolated","Structural placement of CABIN1 within the complex undefined"]},{"year":2012,"claim":"Detailed HUCA architecture by quantifying the UBN1 NHRD–HIRA WD-repeat interface required for complex stability.","evidence":"Analytical ultracentrifugation, mutagenesis and in vivo chromatin organization assays","pmids":["22401310"],"confidence":"Medium","gaps":["Focused on UBN1–HIRA interface with CABIN1 only as complex context","Direct CABIN1 contacts within HUCA not measured"]},{"year":2022,"claim":"Refined the calcineurin-inhibitory mechanism to a minimal PxIxIT/PPTP peptide whose affinity is tuned by p38MAPK phosphorylation, selectively blocking NFAT without altering phosphatase activity.","evidence":"Peptide binding, mutagenesis, kinase phosphorylation, NFAT reporter and T cell activation assays","pmids":["35550603"],"confidence":"Medium","gaps":["Single-lab peptide-based study; full-length regulation not confirmed","Physiological trigger for p38MAPK-mediated control not established"]},{"year":2020,"claim":"Proposed a tissue-specific role in renal cells, placing Cabin1 upstream of a SIRT1/p53 axis and cytoskeletal/mitochondrial homeostasis in podocytes and tubular epithelium.","evidence":"siRNA knockdown with western blot, immunofluorescence and electron microscopy in AngII-treated renal cells","pmids":["26275115","29368245","32000560"],"confidence":"Low","gaps":["Single-lab siRNA phenotypes without mechanistic reconstitution","Direct molecular interactions with SIRT1/p53 not demonstrated","Relationship to CABIN1's established corepressor functions unclear"]},{"year":null,"claim":"How CABIN1's distinct functions — MEF2/p53 corepression, calcineurin inhibition, and H3.3 chaperone activity — are coordinated or partitioned within a single protein and across cell types remains unresolved.","evidence":"","pmids":[],"confidence":"Medium","gaps":["No full-length structure integrating the corepressor, calcineurin-binding and HUCA domains","Interplay between cytoplasmic calcineurin inhibition and nuclear chromatin roles undefined","Genome-wide CABIN1 target landscape not mapped"]}],"mechanism_profile":{"molecular_activity":[{"term_id":"GO:0140110","term_label":"transcription regulator activity","supporting_discovery_ids":[0,5,7]},{"term_id":"GO:0098772","term_label":"molecular function regulator activity","supporting_discovery_ids":[1,6,11]},{"term_id":"GO:0060090","term_label":"molecular adaptor activity","supporting_discovery_ids":[0,5,8]},{"term_id":"GO:0042393","term_label":"histone binding","supporting_discovery_ids":[8]}],"localization":[{"term_id":"GO:0005634","term_label":"nucleus","supporting_discovery_ids":[0,4,5,7]},{"term_id":"GO:0005829","term_label":"cytosol","supporting_discovery_ids":[4]},{"term_id":"GO:0000228","term_label":"nuclear chromosome","supporting_discovery_ids":[8]}],"pathway":[{"term_id":"R-HSA-74160","term_label":"Gene expression (Transcription)","supporting_discovery_ids":[0,5,7]},{"term_id":"R-HSA-4839726","term_label":"Chromatin organization","supporting_discovery_ids":[5,8]},{"term_id":"R-HSA-168256","term_label":"Immune System","supporting_discovery_ids":[0,4,11]},{"term_id":"R-HSA-162582","term_label":"Signal Transduction","supporting_discovery_ids":[1,11]},{"term_id":"R-HSA-5357801","term_label":"Programmed Cell Death","supporting_discovery_ids":[1,7]}],"complexes":["HUCA (HIRA/UBN1/CABIN1/ASF1a) H3.3 chaperone complex","mSin3/HDAC corepressor complex"],"partners":["MEF2","HDAC1","HDAC2","SUV39H1","P53","CALCINEURIN","HIRA","14-3-3"],"other_free_text":[]}},"prefetch_data":{"uniprot":{"accession":"Q9Y6J0","full_name":"Calcineurin-binding protein cabin-1","aliases":["Calcineurin inhibitor","CAIN"],"length_aa":2220,"mass_kda":246.4,"function":"May be required for replication-independent chromatin assembly. May serve as a negative regulator of T-cell receptor (TCR) signaling via inhibition of calcineurin. Inhibition of activated calcineurin is dependent on both PKC and calcium signals. Acts as a negative regulator of p53/TP53 by keeping p53 in an inactive state on chromatin at promoters of a subset of its target genes","subcellular_location":"Nucleus","url":"https://www.uniprot.org/uniprotkb/Q9Y6J0/entry"},"depmap":{"release":"DepMap","has_data":true,"is_common_essential":false,"resolved_as":"","url":"https://depmap.org/portal/gene/CABIN1","classification":"Not Classified","n_dependent_lines":79,"n_total_lines":1208,"dependency_fraction":0.06539735099337748},"opencell":{"profiled":false,"resolved_as":"","ensg_id":"","cell_line_id":"","localizations":[],"interactors":[{"gene":"CALD1","stoichiometry":0.2},{"gene":"CAPZB","stoichiometry":0.2},{"gene":"CTTN","stoichiometry":0.2}],"url":"https://opencell.sf.czbiohub.org/search/CABIN1","total_profiled":1310},"omim":[{"mim_id":"606543","title":"HISTONE DEACETYLASE 9; HDAC9","url":"https://www.omim.org/entry/606543"},{"mim_id":"605314","title":"HISTONE DEACETYLASE 4; HDAC4","url":"https://www.omim.org/entry/605314"},{"mim_id":"604251","title":"CALCINEURIN-BINDING PROTEIN 1","url":"https://www.omim.org/entry/604251"},{"mim_id":"600661","title":"MYOCYTE ENHANCER FACTOR 2B; MEF2B","url":"https://www.omim.org/entry/600661"},{"mim_id":"162091","title":"SCHWANNOMATOSIS 1; SWN1","url":"https://www.omim.org/entry/162091"}],"hpa":{"profiled":true,"resolved_as":"","reliability":"Approved","locations":[{"location":"Nucleoplasm","reliability":"Approved"},{"location":"Cytosol","reliability":"Approved"}],"tissue_specificity":"Low tissue specificity","tissue_distribution":"Detected in all","driving_tissues":[],"url":"https://www.proteinatlas.org/search/CABIN1"},"hgnc":{"alias_symbol":["KIAA0330","PPP3IN"],"prev_symbol":[]},"alphafold":{"accession":"Q9Y6J0","domains":[{"cath_id":"1.25.40.10","chopping":"30-250","consensus_level":"medium","plddt":88.9167,"start":30,"end":250},{"cath_id":"-","chopping":"259-301_464-523","consensus_level":"medium","plddt":88.1261,"start":259,"end":523},{"cath_id":"-","chopping":"531-564_583-687","consensus_level":"medium","plddt":82.1676,"start":531,"end":687},{"cath_id":"-","chopping":"750-868","consensus_level":"medium","plddt":82.2381,"start":750,"end":868},{"cath_id":"-","chopping":"886-973","consensus_level":"medium","plddt":84.3364,"start":886,"end":973},{"cath_id":"-","chopping":"974-1026_1036-1087","consensus_level":"medium","plddt":86.321,"start":974,"end":1087},{"cath_id":"-","chopping":"1228-1304_1498-1524","consensus_level":"medium","plddt":85.4946,"start":1228,"end":1524},{"cath_id":"-","chopping":"1854-1917","consensus_level":"medium","plddt":83.6878,"start":1854,"end":1917}],"viewer_url":"https://alphafold.ebi.ac.uk/entry/Q9Y6J0","model_url":"https://alphafold.ebi.ac.uk/files/AF-Q9Y6J0-F1-model_v6.cif","pae_url":"https://alphafold.ebi.ac.uk/files/AF-Q9Y6J0-F1-predicted_aligned_error_v6.png","plddt_mean":63.72},"mouse_models":{"mgi_url":"https://www.informatics.jax.org/marker/summary?nomen=CABIN1","jax_strain_url":"https://www.jax.org/strain/search?query=CABIN1"},"sequence":{"accession":"Q9Y6J0","fasta_url":"https://rest.uniprot.org/uniprotkb/Q9Y6J0.fasta","uniprot_url":"https://www.uniprot.org/uniprotkb/Q9Y6J0/entry","alphafold_viewer_url":"https://alphafold.ebi.ac.uk/entry/Q9Y6J0"}},"corpus_meta":[{"pmid":"10933397","id":"PMC_10933397","title":"Cabin1 represses MEF2-dependent Nur77 expression and T cell apoptosis by controlling association of histone deacetylases and acetylases with MEF2.","date":"2000","source":"Immunity","url":"https://pubmed.ncbi.nlm.nih.gov/10933397","citation_count":145,"is_preprint":false},{"pmid":"12114545","id":"PMC_12114545","title":"Calpain-dependent cleavage of cain/cabin1 activates calcineurin to mediate calcium-triggered cell death.","date":"2002","source":"Proceedings of the National Academy of Sciences of the United States of America","url":"https://pubmed.ncbi.nlm.nih.gov/12114545","citation_count":110,"is_preprint":false},{"pmid":"12700764","id":"PMC_12700764","title":"Sequence-specific recruitment of transcriptional co-repressor Cabin1 by myocyte enhancer factor-2.","date":"2003","source":"Nature","url":"https://pubmed.ncbi.nlm.nih.gov/12700764","citation_count":93,"is_preprint":false},{"pmid":"21807893","id":"PMC_21807893","title":"Human CABIN1 is a functional member of the human HIRA/UBN1/ASF1a histone H3.3 chaperone complex.","date":"2011","source":"Molecular and cellular biology","url":"https://pubmed.ncbi.nlm.nih.gov/21807893","citation_count":90,"is_preprint":false},{"pmid":"19668210","id":"PMC_19668210","title":"Cabin1 restrains p53 activity on chromatin.","date":"2009","source":"Nature structural & molecular biology","url":"https://pubmed.ncbi.nlm.nih.gov/19668210","citation_count":39,"is_preprint":false},{"pmid":"22401310","id":"PMC_22401310","title":"Identification of an ubinuclein 1 region required for stability and function of the human HIRA/UBN1/CABIN1/ASF1a histone H3.3 chaperone complex.","date":"2012","source":"Biochemistry","url":"https://pubmed.ncbi.nlm.nih.gov/22401310","citation_count":32,"is_preprint":false},{"pmid":"17172641","id":"PMC_17172641","title":"Cabin1 represses MEF2 transcriptional activity by association with a methyltransferase, SUV39H1.","date":"2006","source":"The Journal of biological 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transcriptional reporter assays, protein interaction studies\",\n      \"journal\": \"Immunity\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — reciprocal Co-IP and functional reporter assays, replicated across multiple mechanistic angles in a focused study\",\n      \"pmids\": [\"10933397\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2002,\n      \"finding\": \"During apoptosis, calpain cleaves Cain/Cabin1 at its calcineurin-binding domain (C-terminus) to generate a 32 kDa fragment, preventing Cabin1 from binding calcineurin and thereby activating calcineurin to mediate calcium-triggered cell death. In vitro binding assays showed Cabin1 binds the Cn B-binding domain of calcineurin A.\",\n      \"method\": \"In vitro calpain cleavage assay, immunoprecipitation with deletion mutants, calpain inhibitor treatment, in vitro binding assays\",\n      \"journal\": \"Proceedings of the National Academy of Sciences of the United States of America\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 / Moderate — in vitro reconstitution (cleavage and binding assays) combined with mutagenesis (deletion mutants) and pharmacological inhibition, single lab but multiple orthogonal methods\",\n      \"pmids\": [\"12114545\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2003,\n      \"finding\": \"Crystal structure of the MADS-box/MEF2S domain of human MEF2B bound to a Cabin1 motif and DNA at 2.2 Å resolution revealed that Cabin1 adopts an amphipathic alpha-helix to bind a hydrophobic groove on the MEF2S domain, forming a triple-helical interaction that constitutes the general mechanism for MEF2 recruitment of Cabin1 and class II HDACs to specific DNA sites.\",\n      \"method\": \"X-ray crystallography at 2.2 Å resolution, structural analysis of ternary complex\",\n      \"journal\": \"Nature\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 / Strong — high-resolution crystal structure with functional validation, published in Nature\",\n      \"pmids\": [\"12700764\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2001,\n      \"finding\": \"Overexpression of Cabin1 inhibits thapsigargin-induced Nur77 expression and apoptosis in T cell hybridomas, placing Cabin1 as a negative regulator of the MEF2-Nur77 axis downstream of calcium signaling; Nur77 induction was calcineurin-dependent (sensitive to cyclosporin A).\",\n      \"method\": \"Overexpression in T cell hybridomas, pharmacological inhibition (cyclosporin A), apoptosis assay\",\n      \"journal\": \"European journal of immunology\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 3 / Moderate — functional overexpression with defined phenotypic readout, consistent with mechanistic framework from other papers\",\n      \"pmids\": [\"11385620\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2005,\n      \"finding\": \"CaMKIV directly phosphorylates Cabin1, creating a docking site for 14-3-3 proteins, which causes nuclear export of Cabin1 during T cell activation; CaMKIV knockdown abrogated TCR-mediated IL-2 transcription in human T cells.\",\n      \"method\": \"Lentivirus-mediated RNAi knockdown of CaMKIV, direct phosphorylation assay, 14-3-3 binding assay, nuclear export assay\",\n      \"journal\": \"The EMBO journal\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — direct kinase phosphorylation assay plus 14-3-3 interaction and nuclear export readout, multiple orthogonal methods in single study\",\n      \"pmids\": [\"15902271\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2006,\n      \"finding\": \"Cabin1 recruits the histone methyltransferase SUV39H1 via its 501–900 amino acid region (distinct from its HDAC-recruiting domain) to methylate histone H3, thereby repressing MEF2 transcriptional activity; both SUV39H1 and Cabin1 bind the MEF2 target promoter in a calcium-dependent manner.\",\n      \"method\": \"Co-immunoprecipitation, histone methyltransferase assay, Gal4-reporter assay, chromatin immunoprecipitation\",\n      \"journal\": \"The Journal of biological chemistry\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — enzymatic methyltransferase assay combined with ChIP and domain-mapping mutagenesis, multiple orthogonal methods\",\n      \"pmids\": [\"17172641\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2007,\n      \"finding\": \"Cabin1 contains an additional calcineurin-binding domain within residues 701–900 (beyond the previously identified C-terminal domain); this domain blocked calcineurin-mediated dephosphorylation and nuclear import of NFAT and inhibited IL-2 production, explaining why Cabin1ΔC mice show no significant defect in calcineurin signaling.\",\n      \"method\": \"In vitro dephosphorylation assay, NFAT nuclear import assay, IL-2 reporter assay, deletion mutagenesis\",\n      \"journal\": \"Biochemical and biophysical research communications\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Weak — functional in vitro and cellular assays with defined domain mutants, single lab single study\",\n      \"pmids\": [\"17531200\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2009,\n      \"finding\": \"Cabin1 physically interacts with p53 on target promoters and represses p53 transcriptional activity in the absence of genotoxic stress by regulating histone modification and p53 acetylation marks; Cabin1 knockdown induces activation of a subset of p53 target genes and promotes cell death after DNA damage in a p53-dependent manner.\",\n      \"method\": \"Chromatin immunoprecipitation, Co-immunoprecipitation, siRNA knockdown, reporter assays, histone modification analysis\",\n      \"journal\": \"Nature structural & molecular biology\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — ChIP, Co-IP, and functional knockdown with p53-dependent phenotypic rescue, multiple orthogonal methods\",\n      \"pmids\": [\"19668210\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2011,\n      \"finding\": \"CABIN1 is a functional member of the human HIRA/UBN1/CABIN1/ASF1a (HUCA) histone H3.3 chaperone quaternary complex; HIRA acts as a scaffold to bring together UBN1, ASF1a, and CABIN1. CABIN1 interacts with HIRA at endogenous levels, and CABIN1 is involved in heterochromatinization of the genome in senescent human cells. CABIN1 is likely the ortholog of yeast Hir3p.\",\n      \"method\": \"Co-immunoprecipitation (endogenous and ectopic), recombinant protein complex reconstitution, mutational analysis, senescence chromatin assays\",\n      \"journal\": \"Molecular and cellular biology\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 / Moderate — quaternary complex reconstituted from recombinant proteins, supported by endogenous Co-IP and functional senescence assay, multiple orthogonal methods\",\n      \"pmids\": [\"21807893\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2012,\n      \"finding\": \"The NHRD (residues 41–77) of UBN1 is essential for interaction with the HIRA WD repeat domain and for stability of the HUCA complex in vitro and in vivo; the UBN1 NHRD and HIRA WD repeats form a tight 1:1 complex with nanomolar dissociation constant, and key NHRD residues are required for chromatin organization in primary human cells.\",\n      \"method\": \"Analytical ultracentrifugation, mutational analysis, biochemical reconstitution, in vivo chromatin organization assays\",\n      \"journal\": \"Biochemistry\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 1 / Weak — biophysical binding measurements and mutagenesis defining the HUCA complex architecture, but focused on UBN1-HIRA interface with CABIN1 as complex context\",\n      \"pmids\": [\"22401310\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2013,\n      \"finding\": \"Upon DNA damage, ATM and CHK2 phosphorylate CABIN1, promoting its ubiquitin-dependent proteasomal degradation via the CRL4DDB2 ubiquitin ligase complex; this degradation releases p53 for transcriptional activation. Both phosphorylation and ubiquitination are required for controlling CABIN1 protein levels upon genotoxic stress.\",\n      \"method\": \"In vitro kinase assay, knockdown/overexpression of ATM and CHK2, ubiquitination assay, proteasome inhibition, identification of CRL4DDB2 as E3 ligase\",\n      \"journal\": \"Nucleic acids research\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — kinase assay, E3 ligase identification, and functional rescue experiments with multiple orthogonal methods in a single focused study\",\n      \"pmids\": [\"23303793\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2022,\n      \"finding\": \"A decameric CABIN1 peptide (residues 2146–2155) containing a 'PPTP' C-terminal sequence and 'PxIxIT' N-terminal motif is minimally required for binding to calcineurin; p38MAPK phosphorylates the threonine in the 'PPTP' sequence under physiological conditions, dramatically enhancing binding affinity to calcineurin and inhibiting the calcineurin-NFAT pathway without affecting calcineurin phosphatase activity.\",\n      \"method\": \"Peptide binding assay, mutagenesis, kinase phosphorylation assay, NFAT reporter assay, T cell activation assay\",\n      \"journal\": \"Experimental & molecular medicine\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Weak — peptide binding and kinase assay with functional NFAT/T cell readout, single lab single study\",\n      \"pmids\": [\"35550603\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2015,\n      \"finding\": \"In cultured podocytes, Cabin1 undergoes nuclear translocation upon AngII-induced injury; knockdown of Cabin1 by siRNA disrupts F-actin cytoskeleton and increases cytochrome c expression, indicating Cabin1 is required for cytoskeletal integrity and mitochondrial homeostasis in podocytes.\",\n      \"method\": \"siRNA knockdown, immunofluorescence, subcellular fractionation, western blot\",\n      \"journal\": \"International urology and nephrology / Renal failure\",\n      \"confidence\": \"Low\",\n      \"confidence_rationale\": \"Tier 3 / Weak — single lab siRNA knockdown with phenotypic readout, limited mechanistic pathway placement\",\n      \"pmids\": [\"26275115\", \"29368245\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2020,\n      \"finding\": \"In AngII-treated renal tubular epithelial cells, Cabin1 knockdown further decreases SIRT1 levels and increases p53 and cytochrome c, placing Cabin1 upstream of a SIRT1/p53 pathway in mitochondrial dysfunction.\",\n      \"method\": \"siRNA knockdown, western blot, electron microscopy\",\n      \"journal\": \"Journal of receptor and signal transduction research\",\n      \"confidence\": \"Low\",\n      \"confidence_rationale\": \"Tier 3 / Weak — single lab, single siRNA knockdown method, limited mechanistic validation\",\n      \"pmids\": [\"32000560\"],\n      \"is_preprint\": false\n    }\n  ],\n  \"current_model\": \"CABIN1 is a multifunctional scaffold protein that represses MEF2-dependent transcription by recruiting mSin3/HDACs and the histone methyltransferase SUV39H1 to target promoters while competing with p300, represses p53 activity on chromatin in unstressed cells (with ATM/CHK2-mediated phosphorylation and CRL4DDB2-driven ubiquitination triggering its proteasomal degradation to release p53 upon DNA damage), inhibits calcineurin phosphatase activity through a C-terminal PxIxIT/PPTP motif (itself regulated by p38MAPK phosphorylation and calpain cleavage), undergoes CaMKIV-mediated phosphorylation creating a 14-3-3 docking site for nuclear export during T cell activation, and functions as an integral structural member of the HIRA/UBN1/CABIN1/ASF1a (HUCA) histone H3.3 chaperone complex involved in replication-independent chromatin assembly and heterochromatinization in senescent cells.\"\n}\n```","stage2_raw":"{\n  \"mechanistic_narrative\": \"CABIN1 is a multifunctional nuclear scaffold and transcriptional corepressor that integrates calcium signaling with chromatin regulation in T cells and other contexts [#0, #5]. It represses MEF2-dependent transcription by two complementary routes: recruiting the mSin3 corepressor with associated histone deacetylases HDAC1/2 and competing with the p300 coactivator for MEF2 binding, thereby controlling calcium-dependent Nur77 induction and T cell apoptosis [#0, #3]. A distinct internal region (residues 501–900) additionally recruits the histone methyltransferase SUV39H1 to methylate histone H3 at MEF2 target promoters in a calcium-dependent manner [#5], and a crystal structure of MEF2 bound to a CABIN1 motif showed CABIN1 engages a hydrophobic groove on the MEF2S domain via an amphipathic α-helix, defining the general mechanism for MEF2 recruitment of corepressors [#2]. CABIN1 also restrains p53: it binds p53 on target promoters and represses its activity through histone-modification and p53-acetylation control in unstressed cells, and upon DNA damage ATM/CHK2 phosphorylation drives CRL4DDB2-dependent ubiquitination and proteasomal degradation of CABIN1 to release p53 for transcriptional activation [#7, #10]. Beyond chromatin, CABIN1 inhibits calcineurin through C-terminal and internal calcineurin-binding determinants, including a minimal PxIxIT/PPTP-containing peptide whose binding is enhanced by p38MAPK phosphorylation; calpain cleavage of this region during apoptosis liberates calcineurin to promote calcium-triggered cell death [#1, #11, #6]. CABIN1 nucleocytoplasmic distribution is itself regulated, as CaMKIV phosphorylation creates a 14-3-3 docking site that exports CABIN1 during T cell activation [#4]. Finally, CABIN1 is an integral structural subunit of the HIRA/UBN1/CABIN1/ASF1a (HUCA) histone H3.3 chaperone complex, interacting with HIRA at endogenous levels and contributing to heterochromatinization in senescent human cells [#8].\",\n  \"teleology\": [\n    {\n      \"year\": 2000,\n      \"claim\": \"Established CABIN1 as a MEF2 corepressor, answering how MEF2-driven Nur77 transcription and T cell apoptosis are negatively controlled downstream of calcium signaling.\",\n      \"evidence\": \"Co-IP, transcriptional reporter and protein interaction assays defining mSin3/HDAC recruitment and p300 competition\",\n      \"pmids\": [\"10933397\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Did not resolve the structural basis of the MEF2-CABIN1 interaction\", \"Calcium-dependent regulation of recruitment not defined at the chromatin level\"]\n    },\n    {\n      \"year\": 2001,\n      \"claim\": \"Placed CABIN1 functionally within the calcium/calcineurin–MEF2–Nur77 apoptotic axis by showing overexpression blocks thapsigargin-induced Nur77 and apoptosis.\",\n      \"evidence\": \"Overexpression in T cell hybridomas with cyclosporin A inhibition and apoptosis readout\",\n      \"pmids\": [\"11385620\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Overexpression phenotype does not establish endogenous requirement\", \"Did not separate calcineurin-inhibitory from MEF2-corepressor functions\"]\n    },\n    {\n      \"year\": 2002,\n      \"claim\": \"Defined how CABIN1 inhibition of calcineurin is relieved during apoptosis, showing calpain cleaves the C-terminal calcineurin-binding domain to activate calcineurin for calcium-triggered death.\",\n      \"evidence\": \"In vitro calpain cleavage, binding assays with deletion mutants, and calpain inhibitor treatment\",\n      \"pmids\": [\"12114545\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"In vivo relevance of the 32 kDa fragment not established\", \"Did not address other calcineurin-binding determinants later found internally\"]\n    },\n    {\n      \"year\": 2003,\n      \"claim\": \"Provided the structural mechanism of MEF2 corepressor recruitment by solving the MEF2B/CABIN1-peptide/DNA ternary complex.\",\n      \"evidence\": \"X-ray crystallography at 2.2 Å of the MADS-box/MEF2S domain bound to a CABIN1 motif and DNA\",\n      \"pmids\": [\"12700764\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Structure limited to a short CABIN1 motif, not full-length protein\", \"Does not show how HDAC/SUV39H1 recruitment is coordinated on chromatin\"]\n    },\n    {\n      \"year\": 2005,\n      \"claim\": \"Explained dynamic control of CABIN1 localization, showing CaMKIV phosphorylation creates a 14-3-3 docking site driving nuclear export during T cell activation.\",\n      \"evidence\": \"RNAi knockdown of CaMKIV, direct phosphorylation, 14-3-3 binding and nuclear export assays with IL-2 transcription readout\",\n      \"pmids\": [\"15902271\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Phosphorylation site(s) on CABIN1 not fully mapped in this account\", \"Link between export and derepression of specific target genes not quantified\"]\n    },\n    {\n      \"year\": 2006,\n      \"claim\": \"Identified a second corepressor arm, showing CABIN1 recruits SUV39H1 through a distinct internal region to methylate H3 and repress MEF2 at promoters.\",\n      \"evidence\": \"Co-IP, HMT assay, Gal4 reporter and ChIP with domain mapping\",\n      \"pmids\": [\"17172641\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Interplay between HDAC and SUV39H1 arms on the same promoter not resolved\", \"Genome-wide targets not defined\"]\n    },\n    {\n      \"year\": 2007,\n      \"claim\": \"Resolved why C-terminal deletion mice retain calcineurin signaling by identifying a second internal calcineurin-binding domain (residues 701–900).\",\n      \"evidence\": \"In vitro dephosphorylation, NFAT nuclear import, IL-2 reporter assays with deletion mutants\",\n      \"pmids\": [\"17531200\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Single-lab functional study without structural validation\", \"Relative contribution of the two calcineurin-binding regions in vivo unclear\"]\n    },\n    {\n      \"year\": 2009,\n      \"claim\": \"Extended CABIN1 corepressor function to p53, showing it binds p53 on promoters and restrains its activity in unstressed cells via histone and p53-acetylation marks.\",\n      \"evidence\": \"ChIP, Co-IP, siRNA knockdown and reporter assays with p53-dependent cell-death rescue\",\n      \"pmids\": [\"19668210\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Mechanism linking CABIN1 to specific acetyltransferases/deacetylases on p53 not defined\", \"Did not address how stress relieves repression\"]\n    },\n    {\n      \"year\": 2013,\n      \"claim\": \"Defined the switch that releases p53 upon DNA damage, showing ATM/CHK2 phosphorylation and CRL4DDB2-mediated ubiquitination drive CABIN1 degradation.\",\n      \"evidence\": \"In vitro kinase assay, ATM/CHK2 manipulation, ubiquitination and proteasome inhibition assays, CRL4DDB2 identification\",\n      \"pmids\": [\"23303793\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Precise phosphodegron and ubiquitination sites not fully mapped\", \"Kinetics of CABIN1 loss relative to p53 target activation not quantified\"]\n    },\n    {\n      \"year\": 2011,\n      \"claim\": \"Established CABIN1 as a stable structural subunit of the HUCA H3.3 chaperone complex, linking it to replication-independent chromatin assembly and senescence heterochromatin.\",\n      \"evidence\": \"Endogenous and ectopic Co-IP, recombinant complex reconstitution, mutational analysis and senescence chromatin assays\",\n      \"pmids\": [\"21807893\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Specific contribution of CABIN1 to H3.3 deposition activity not isolated\", \"Structural placement of CABIN1 within the complex undefined\"]\n    },\n    {\n      \"year\": 2012,\n      \"claim\": \"Detailed HUCA architecture by quantifying the UBN1 NHRD–HIRA WD-repeat interface required for complex stability.\",\n      \"evidence\": \"Analytical ultracentrifugation, mutagenesis and in vivo chromatin organization assays\",\n      \"pmids\": [\"22401310\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Focused on UBN1–HIRA interface with CABIN1 only as complex context\", \"Direct CABIN1 contacts within HUCA not measured\"]\n    },\n    {\n      \"year\": 2022,\n      \"claim\": \"Refined the calcineurin-inhibitory mechanism to a minimal PxIxIT/PPTP peptide whose affinity is tuned by p38MAPK phosphorylation, selectively blocking NFAT without altering phosphatase activity.\",\n      \"evidence\": \"Peptide binding, mutagenesis, kinase phosphorylation, NFAT reporter and T cell activation assays\",\n      \"pmids\": [\"35550603\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Single-lab peptide-based study; full-length regulation not confirmed\", \"Physiological trigger for p38MAPK-mediated control not established\"]\n    },\n    {\n      \"year\": 2020,\n      \"claim\": \"Proposed a tissue-specific role in renal cells, placing Cabin1 upstream of a SIRT1/p53 axis and cytoskeletal/mitochondrial homeostasis in podocytes and tubular epithelium.\",\n      \"evidence\": \"siRNA knockdown with western blot, immunofluorescence and electron microscopy in AngII-treated renal cells\",\n      \"pmids\": [\"26275115\", \"29368245\", \"32000560\"],\n      \"confidence\": \"Low\",\n      \"gaps\": [\"Single-lab siRNA phenotypes without mechanistic reconstitution\", \"Direct molecular interactions with SIRT1/p53 not demonstrated\", \"Relationship to CABIN1's established corepressor functions unclear\"]\n    },\n    {\n      \"year\": null,\n      \"claim\": \"How CABIN1's distinct functions — MEF2/p53 corepression, calcineurin inhibition, and H3.3 chaperone activity — are coordinated or partitioned within a single protein and across cell types remains unresolved.\",\n      \"evidence\": \"\",\n      \"pmids\": [],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"No full-length structure integrating the corepressor, calcineurin-binding and HUCA domains\", \"Interplay between cytoplasmic calcineurin inhibition and nuclear chromatin roles undefined\", \"Genome-wide CABIN1 target landscape not mapped\"]\n    }\n  ],\n  \"mechanism_profile\": {\n    \"molecular_activity\": [\n      {\"term_id\": \"GO:0140110\", \"supporting_discovery_ids\": [0, 5, 7]},\n      {\"term_id\": \"GO:0098772\", \"supporting_discovery_ids\": [1, 6, 11]},\n      {\"term_id\": \"GO:0060090\", \"supporting_discovery_ids\": [0, 5, 8]},\n      {\"term_id\": \"GO:0042393\", \"supporting_discovery_ids\": [8]}\n    ],\n    \"localization\": [\n      {\"term_id\": \"GO:0005634\", \"supporting_discovery_ids\": [0, 4, 5, 7]},\n      {\"term_id\": \"GO:0005829\", \"supporting_discovery_ids\": [4]},\n      {\"term_id\": \"GO:0000228\", \"supporting_discovery_ids\": [8]}\n    ],\n    \"pathway\": [\n      {\"term_id\": \"R-HSA-74160\", \"supporting_discovery_ids\": [0, 5, 7]},\n      {\"term_id\": \"R-HSA-4839726\", \"supporting_discovery_ids\": [5, 8]},\n      {\"term_id\": \"R-HSA-168256\", \"supporting_discovery_ids\": [0, 4, 11]},\n      {\"term_id\": \"R-HSA-162582\", \"supporting_discovery_ids\": [1, 11]},\n      {\"term_id\": \"R-HSA-5357801\", \"supporting_discovery_ids\": [1, 7]}\n    ],\n    \"complexes\": [\n      \"HUCA (HIRA/UBN1/CABIN1/ASF1a) H3.3 chaperone complex\",\n      \"mSin3/HDAC corepressor complex\"\n    ],\n    \"partners\": [\n      \"MEF2\",\n      \"HDAC1\",\n      \"HDAC2\",\n      \"SUV39H1\",\n      \"p53\",\n      \"calcineurin\",\n      \"HIRA\",\n      \"14-3-3\"\n    ],\n    \"other_free_text\": []\n  }\n}","audit_flag":null,"evaluation":{"pairwise":"win","faith_supported":6,"faith_total":7,"faith_pct":85.71428571428571}}