{"gene":"CDR2","run_date":"2026-06-09T22:57:18","timeline":{"discoveries":[{"year":1999,"finding":"CDR2 (cdr2), a cytoplasmic protein harboring a helix-leucine zipper (HLZ) motif, interacts specifically with the HLZ motif of c-Myc. Both proteins colocalize in the cytoplasm of adult cerebellar Purkinje neurons and co-immunoprecipitate from tumor cell lines and cerebellar extracts. cdr2 down-regulates c-Myc-dependent transcription in cotransfection assays and redistributes Myc protein to the cytoplasm, indicating that cdr2 normally sequesters c-Myc in the neuronal cytoplasm to inhibit its transcriptional activity.","method":"Co-immunoprecipitation from tumor cell lines and cerebellar extracts; cotransfection transcription assays; immunofluorescence colocalization; in vitro interaction blockade by PCD patient antisera","journal":"Genes & development","confidence":"High","confidence_rationale":"Tier 2 / Strong — reciprocal Co-IP from multiple cell types, cotransfection reporter assays, and immunofluorescence colocalization, all in one study with functional follow-up","pmids":["10465786"],"is_preprint":false},{"year":1997,"finding":"cdr2 mRNA is expressed in almost all tissues, but cdr2 protein is expressed only in brain and testis (immune-privileged sites) due to post-transcriptional regulation, establishing that CDR2 protein expression is restricted by a post-transcriptional mechanism rather than transcriptional control.","method":"Northern blot (mRNA distribution across tissues), Western blot and immunohistochemistry (protein distribution); comparison of mRNA vs. protein levels across tissues","journal":"The Journal of neuroscience","confidence":"High","confidence_rationale":"Tier 2 / Strong — orthogonal methods (Northern blot + Western blot + IHC) in a single focused study demonstrating clear mRNA-protein discordance across tissues","pmids":["9006982"],"is_preprint":false},{"year":2010,"finding":"In tumor cells, cdr2 protein levels peak in mitosis and are cell-cycle regulated. As cells exit mitosis, cdr2 is ubiquitinated by the anaphase promoting complex/cyclosome (APC/C) and rapidly degraded by the proteasome. During mitosis, cdr2 and c-Myc interact to synergistically regulate c-Myc-dependent transcription. Loss of cdr2 causes aberrant mitotic spindle formation and impaired proliferation, while cdr2 overexpression drives cell proliferation.","method":"Cell cycle synchronization with Western blot; ubiquitination assays; APC/C inhibition experiments; cotransfection transcription assays; siRNA knockdown with mitotic spindle phenotype readout; overexpression proliferation assay","journal":"PloS one","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — multiple complementary methods in a single lab study demonstrating APC/C-dependent degradation and functional mitotic role","pmids":["20383333"],"is_preprint":false},{"year":2009,"finding":"CDR2 was identified as a novel interactor of the hypoxia-inducible factor (HIF) prolyl-4-hydroxylase PHD1. CDR2 overexpression in tumor cell lines reduced HIF-dependent transcriptional regulation by attenuating hypoxic protein accumulation and suppressing the transactivation activity of HIF-1alpha.","method":"Protein interaction screen identifying CDR2 as PHD1 interactor; CDR2 overexpression in cell lines with HIF-target gene expression assays; HIF-1alpha transactivation reporter assays","journal":"Oncogene","confidence":"Medium","confidence_rationale":"Tier 2-3 / Moderate — protein interaction identification plus functional overexpression assays in a single lab, but interaction details not fully elaborated in abstract","pmids":["19581925"],"is_preprint":false},{"year":2014,"finding":"CDR2 antibodies (paraneoplastic Yo antibodies) are internalized by Purkinje cells and cause calcium homeostasis dysregulation. CDR2 co-immunoprecipitates with calbindin D28K. CDR2 antibody internalization leads to reduced calbindin immunoreactivity, increased Cav2.1 (voltage-gated calcium channel), protein kinase C gamma, and calpain-2 expression. Pharmacological inhibition of these pathways prevented CDR2-antibody-induced morphological changes, establishing a mechanistic pathway from CDR2 antibody binding to calcium dysregulation and Purkinje cell degeneration.","method":"Cerebellar organotypic slice culture; high-resolution multiphoton imaging; co-immunoprecipitation (CDR2 with calbindin D28K); Western blot; pharmacological inhibition experiments","journal":"Acta neuropathologica","confidence":"Medium","confidence_rationale":"Tier 2-3 / Moderate — co-IP of CDR2 with calbindin, multiple signaling pathway readouts with pharmacological rescue, single lab","pmids":["25341622"],"is_preprint":false},{"year":2015,"finding":"Anti-Yo (CDR2) IgG antibodies cause Purkinje cell death specifically through binding to the intracellular 62 kDa CDR2 antigen. Adsorption of anti-Yo IgG with its 62 kDa target antigen abolished both intracellular antibody accumulation and cytotoxicity. Other antibodies against intracellular Purkinje cell proteins (calbindin, calmodulin, PCP-2) were also taken up but did not cause cell death, demonstrating that cell death requires specific antibody-antigen interaction with CDR2, not merely intracellular antibody accumulation.","method":"Rat cerebellar slice culture; antibody adsorption/pre-absorption experiments; immunofluorescence for intracellular antibody accumulation; cell viability assays; comparison with control antibodies against other intracellular Purkinje cell proteins","journal":"PloS one","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — antigen-specific adsorption controls and multiple antibody comparisons in a single lab using organotypic culture system","pmids":["25885452"],"is_preprint":false},{"year":2020,"finding":"CDR2 localizes to the nucleus (not the cytoplasm) in Purkinje neurons, where it co-localizes with nuclear speckle proteins SON, eukaryotic initiation factor 4A-III, and serine/arginine-rich splicing factor 2. In contrast, CDR2L (the paralog) localizes to the cytoplasm and co-localizes with the 40S ribosomal protein S6. Yo antibodies were confirmed by mass spectrometry-based proteomics to specifically bind CDR2L, not endogenous CDR2.","method":"Mass spectrometry-based proteomics; super-resolution microscopy; proximity ligation assay; co-immunoprecipitation; immunofluorescence in cancer cells, rat Purkinje neuron cultures, and human cerebellar sections","journal":"Annals of clinical and translational neurology","confidence":"High","confidence_rationale":"Tier 1-2 / Strong — multiple orthogonal methods (mass spec, super-resolution microscopy, PLA, Co-IP) converging on subcellular localization and binding partners","pmids":["33009713"],"is_preprint":false},{"year":2018,"finding":"Yo antibody internalization into Purkinje neurons causes depletion of calbindin immunoreactivity and alters mitochondrial calcium retention capacity. Specifically, Yo-CDR2 binding did NOT alter mitochondrial calcium retention capacity, cyclophilin D-independent opening of the mitochondrial permeability transition pore (MPTP), or NCX activity — whereas Yo-CDR2L binding did produce these mitochondrial effects, indicating distinct pathological mechanisms for the two targets.","method":"Cerebellar organotypic slice culture treated with patient Yo antisera or purified CDR2/CDR2L antibodies; pharmacological modulation of mitochondrial pathways (cyclosporin-A, cannabidiol, ROS scavenger); immunohistochemistry","journal":"Neuropathology and applied neurobiology","confidence":"Medium","confidence_rationale":"Tier 2-3 / Moderate — pharmacological dissection of pathways in organotypic cultures, single lab, with specific negative finding for CDR2 vs. CDR2L","pmids":["29679372"],"is_preprint":false}],"current_model":"Human CDR2 (cerebellar degeneration-related protein 2) is a cytoplasmic/nuclear leucine-zipper protein that sequesters c-Myc in the neuronal cytoplasm to suppress its transcriptional activity, is cell-cycle regulated in tumor cells with APC/C-mediated proteasomal degradation at mitotic exit, interacts with the HIF prolyl-4-hydroxylase PHD1 to attenuate hypoxic signaling, co-immunoprecipitates with calbindin D28K and localizes to nuclear speckles in Purkinje neurons; its expression is post-transcriptionally restricted to immune-privileged tissues (brain and testis), and paraneoplastic Yo autoantibodies cause Purkinje cell death specifically through binding to the intracellular CDR2 antigen (or its paralog CDR2L), triggering calcium homeostasis dysregulation."},"narrative":{"mechanistic_narrative":"CDR2 (cerebellar degeneration-related protein 2) is a leucine-zipper protein that functions as a regulator of transcription factor activity and cell proliferation, principally through sequestration of the oncoprotein c-Myc [PMID:10465786]. Via its helix-leucine zipper motif, CDR2 binds the homologous HLZ motif of c-Myc, redistributing Myc to the cytoplasm of Purkinje neurons and tumor cells and downregulating c-Myc-dependent transcription [PMID:10465786]. Its abundance is cell-cycle gated: CDR2 protein peaks in mitosis and is ubiquitinated by the APC/C and degraded by the proteasome upon mitotic exit, and its loss produces aberrant mitotic spindles and impaired proliferation while overexpression drives proliferation [PMID:20383333]. CDR2 also interacts with the HIF prolyl-4-hydroxylase PHD1 and attenuates hypoxic HIF-1alpha transactivation when overexpressed [PMID:19581925]. CDR2 protein expression is restricted to immune-privileged brain and testis by a post-transcriptional mechanism, despite near-ubiquitous mRNA [PMID:9006982]. Within Purkinje neurons CDR2 localizes to nuclear speckles, co-localizing with SON, eIF4A-III, and SRSF2, distinguishing it from its cytoplasmic, ribosome-associated paralog CDR2L [PMID:33009713]. As the canonical paraneoplastic Yo autoantigen, CDR2 (and CDR2L) antibody uptake into Purkinje cells triggers calcium homeostasis dysregulation and cell death [PMID:25341622, PMID:25885452], with mass-spectrometry proteomics indicating that endogenous Yo reactivity is directed at CDR2L rather than CDR2 [PMID:33009713].","teleology":[{"year":1997,"claim":"Resolved why the Yo antigen is confined to immune-privileged tissue by showing the restriction is post-transcriptional, not transcriptional.","evidence":"Northern blot for mRNA versus Western blot and IHC for protein across tissues","pmids":["9006982"],"confidence":"High","gaps":["The specific post-transcriptional mechanism (translational control, RNA stability) was not identified","No identification of the regulatory factors enforcing restriction"]},{"year":1999,"claim":"Established CDR2's first molecular function: it binds c-Myc through their shared leucine-zipper motifs and sequesters Myc in the cytoplasm to suppress its transcriptional output.","evidence":"Reciprocal Co-IP from tumor and cerebellar extracts, cotransfection reporter assays, and immunofluorescence colocalization","pmids":["10465786"],"confidence":"High","gaps":["Whether cytoplasmic sequestration occurs in non-neuronal cells in vivo was not established","Structural basis of the HLZ-HLZ interaction not resolved"]},{"year":2009,"claim":"Extended CDR2 function beyond c-Myc by linking it to hypoxic signaling through interaction with the prolyl-4-hydroxylase PHD1.","evidence":"Interaction screen plus CDR2 overexpression with HIF-target and HIF-1alpha transactivation reporter assays in tumor cell lines","pmids":["19581925"],"confidence":"Medium","gaps":["Interaction interface and stoichiometry not characterized","Effect demonstrated by overexpression, not loss-of-function","Endogenous role in neurons untested"]},{"year":2010,"claim":"Connected CDR2 to mitotic control by showing its abundance is APC/C-regulated and that it is functionally required for normal spindle formation and proliferation.","evidence":"Cell-cycle synchronization, ubiquitination and APC/C inhibition assays, siRNA knockdown with spindle readout, and overexpression proliferation assays","pmids":["20383333"],"confidence":"Medium","gaps":["The APC/C degron in CDR2 not mapped","Mechanism linking CDR2 to spindle integrity not defined","Single-lab evidence"]},{"year":2014,"claim":"Began defining the pathological cascade of Yo autoimmunity by linking internalized CDR2 antibodies to calcium dysregulation via calbindin D28K and downstream effectors.","evidence":"Organotypic cerebellar slice culture, multiphoton imaging, Co-IP of CDR2 with calbindin, and pharmacological rescue","pmids":["25341622"],"confidence":"Medium","gaps":["Direct versus indirect nature of CDR2-calbindin association unclear","Single-lab study"]},{"year":2015,"claim":"Demonstrated that Yo antibody cytotoxicity requires specific binding to the 62 kDa CDR2 antigen rather than mere intracellular antibody accumulation.","evidence":"Rat cerebellar slice culture with antigen adsorption controls and comparison against antibodies to other intracellular Purkinje proteins","pmids":["25885452"],"confidence":"Medium","gaps":["The intracellular event triggered by antibody-antigen binding not defined","Mechanism of antibody internalization unresolved"]},{"year":2018,"claim":"Dissected the mitochondrial component of Yo pathology and revealed that CDR2 and its paralog CDR2L produce distinct effects, with mitochondrial calcium handling altered by CDR2L but not CDR2.","evidence":"Organotypic slice culture with purified CDR2/CDR2L antibodies and pharmacological modulation of mitochondrial pathways","pmids":["29679372"],"confidence":"Medium","gaps":["The CDR2-specific death mechanism distinct from CDR2L remains undefined","Single-lab pharmacological dissection"]},{"year":2020,"claim":"Reassigned subcellular localization and antigen identity, placing CDR2 in nuclear speckles and showing endogenous Yo reactivity targets cytoplasmic CDR2L.","evidence":"Mass-spectrometry proteomics, super-resolution microscopy, proximity ligation assay, and Co-IP in cancer cells and Purkinje neurons","pmids":["33009713"],"confidence":"High","gaps":["Functional role of CDR2 in nuclear speckles not established","Reconciliation with earlier cytoplasmic c-Myc sequestration model not resolved"]},{"year":null,"claim":"How CDR2's nuclear speckle localization integrates with its reported c-Myc, PHD1, and APC/C-linked functions, and which mechanism drives CDR2-specific Purkinje cell death, remain unresolved.","evidence":"","pmids":[],"confidence":"Medium","gaps":["No structural model of CDR2 complexes","No unified model linking nuclear localization to transcriptional/cell-cycle roles","CDR2-specific neurodegeneration mechanism undefined"]}],"mechanism_profile":{"molecular_activity":[{"term_id":"GO:0140110","term_label":"transcription regulator activity","supporting_discovery_ids":[0,2]},{"term_id":"GO:0098772","term_label":"molecular function regulator activity","supporting_discovery_ids":[0,3]}],"localization":[{"term_id":"GO:0005829","term_label":"cytosol","supporting_discovery_ids":[0]},{"term_id":"GO:0005654","term_label":"nucleoplasm","supporting_discovery_ids":[6]}],"pathway":[{"term_id":"R-HSA-1640170","term_label":"Cell Cycle","supporting_discovery_ids":[2]},{"term_id":"R-HSA-74160","term_label":"Gene expression (Transcription)","supporting_discovery_ids":[0]}],"complexes":[],"partners":["MYC","PHD1","CALB1"],"other_free_text":[]}},"prefetch_data":{"uniprot":{"accession":"Q01850","full_name":"Cerebellar degeneration-related protein 2","aliases":["Major Yo paraneoplastic antigen","Paraneoplastic cerebellar degeneration-associated antigen"],"length_aa":454,"mass_kda":51.9,"function":"","subcellular_location":"","url":"https://www.uniprot.org/uniprotkb/Q01850/entry"},"depmap":{"release":"DepMap","has_data":true,"is_common_essential":false,"resolved_as":"","url":"https://depmap.org/portal/gene/CDR2","classification":"Not Classified","n_dependent_lines":0,"n_total_lines":1208,"dependency_fraction":0.0},"opencell":{"profiled":false,"resolved_as":"","ensg_id":"","cell_line_id":"","localizations":[],"interactors":[],"url":"https://opencell.sf.czbiohub.org/search/CDR2","total_profiled":1310},"omim":[{"mim_id":"609236","title":"BR SERINE/THREONINE KINASE 2; BRSK2","url":"https://www.omim.org/entry/609236"},{"mim_id":"605086","title":"TRIGGERING RECEPTOR EXPRESSED ON MYELOID CELLS 2; TREM2","url":"https://www.omim.org/entry/605086"},{"mim_id":"602197","title":"CEREBELLAR DEGENERATION-RELATED AUTOANTIGEN 3","url":"https://www.omim.org/entry/602197"},{"mim_id":"300005","title":"METHYL-CpG-BINDING PROTEIN 2; MECP2","url":"https://www.omim.org/entry/300005"},{"mim_id":"117340","title":"CEREBELLAR DEGENERATION-RELATED AUTOANTIGEN 2; CDR2","url":"https://www.omim.org/entry/117340"}],"hpa":{"profiled":true,"resolved_as":"","reliability":"Approved","locations":[{"location":"Nucleoplasm","reliability":"Approved"}],"tissue_specificity":"Low tissue specificity","tissue_distribution":"Detected in all","driving_tissues":[],"url":"https://www.proteinatlas.org/search/CDR2"},"hgnc":{"alias_symbol":["CDR62","Yo"],"prev_symbol":[]},"alphafold":{"accession":"Q01850","domains":[],"viewer_url":"https://alphafold.ebi.ac.uk/entry/Q01850","model_url":"https://alphafold.ebi.ac.uk/files/AF-Q01850-F1-model_v6.cif","pae_url":"https://alphafold.ebi.ac.uk/files/AF-Q01850-F1-predicted_aligned_error_v6.png","plddt_mean":74.12},"mouse_models":{"mgi_url":"https://www.informatics.jax.org/marker/summary?nomen=CDR2","jax_strain_url":"https://www.jax.org/strain/search?query=CDR2"},"sequence":{"accession":"Q01850","fasta_url":"https://rest.uniprot.org/uniprotkb/Q01850.fasta","uniprot_url":"https://www.uniprot.org/uniprotkb/Q01850/entry","alphafold_viewer_url":"https://alphafold.ebi.ac.uk/entry/Q01850"}},"corpus_meta":[{"pmid":"1407575","id":"PMC_1407575","title":"Paraneoplastic cerebellar degeneration. 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A clinical analysis of 55 anti-Yo antibody-positive patients.","date":"1992","source":"Neurology","url":"https://pubmed.ncbi.nlm.nih.gov/1407575","citation_count":491,"is_preprint":false},{"pmid":"9043118","id":"PMC_9043118","title":"Cloning of Candida albicans genes conferring resistance to azole antifungal agents: characterization of CDR2, a new multidrug ABC transporter gene.","date":"1997","source":"Microbiology (Reading, England)","url":"https://pubmed.ncbi.nlm.nih.gov/9043118","citation_count":475,"is_preprint":false},{"pmid":"16452151","id":"PMC_16452151","title":"A mutation in Tac1p, a transcription factor regulating CDR1 and CDR2, is coupled with loss of heterozygosity at chromosome 5 to mediate antifungal resistance in Candida albicans.","date":"2006","source":"Genetics","url":"https://pubmed.ncbi.nlm.nih.gov/16452151","citation_count":300,"is_preprint":false},{"pmid":"11918807","id":"PMC_11918807","title":"A common drug-responsive element mediates the upregulation of the Candida albicans ABC transporters CDR1 and CDR2, two genes involved in antifungal drug resistance.","date":"2002","source":"Molecular microbiology","url":"https://pubmed.ncbi.nlm.nih.gov/11918807","citation_count":141,"is_preprint":false},{"pmid":"1779243","id":"PMC_1779243","title":"Effect of intraventricular injection of an anti-Purkinje cell antibody (anti-Yo) in a guinea pig model.","date":"1991","source":"Journal of the neurological sciences","url":"https://pubmed.ncbi.nlm.nih.gov/1779243","citation_count":140,"is_preprint":false},{"pmid":"8688082","id":"PMC_8688082","title":"Control of MHC restriction by TCR Valpha CDR1 and CDR2.","date":"1996","source":"Science (New York, N.Y.)","url":"https://pubmed.ncbi.nlm.nih.gov/8688082","citation_count":131,"is_preprint":false},{"pmid":"7510746","id":"PMC_7510746","title":"Immunity to TCR peptides in multiple sclerosis. 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Successful immunization of patients with synthetic V beta 5.2 and V beta 6.1 CDR2 peptides.","date":"1994","source":"Journal of immunology (Baltimore, Md. : 1950)","url":"https://pubmed.ncbi.nlm.nih.gov/7510746","citation_count":105,"is_preprint":false},{"pmid":"8604342","id":"PMC_8604342","title":"Single- and double-strand photocleavage of DNA by YO, YOYO and TOTO.","date":"1996","source":"Nucleic acids research","url":"https://pubmed.ncbi.nlm.nih.gov/8604342","citation_count":98,"is_preprint":false},{"pmid":"16600963","id":"PMC_16600963","title":"Directed evolution of human T cell receptor CDR2 residues by phage display dramatically enhances affinity for cognate peptide-MHC without increasing apparent cross-reactivity.","date":"2006","source":"Protein science : a publication of the Protein Society","url":"https://pubmed.ncbi.nlm.nih.gov/16600963","citation_count":98,"is_preprint":false},{"pmid":"26377319","id":"PMC_26377319","title":"'Medusa head ataxia': the expanding spectrum of Purkinje cell antibodies in autoimmune cerebellar ataxia. 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CB","url":"https://pubmed.ncbi.nlm.nih.gov/28162898","citation_count":12,"is_preprint":false}],"cost":{"stage1":{"model":"claude-sonnet-4-6","input_tokens":48715,"output_tokens":2583,"usd":0.092445,"stage1_stop_reason":"end_turn"},"stage2":{"model":"claude-opus-4-8","input_tokens":9828,"output_tokens":2922,"usd":0.061095,"stage2_stop_reason":"end_turn"},"total_usd":0.15354,"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\": 1999,\n      \"finding\": \"CDR2 (cdr2), a cytoplasmic protein harboring a helix-leucine zipper (HLZ) motif, interacts specifically with the HLZ motif of c-Myc. Both proteins colocalize in the cytoplasm of adult cerebellar Purkinje neurons and co-immunoprecipitate from tumor cell lines and cerebellar extracts. cdr2 down-regulates c-Myc-dependent transcription in cotransfection assays and redistributes Myc protein to the cytoplasm, indicating that cdr2 normally sequesters c-Myc in the neuronal cytoplasm to inhibit its transcriptional activity.\",\n      \"method\": \"Co-immunoprecipitation from tumor cell lines and cerebellar extracts; cotransfection transcription assays; immunofluorescence colocalization; in vitro interaction blockade by PCD patient antisera\",\n      \"journal\": \"Genes & development\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — reciprocal Co-IP from multiple cell types, cotransfection reporter assays, and immunofluorescence colocalization, all in one study with functional follow-up\",\n      \"pmids\": [\"10465786\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 1997,\n      \"finding\": \"cdr2 mRNA is expressed in almost all tissues, but cdr2 protein is expressed only in brain and testis (immune-privileged sites) due to post-transcriptional regulation, establishing that CDR2 protein expression is restricted by a post-transcriptional mechanism rather than transcriptional control.\",\n      \"method\": \"Northern blot (mRNA distribution across tissues), Western blot and immunohistochemistry (protein distribution); comparison of mRNA vs. protein levels across tissues\",\n      \"journal\": \"The Journal of neuroscience\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — orthogonal methods (Northern blot + Western blot + IHC) in a single focused study demonstrating clear mRNA-protein discordance across tissues\",\n      \"pmids\": [\"9006982\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2010,\n      \"finding\": \"In tumor cells, cdr2 protein levels peak in mitosis and are cell-cycle regulated. As cells exit mitosis, cdr2 is ubiquitinated by the anaphase promoting complex/cyclosome (APC/C) and rapidly degraded by the proteasome. During mitosis, cdr2 and c-Myc interact to synergistically regulate c-Myc-dependent transcription. Loss of cdr2 causes aberrant mitotic spindle formation and impaired proliferation, while cdr2 overexpression drives cell proliferation.\",\n      \"method\": \"Cell cycle synchronization with Western blot; ubiquitination assays; APC/C inhibition experiments; cotransfection transcription assays; siRNA knockdown with mitotic spindle phenotype readout; overexpression proliferation assay\",\n      \"journal\": \"PloS one\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — multiple complementary methods in a single lab study demonstrating APC/C-dependent degradation and functional mitotic role\",\n      \"pmids\": [\"20383333\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2009,\n      \"finding\": \"CDR2 was identified as a novel interactor of the hypoxia-inducible factor (HIF) prolyl-4-hydroxylase PHD1. CDR2 overexpression in tumor cell lines reduced HIF-dependent transcriptional regulation by attenuating hypoxic protein accumulation and suppressing the transactivation activity of HIF-1alpha.\",\n      \"method\": \"Protein interaction screen identifying CDR2 as PHD1 interactor; CDR2 overexpression in cell lines with HIF-target gene expression assays; HIF-1alpha transactivation reporter assays\",\n      \"journal\": \"Oncogene\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2-3 / Moderate — protein interaction identification plus functional overexpression assays in a single lab, but interaction details not fully elaborated in abstract\",\n      \"pmids\": [\"19581925\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2014,\n      \"finding\": \"CDR2 antibodies (paraneoplastic Yo antibodies) are internalized by Purkinje cells and cause calcium homeostasis dysregulation. CDR2 co-immunoprecipitates with calbindin D28K. CDR2 antibody internalization leads to reduced calbindin immunoreactivity, increased Cav2.1 (voltage-gated calcium channel), protein kinase C gamma, and calpain-2 expression. Pharmacological inhibition of these pathways prevented CDR2-antibody-induced morphological changes, establishing a mechanistic pathway from CDR2 antibody binding to calcium dysregulation and Purkinje cell degeneration.\",\n      \"method\": \"Cerebellar organotypic slice culture; high-resolution multiphoton imaging; co-immunoprecipitation (CDR2 with calbindin D28K); Western blot; pharmacological inhibition experiments\",\n      \"journal\": \"Acta neuropathologica\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2-3 / Moderate — co-IP of CDR2 with calbindin, multiple signaling pathway readouts with pharmacological rescue, single lab\",\n      \"pmids\": [\"25341622\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2015,\n      \"finding\": \"Anti-Yo (CDR2) IgG antibodies cause Purkinje cell death specifically through binding to the intracellular 62 kDa CDR2 antigen. Adsorption of anti-Yo IgG with its 62 kDa target antigen abolished both intracellular antibody accumulation and cytotoxicity. Other antibodies against intracellular Purkinje cell proteins (calbindin, calmodulin, PCP-2) were also taken up but did not cause cell death, demonstrating that cell death requires specific antibody-antigen interaction with CDR2, not merely intracellular antibody accumulation.\",\n      \"method\": \"Rat cerebellar slice culture; antibody adsorption/pre-absorption experiments; immunofluorescence for intracellular antibody accumulation; cell viability assays; comparison with control antibodies against other intracellular Purkinje cell proteins\",\n      \"journal\": \"PloS one\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — antigen-specific adsorption controls and multiple antibody comparisons in a single lab using organotypic culture system\",\n      \"pmids\": [\"25885452\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2020,\n      \"finding\": \"CDR2 localizes to the nucleus (not the cytoplasm) in Purkinje neurons, where it co-localizes with nuclear speckle proteins SON, eukaryotic initiation factor 4A-III, and serine/arginine-rich splicing factor 2. In contrast, CDR2L (the paralog) localizes to the cytoplasm and co-localizes with the 40S ribosomal protein S6. Yo antibodies were confirmed by mass spectrometry-based proteomics to specifically bind CDR2L, not endogenous CDR2.\",\n      \"method\": \"Mass spectrometry-based proteomics; super-resolution microscopy; proximity ligation assay; co-immunoprecipitation; immunofluorescence in cancer cells, rat Purkinje neuron cultures, and human cerebellar sections\",\n      \"journal\": \"Annals of clinical and translational neurology\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1-2 / Strong — multiple orthogonal methods (mass spec, super-resolution microscopy, PLA, Co-IP) converging on subcellular localization and binding partners\",\n      \"pmids\": [\"33009713\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2018,\n      \"finding\": \"Yo antibody internalization into Purkinje neurons causes depletion of calbindin immunoreactivity and alters mitochondrial calcium retention capacity. Specifically, Yo-CDR2 binding did NOT alter mitochondrial calcium retention capacity, cyclophilin D-independent opening of the mitochondrial permeability transition pore (MPTP), or NCX activity — whereas Yo-CDR2L binding did produce these mitochondrial effects, indicating distinct pathological mechanisms for the two targets.\",\n      \"method\": \"Cerebellar organotypic slice culture treated with patient Yo antisera or purified CDR2/CDR2L antibodies; pharmacological modulation of mitochondrial pathways (cyclosporin-A, cannabidiol, ROS scavenger); immunohistochemistry\",\n      \"journal\": \"Neuropathology and applied neurobiology\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2-3 / Moderate — pharmacological dissection of pathways in organotypic cultures, single lab, with specific negative finding for CDR2 vs. CDR2L\",\n      \"pmids\": [\"29679372\"],\n      \"is_preprint\": false\n    }\n  ],\n  \"current_model\": \"Human CDR2 (cerebellar degeneration-related protein 2) is a cytoplasmic/nuclear leucine-zipper protein that sequesters c-Myc in the neuronal cytoplasm to suppress its transcriptional activity, is cell-cycle regulated in tumor cells with APC/C-mediated proteasomal degradation at mitotic exit, interacts with the HIF prolyl-4-hydroxylase PHD1 to attenuate hypoxic signaling, co-immunoprecipitates with calbindin D28K and localizes to nuclear speckles in Purkinje neurons; its expression is post-transcriptionally restricted to immune-privileged tissues (brain and testis), and paraneoplastic Yo autoantibodies cause Purkinje cell death specifically through binding to the intracellular CDR2 antigen (or its paralog CDR2L), triggering calcium homeostasis dysregulation.\"\n}\n```","stage2_raw":"{\n  \"mechanistic_narrative\": \"CDR2 (cerebellar degeneration-related protein 2) is a leucine-zipper protein that functions as a regulator of transcription factor activity and cell proliferation, principally through sequestration of the oncoprotein c-Myc [#0]. Via its helix-leucine zipper motif, CDR2 binds the homologous HLZ motif of c-Myc, redistributing Myc to the cytoplasm of Purkinje neurons and tumor cells and downregulating c-Myc-dependent transcription [#0]. Its abundance is cell-cycle gated: CDR2 protein peaks in mitosis and is ubiquitinated by the APC/C and degraded by the proteasome upon mitotic exit, and its loss produces aberrant mitotic spindles and impaired proliferation while overexpression drives proliferation [#2]. CDR2 also interacts with the HIF prolyl-4-hydroxylase PHD1 and attenuates hypoxic HIF-1alpha transactivation when overexpressed [#3]. CDR2 protein expression is restricted to immune-privileged brain and testis by a post-transcriptional mechanism, despite near-ubiquitous mRNA [#1]. Within Purkinje neurons CDR2 localizes to nuclear speckles, co-localizing with SON, eIF4A-III, and SRSF2, distinguishing it from its cytoplasmic, ribosome-associated paralog CDR2L [#6]. As the canonical paraneoplastic Yo autoantigen, CDR2 (and CDR2L) antibody uptake into Purkinje cells triggers calcium homeostasis dysregulation and cell death [#4, #5], with mass-spectrometry proteomics indicating that endogenous Yo reactivity is directed at CDR2L rather than CDR2 [#6].\"\n  ,\n  \"teleology\": [\n    {\n      \"year\": 1997,\n      \"claim\": \"Resolved why the Yo antigen is confined to immune-privileged tissue by showing the restriction is post-transcriptional, not transcriptional.\",\n      \"evidence\": \"Northern blot for mRNA versus Western blot and IHC for protein across tissues\",\n      \"pmids\": [\"9006982\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"The specific post-transcriptional mechanism (translational control, RNA stability) was not identified\", \"No identification of the regulatory factors enforcing restriction\"]\n    },\n    {\n      \"year\": 1999,\n      \"claim\": \"Established CDR2's first molecular function: it binds c-Myc through their shared leucine-zipper motifs and sequesters Myc in the cytoplasm to suppress its transcriptional output.\",\n      \"evidence\": \"Reciprocal Co-IP from tumor and cerebellar extracts, cotransfection reporter assays, and immunofluorescence colocalization\",\n      \"pmids\": [\"10465786\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Whether cytoplasmic sequestration occurs in non-neuronal cells in vivo was not established\", \"Structural basis of the HLZ-HLZ interaction not resolved\"]\n    },\n    {\n      \"year\": 2009,\n      \"claim\": \"Extended CDR2 function beyond c-Myc by linking it to hypoxic signaling through interaction with the prolyl-4-hydroxylase PHD1.\",\n      \"evidence\": \"Interaction screen plus CDR2 overexpression with HIF-target and HIF-1alpha transactivation reporter assays in tumor cell lines\",\n      \"pmids\": [\"19581925\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Interaction interface and stoichiometry not characterized\", \"Effect demonstrated by overexpression, not loss-of-function\", \"Endogenous role in neurons untested\"]\n    },\n    {\n      \"year\": 2010,\n      \"claim\": \"Connected CDR2 to mitotic control by showing its abundance is APC/C-regulated and that it is functionally required for normal spindle formation and proliferation.\",\n      \"evidence\": \"Cell-cycle synchronization, ubiquitination and APC/C inhibition assays, siRNA knockdown with spindle readout, and overexpression proliferation assays\",\n      \"pmids\": [\"20383333\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"The APC/C degron in CDR2 not mapped\", \"Mechanism linking CDR2 to spindle integrity not defined\", \"Single-lab evidence\"]\n    },\n    {\n      \"year\": 2014,\n      \"claim\": \"Began defining the pathological cascade of Yo autoimmunity by linking internalized CDR2 antibodies to calcium dysregulation via calbindin D28K and downstream effectors.\",\n      \"evidence\": \"Organotypic cerebellar slice culture, multiphoton imaging, Co-IP of CDR2 with calbindin, and pharmacological rescue\",\n      \"pmids\": [\"25341622\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Direct versus indirect nature of CDR2-calbindin association unclear\", \"Single-lab study\"]\n    },\n    {\n      \"year\": 2015,\n      \"claim\": \"Demonstrated that Yo antibody cytotoxicity requires specific binding to the 62 kDa CDR2 antigen rather than mere intracellular antibody accumulation.\",\n      \"evidence\": \"Rat cerebellar slice culture with antigen adsorption controls and comparison against antibodies to other intracellular Purkinje proteins\",\n      \"pmids\": [\"25885452\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"The intracellular event triggered by antibody-antigen binding not defined\", \"Mechanism of antibody internalization unresolved\"]\n    },\n    {\n      \"year\": 2018,\n      \"claim\": \"Dissected the mitochondrial component of Yo pathology and revealed that CDR2 and its paralog CDR2L produce distinct effects, with mitochondrial calcium handling altered by CDR2L but not CDR2.\",\n      \"evidence\": \"Organotypic slice culture with purified CDR2/CDR2L antibodies and pharmacological modulation of mitochondrial pathways\",\n      \"pmids\": [\"29679372\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"The CDR2-specific death mechanism distinct from CDR2L remains undefined\", \"Single-lab pharmacological dissection\"]\n    },\n    {\n      \"year\": 2020,\n      \"claim\": \"Reassigned subcellular localization and antigen identity, placing CDR2 in nuclear speckles and showing endogenous Yo reactivity targets cytoplasmic CDR2L.\",\n      \"evidence\": \"Mass-spectrometry proteomics, super-resolution microscopy, proximity ligation assay, and Co-IP in cancer cells and Purkinje neurons\",\n      \"pmids\": [\"33009713\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Functional role of CDR2 in nuclear speckles not established\", \"Reconciliation with earlier cytoplasmic c-Myc sequestration model not resolved\"]\n    },\n    {\n      \"year\": null,\n      \"claim\": \"How CDR2's nuclear speckle localization integrates with its reported c-Myc, PHD1, and APC/C-linked functions, and which mechanism drives CDR2-specific Purkinje cell death, remain unresolved.\",\n      \"evidence\": \"\",\n      \"pmids\": [],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"No structural model of CDR2 complexes\", \"No unified model linking nuclear localization to transcriptional/cell-cycle roles\", \"CDR2-specific neurodegeneration mechanism undefined\"]\n    }\n  ],\n  \"mechanism_profile\": {\n    \"molecular_activity\": [\n      {\"term_id\": \"GO:0140110\", \"supporting_discovery_ids\": [0, 2]},\n      {\"term_id\": \"GO:0098772\", \"supporting_discovery_ids\": [0, 3]}\n    ],\n    \"localization\": [\n      {\"term_id\": \"GO:0005829\", \"supporting_discovery_ids\": [0]},\n      {\"term_id\": \"GO:0005654\", \"supporting_discovery_ids\": [6]}\n    ],\n    \"pathway\": [\n      {\"term_id\": \"R-HSA-1640170\", \"supporting_discovery_ids\": [2]},\n      {\"term_id\": \"R-HSA-74160\", \"supporting_discovery_ids\": [0]}\n    ],\n    \"complexes\": [],\n    \"partners\": [\"MYC\", \"PHD1\", \"CALB1\"],\n    \"other_free_text\": []\n  }\n}","audit_flag":null,"evaluation":{"faith_supported":7,"faith_total":7,"faith_pct":100.0}}