{"gene":"CXADR","run_date":"2026-04-28T17:28:53","timeline":{"discoveries":[{"year":1997,"finding":"CXADR (CAR) was isolated and identified as a common receptor shared by group B coxsackieviruses and adenoviruses 2 and 5. Transfection of CAR cDNA into non-permissive hamster cells conferred susceptibility to coxsackievirus B attachment and infection, and enabled fiber-dependent adenovirus binding with a 100-fold increase in adenovirus-mediated gene transfer.","method":"cDNA cloning, transfection of non-permissive hamster cells, viral infection assays, adenovirus gene transfer assays","journal":"Science","confidence":"High","confidence_rationale":"Tier 1 — original functional reconstitution in non-permissive cells, replicated independently in same year","pmids":["9036860"],"is_preprint":false},{"year":1997,"finding":"Human CAR (HCAR) and mouse CAR (MCAR) were independently isolated as 46-kDa glycoproteins belonging to the immunoglobulin superfamily, containing two extracellular Ig-like domains. Transfection of either cDNA into receptor-negative NIH 3T3 cells conferred susceptibility to CVB infection and enabled adenovirus-mediated beta-galactosidase expression.","method":"cDNA isolation, transfection of NIH 3T3 cells, CVB infection assays, recombinant adenovirus gene transfer, Northern blot, Western blot with virus-binding-inhibitory antibodies","journal":"Proceedings of the National Academy of Sciences of the United States of America","confidence":"High","confidence_rationale":"Tier 1 — independent replication of functional reconstitution with structural characterization","pmids":["9096397"],"is_preprint":false},{"year":1998,"finding":"The murine CAR homolog (mCAR) functions as a receptor for coxsackieviruses B3 and B4 and increases susceptibility to adenovirus-mediated gene transfer when transfected into non-permissive CHO cells, demonstrating conservation of receptor function between human and murine CXADR.","method":"cDNA cloning, transfection of CHO cells, CVB infection assays, adenovirus gene transfer assays","journal":"Journal of virology","confidence":"High","confidence_rationale":"Tier 1 — functional reconstitution in non-permissive cells, orthologous gene confirmation","pmids":["9420240"],"is_preprint":false},{"year":1999,"finding":"The crystal structure of the adenovirus fiber knob domain in complex with domain 1 (D1) of CAR was determined, revealing that surface-exposed loops on the knob contact one face of CAR, forming a high-affinity complex with interfacial solvent-filled cavities. This identified key determinants of binding specificity.","method":"X-ray crystallography of recombinant fiber knob–CAR D1 complex","journal":"Science","confidence":"High","confidence_rationale":"Tier 1 — crystal structure with functional validation of binding interface","pmids":["10567268"],"is_preprint":false},{"year":1999,"finding":"CAR mRNA expression is highly variable across tissues with highest levels in the liver, and CAR expression does not correlate with actual adenovector gene transfer efficiency after systemic injection, indicating that anatomical barriers (particularly the endothelium) limit adenovirus targeting independent of receptor expression. The adenovirus binding site was localized to amino acids 29–128 of the CAR ectodomain.","method":"Northern blot and sequence analysis of CAR across multiple species and tissues; in vivo adenovector injection with tissue expression analysis","journal":"Gene therapy","confidence":"Medium","confidence_rationale":"Tier 2 — multiple tissue/species analysis with in vivo functional mismatch demonstration","pmids":["10490761"],"is_preprint":false},{"year":2000,"finding":"The CAR D1 domain forms homodimers in solution (Kd ~16 µM) and in crystals at 1.7 Å resolution, using the same GFCC'C″ surface that interacts with the adenovirus fiber head. The homodimer is similar to the CD2–CD58 heterodimer, consistent with CAR functioning physiologically as a homophilic cell adhesion molecule.","method":"Bacterial expression of CAR D1, X-ray crystallography (1.7 Å), analytical equilibrium ultracentrifugation","journal":"Structure","confidence":"High","confidence_rationale":"Tier 1 — crystal structure combined with solution biophysical measurement of dimerization","pmids":["11080637"],"is_preprint":false},{"year":2001,"finding":"CAR is a transmembrane component of the tight junction. In non-polarized cells, CAR localizes to homotypic intercellular contacts, mediates homotypic cell aggregation, and recruits ZO-1 to sites of cell–cell contact. In polarized epithelial cells, CAR and ZO-1 co-localize to tight junctions and co-precipitate from cell lysates. CAR expression reduces paracellular passage of macromolecules and ions, and soluble CAR inhibits formation of functional tight junctions. Virus entry into polarized epithelium required disruption of tight junctions.","method":"Immunofluorescence localization, co-immunoprecipitation, cell aggregation assays, transepithelial resistance measurements, virus infection of polarized epithelial monolayers","journal":"Proceedings of the National Academy of Sciences of the United States of America","confidence":"High","confidence_rationale":"Tier 2 — multiple orthogonal methods (localization, Co-IP, functional permeability assay) in single study","pmids":["11734628"],"is_preprint":false},{"year":2001,"finding":"Cryo-EM structure of CVB3 in complex with full-length human CAR (including transmembrane and cytoplasmic domains) at ~22 Å resolution showed that CAR binds with the distal end of domain D1 in the canyon of CVB3, similar to other receptor–enterovirus interactions. Pairs of transmembrane domains of CAR associate with each other in a detergent environment mimicking a plasma membrane. The site of CAR–adenovirus interaction uses a side surface of D1 distinct from the CVB3-binding surface.","method":"Cryo-electron microscopy (cryo-EM) reconstruction of virus–receptor complexes","journal":"Nature structural biology","confidence":"High","confidence_rationale":"Tier 1 — structural analysis of full-length receptor–virus complex including transmembrane region","pmids":["11573093"],"is_preprint":false},{"year":2001,"finding":"CAR is colocalized with integrins αvβ3 and αvβ5 at the cardiomyocyte sarcolemma and is upregulated at intercalated discs in dilated cardiomyopathy (DCM) hearts. Human CAR expressed in rat cardiomyocytes was targeted to cell–cell contacts and resulted in a 15-fold increase in adenovirus uptake, demonstrating that CAR subcellular localization directly determines viral susceptibility.","method":"Immunohistochemistry with colocalization analysis, transfection of rat cardiomyocytes with human CAR, adenovirus uptake assays","journal":"Circulation","confidence":"High","confidence_rationale":"Tier 2 — direct functional consequence of CAR localization demonstrated by transfection and viral uptake assay","pmids":["11457744"],"is_preprint":false},{"year":2002,"finding":"Adenovirus fiber protein, produced during viral replication, binds CAR at the basolateral surface of airway epithelia and disrupts CAR-mediated tight junction integrity, enabling virus to travel between epithelial cells and emerge apically. This demonstrates CAR is used by adenovirus for both cell entry and escape across epithelial barriers via disruption of its junctional adhesion function.","method":"Infection of polarized human airway epithelia, fiber protein binding assays, tight junction integrity measurements, viral tracking assays","journal":"Cell","confidence":"High","confidence_rationale":"Tier 2 — mechanistic dissection of dual CAR functions (entry and escape) with multiple functional readouts","pmids":["12297051"],"is_preprint":false},{"year":2005,"finding":"Neutrophil transepithelial migration across tight junctions is mediated by binding of neutrophil-expressed junctional adhesion molecule-like protein (JAML) to epithelial CAR. The interaction is via the membrane-distal Ig loop of CAR and the membrane-proximal Ig loop of JAML, is divalent cation-independent, and is required for neutrophil transmigration as shown by inhibition with JAML/CAR fusion proteins and antibodies.","method":"JAML fusion protein binding assays, co-localization by immunofluorescence, transepithelial migration assays with blocking reagents, domain mapping","journal":"Molecular biology of the cell","confidence":"High","confidence_rationale":"Tier 2 — binding partner identified with domain mapping and functional inhibition in a defined transmigration assay","pmids":["15800062"],"is_preprint":false},{"year":2009,"finding":"Human erythrocytes present CAR on their surface, providing an adenovirus type 5 (Ad5) sequestration mechanism. Erythrocytes from mice and rhesus macaques do not present CAR. Ad5 binding to erythrocyte CAR is mediated through the fiber protein, bringing virus into close juxtaposition with the erythrocyte membrane. Transplantation of human erythrocytes into mice extended Ad5 blood circulation but decreased tumor extravasation, demonstrating that erythrocyte CAR sequesters Ad5 and inhibits hepatic infection.","method":"Flow cytometry, cryo-electron microscopy, anti-CAR antibody and fiber protein competition assays, xenograft mouse models with human erythrocyte transplantation, transgenic mouse models expressing erythrocyte CAR","journal":"Blood","confidence":"High","confidence_rationale":"Tier 1–2 — cryo-EM structural evidence plus multiple in vivo functional models","pmids":["19131551"],"is_preprint":false},{"year":2011,"finding":"Adenovirus engagement of CAR at the plasma membrane generates diffusive motions and actomyosin-2-dependent drifts of CAR, while integrin-targeted viruses are spatially more confined. CAR-mediated drifts together with immobile integrin binding support fiber shedding from adenovirus particles, leading to exposure of the membrane-lytic internal virion protein VI and enhanced viral escape from endosomes. Thus, adenovirus uncoating is initiated at the plasma membrane by CAR drifting motion.","method":"Single-particle live-cell imaging, FRAP, pharmacological inhibition of actomyosin-2, quantitative tracking of virus and receptor motions, endosomal escape assays","journal":"Cell host & microbe","confidence":"High","confidence_rationale":"Tier 2 — direct live-cell imaging of receptor dynamics linked to mechanistic consequence (virus uncoating), multiple orthogonal methods","pmids":["21843868"],"is_preprint":false},{"year":2017,"finding":"CAR controls cell–cell adhesion in epithelial cells and plays a key role in co-ordinating neutrophil and leukocyte transmigration during inflammation. CAR also participates in neuronal and cardiac development and cell junction stability, and has been implicated in cancer growth and tumorigenesis through its adhesion functions.","method":"Review synthesizing experimental findings including loss-of-function studies, imaging, and transmigration assays","journal":"The international journal of biochemistry & cell biology","confidence":"Medium","confidence_rationale":"Tier 3 — review consolidating multiple experimental findings without new primary data","pmids":["28545889"],"is_preprint":false}],"current_model":"CXADR (CAR) is a transmembrane immunoglobulin superfamily protein with two extracellular Ig-like domains that functions as the primary cell-surface receptor for group B coxsackieviruses (binding via domain D1 in the viral canyon) and subgroup C adenoviruses (binding via the fiber knob to the GFCC'C″ face of D1); it localizes to tight junctions where it recruits ZO-1 and maintains paracellular barrier integrity through homophilic dimerization, mediates neutrophil transepithelial migration by binding JAML on neutrophils, is exploited by adenovirus fiber protein to disrupt junctional integrity for viral escape, and undergoes actomyosin-dependent lateral drifting on the plasma membrane that initiates adenovirus uncoating."},"narrative":{"teleology":[{"year":1997,"claim":"Identification of a shared entry receptor for coxsackieviruses B and adenoviruses 2/5 resolved how two unrelated virus families could target the same cell types, establishing CXADR as a dual-tropism determinant.","evidence":"cDNA cloning and transfection of non-permissive hamster and NIH 3T3 cells conferring viral susceptibility, replicated in two independent laboratories","pmids":["9036860","9096397"],"confidence":"High","gaps":["Physiological (non-viral) function of CAR unknown at this point","Binding interface with each virus uncharacterized","Tissue-level determinants of infection beyond receptor expression not addressed"]},{"year":1999,"claim":"Crystal structures of the adenovirus fiber knob–CAR D1 complex and biophysical demonstration of D1 homodimerization revealed that the GFCC'C″ face of D1 serves a dual role in homophilic adhesion and viral attachment, explaining how adenovirus co-opts a cell adhesion interface.","evidence":"X-ray crystallography of fiber knob–CAR D1 (1999) and CAR D1 homodimer at 1.7 Å with analytical ultracentrifugation (2000)","pmids":["10567268","11080637"],"confidence":"High","gaps":["Full-length CAR structure including transmembrane and cytoplasmic domains not resolved at atomic level","Structural basis of CVB3 binding not yet determined at high resolution"]},{"year":2001,"claim":"Localization of CAR to tight junctions and demonstration that it recruits ZO-1 and controls paracellular permeability established CAR's physiological role as a junctional adhesion molecule, not merely a viral receptor.","evidence":"Immunofluorescence, co-immunoprecipitation with ZO-1, transepithelial resistance measurements, and virus infection of polarized epithelial monolayers","pmids":["11734628"],"confidence":"High","gaps":["Cytoplasmic signaling pathways downstream of CAR–ZO-1 interaction not defined","Relative contribution of CAR versus other tight junction proteins to barrier integrity unclear"]},{"year":2001,"claim":"Cryo-EM of the CVB3–CAR complex showed that CVB3 binds the distal tip of D1 in the canyon—a surface distinct from the adenovirus-binding face—explaining how two unrelated viruses share one receptor without competing for the same epitope.","evidence":"Cryo-EM reconstruction (~22 Å) of full-length CAR complexed with CVB3 virions","pmids":["11573093"],"confidence":"High","gaps":["Atomic-resolution details of CVB3–CAR interface not available from cryo-EM at this resolution","Mechanism by which CVB3 binding triggers capsid conformational changes and RNA release not resolved"]},{"year":2002,"claim":"Discovery that adenovirus fiber protein disrupts CAR-mediated tight junctions to enable apical viral escape revealed a second exploitation mechanism: CAR is used not only for entry but also for egress across polarized epithelia.","evidence":"Infection of polarized human airway epithelia with fiber protein binding assays and tight junction integrity measurements","pmids":["12297051"],"confidence":"High","gaps":["Quantitative threshold of fiber protein needed to disrupt junctions not established","Whether other junction-disrupting mechanisms act in parallel during adenovirus exit not tested"]},{"year":2005,"claim":"Identification of JAML as a heterophilic ligand for CAR extended CAR's physiological role beyond adhesion to regulation of neutrophil transepithelial migration, linking it to innate immune function.","evidence":"JAML fusion protein binding assays, domain mapping, and transepithelial migration assays with blocking reagents","pmids":["15800062"],"confidence":"High","gaps":["Structural basis of CAR–JAML interaction not determined","In vivo validation in CAR-knockout models for neutrophil transmigration not reported in this study"]},{"year":2009,"claim":"Demonstration that human erythrocytes present CAR and sequester adenovirus type 5 in the bloodstream revealed a species-specific innate defense mechanism that limits systemic adenoviral spread.","evidence":"Flow cytometry, cryo-EM, and xenograft mouse models with human erythrocyte transplantation showing extended Ad5 circulation and reduced hepatic infection","pmids":["19131551"],"confidence":"High","gaps":["Mechanism controlling CAR surface expression on erythrocytes versus other blood cells not characterized","Impact on other adenovirus serotypes beyond Ad5 not systematically tested"]},{"year":2011,"claim":"Live-cell imaging showed that actomyosin-2-dependent lateral drifting of CAR on the plasma membrane mechanically initiates adenovirus uncoating by generating opposing forces with immobile integrin contacts, revealing that virus disassembly begins before endocytosis.","evidence":"Single-particle tracking, FRAP, pharmacological inhibition of actomyosin-2 in live cells, and endosomal escape assays","pmids":["21843868"],"confidence":"High","gaps":["Whether CAR lateral mobility is regulated in different cell types or polarization states not addressed","Precise force magnitude required for fiber shedding not measured"]},{"year":null,"claim":"Key open questions include: the full atomic structure of intact CAR (transmembrane + cytoplasmic domain), the signaling cascades downstream of CAR's cytoplasmic tail during junction formation and leukocyte transmigration, the structural basis of CAR–JAML interaction, and the in vivo contribution of CAR to cardiac and neuronal development observed in loss-of-function models.","evidence":"","pmids":[],"confidence":"Low","gaps":["No atomic-resolution structure of full-length CAR available","Cytoplasmic signaling cascades downstream of CAR remain uncharacterized","In vivo developmental phenotypes from CAR knockout not mechanistically resolved in the primary literature surveyed"]}],"mechanism_profile":{"molecular_activity":[{"term_id":"GO:0098631","term_label":"cell adhesion mediator activity","supporting_discovery_ids":[5,6,10]},{"term_id":"GO:0001618","term_label":"virus receptor activity","supporting_discovery_ids":[0,1,2,7]},{"term_id":"GO:0005198","term_label":"structural molecule activity","supporting_discovery_ids":[6]}],"localization":[{"term_id":"GO:0005886","term_label":"plasma membrane","supporting_discovery_ids":[0,6,8,11,12]}],"pathway":[{"term_id":"R-HSA-1500931","term_label":"Cell-Cell communication","supporting_discovery_ids":[5,6,10]},{"term_id":"R-HSA-168256","term_label":"Immune System","supporting_discovery_ids":[10,11]},{"term_id":"R-HSA-1643685","term_label":"Disease","supporting_discovery_ids":[0,1,7,9]}],"complexes":[],"partners":["ZO-1","JAML","ITGAV"],"other_free_text":[]},"mechanistic_narrative":"CXADR (CAR) is a transmembrane immunoglobulin superfamily protein that functions as a homophilic cell adhesion molecule at tight junctions and as the primary cell-surface receptor for group B coxsackieviruses and subgroup C adenoviruses. CAR localizes to tight junctions in polarized epithelia, where it recruits ZO-1, maintains paracellular barrier integrity, and mediates neutrophil transepithelial migration through heterophilic interaction with JAML on neutrophils [PMID:11734628, PMID:15800062]. Its D1 immunoglobulin domain homodimerizes via the GFCC'C″ face—the same surface hijacked by the adenovirus fiber knob for cell entry—while CVB3 binds the distal tip of D1 in the viral canyon, and adenovirus further exploits CAR by using newly synthesized fiber protein to disrupt junctional integrity and enable apical viral escape [PMID:10567268, PMID:11573093, PMID:12297051]. Actomyosin-dependent lateral drifting of CAR on the plasma membrane initiates adenovirus uncoating by promoting fiber shedding and exposure of the membrane-lytic protein VI [PMID:21843868]."},"prefetch_data":{"uniprot":{"accession":"P78310","full_name":"Coxsackievirus and adenovirus receptor","aliases":["CVB3-binding protein","Coxsackievirus B-adenovirus receptor","HCVADR"],"length_aa":365,"mass_kda":40.0,"function":"Component of the epithelial apical junction complex that may function as a homophilic cell adhesion molecule and is essential for tight junction integrity. Also involved in transepithelial migration of leukocytes through adhesive interactions with JAML a transmembrane protein of the plasma membrane of leukocytes. The interaction between both receptors also mediates the activation of gamma-delta T-cells, a subpopulation of T-cells residing in epithelia and involved in tissue homeostasis and repair. Upon epithelial CXADR-binding, JAML induces downstream cell signaling events in gamma-delta T-cells through PI3-kinase and MAP kinases. It results in proliferation and production of cytokines and growth factors by T-cells that in turn stimulate epithelial tissues repair (Microbial infection) Acts as a receptor for adenovirus type C (Microbial infection) Acts as a receptor for Coxsackievirus B1 to B6","subcellular_location":"Secreted","url":"https://www.uniprot.org/uniprotkb/P78310/entry"},"depmap":{"release":"DepMap","has_data":true,"is_common_essential":false,"resolved_as":"","url":"https://depmap.org/portal/gene/CXADR","classification":"Not Classified","n_dependent_lines":57,"n_total_lines":383,"dependency_fraction":0.14882506527415143},"opencell":{"profiled":false,"resolved_as":"","ensg_id":"","cell_line_id":"","localizations":[],"interactors":[{"gene":"CANX","stoichiometry":0.2}],"url":"https://opencell.sf.czbiohub.org/search/CXADR","total_profiled":1310},"omim":[{"mim_id":"611693","title":"COXSACKIEVIRUS- AND ADENOVIRUS RECEPTOR-LIKE MEMBRANE PROTEIN; CLMP","url":"https://www.omim.org/entry/611693"},{"mim_id":"609770","title":"JUNCTIONAL ADHESION MOLECULE-LIKE; JAML","url":"https://www.omim.org/entry/609770"},{"mim_id":"608351","title":"IMMUNOGLOBULIN SUPERFAMILY, MEMBER 11; IGSF11","url":"https://www.omim.org/entry/608351"},{"mim_id":"603829","title":"VENTRICULAR FIBRILLATION, PAROXYSMAL FAMILIAL, 1; VF1","url":"https://www.omim.org/entry/603829"},{"mim_id":"602621","title":"COXSACKIEVIRUS AND ADENOVIRUS RECEPTOR; CXADR","url":"https://www.omim.org/entry/602621"}],"hpa":{"profiled":true,"resolved_as":"","reliability":"Supported","locations":[{"location":"Plasma membrane","reliability":"Supported"},{"location":"Cell Junctions","reliability":"Supported"},{"location":"Nucleoplasm","reliability":"Additional"}],"tissue_specificity":"Tissue enhanced","tissue_distribution":"Detected in many","driving_tissues":[{"tissue":"skin 1","ntpm":50.3}],"url":"https://www.proteinatlas.org/search/CXADR"},"hgnc":{"alias_symbol":["CAR"],"prev_symbol":[]},"alphafold":{"accession":"P78310","domains":[{"cath_id":"2.60.40.10","chopping":"20-137","consensus_level":"high","plddt":91.9762,"start":20,"end":137},{"cath_id":"2.60.40.10","chopping":"141-226","consensus_level":"high","plddt":95.0823,"start":141,"end":226}],"viewer_url":"https://alphafold.ebi.ac.uk/entry/P78310","model_url":"https://alphafold.ebi.ac.uk/files/AF-P78310-F1-model_v6.cif","pae_url":"https://alphafold.ebi.ac.uk/files/AF-P78310-F1-predicted_aligned_error_v6.png","plddt_mean":79.31},"mouse_models":{"mgi_url":"https://www.informatics.jax.org/marker/summary?nomen=CXADR","jax_strain_url":"https://www.jax.org/strain/search?query=CXADR"},"sequence":{"accession":"P78310","fasta_url":"https://rest.uniprot.org/uniprotkb/P78310.fasta","uniprot_url":"https://www.uniprot.org/uniprotkb/P78310/entry","alphafold_viewer_url":"https://alphafold.ebi.ac.uk/entry/P78310"}},"corpus_meta":[{"pmid":"35361234","id":"PMC_35361234","title":"CAR race to cancer immunotherapy: from CAR T, CAR NK to CAR macrophage therapy.","date":"2022","source":"Journal of experimental & clinical cancer research : CR","url":"https://pubmed.ncbi.nlm.nih.gov/35361234","citation_count":520,"is_preprint":false,"source_track":"pubmed_title"},{"pmid":"30680780","id":"PMC_30680780","title":"An introduction to chimeric antigen receptor (CAR) T-cell immunotherapy for human cancer.","date":"2019","source":"American journal of hematology","url":"https://pubmed.ncbi.nlm.nih.gov/30680780","citation_count":411,"is_preprint":false,"source_track":"pubmed_title"},{"pmid":"30875739","id":"PMC_30875739","title":"Killing Mechanisms of Chimeric Antigen Receptor (CAR) T Cells.","date":"2019","source":"International journal of molecular sciences","url":"https://pubmed.ncbi.nlm.nih.gov/30875739","citation_count":408,"is_preprint":false,"source_track":"pubmed_title"},{"pmid":"28652918","id":"PMC_28652918","title":"Engineering CAR-T cells.","date":"2017","source":"Biomarker research","url":"https://pubmed.ncbi.nlm.nih.gov/28652918","citation_count":408,"is_preprint":false,"source_track":"pubmed_title"},{"pmid":"12120277","id":"PMC_12120277","title":"PXR, CAR and drug metabolism.","date":"2002","source":"Nature reviews. 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(MGC).","date":"2004","source":"Genome research","url":"https://pubmed.ncbi.nlm.nih.gov/15489334","citation_count":438,"is_preprint":false,"source_track":"gene2pubmed"},{"pmid":"26638075","id":"PMC_26638075","title":"A Dynamic Protein Interaction Landscape of the Human Centrosome-Cilium Interface.","date":"2015","source":"Cell","url":"https://pubmed.ncbi.nlm.nih.gov/26638075","citation_count":433,"is_preprint":false,"source_track":"gene2pubmed"},{"pmid":"35271311","id":"PMC_35271311","title":"OpenCell: Endogenous tagging for the cartography of human cellular organization.","date":"2022","source":"Science (New York, N.Y.)","url":"https://pubmed.ncbi.nlm.nih.gov/35271311","citation_count":432,"is_preprint":false,"source_track":"gene2pubmed"},{"pmid":"10567268","id":"PMC_10567268","title":"Structural analysis of the mechanism of adenovirus binding to its human cellular receptor, CAR.","date":"1999","source":"Science (New York, N.Y.)","url":"https://pubmed.ncbi.nlm.nih.gov/10567268","citation_count":354,"is_preprint":false,"source_track":"gene2pubmed"},{"pmid":"34079125","id":"PMC_34079125","title":"A proximity-dependent biotinylation map of a human cell.","date":"2021","source":"Nature","url":"https://pubmed.ncbi.nlm.nih.gov/34079125","citation_count":339,"is_preprint":false,"source_track":"gene2pubmed"},{"pmid":"12297051","id":"PMC_12297051","title":"Adenovirus fiber disrupts CAR-mediated intercellular adhesion allowing virus escape.","date":"2002","source":"Cell","url":"https://pubmed.ncbi.nlm.nih.gov/12297051","citation_count":309,"is_preprint":false,"source_track":"gene2pubmed"},{"pmid":"27342126","id":"PMC_27342126","title":"Identification of Zika Virus and Dengue Virus Dependency Factors using Functional Genomics.","date":"2016","source":"Cell reports","url":"https://pubmed.ncbi.nlm.nih.gov/27342126","citation_count":306,"is_preprint":false,"source_track":"gene2pubmed"},{"pmid":"9420240","id":"PMC_9420240","title":"The murine CAR homolog is a receptor for coxsackie B viruses and adenoviruses.","date":"1998","source":"Journal of virology","url":"https://pubmed.ncbi.nlm.nih.gov/9420240","citation_count":297,"is_preprint":false,"source_track":"gene2pubmed"},{"pmid":"10490761","id":"PMC_10490761","title":"Expression of coxsackie adenovirus receptor and alphav-integrin does not correlate with adenovector targeting in vivo indicating anatomical vector barriers.","date":"1999","source":"Gene therapy","url":"https://pubmed.ncbi.nlm.nih.gov/10490761","citation_count":262,"is_preprint":false,"source_track":"gene2pubmed"},{"pmid":"35063084","id":"PMC_35063084","title":"Tau interactome maps synaptic and mitochondrial processes associated with neurodegeneration.","date":"2022","source":"Cell","url":"https://pubmed.ncbi.nlm.nih.gov/35063084","citation_count":256,"is_preprint":false,"source_track":"gene2pubmed"},{"pmid":"11573093","id":"PMC_11573093","title":"Interaction of coxsackievirus B3 with the full length coxsackievirus-adenovirus receptor.","date":"2001","source":"Nature structural biology","url":"https://pubmed.ncbi.nlm.nih.gov/11573093","citation_count":176,"is_preprint":false,"source_track":"gene2pubmed"},{"pmid":"19131551","id":"PMC_19131551","title":"Human erythrocytes bind and inactivate type 5 adenovirus by presenting Coxsackie virus-adenovirus receptor and complement receptor 1.","date":"2009","source":"Blood","url":"https://pubmed.ncbi.nlm.nih.gov/19131551","citation_count":171,"is_preprint":false,"source_track":"gene2pubmed"},{"pmid":"25468996","id":"PMC_25468996","title":"E-cadherin interactome complexity and robustness resolved by quantitative proteomics.","date":"2014","source":"Science signaling","url":"https://pubmed.ncbi.nlm.nih.gov/25468996","citation_count":162,"is_preprint":false,"source_track":"gene2pubmed"},{"pmid":"11457744","id":"PMC_11457744","title":"Human coxsackie-adenovirus receptor is colocalized with integrins alpha(v)beta(3) and alpha(v)beta(5) on the cardiomyocyte sarcolemma and upregulated in dilated cardiomyopathy: implications for cardiotropic viral infections.","date":"2001","source":"Circulation","url":"https://pubmed.ncbi.nlm.nih.gov/11457744","citation_count":150,"is_preprint":false,"source_track":"gene2pubmed"},{"pmid":"15800062","id":"PMC_15800062","title":"Neutrophil migration across tight junctions is mediated by adhesive interactions between epithelial coxsackie and adenovirus receptor and a junctional adhesion molecule-like protein on neutrophils.","date":"2005","source":"Molecular biology of the cell","url":"https://pubmed.ncbi.nlm.nih.gov/15800062","citation_count":147,"is_preprint":false,"source_track":"gene2pubmed"},{"pmid":"21843868","id":"PMC_21843868","title":"Drifting motions of the adenovirus receptor CAR and immobile integrins initiate virus uncoating and membrane lytic protein exposure.","date":"2011","source":"Cell host & microbe","url":"https://pubmed.ncbi.nlm.nih.gov/21843868","citation_count":143,"is_preprint":false,"source_track":"gene2pubmed"},{"pmid":"19322201","id":"PMC_19322201","title":"Ubiquitin-mediated proteolysis of HuR by heat shock.","date":"2009","source":"The EMBO journal","url":"https://pubmed.ncbi.nlm.nih.gov/19322201","citation_count":142,"is_preprint":false,"source_track":"gene2pubmed"},{"pmid":"11080637","id":"PMC_11080637","title":"Dimeric structure of the coxsackievirus and adenovirus receptor D1 domain at 1.7 A resolution.","date":"2000","source":"Structure (London, England : 1993)","url":"https://pubmed.ncbi.nlm.nih.gov/11080637","citation_count":137,"is_preprint":false,"source_track":"gene2pubmed"},{"pmid":"31871319","id":"PMC_31871319","title":"Mapping the proximity interaction network of the Rho-family GTPases reveals signalling pathways and regulatory mechanisms.","date":"2019","source":"Nature cell biology","url":"https://pubmed.ncbi.nlm.nih.gov/31871319","citation_count":137,"is_preprint":false,"source_track":"gene2pubmed"}],"cost":{"stage1":{"model":"claude-sonnet-4-6","input_tokens":38216,"output_tokens":1485,"usd":0.068461},"stage2":{"model":"claude-opus-4-6","input_tokens":4410,"output_tokens":1394,"usd":0.08535},"total_usd":0.407191,"stage1_batch_id":"msgbatch_011kfMfE81o6CTcyhVUqumuW","stage2_batch_id":"msgbatch_01DTputS6WNkH745x1nVSoBo","note":"batch pricing = 50% of standard","round2_stage1":{"model":"claude-sonnet-4-6","input_tokens":50170,"output_tokens":4648,"usd":0.110115},"round2_rules_fired":"R3","round2_stage2":{"model":"claude-opus-4-6","input_tokens":7202,"output_tokens":2380,"usd":0.143265}},"stage1_raw":"Looking through the 100 abstracts, the vast majority are about CAR T-cell immunotherapy (chimeric antigen receptor), CAR nuclear receptors (constitutive androstane receptor/NR1I3), or CAR macrophages — none of which are the CXADR gene. I need to identify papers specifically about CXADR (coxsackievirus and adenovirus receptor).\n\nRelevant papers:\n- PMID:11479928 (Carson 2001) — directly about CAR/CXADR as the coxsackievirus and adenovirus receptor\n- PMID:12851705 (Katoh 2003) — mentions CXADR as a type I transmembrane protein with Ig-like domains and PDZ-binding domain, homologous to IGSF11\n- PMID:28545889 (Ortiz-Zapater 2017) — directly about CXADR as adhesion molecule\n- PMID:22914544 (Shetty 2012) — GWAS/association study — EXCLUDE\n- PMID:33084169 (Han 2020) — about CLMP (CXADR-like membrane protein), not CXADR itself — EXCLUDE\n\n```json\n{\n  \"discoveries\": [\n    {\n      \"year\": 2001,\n      \"finding\": \"CAR (CXADR) was identified as a member of the immunoglobulin superfamily containing two Ig domains (an amino-terminal V-like module and a C2-like module), a single membrane-spanning sequence, and a large cytoplasmic domain; recombinant CAR expressed in mammalian cells confers permissivity to coxsackievirus B (CVB) infection, establishing it as the primary receptor for CVB and most adenoviruses.\",\n      \"method\": \"Recombinant protein expression in mammalian cells, viral infection permissivity assay, structural domain analysis\",\n      \"journal\": \"Reviews in medical virology\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 — functional reconstitution (CAR confers viral permissivity) but review article summarizing prior cloning/functional work from a single source in corpus\",\n      \"pmids\": [\"11479928\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2001,\n      \"finding\": \"The crystal structure of the CAR (CXADR) V-like Ig domain complexed with adenovirus fiber knob was determined using recombinant proteins, revealing that three CAR modules associate with a single fiber knob trimer.\",\n      \"method\": \"X-ray crystallography of recombinant CAR ectodomain–adenovirus fiber knob complex\",\n      \"journal\": \"Reviews in medical virology\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 1 — crystal structure with recombinant proteins; single paper in corpus summarizing the finding\",\n      \"pmids\": [\"11479928\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2001,\n      \"finding\": \"CXADR expression is developmentally regulated in rodents, being highly expressed just before birth and declining postnatally; expression increases in regenerating muscle, in response to immunological mediators or inflammation, and at high cell density in certain cell lines, indicating tight regulation of CXADR levels.\",\n      \"method\": \"Expression analysis in rodent tissues at various developmental stages; cell-density experiments in RD cells and umbilical vein endothelial cells\",\n      \"journal\": \"Reviews in medical virology\",\n      \"confidence\": \"Low\",\n      \"confidence_rationale\": \"Tier 3 — expression/localization data without direct functional mechanism assigned\",\n      \"pmids\": [\"11479928\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2003,\n      \"finding\": \"CXADR is a type I transmembrane protein with extracellular immunoglobulin-like domain(s), a cytoplasmic juxtamembrane domain, and a C-terminal PDZ-binding domain, placing it structurally in a family of adhesion molecules that includes ESAM and IGSF11.\",\n      \"method\": \"Bioinformatics/sequence analysis and structural comparison with related family members\",\n      \"journal\": \"International journal of oncology\",\n      \"confidence\": \"Low\",\n      \"confidence_rationale\": \"Tier 4 — computational/bioinformatics prediction only, no direct functional experiment\",\n      \"pmids\": [\"12851705\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2017,\n      \"finding\": \"CXADR functions as an adhesion molecule that controls cell-cell adhesion between adjacent epithelial cells, plays roles in neuronal and cardiac development, maintains cell junction stability, regulates leukocyte transmigration during inflammation, and influences tumorigenesis; these functions involve coordinating cell-cell adhesion under homeostatic and pathological conditions.\",\n      \"method\": \"Review synthesizing loss-of-function studies, cell biology experiments, and in vivo model data across multiple published studies\",\n      \"journal\": \"The international journal of biochemistry & cell biology\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2–3 — review integrating multiple experimental studies showing defined cellular phenotypes from loss-of-function; moderate evidence base\",\n      \"pmids\": [\"28545889\"],\n      \"is_preprint\": false\n    }\n  ],\n  \"current_model\": \"CXADR (coxsackievirus and adenovirus receptor) is a type I transmembrane immunoglobulin superfamily protein with V-like and C2-like extracellular Ig domains and a C-terminal PDZ-binding motif; it serves as the primary docking receptor for group B coxsackieviruses and most adenoviruses (three CAR molecules engage one adenovirus fiber knob trimer), and under physiological conditions acts as an epithelial cell-cell adhesion molecule that regulates junction stability, cardiac and neuronal development, leukocyte transmigration, and tumorigenesis.\"\n}\n```\n\n--- ROUND 2 (R2/R3, augmented corpus) ---\n\nLooking at the corpus, I need to classify papers:\n\n**RETRIEVED PAPERS [1]-[100]**: These are overwhelmingly about CAR T-cell therapy, CAR NK cells, CAR macrophages (chimeric antigen receptor immunotherapy), or CAR/PXR nuclear receptors (constitutive androstane receptor). These are all ALIAS COLLISIONS — they do not describe CXADR (coxsackievirus and adenovirus receptor). EXCLUDE all.\n\nException: Paper [56] \"CAR: A key regulator of adhesion and inflammation\" — this is about the coxsackie and adenovirus receptor (CAR/CXADR). KEEP.\nPaper [28] describes IGSF11 as homologous to CXADR and provides structural context about CXADR. KEEP (provides mechanistic context about CXADR protein family).\nPaper [76] is a GWAS/association study about CXADR variants — EXCLUDE (no mechanistic findings).\nPaper [77] is about CLMP (CXADR-like membrane protein), not CXADR itself — EXCLUDE.\n\n**ADDITIONAL gene2pubmed PAPERS**: These are about CXADR. Classify:\n- [1] PMID:9036860 — KEEP (isolation of CAR/CXADR)\n- [2] PMID:16189514 — proteome-scale interaction map, CXADR mentioned as interaction partner — KEEP only if CXADR-specific mechanistic finding\n- [3] PMID:12477932 — cDNA sequences, no mechanism — EXCLUDE\n- [4] PMID:15302935 — phosphoproteomics of HeLa, CXADR may appear — borderline, EXCLUDE (not CXADR-specific)\n- [5] PMID:26186194 — BioPlex interactome — EXCLUDE (no CXADR-specific mechanism)\n- [6] PMID:28514442 — BioPlex 2.0 — EXCLUDE\n- [7] PMID:9096397 — HCAR/MCAR isolation — KEEP\n- [8] PMID:32296183 — HuRI interactome — EXCLUDE\n- [9] PMID:22939629 — soluble protein complexes — EXCLUDE\n- [10] PMID:21873635 — GO annotation — EXCLUDE\n- [11] PMID:11734628 — CAR is tight junction component — KEEP\n- [12] PMID:15489334 — MGC — EXCLUDE\n- [13] PMID:26638075 — centrosome BioID — EXCLUDE\n- [14] PMID:35271311 — OpenCell — EXCLUDE\n- [15] PMID:10567268 — crystal structure of adenovirus fiber knob + CAR D1 — KEEP\n- [16] PMID:34079125 — BioID map — EXCLUDE\n- [17] PMID:12297051 — adenovirus fiber disrupts CAR-mediated junctions — KEEP\n- [18] PMID:27342126 — flavivirus dependency factors — EXCLUDE (not about CXADR)\n- [19] PMID:9420240 — murine CAR as receptor for CVB and Ad — KEEP\n- [20] PMID:10490761 — CAR expression and adenovector — KEEP\n- [21] PMID:35063084 — Tau interactome — EXCLUDE\n- [22] PMID:11573093 — CVB3 + full-length CAR cryo-EM structure — KEEP\n- [23] PMID:19131551 — human erythrocytes present CAR — KEEP\n- [24] PMID:25468996 — E-cadherin interactome — EXCLUDE\n- [25] PMID:11457744 — CAR colocalized with integrins in cardiomyocyte — KEEP\n- [26] PMID:15800062 — neutrophil JAML-CAR interaction — KEEP\n- [27] PMID:21843868 — adenovirus receptor CAR drifting motions — KEEP\n- [28] PMID:19322201 — HuR ubiquitination — EXCLUDE\n- [29] PMID:11080637 — CAR D1 crystal structure, homodimerization — KEEP\n- [30] PMID:31871319 — Rho GTPase proximity network — EXCLUDE\n\nRetrieved paper [56] PMID:28545889 — KEEP (review of CAR adhesion/inflammation functions)\n\n```json\n{\n  \"discoveries\": [\n    {\n      \"year\": 1997,\n      \"finding\": \"CXADR (CAR) was isolated and identified as a common receptor shared by group B coxsackieviruses and adenoviruses 2 and 5. Transfection of CAR cDNA into non-permissive hamster cells conferred susceptibility to coxsackievirus B attachment and infection, and enabled fiber-dependent adenovirus binding with a 100-fold increase in adenovirus-mediated gene transfer.\",\n      \"method\": \"cDNA cloning, transfection of non-permissive hamster cells, viral infection assays, adenovirus gene transfer assays\",\n      \"journal\": \"Science\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 — original functional reconstitution in non-permissive cells, replicated independently in same year\",\n      \"pmids\": [\"9036860\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 1997,\n      \"finding\": \"Human CAR (HCAR) and mouse CAR (MCAR) were independently isolated as 46-kDa glycoproteins belonging to the immunoglobulin superfamily, containing two extracellular Ig-like domains. Transfection of either cDNA into receptor-negative NIH 3T3 cells conferred susceptibility to CVB infection and enabled adenovirus-mediated beta-galactosidase expression.\",\n      \"method\": \"cDNA isolation, transfection of NIH 3T3 cells, CVB infection assays, recombinant adenovirus gene transfer, Northern blot, Western blot with virus-binding-inhibitory antibodies\",\n      \"journal\": \"Proceedings of the National Academy of Sciences of the United States of America\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 — independent replication of functional reconstitution with structural characterization\",\n      \"pmids\": [\"9096397\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 1998,\n      \"finding\": \"The murine CAR homolog (mCAR) functions as a receptor for coxsackieviruses B3 and B4 and increases susceptibility to adenovirus-mediated gene transfer when transfected into non-permissive CHO cells, demonstrating conservation of receptor function between human and murine CXADR.\",\n      \"method\": \"cDNA cloning, transfection of CHO cells, CVB infection assays, adenovirus gene transfer assays\",\n      \"journal\": \"Journal of virology\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 — functional reconstitution in non-permissive cells, orthologous gene confirmation\",\n      \"pmids\": [\"9420240\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 1999,\n      \"finding\": \"The crystal structure of the adenovirus fiber knob domain in complex with domain 1 (D1) of CAR was determined, revealing that surface-exposed loops on the knob contact one face of CAR, forming a high-affinity complex with interfacial solvent-filled cavities. This identified key determinants of binding specificity.\",\n      \"method\": \"X-ray crystallography of recombinant fiber knob–CAR D1 complex\",\n      \"journal\": \"Science\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 — crystal structure with functional validation of binding interface\",\n      \"pmids\": [\"10567268\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 1999,\n      \"finding\": \"CAR mRNA expression is highly variable across tissues with highest levels in the liver, and CAR expression does not correlate with actual adenovector gene transfer efficiency after systemic injection, indicating that anatomical barriers (particularly the endothelium) limit adenovirus targeting independent of receptor expression. The adenovirus binding site was localized to amino acids 29–128 of the CAR ectodomain.\",\n      \"method\": \"Northern blot and sequence analysis of CAR across multiple species and tissues; in vivo adenovector injection with tissue expression analysis\",\n      \"journal\": \"Gene therapy\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 — multiple tissue/species analysis with in vivo functional mismatch demonstration\",\n      \"pmids\": [\"10490761\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2000,\n      \"finding\": \"The CAR D1 domain forms homodimers in solution (Kd ~16 µM) and in crystals at 1.7 Å resolution, using the same GFCC'C″ surface that interacts with the adenovirus fiber head. The homodimer is similar to the CD2–CD58 heterodimer, consistent with CAR functioning physiologically as a homophilic cell adhesion molecule.\",\n      \"method\": \"Bacterial expression of CAR D1, X-ray crystallography (1.7 Å), analytical equilibrium ultracentrifugation\",\n      \"journal\": \"Structure\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 — crystal structure combined with solution biophysical measurement of dimerization\",\n      \"pmids\": [\"11080637\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2001,\n      \"finding\": \"CAR is a transmembrane component of the tight junction. In non-polarized cells, CAR localizes to homotypic intercellular contacts, mediates homotypic cell aggregation, and recruits ZO-1 to sites of cell–cell contact. In polarized epithelial cells, CAR and ZO-1 co-localize to tight junctions and co-precipitate from cell lysates. CAR expression reduces paracellular passage of macromolecules and ions, and soluble CAR inhibits formation of functional tight junctions. Virus entry into polarized epithelium required disruption of tight junctions.\",\n      \"method\": \"Immunofluorescence localization, co-immunoprecipitation, cell aggregation assays, transepithelial resistance measurements, virus infection of polarized epithelial monolayers\",\n      \"journal\": \"Proceedings of the National Academy of Sciences of the United States of America\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 — multiple orthogonal methods (localization, Co-IP, functional permeability assay) in single study\",\n      \"pmids\": [\"11734628\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2001,\n      \"finding\": \"Cryo-EM structure of CVB3 in complex with full-length human CAR (including transmembrane and cytoplasmic domains) at ~22 Å resolution showed that CAR binds with the distal end of domain D1 in the canyon of CVB3, similar to other receptor–enterovirus interactions. Pairs of transmembrane domains of CAR associate with each other in a detergent environment mimicking a plasma membrane. The site of CAR–adenovirus interaction uses a side surface of D1 distinct from the CVB3-binding surface.\",\n      \"method\": \"Cryo-electron microscopy (cryo-EM) reconstruction of virus–receptor complexes\",\n      \"journal\": \"Nature structural biology\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 — structural analysis of full-length receptor–virus complex including transmembrane region\",\n      \"pmids\": [\"11573093\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2001,\n      \"finding\": \"CAR is colocalized with integrins αvβ3 and αvβ5 at the cardiomyocyte sarcolemma and is upregulated at intercalated discs in dilated cardiomyopathy (DCM) hearts. Human CAR expressed in rat cardiomyocytes was targeted to cell–cell contacts and resulted in a 15-fold increase in adenovirus uptake, demonstrating that CAR subcellular localization directly determines viral susceptibility.\",\n      \"method\": \"Immunohistochemistry with colocalization analysis, transfection of rat cardiomyocytes with human CAR, adenovirus uptake assays\",\n      \"journal\": \"Circulation\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 — direct functional consequence of CAR localization demonstrated by transfection and viral uptake assay\",\n      \"pmids\": [\"11457744\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2002,\n      \"finding\": \"Adenovirus fiber protein, produced during viral replication, binds CAR at the basolateral surface of airway epithelia and disrupts CAR-mediated tight junction integrity, enabling virus to travel between epithelial cells and emerge apically. This demonstrates CAR is used by adenovirus for both cell entry and escape across epithelial barriers via disruption of its junctional adhesion function.\",\n      \"method\": \"Infection of polarized human airway epithelia, fiber protein binding assays, tight junction integrity measurements, viral tracking assays\",\n      \"journal\": \"Cell\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 — mechanistic dissection of dual CAR functions (entry and escape) with multiple functional readouts\",\n      \"pmids\": [\"12297051\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2005,\n      \"finding\": \"Neutrophil transepithelial migration across tight junctions is mediated by binding of neutrophil-expressed junctional adhesion molecule-like protein (JAML) to epithelial CAR. The interaction is via the membrane-distal Ig loop of CAR and the membrane-proximal Ig loop of JAML, is divalent cation-independent, and is required for neutrophil transmigration as shown by inhibition with JAML/CAR fusion proteins and antibodies.\",\n      \"method\": \"JAML fusion protein binding assays, co-localization by immunofluorescence, transepithelial migration assays with blocking reagents, domain mapping\",\n      \"journal\": \"Molecular biology of the cell\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 — binding partner identified with domain mapping and functional inhibition in a defined transmigration assay\",\n      \"pmids\": [\"15800062\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2009,\n      \"finding\": \"Human erythrocytes present CAR on their surface, providing an adenovirus type 5 (Ad5) sequestration mechanism. Erythrocytes from mice and rhesus macaques do not present CAR. Ad5 binding to erythrocyte CAR is mediated through the fiber protein, bringing virus into close juxtaposition with the erythrocyte membrane. Transplantation of human erythrocytes into mice extended Ad5 blood circulation but decreased tumor extravasation, demonstrating that erythrocyte CAR sequesters Ad5 and inhibits hepatic infection.\",\n      \"method\": \"Flow cytometry, cryo-electron microscopy, anti-CAR antibody and fiber protein competition assays, xenograft mouse models with human erythrocyte transplantation, transgenic mouse models expressing erythrocyte CAR\",\n      \"journal\": \"Blood\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1–2 — cryo-EM structural evidence plus multiple in vivo functional models\",\n      \"pmids\": [\"19131551\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2011,\n      \"finding\": \"Adenovirus engagement of CAR at the plasma membrane generates diffusive motions and actomyosin-2-dependent drifts of CAR, while integrin-targeted viruses are spatially more confined. CAR-mediated drifts together with immobile integrin binding support fiber shedding from adenovirus particles, leading to exposure of the membrane-lytic internal virion protein VI and enhanced viral escape from endosomes. Thus, adenovirus uncoating is initiated at the plasma membrane by CAR drifting motion.\",\n      \"method\": \"Single-particle live-cell imaging, FRAP, pharmacological inhibition of actomyosin-2, quantitative tracking of virus and receptor motions, endosomal escape assays\",\n      \"journal\": \"Cell host & microbe\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 — direct live-cell imaging of receptor dynamics linked to mechanistic consequence (virus uncoating), multiple orthogonal methods\",\n      \"pmids\": [\"21843868\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2017,\n      \"finding\": \"CAR controls cell–cell adhesion in epithelial cells and plays a key role in co-ordinating neutrophil and leukocyte transmigration during inflammation. CAR also participates in neuronal and cardiac development and cell junction stability, and has been implicated in cancer growth and tumorigenesis through its adhesion functions.\",\n      \"method\": \"Review synthesizing experimental findings including loss-of-function studies, imaging, and transmigration assays\",\n      \"journal\": \"The international journal of biochemistry & cell biology\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 3 — review consolidating multiple experimental findings without new primary data\",\n      \"pmids\": [\"28545889\"],\n      \"is_preprint\": false\n    }\n  ],\n  \"current_model\": \"CXADR (CAR) is a transmembrane immunoglobulin superfamily protein with two extracellular Ig-like domains that functions as the primary cell-surface receptor for group B coxsackieviruses (binding via domain D1 in the viral canyon) and subgroup C adenoviruses (binding via the fiber knob to the GFCC'C″ face of D1); it localizes to tight junctions where it recruits ZO-1 and maintains paracellular barrier integrity through homophilic dimerization, mediates neutrophil transepithelial migration by binding JAML on neutrophils, is exploited by adenovirus fiber protein to disrupt junctional integrity for viral escape, and undergoes actomyosin-dependent lateral drifting on the plasma membrane that initiates adenovirus uncoating.\"\n}\n```","stage2_raw":"```json\n{\n  \"mechanistic_narrative\": \"CXADR is a type I transmembrane immunoglobulin superfamily protein containing an N-terminal V-like Ig domain and a membrane-proximal C2-like Ig domain, a single transmembrane helix, and a cytoplasmic tail with a C-terminal PDZ-binding motif; it serves as the primary attachment receptor for coxsackievirus B and most adenoviruses, with three CAR ectodomains engaging one adenovirus fiber knob trimer as revealed by crystal structure analysis [PMID:11479928]. Beyond its role as a viral receptor, CXADR functions as an epithelial cell–cell adhesion molecule that maintains junction stability and participates in cardiac and neuronal development, leukocyte transmigration, and regulation of tumorigenesis [PMID:28545889]. CXADR expression is developmentally regulated, peaking before birth and declining postnatally, and is re-induced during tissue regeneration and inflammation [PMID:11479928].\",\n  \"teleology\": [\n    {\n      \"year\": 2001,\n      \"claim\": \"Establishing that CXADR is a two-Ig-domain transmembrane protein whose expression confers permissivity to coxsackievirus B and adenovirus infection answered the key question of the molecular identity of the shared viral receptor.\",\n      \"evidence\": \"Recombinant CAR expression in mammalian cells with viral infection permissivity assays and domain analysis\",\n      \"pmids\": [\"11479928\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\n        \"Functional data were summarized from earlier cloning work rather than independently reconstituted in this study\",\n        \"Mechanism by which CAR mediates viral entry beyond initial attachment not defined\",\n        \"Endogenous physiological ligand(s) not identified\"\n      ]\n    },\n    {\n      \"year\": 2001,\n      \"claim\": \"Determination of the crystal structure of the CAR V-domain–adenovirus fiber knob complex revealed a 3:1 stoichiometry, establishing the molecular basis of virus–receptor engagement.\",\n      \"evidence\": \"X-ray crystallography of recombinant CAR ectodomain complexed with adenovirus fiber knob\",\n      \"pmids\": [\"11479928\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\n        \"Structural basis of coxsackievirus B binding to CAR not resolved in this study\",\n        \"Whether stoichiometry is conserved across all adenovirus serotypes not addressed\"\n      ]\n    },\n    {\n      \"year\": 2001,\n      \"claim\": \"Showing that CXADR expression is developmentally regulated—peaking perinatally and declining postnatally, then re-induced by inflammation and during regeneration—suggested dynamic physiological roles beyond viral entry.\",\n      \"evidence\": \"Expression analysis across developmental stages in rodent tissues and cell-density experiments in RD and endothelial cells\",\n      \"pmids\": [\"11479928\"],\n      \"confidence\": \"Low\",\n      \"gaps\": [\n        \"Expression data only; no loss-of-function or gain-of-function experiments to assign specific developmental mechanism\",\n        \"Transcriptional or post-transcriptional regulatory mechanisms controlling expression not identified\"\n      ]\n    },\n    {\n      \"year\": 2017,\n      \"claim\": \"Integrating multiple loss-of-function and cell biology studies established that CXADR functions physiologically as an epithelial adhesion molecule controlling junction stability, cardiac and neuronal development, leukocyte transmigration, and tumorigenesis.\",\n      \"evidence\": \"Synthesis of loss-of-function studies and in vivo model data across multiple published investigations\",\n      \"pmids\": [\"28545889\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\n        \"Direct signaling pathways downstream of CXADR's cytoplasmic PDZ-binding motif remain incompletely mapped\",\n        \"Relative contributions of homophilic versus heterophilic interactions to junction stability not resolved\",\n        \"Mechanism by which CXADR influences tumorigenesis (tumor suppressor versus context-dependent) not fully defined\"\n      ]\n    },\n    {\n      \"year\": null,\n      \"claim\": \"The signaling cascades initiated by CXADR engagement at cell junctions, the identity of cytoplasmic PDZ-domain partners that mediate its adhesive and developmental functions, and its precise mechanistic role in tumorigenesis remain to be elucidated.\",\n      \"evidence\": \"\",\n      \"pmids\": [],\n      \"confidence\": \"Low\",\n      \"gaps\": [\n        \"No systematic interactome for CXADR cytoplasmic domain reported in the timeline\",\n        \"Structural basis of homophilic CAR–CAR interaction at tight junctions not resolved\",\n        \"Conditional knockout phenotypes in specific adult tissues not comprehensively characterized in timeline\"\n      ]\n    }\n  ],\n  \"mechanism_profile\": {\n    \"molecular_activity\": [\n      {\"term_id\": \"GO:0098631\", \"supporting_discovery_ids\": [0, 4]},\n      {\"term_id\": \"GO:0001618\", \"supporting_discovery_ids\": [0, 1]}\n    ],\n    \"localization\": [\n      {\"term_id\": \"GO:0005886\", \"supporting_discovery_ids\": [0, 3, 4]}\n    ],\n    \"pathway\": [\n      {\"term_id\": \"R-HSA-1500931\", \"supporting_discovery_ids\": [4]},\n      {\"term_id\": \"R-HSA-1266738\", \"supporting_discovery_ids\": [2, 4]}\n    ],\n    \"complexes\": [],\n    \"partners\": [],\n    \"other_free_text\": []\n  }\n}\n```\n\n--- ROUND 2 (R2/R3, augmented corpus) ---\n\n```json\n{\n  \"mechanistic_narrative\": \"CXADR (CAR) is a transmembrane immunoglobulin superfamily protein that functions as a homophilic cell adhesion molecule at tight junctions and as the primary cell-surface receptor for group B coxsackieviruses and subgroup C adenoviruses. CAR localizes to tight junctions in polarized epithelia, where it recruits ZO-1, maintains paracellular barrier integrity, and mediates neutrophil transepithelial migration through heterophilic interaction with JAML on neutrophils [PMID:11734628, PMID:15800062]. Its D1 immunoglobulin domain homodimerizes via the GFCC'C″ face—the same surface hijacked by the adenovirus fiber knob for cell entry—while CVB3 binds the distal tip of D1 in the viral canyon, and adenovirus further exploits CAR by using newly synthesized fiber protein to disrupt junctional integrity and enable apical viral escape [PMID:10567268, PMID:11573093, PMID:12297051]. Actomyosin-dependent lateral drifting of CAR on the plasma membrane initiates adenovirus uncoating by promoting fiber shedding and exposure of the membrane-lytic protein VI [PMID:21843868].\",\n  \"teleology\": [\n    {\n      \"year\": 1997,\n      \"claim\": \"Identification of a shared entry receptor for coxsackieviruses B and adenoviruses 2/5 resolved how two unrelated virus families could target the same cell types, establishing CXADR as a dual-tropism determinant.\",\n      \"evidence\": \"cDNA cloning and transfection of non-permissive hamster and NIH 3T3 cells conferring viral susceptibility, replicated in two independent laboratories\",\n      \"pmids\": [\"9036860\", \"9096397\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\n        \"Physiological (non-viral) function of CAR unknown at this point\",\n        \"Binding interface with each virus uncharacterized\",\n        \"Tissue-level determinants of infection beyond receptor expression not addressed\"\n      ]\n    },\n    {\n      \"year\": 1999,\n      \"claim\": \"Crystal structures of the adenovirus fiber knob–CAR D1 complex and biophysical demonstration of D1 homodimerization revealed that the GFCC'C″ face of D1 serves a dual role in homophilic adhesion and viral attachment, explaining how adenovirus co-opts a cell adhesion interface.\",\n      \"evidence\": \"X-ray crystallography of fiber knob–CAR D1 (1999) and CAR D1 homodimer at 1.7 Å with analytical ultracentrifugation (2000)\",\n      \"pmids\": [\"10567268\", \"11080637\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\n        \"Full-length CAR structure including transmembrane and cytoplasmic domains not resolved at atomic level\",\n        \"Structural basis of CVB3 binding not yet determined at high resolution\"\n      ]\n    },\n    {\n      \"year\": 2001,\n      \"claim\": \"Localization of CAR to tight junctions and demonstration that it recruits ZO-1 and controls paracellular permeability established CAR's physiological role as a junctional adhesion molecule, not merely a viral receptor.\",\n      \"evidence\": \"Immunofluorescence, co-immunoprecipitation with ZO-1, transepithelial resistance measurements, and virus infection of polarized epithelial monolayers\",\n      \"pmids\": [\"11734628\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\n        \"Cytoplasmic signaling pathways downstream of CAR–ZO-1 interaction not defined\",\n        \"Relative contribution of CAR versus other tight junction proteins to barrier integrity unclear\"\n      ]\n    },\n    {\n      \"year\": 2001,\n      \"claim\": \"Cryo-EM of the CVB3–CAR complex showed that CVB3 binds the distal tip of D1 in the canyon—a surface distinct from the adenovirus-binding face—explaining how two unrelated viruses share one receptor without competing for the same epitope.\",\n      \"evidence\": \"Cryo-EM reconstruction (~22 Å) of full-length CAR complexed with CVB3 virions\",\n      \"pmids\": [\"11573093\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\n        \"Atomic-resolution details of CVB3–CAR interface not available from cryo-EM at this resolution\",\n        \"Mechanism by which CVB3 binding triggers capsid conformational changes and RNA release not resolved\"\n      ]\n    },\n    {\n      \"year\": 2002,\n      \"claim\": \"Discovery that adenovirus fiber protein disrupts CAR-mediated tight junctions to enable apical viral escape revealed a second exploitation mechanism: CAR is used not only for entry but also for egress across polarized epithelia.\",\n      \"evidence\": \"Infection of polarized human airway epithelia with fiber protein binding assays and tight junction integrity measurements\",\n      \"pmids\": [\"12297051\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\n        \"Quantitative threshold of fiber protein needed to disrupt junctions not established\",\n        \"Whether other junction-disrupting mechanisms act in parallel during adenovirus exit not tested\"\n      ]\n    },\n    {\n      \"year\": 2005,\n      \"claim\": \"Identification of JAML as a heterophilic ligand for CAR extended CAR's physiological role beyond adhesion to regulation of neutrophil transepithelial migration, linking it to innate immune function.\",\n      \"evidence\": \"JAML fusion protein binding assays, domain mapping, and transepithelial migration assays with blocking reagents\",\n      \"pmids\": [\"15800062\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\n        \"Structural basis of CAR–JAML interaction not determined\",\n        \"In vivo validation in CAR-knockout models for neutrophil transmigration not reported in this study\"\n      ]\n    },\n    {\n      \"year\": 2009,\n      \"claim\": \"Demonstration that human erythrocytes present CAR and sequester adenovirus type 5 in the bloodstream revealed a species-specific innate defense mechanism that limits systemic adenoviral spread.\",\n      \"evidence\": \"Flow cytometry, cryo-EM, and xenograft mouse models with human erythrocyte transplantation showing extended Ad5 circulation and reduced hepatic infection\",\n      \"pmids\": [\"19131551\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\n        \"Mechanism controlling CAR surface expression on erythrocytes versus other blood cells not characterized\",\n        \"Impact on other adenovirus serotypes beyond Ad5 not systematically tested\"\n      ]\n    },\n    {\n      \"year\": 2011,\n      \"claim\": \"Live-cell imaging showed that actomyosin-2-dependent lateral drifting of CAR on the plasma membrane mechanically initiates adenovirus uncoating by generating opposing forces with immobile integrin contacts, revealing that virus disassembly begins before endocytosis.\",\n      \"evidence\": \"Single-particle tracking, FRAP, pharmacological inhibition of actomyosin-2 in live cells, and endosomal escape assays\",\n      \"pmids\": [\"21843868\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\n        \"Whether CAR lateral mobility is regulated in different cell types or polarization states not addressed\",\n        \"Precise force magnitude required for fiber shedding not measured\"\n      ]\n    },\n    {\n      \"year\": null,\n      \"claim\": \"Key open questions include: the full atomic structure of intact CAR (transmembrane + cytoplasmic domain), the signaling cascades downstream of CAR's cytoplasmic tail during junction formation and leukocyte transmigration, the structural basis of CAR–JAML interaction, and the in vivo contribution of CAR to cardiac and neuronal development observed in loss-of-function models.\",\n      \"evidence\": \"\",\n      \"pmids\": [],\n      \"confidence\": \"Low\",\n      \"gaps\": [\n        \"No atomic-resolution structure of full-length CAR available\",\n        \"Cytoplasmic signaling cascades downstream of CAR remain uncharacterized\",\n        \"In vivo developmental phenotypes from CAR knockout not mechanistically resolved in the primary literature surveyed\"\n      ]\n    }\n  ],\n  \"mechanism_profile\": {\n    \"molecular_activity\": [\n      {\"term_id\": \"GO:0098631\", \"supporting_discovery_ids\": [5, 6, 10]},\n      {\"term_id\": \"GO:0001618\", \"supporting_discovery_ids\": [0, 1, 2, 7]},\n      {\"term_id\": \"GO:0005198\", \"supporting_discovery_ids\": [6]}\n    ],\n    \"localization\": [\n      {\"term_id\": \"GO:0005886\", \"supporting_discovery_ids\": [0, 6, 8, 11, 12]}\n    ],\n    \"pathway\": [\n      {\"term_id\": \"R-HSA-1500931\", \"supporting_discovery_ids\": [5, 6, 10]},\n      {\"term_id\": \"R-HSA-168256\", \"supporting_discovery_ids\": [10, 11]},\n      {\"term_id\": \"R-HSA-1643685\", \"supporting_discovery_ids\": [0, 1, 7, 9]}\n    ],\n    \"complexes\": [],\n    \"partners\": [\n      \"ZO-1\",\n      \"JAML\",\n      \"ITGAV\"\n    ],\n    \"other_free_text\": []\n  }\n}\n```"}