{"gene":"KIAA0319L","run_date":"2026-06-10T02:59:49","timeline":{"discoveries":[{"year":2019,"finding":"Cryo-EM structure of AAV2 bound to AAVR (KIAA0319L) at 2.8 Å resolution reveals that PKD2 domain of AAVR binds directly to the spike region of the AAV2 capsid adjacent to the icosahedral three-fold axis; residues in strands B and E, and the BC loop of PKD2 interact with AAV2 capsid; mutagenesis of interface residues reduces binding and viral infectivity.","method":"Cryo-EM structure determination + site-directed mutagenesis + infectivity assay","journal":"Nature microbiology","confidence":"High","confidence_rationale":"Tier 1 / Strong — high-resolution cryo-EM structure with mutagenesis validation, replicated in independent study (PMID:31115336)","pmids":["30742069"],"is_preprint":false},{"year":2019,"finding":"Cryo-EM and cryo-electron tomography of AAV2-AAVR complex at 2.4 Å resolution (two-domain PKD1-2 fragment) confirms PKD2 binds between AAV spikes on a conserved plateau; cross-linking/mass spectrometry identifies regions in close physical proximity; AAVR footprint overlaps epitopes of several neutralizing antibodies.","method":"Cryo-electron tomography, cryo-EM at 2.4 Å, cross-linking/mass spectrometry","journal":"eLife","confidence":"High","confidence_rationale":"Tier 1 / Strong — independent replication of structure with multiple orthogonal methods (cryo-ET, cryo-EM, XL-MS) in one study","pmids":["31115336"],"is_preprint":false},{"year":2019,"finding":"Cryo-EM structures of AAV1-AAVR and AAV5-AAVR complexes reveal divergent binding rules: PKD2 domain solely engages AAV1 (plateau region), while PKD1 domain uniquely binds AAV5 at the opposite side of the spike; strands F/G and the CD loop of PKD1 contact AAV5, whereas strands B/C/E and the BC loop of PKD2 contact AAV1.","method":"Cryo-EM structure determination of two separate AAV-AAVR complexes","journal":"Nature communications","confidence":"High","confidence_rationale":"Tier 1 / Strong — atomic-resolution cryo-EM structures for two serotypes establishing divergent receptor-engagement mechanisms","pmids":["31434885"],"is_preprint":false},{"year":2020,"finding":"Cryo-EM structure of AAV5-AAVR at 2.5 Å resolution shows AAV5 binds exclusively to PKD1 of AAVR; binding sites for neutralizing antibodies ADK5a, ADK5b, and 3C5 on AAV5 overlap with the AAVR binding site.","method":"Cryo-EM structure determination at 2.5 Å + molecular modeling","journal":"Viruses","confidence":"High","confidence_rationale":"Tier 1 / Strong — independent atomic-resolution cryo-EM structure with detailed interface analysis, consistent with prior structures","pmids":["33218165"],"is_preprint":false},{"year":2022,"finding":"Cryo-EM structure of goat AAVGo.1 in complex with AAVR PKD12 fragment at 2.4 Å resolution shows AAVGo.1 binds exclusively PKD1, forming a class with AAV5 whose mode of receptor-binding is completely different from PKD2-binding AAVs; ELISA demonstrates AAVGo.1 binds human AAVR more strongly than AAV2 or AAV5.","method":"Cryo-EM structure determination at 2.9 Å (virus) and 2.4 Å (complex) + ELISA binding assay","journal":"Journal of virology","confidence":"High","confidence_rationale":"Tier 1 / Moderate — atomic-resolution cryo-EM structure plus orthogonal ELISA binding quantification in single study","pmids":["36453885"],"is_preprint":false},{"year":2019,"finding":"AAVR is basolaterally localized in polarized human airway epithelia; overexpression localizes AAVR to the basolateral membrane and preferentially increases AAV2 transduction from that side; anti-AAVR antibodies block AAV2 transduction basolaterally; CRISPR knockout of AAVR blocks AAV2 but not AAV2.5T infection, indicating AAVR-dependent vs. AAVR-independent entry routes.","method":"Immunocytochemistry for localization, antibody-blocking assay, CRISPR knockout + transduction assay","journal":"Gene therapy","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — CRISPR KO + antibody blockade + localization by ICC, single lab, multiple orthogonal methods","pmids":["30962536"],"is_preprint":false},{"year":2023,"finding":"Bio-layer interferometry, SEC-MALS, and SV-AUC measurements show AAV5 has the strongest binding affinity to AAVR, followed by AAV1, while AAV8 binds weakest; lower pH promotes AAV-AAVR binding while neutral/basic pH leads to very weak binding, suggesting AAVR may play a prominent role in trafficking AAV to the Golgi for certain serotypes rather than solely acting as cell surface receptor.","method":"Bio-layer interferometry (BLI), SEC-MALS, sedimentation velocity analytical ultracentrifugation under varying pH conditions","journal":"Journal of pharmaceutical and biomedical analysis","confidence":"Medium","confidence_rationale":"Tier 1 / Moderate — multiple orthogonal biophysical methods in one study, single lab","pmids":["37441888"],"is_preprint":false},{"year":2025,"finding":"AAVR expression in outer hair cells (OHCs) and vestibular hair cells decreases significantly in mature mice; anti-AAVR antibody blockade significantly inhibits AAV transduction in sensory hair cells in cochlear explants; AAVR knockout mice confirm inhibition of AAV transduction in sensory hair cells in vivo; conditional overexpression of AAVR in sensory hair cells restores AAV transduction efficiency in OHCs and vestibular hair cells.","method":"Immunocytochemistry, antibody blocking assay, AAVR knockout mice, conditional AAVR overexpression + transduction assay in vivo and ex vivo","journal":"Advanced science","confidence":"High","confidence_rationale":"Tier 2 / Strong — multiple orthogonal methods (KO, OE, antibody blockade, complex formation), functional readout in vivo and ex vivo","pmids":["39776318"],"is_preprint":false},{"year":2017,"finding":"Kiaa0319L (AU040320) knockout mice show no impaired cortical lamination, neuronal migration, or neurogenesis, but AU040320-KO mice display suprathreshold deficits in auditory brainstem response wave III amplitude; double Kiaa0319;AU040320 KO mice show auditory gap-in-noise detection deficits and more general auditory brainstem response deficits, indicating a role in auditory brainstem function rather than neuronal migration.","method":"Knockout mouse analysis: cortical lamination histology, auditory brainstem response recordings, behavioral gap-in-noise detection task","journal":"Cerebral cortex","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — clean KO with defined phenotypic readout using multiple assays, but single lab","pmids":["29045729"],"is_preprint":false},{"year":2023,"finding":"Knockdown of KIAA0319L in the chick optic tectum via electroporated miRNA constructs results in abnormal neuronal migration, supporting a role for KIAA0319L in neuronal migration in the developing visual system.","method":"In ovo electroporation of miRNA knockdown constructs + histological analysis of neuronal migration in chick optic tectum","journal":"The International journal of developmental biology","confidence":"Low","confidence_rationale":"Tier 3 / Weak — single lab, single method (miRNA KD in chick), no mechanistic pathway placement","pmids":["37410671"],"is_preprint":false},{"year":2026,"finding":"Four nonsense variants of KIAA0319L (AAVR) caused significant reductions in AAV gene transfer for serotypes 2, 5, 6, 8, 9, rh.10 but not for AAVR-independent AAVrh32.33; several missense variants reduced protein expression and decreased AAV8/9/rh.10 transduction; Ser1031Phe and Gly1022Arg missense variants increased AAV5 transduction (Ser1031Phe by enhanced nuclear trafficking); Ala563Val increased AAV9 transduction; AAV2 transduction significantly decreased only by Lys3Thr.","method":"Transfection of AAVR variant constructs in AAVR-null cells + serotype-specific transduction assays + protein expression analysis + cell binding and nuclear trafficking assays","journal":"Molecular therapy. Advances","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — systematic mutagenesis panel with functional transduction readouts and trafficking analysis, single lab","pmids":["42137583"],"is_preprint":false},{"year":2025,"finding":"In vitro reconstitution assays demonstrate that AAVR's cytosolic tail is sufficient to engage the SNX3-retromer complex and drive membrane tubulation, a hallmark of retrograde trafficking; in AAVR-knockout HuH-7 cells, AAV2 particles are internalized but fail to reach the trans-Golgi network (TGN) and support transgene expression; Galectin-8 recruitment assays reveal no endosomal membrane rupture during productive AAV2 transduction; VP1u-deficient and PLA2-mutant AAV2 capsids accumulate at the TGN, indicating VP1u is dispensable for early AAVR-dependent trafficking but required for post-TGN progression.","method":"In vitro reconstitution assay (SNX3-retromer tubulation), AAVR-KO cells + live imaging of AAV trafficking, Galectin-8 recruitment assay, VP1u/PLA2-mutant capsid analysis","journal":"bioRxiv","confidence":"Medium","confidence_rationale":"Tier 1 / Moderate — reconstitution assay plus KO cell trafficking studies and multiple orthogonal assays, single lab, preprint not yet peer-reviewed","pmids":["bio_10.1101_2025.11.22.689972"],"is_preprint":true},{"year":2025,"finding":"Human AAVR PKD2 domain sequence variation relative to mouse AAVR (four amino acid differences, with I426V having the greatest effect) is responsible for the species tropism of AAV-LK03; human AAVR supplementation rescues low murine transduction of AAV-LK03 in vitro and in vivo; the AAV-AM capsid 265G insertion is surface-exposed and facilitates binding to AAVR.","method":"Sequence swap experiments between human and mouse AAVR PKD2, human AAVR complementation in mouse cells/mice, in vitro and in vivo transduction assays","journal":"Research square","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — genetic complementation + domain swap experiments with functional readout in vitro and in vivo, single lab, preprint","pmids":["41377965"],"is_preprint":true},{"year":2025,"finding":"Cryo-EM structures of engineered AAV capsid CAP-B10 alone (2.22 Å) and in complex with AAVR PKD2 (2.20 Å) reveal a structural motif that hinders AAVR binding; reduced AAVR affinity correlates with liver de-targeting; this motif is transferable to other capsids (AAV9-X1, AAV9-X1.1 structures solved), enabling rational design of AAV variants with reduced liver tropism.","method":"Cryo-EM structure determination of AAV-AAVR complex + affinity measurements + in vivo transduction assays","journal":"bioRxiv","confidence":"Medium","confidence_rationale":"Tier 1 / Moderate — atomic-resolution cryo-EM structures with functional validation in vivo, single lab, preprint","pmids":["bio_10.1101_2025.06.02.655683"],"is_preprint":true}],"current_model":"KIAA0319L/AAVR is a multi-domain cell-surface receptor (containing five PKD domains) that serves as the essential entry receptor for multiple AAV serotypes: PKD2 mediates binding for AAV1, AAV2, and most other serotypes at a conserved plateau region of the capsid, while PKD1 exclusively mediates binding for AAV5 and related serotypes at a structurally distinct site; upon internalization, AAVR's cytosolic tail engages the SNX3-retromer complex to direct AAV via retrograde trafficking through the trans-Golgi network (rather than direct endosomal escape) en route to productive transduction; AAVR expression levels directly determine transduction efficiency in polarized epithelia, sensory hair cells, and hippocampal neurons, and human genetic variants in KIAA0319L modulate AAV gene therapy efficacy in a serotype-specific manner."},"narrative":{"mechanistic_narrative":"KIAA0319L (AAVR) is a multi-domain cell-surface receptor that serves as the essential entry receptor for adeno-associated virus (AAV) across multiple serotypes, with its PKD domains directly engaging the viral capsid to determine transduction efficiency [PMID:30742069, PMID:31434885]. Receptor engagement follows two divergent structural rules: the PKD2 domain binds at a conserved plateau region adjacent to the icosahedral three-fold axis for AAV1, AAV2, and most serotypes (via strands B/C/E and the BC loop), whereas the PKD1 domain uniquely binds AAV5 and the related goat AAVGo.1 at a structurally distinct site on the opposite side of the spike (via strands F/G and the CD loop) [PMID:30742069, PMID:31434885, PMID:33218165, PMID:36453885]. The AAVR footprint overlaps epitopes of several neutralizing antibodies, marking the receptor-binding surface as an immunodominant capsid site [PMID:31115336, PMID:33218165]. Beyond surface attachment, AAVR functions in intracellular trafficking: its cytosolic tail engages the SNX3-retromer complex to drive membrane tubulation and direct internalized AAV2 to the trans-Golgi network for productive transduction, a route that proceeds without endosomal membrane rupture [PMID:bio_10.1101_2025.11.22.689972]. AAVR expression levels directly determine transduction in physiologically relevant cells, including basolaterally polarized airway epithelia and cochlear/vestibular sensory hair cells, where knockout abolishes and overexpression restores AAV transduction [PMID:30962536, PMID:39776318]. Human KIAA0319L sequence variants modulate AAV gene-transfer efficacy in a serotype-specific manner, and PKD2 sequence differences between human and mouse AAVR govern species tropism of engineered capsids [PMID:42137583, PMID:41377965]. Independent of its viral-receptor role, mouse knockout links Kiaa0319L to auditory brainstem function rather than to cortical neuronal migration [PMID:29045729].","teleology":[{"year":2017,"claim":"Established whether KIAA0319L contributes to neurodevelopment as had been hypothesized, distinguishing a neuronal-migration role from an auditory one.","evidence":"Knockout mouse cortical histology, auditory brainstem response recordings, and gap-in-noise behavior","pmids":["29045729"],"confidence":"Medium","gaps":["Molecular mechanism underlying the auditory deficit not defined","No link drawn to AAVR's receptor or trafficking activities","Single lab; effect partly emerges only in double KO with Kiaa0319"]},{"year":2019,"claim":"Resolved the atomic basis of AAV-receptor engagement, showing the PKD2 domain binds the AAV2 capsid spike and that interface residues are required for infectivity.","evidence":"Cryo-EM at 2.8 Å with site-directed mutagenesis and infectivity assays; independently replicated by cryo-ET/cryo-EM/XL-MS at 2.4 Å","pmids":["30742069","31115336"],"confidence":"High","gaps":["Did not address serotypes engaging a different PKD domain","Post-binding internalization and trafficking steps not resolved structurally"]},{"year":2019,"claim":"Demonstrated that AAVR expression and basolateral localization control AAV2 entry in a physiological epithelium and that AAVR-independent entry routes exist.","evidence":"Immunocytochemistry, anti-AAVR antibody blockade, and CRISPR knockout with transduction assays in polarized airway epithelia","pmids":["30962536"],"confidence":"Medium","gaps":["Molecular basis of AAVR-independent AAV2.5T entry not identified","Mechanism of basolateral targeting unknown"]},{"year":2019,"claim":"Defined divergent receptor-engagement rules, revealing PKD1 as the exclusive binding domain for AAV5 versus PKD2 for AAV1/AAV2.","evidence":"Cryo-EM structures of AAV1-AAVR and AAV5-AAVR complexes","pmids":["31434885"],"confidence":"High","gaps":["Functional consequence of two-site binding for trafficking not addressed","Did not establish why some serotypes select PKD1 over PKD2"]},{"year":2020,"claim":"Confirmed AAV5's exclusive PKD1 engagement at high resolution and mapped overlap with neutralizing-antibody epitopes.","evidence":"Cryo-EM at 2.5 Å with molecular modeling of antibody footprints","pmids":["33218165"],"confidence":"High","gaps":["Affinity and stoichiometry of PKD1 binding not quantified","Trafficking fate after PKD1 binding not addressed"]},{"year":2022,"claim":"Showed the PKD1-binding mode generalizes beyond AAV5 to a wider capsid class and quantified differential receptor affinity.","evidence":"Cryo-EM of goat AAVGo.1-AAVR PKD12 complex at 2.4 Å plus ELISA binding comparison","pmids":["36453885"],"confidence":"High","gaps":["Relationship between higher binding affinity and transduction outcome not tested","Biological host range of AAVGo.1 via human AAVR unexplored"]},{"year":2023,"claim":"Provided biophysical evidence that AAVR affinity is serotype-specific and pH-dependent, supporting a trafficking role beyond surface attachment.","evidence":"BLI, SEC-MALS, and SV-AUC binding measurements under varying pH","pmids":["37441888"],"confidence":"Medium","gaps":["Direct demonstration of pH-driven Golgi trafficking not provided here","Single lab; cellular relevance of in vitro pH dependence not validated"]},{"year":2025,"claim":"Established AAVR as a determinant of AAV transduction in sensory hair cells in vivo, linking receptor abundance to gene-therapy-relevant cell targeting.","evidence":"Immunocytochemistry, antibody blockade, AAVR knockout mice, and conditional overexpression with transduction assays in vivo and ex vivo","pmids":["39776318"],"confidence":"High","gaps":["Trafficking mechanism in hair cells not dissected","Cause of developmental decline in AAVR expression unknown"]},{"year":2025,"claim":"Defined the intracellular itinerary by showing AAVR's cytosolic tail recruits the SNX3-retromer to route AAV via retrograde trafficking to the TGN without endosomal rupture.","evidence":"In vitro SNX3-retromer tubulation reconstitution, AAVR-KO cell trafficking imaging, Galectin-8 recruitment, and VP1u/PLA2-mutant capsid analysis (preprint)","pmids":["bio_10.1101_2025.11.22.689972"],"confidence":"Medium","gaps":["Preprint not yet peer-reviewed","Post-TGN steps requiring VP1u not mechanistically resolved","Whether the same route applies to PKD1-engaging serotypes untested"]},{"year":2025,"claim":"Identified the PKD2 sequence determinants of species tropism, with human-versus-mouse residue differences controlling engineered-capsid transduction.","evidence":"Human/mouse PKD2 domain swaps and human AAVR complementation with in vitro and in vivo transduction (preprint)","pmids":["41377965"],"confidence":"Medium","gaps":["Preprint; single lab","Structural basis of the I426V effect not resolved"]},{"year":2025,"claim":"Demonstrated that engineering capsid motifs to weaken AAVR binding rationally de-targets the liver, validating AAVR affinity as a tropism-tuning lever.","evidence":"Cryo-EM of CAP-B10-AAVR PKD2 complexes with affinity measurements and in vivo transduction (preprint)","pmids":["bio_10.1101_2025.06.02.655683"],"confidence":"Medium","gaps":["Preprint; not peer-reviewed","Off-target effects of reduced AAVR binding on other tissues not fully mapped"]},{"year":2026,"claim":"Systematically linked human KIAA0319L coding variants to serotype-specific changes in AAV transduction, including loss-of-function and gain-of-function alleles affecting trafficking.","evidence":"Transfection of AAVR variant constructs in AAVR-null cells with serotype-specific transduction, expression, binding, and nuclear trafficking assays","pmids":["42137583"],"confidence":"Medium","gaps":["Population frequency and clinical impact of variants not assessed","Mechanism by which Ser1031Phe enhances nuclear trafficking only partly defined"]},{"year":null,"claim":"How AAVR's distinct PKD1- versus PKD2-engagement modes feed into a common or divergent retrograde trafficking pathway, and what its endogenous (non-viral) cellular ligand or function is, remain unresolved.","evidence":"","pmids":[],"confidence":"Low","gaps":["No endogenous ligand or native physiological function of AAVR identified","Whether PKD1-binding serotypes use the SNX3-retromer route is untested","Connection between auditory brainstem phenotype and AAVR's molecular activity unknown"]}],"mechanism_profile":{"molecular_activity":[{"term_id":"GO:0001618","term_label":"virus receptor activity","supporting_discovery_ids":[0,2,5,7]},{"term_id":"GO:0060089","term_label":"molecular transducer activity","supporting_discovery_ids":[0,2]}],"localization":[{"term_id":"GO:0005886","term_label":"plasma membrane","supporting_discovery_ids":[5]},{"term_id":"GO:0005794","term_label":"Golgi apparatus","supporting_discovery_ids":[11,6]},{"term_id":"GO:0005768","term_label":"endosome","supporting_discovery_ids":[11]}],"pathway":[{"term_id":"R-HSA-5653656","term_label":"Vesicle-mediated transport","supporting_discovery_ids":[11]},{"term_id":"R-HSA-9609507","term_label":"Protein localization","supporting_discovery_ids":[11]}],"complexes":["SNX3-retromer"],"partners":["SNX3"],"other_free_text":[]}},"prefetch_data":{"uniprot":{"accession":"Q8IZA0","full_name":"Dyslexia-associated protein KIAA0319-like protein","aliases":["Adeno-associated virus receptor","AAVR"],"length_aa":1049,"mass_kda":115.7,"function":"Possible role in axon guidance through interaction with RTN4R (Microbial infection) Acts as a receptor for adeno-associated virus and is involved in adeno-associated virus infection through endocytosis system","subcellular_location":"Cytoplasmic granule membrane; Golgi apparatus membrane; Golgi apparatus, trans-Golgi network membrane; Cell membrane","url":"https://www.uniprot.org/uniprotkb/Q8IZA0/entry"},"depmap":{"release":"DepMap","has_data":true,"is_common_essential":false,"resolved_as":"","url":"https://depmap.org/portal/gene/KIAA0319L","classification":"Not Classified","n_dependent_lines":0,"n_total_lines":1208,"dependency_fraction":0.0},"opencell":{"profiled":true,"resolved_as":"","ensg_id":"ENSG00000142687","cell_line_id":"CID000887","localizations":[{"compartment":"vesicles","grade":3},{"compartment":"golgi","grade":2}],"interactors":[{"gene":"CANX","stoichiometry":0.2},{"gene":"MSN","stoichiometry":0.2}],"url":"https://opencell.sf.czbiohub.org/target/CID000887","total_profiled":1310},"omim":[{"mim_id":"613535","title":"KIAA0319-LIKE; KIAA0319L","url":"https://www.omim.org/entry/613535"}],"hpa":{"profiled":true,"resolved_as":"","reliability":"Supported","locations":[{"location":"Golgi apparatus","reliability":"Supported"},{"location":"Nucleoli","reliability":"Additional"}],"tissue_specificity":"Low tissue specificity","tissue_distribution":"Detected in all","driving_tissues":[],"url":"https://www.proteinatlas.org/search/KIAA0319L"},"hgnc":{"alias_symbol":["KIAA1837","AAVR"],"prev_symbol":[]},"alphafold":{"accession":"Q8IZA0","domains":[{"cath_id":"3.50.4.10","chopping":"55-134","consensus_level":"high","plddt":80.3046,"start":55,"end":134},{"cath_id":"2.60.40.10","chopping":"310-400","consensus_level":"medium","plddt":84.8335,"start":310,"end":400},{"cath_id":"2.60.40.10","chopping":"417-497","consensus_level":"medium","plddt":87.6235,"start":417,"end":497},{"cath_id":"2.60.40.10","chopping":"512-593","consensus_level":"medium","plddt":87.5804,"start":512,"end":593},{"cath_id":"2.60.40.10","chopping":"608-688","consensus_level":"medium","plddt":89.6533,"start":608,"end":688},{"cath_id":"2.60.40.10","chopping":"702-784","consensus_level":"high","plddt":92.3186,"start":702,"end":784},{"cath_id":"-","chopping":"793-945","consensus_level":"medium","plddt":87.9123,"start":793,"end":945}],"viewer_url":"https://alphafold.ebi.ac.uk/entry/Q8IZA0","model_url":"https://alphafold.ebi.ac.uk/files/AF-Q8IZA0-F1-model_v6.cif","pae_url":"https://alphafold.ebi.ac.uk/files/AF-Q8IZA0-F1-predicted_aligned_error_v6.png","plddt_mean":71.69},"mouse_models":{"mgi_url":"https://www.informatics.jax.org/marker/summary?nomen=KIAA0319L","jax_strain_url":"https://www.jax.org/strain/search?query=KIAA0319L"},"sequence":{"accession":"Q8IZA0","fasta_url":"https://rest.uniprot.org/uniprotkb/Q8IZA0.fasta","uniprot_url":"https://www.uniprot.org/uniprotkb/Q8IZA0/entry","alphafold_viewer_url":"https://alphafold.ebi.ac.uk/entry/Q8IZA0"}},"corpus_meta":[{"pmid":"30742069","id":"PMC_30742069","title":"Adeno-associated virus 2 bound to its cellular receptor AAVR.","date":"2019","source":"Nature microbiology","url":"https://pubmed.ncbi.nlm.nih.gov/30742069","citation_count":98,"is_preprint":false},{"pmid":"31115336","id":"PMC_31115336","title":"Structure of the gene therapy vector, adeno-associated virus with its cell receptor, AAVR.","date":"2019","source":"eLife","url":"https://pubmed.ncbi.nlm.nih.gov/31115336","citation_count":76,"is_preprint":false},{"pmid":"31434885","id":"PMC_31434885","title":"Divergent engagements between adeno-associated viruses with their cellular receptor AAVR.","date":"2019","source":"Nature communications","url":"https://pubmed.ncbi.nlm.nih.gov/31434885","citation_count":75,"is_preprint":false},{"pmid":"19085271","id":"PMC_19085271","title":"The KIAA0319-like (KIAA0319L) gene on chromosome 1p34 as a candidate for reading disabilities.","date":"2008","source":"Journal of neurogenetics","url":"https://pubmed.ncbi.nlm.nih.gov/19085271","citation_count":42,"is_preprint":false},{"pmid":"33218165","id":"PMC_33218165","title":"The Structure of an AAV5-AAVR Complex at 2.5 Å Resolution: Implications for Cellular Entry and Immune Neutralization of AAV Gene Therapy Vectors.","date":"2020","source":"Viruses","url":"https://pubmed.ncbi.nlm.nih.gov/33218165","citation_count":25,"is_preprint":false},{"pmid":"30962536","id":"PMC_30962536","title":"Polarized AAVR expression determines infectivity by AAV gene therapy vectors.","date":"2019","source":"Gene therapy","url":"https://pubmed.ncbi.nlm.nih.gov/30962536","citation_count":24,"is_preprint":false},{"pmid":"29045729","id":"PMC_29045729","title":"Knockout Mice for Dyslexia Susceptibility Gene Homologs KIAA0319 and KIAA0319L have Unaffected Neuronal Migration but Display Abnormal Auditory Processing.","date":"2017","source":"Cerebral cortex (New York, N.Y. : 1991)","url":"https://pubmed.ncbi.nlm.nih.gov/29045729","citation_count":16,"is_preprint":false},{"pmid":"36453885","id":"PMC_36453885","title":"Cross-Species Permissivity: Structure of a Goat Adeno-Associated Virus and Its Complex with the Human Receptor AAVR.","date":"2022","source":"Journal of virology","url":"https://pubmed.ncbi.nlm.nih.gov/36453885","citation_count":9,"is_preprint":false},{"pmid":"31670142","id":"PMC_31670142","title":"AAVR-Displaying Interfaces: Serotype-Independent Adeno-Associated Virus Capture and Local Delivery Systems.","date":"2019","source":"Molecular therapy. Nucleic acids","url":"https://pubmed.ncbi.nlm.nih.gov/31670142","citation_count":9,"is_preprint":false},{"pmid":"39776318","id":"PMC_39776318","title":"AAVR Expression is Essential for AAV Vector Transduction in Sensory Hair Cells.","date":"2025","source":"Advanced science (Weinheim, Baden-Wurttemberg, Germany)","url":"https://pubmed.ncbi.nlm.nih.gov/39776318","citation_count":8,"is_preprint":false},{"pmid":"37441888","id":"PMC_37441888","title":"Comprehensive biophysical characterization of AAV-AAVR interaction uncovers serotype- and pH-dependent interaction.","date":"2023","source":"Journal of pharmaceutical and biomedical analysis","url":"https://pubmed.ncbi.nlm.nih.gov/37441888","citation_count":8,"is_preprint":false},{"pmid":"37188274","id":"PMC_37188274","title":"Enhanced sensitivity of neutralizing antibody detection for different AAV serotypes using HeLa cells with overexpressed AAVR.","date":"2023","source":"Frontiers in pharmacology","url":"https://pubmed.ncbi.nlm.nih.gov/37188274","citation_count":8,"is_preprint":false},{"pmid":"33654738","id":"PMC_33654738","title":"Expression and Purification of Adeno-associated Virus Virus-like Particles in a Baculovirus System and AAVR Ectodomain Constructs in E. coli.","date":"2020","source":"Bio-protocol","url":"https://pubmed.ncbi.nlm.nih.gov/33654738","citation_count":6,"is_preprint":false},{"pmid":"37410671","id":"PMC_37410671","title":"The Dyslexia-associated gene KIAA0319L is involved in neuronal migration in the developing chick visual system.","date":"2023","source":"The International journal of developmental biology","url":"https://pubmed.ncbi.nlm.nih.gov/37410671","citation_count":3,"is_preprint":false},{"pmid":"25596907","id":"PMC_25596907","title":"Association between KIAA0319L, PXK and JAZF1 gene polymorphisms and unexplained recurrent pregnancy loss in Chinese Han couples.","date":"2014","source":"Reproductive biomedicine online","url":"https://pubmed.ncbi.nlm.nih.gov/25596907","citation_count":3,"is_preprint":false},{"pmid":"41377965","id":"PMC_41377965","title":"Species-specific AAVR dominates species-tropism of adeno-associated virus (AAV) vectors.","date":"2025","source":"Research square","url":"https://pubmed.ncbi.nlm.nih.gov/41377965","citation_count":0,"is_preprint":false},{"pmid":"42137583","id":"PMC_42137583","title":"Consequences of human genetic variations in KIAA0319L, encoding adeno-associated virus receptor, on AAV-mediated gene transfer.","date":"2026","source":"Molecular therapy. Advances","url":"https://pubmed.ncbi.nlm.nih.gov/42137583","citation_count":0,"is_preprint":false},{"pmid":"42137287","id":"PMC_42137287","title":"Interrogating the dependency of AAV capsids on AAVR for retinal transduction.","date":"2026","source":"Molecular therapy. Advances","url":"https://pubmed.ncbi.nlm.nih.gov/42137287","citation_count":0,"is_preprint":false},{"pmid":null,"id":"bio_10.1101_2025.11.22.689972","title":"AAV2 Bypasses Direct Endosomal Escape by Using AAVR to Access the Trans-Golgi Network en Route to the Nucleus","date":"2025-11-25","source":"bioRxiv","url":"https://doi.org/10.1101/2025.11.22.689972","citation_count":0,"is_preprint":true},{"pmid":null,"id":"bio_10.1101_2025.06.02.655683","title":"Structural basis of liver de-targeting and neuronal tropism of CNS-targeted AAV capsids","date":"2025-06-03","source":"bioRxiv","url":"https://doi.org/10.1101/2025.06.02.655683","citation_count":0,"is_preprint":true},{"pmid":null,"id":"bio_10.1101_2024.11.27.625768","title":"Hippocampal CA2 neurons disproportionately express AAV-delivered genetic cargo","date":"2024-11-28","source":"bioRxiv","url":"https://doi.org/10.1101/2024.11.27.625768","citation_count":0,"is_preprint":true},{"pmid":null,"id":"bio_10.1101_2024.10.16.618764","title":"Identification of SLC35A1 as an essential host factor for the transduction of multi-serotype recombinant adeno-associated virus (AAV) vectors","date":"2024-10-17","source":"bioRxiv","url":"https://doi.org/10.1101/2024.10.16.618764","citation_count":0,"is_preprint":true}],"cost":{"stage1":{"model":"claude-sonnet-4-6","input_tokens":12882,"output_tokens":3795,"usd":0.047786,"stage1_stop_reason":"end_turn"},"stage2":{"model":"claude-opus-4-8","input_tokens":11468,"output_tokens":3888,"usd":0.07727,"stage2_stop_reason":"end_turn"},"total_usd":0.125056,"stage1_batch_id":"msgbatch_01BbTCMyrRPyhtEq6b1MdwCN","stage2_batch_id":"msgbatch_011dEed5bbxYvTAaQWKJevxu","note":"batch pricing = 50% of standard"},"stage1_raw":"```json\n{\n  \"discoveries\": [\n    {\n      \"year\": 2019,\n      \"finding\": \"Cryo-EM structure of AAV2 bound to AAVR (KIAA0319L) at 2.8 Å resolution reveals that PKD2 domain of AAVR binds directly to the spike region of the AAV2 capsid adjacent to the icosahedral three-fold axis; residues in strands B and E, and the BC loop of PKD2 interact with AAV2 capsid; mutagenesis of interface residues reduces binding and viral infectivity.\",\n      \"method\": \"Cryo-EM structure determination + site-directed mutagenesis + infectivity assay\",\n      \"journal\": \"Nature microbiology\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 / Strong — high-resolution cryo-EM structure with mutagenesis validation, replicated in independent study (PMID:31115336)\",\n      \"pmids\": [\"30742069\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2019,\n      \"finding\": \"Cryo-EM and cryo-electron tomography of AAV2-AAVR complex at 2.4 Å resolution (two-domain PKD1-2 fragment) confirms PKD2 binds between AAV spikes on a conserved plateau; cross-linking/mass spectrometry identifies regions in close physical proximity; AAVR footprint overlaps epitopes of several neutralizing antibodies.\",\n      \"method\": \"Cryo-electron tomography, cryo-EM at 2.4 Å, cross-linking/mass spectrometry\",\n      \"journal\": \"eLife\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 / Strong — independent replication of structure with multiple orthogonal methods (cryo-ET, cryo-EM, XL-MS) in one study\",\n      \"pmids\": [\"31115336\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2019,\n      \"finding\": \"Cryo-EM structures of AAV1-AAVR and AAV5-AAVR complexes reveal divergent binding rules: PKD2 domain solely engages AAV1 (plateau region), while PKD1 domain uniquely binds AAV5 at the opposite side of the spike; strands F/G and the CD loop of PKD1 contact AAV5, whereas strands B/C/E and the BC loop of PKD2 contact AAV1.\",\n      \"method\": \"Cryo-EM structure determination of two separate AAV-AAVR complexes\",\n      \"journal\": \"Nature communications\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 / Strong — atomic-resolution cryo-EM structures for two serotypes establishing divergent receptor-engagement mechanisms\",\n      \"pmids\": [\"31434885\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2020,\n      \"finding\": \"Cryo-EM structure of AAV5-AAVR at 2.5 Å resolution shows AAV5 binds exclusively to PKD1 of AAVR; binding sites for neutralizing antibodies ADK5a, ADK5b, and 3C5 on AAV5 overlap with the AAVR binding site.\",\n      \"method\": \"Cryo-EM structure determination at 2.5 Å + molecular modeling\",\n      \"journal\": \"Viruses\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 / Strong — independent atomic-resolution cryo-EM structure with detailed interface analysis, consistent with prior structures\",\n      \"pmids\": [\"33218165\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2022,\n      \"finding\": \"Cryo-EM structure of goat AAVGo.1 in complex with AAVR PKD12 fragment at 2.4 Å resolution shows AAVGo.1 binds exclusively PKD1, forming a class with AAV5 whose mode of receptor-binding is completely different from PKD2-binding AAVs; ELISA demonstrates AAVGo.1 binds human AAVR more strongly than AAV2 or AAV5.\",\n      \"method\": \"Cryo-EM structure determination at 2.9 Å (virus) and 2.4 Å (complex) + ELISA binding assay\",\n      \"journal\": \"Journal of virology\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 / Moderate — atomic-resolution cryo-EM structure plus orthogonal ELISA binding quantification in single study\",\n      \"pmids\": [\"36453885\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2019,\n      \"finding\": \"AAVR is basolaterally localized in polarized human airway epithelia; overexpression localizes AAVR to the basolateral membrane and preferentially increases AAV2 transduction from that side; anti-AAVR antibodies block AAV2 transduction basolaterally; CRISPR knockout of AAVR blocks AAV2 but not AAV2.5T infection, indicating AAVR-dependent vs. AAVR-independent entry routes.\",\n      \"method\": \"Immunocytochemistry for localization, antibody-blocking assay, CRISPR knockout + transduction assay\",\n      \"journal\": \"Gene therapy\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — CRISPR KO + antibody blockade + localization by ICC, single lab, multiple orthogonal methods\",\n      \"pmids\": [\"30962536\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2023,\n      \"finding\": \"Bio-layer interferometry, SEC-MALS, and SV-AUC measurements show AAV5 has the strongest binding affinity to AAVR, followed by AAV1, while AAV8 binds weakest; lower pH promotes AAV-AAVR binding while neutral/basic pH leads to very weak binding, suggesting AAVR may play a prominent role in trafficking AAV to the Golgi for certain serotypes rather than solely acting as cell surface receptor.\",\n      \"method\": \"Bio-layer interferometry (BLI), SEC-MALS, sedimentation velocity analytical ultracentrifugation under varying pH conditions\",\n      \"journal\": \"Journal of pharmaceutical and biomedical analysis\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 1 / Moderate — multiple orthogonal biophysical methods in one study, single lab\",\n      \"pmids\": [\"37441888\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2025,\n      \"finding\": \"AAVR expression in outer hair cells (OHCs) and vestibular hair cells decreases significantly in mature mice; anti-AAVR antibody blockade significantly inhibits AAV transduction in sensory hair cells in cochlear explants; AAVR knockout mice confirm inhibition of AAV transduction in sensory hair cells in vivo; conditional overexpression of AAVR in sensory hair cells restores AAV transduction efficiency in OHCs and vestibular hair cells.\",\n      \"method\": \"Immunocytochemistry, antibody blocking assay, AAVR knockout mice, conditional AAVR overexpression + transduction assay in vivo and ex vivo\",\n      \"journal\": \"Advanced science\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — multiple orthogonal methods (KO, OE, antibody blockade, complex formation), functional readout in vivo and ex vivo\",\n      \"pmids\": [\"39776318\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2017,\n      \"finding\": \"Kiaa0319L (AU040320) knockout mice show no impaired cortical lamination, neuronal migration, or neurogenesis, but AU040320-KO mice display suprathreshold deficits in auditory brainstem response wave III amplitude; double Kiaa0319;AU040320 KO mice show auditory gap-in-noise detection deficits and more general auditory brainstem response deficits, indicating a role in auditory brainstem function rather than neuronal migration.\",\n      \"method\": \"Knockout mouse analysis: cortical lamination histology, auditory brainstem response recordings, behavioral gap-in-noise detection task\",\n      \"journal\": \"Cerebral cortex\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — clean KO with defined phenotypic readout using multiple assays, but single lab\",\n      \"pmids\": [\"29045729\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2023,\n      \"finding\": \"Knockdown of KIAA0319L in the chick optic tectum via electroporated miRNA constructs results in abnormal neuronal migration, supporting a role for KIAA0319L in neuronal migration in the developing visual system.\",\n      \"method\": \"In ovo electroporation of miRNA knockdown constructs + histological analysis of neuronal migration in chick optic tectum\",\n      \"journal\": \"The International journal of developmental biology\",\n      \"confidence\": \"Low\",\n      \"confidence_rationale\": \"Tier 3 / Weak — single lab, single method (miRNA KD in chick), no mechanistic pathway placement\",\n      \"pmids\": [\"37410671\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2026,\n      \"finding\": \"Four nonsense variants of KIAA0319L (AAVR) caused significant reductions in AAV gene transfer for serotypes 2, 5, 6, 8, 9, rh.10 but not for AAVR-independent AAVrh32.33; several missense variants reduced protein expression and decreased AAV8/9/rh.10 transduction; Ser1031Phe and Gly1022Arg missense variants increased AAV5 transduction (Ser1031Phe by enhanced nuclear trafficking); Ala563Val increased AAV9 transduction; AAV2 transduction significantly decreased only by Lys3Thr.\",\n      \"method\": \"Transfection of AAVR variant constructs in AAVR-null cells + serotype-specific transduction assays + protein expression analysis + cell binding and nuclear trafficking assays\",\n      \"journal\": \"Molecular therapy. Advances\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — systematic mutagenesis panel with functional transduction readouts and trafficking analysis, single lab\",\n      \"pmids\": [\"42137583\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2025,\n      \"finding\": \"In vitro reconstitution assays demonstrate that AAVR's cytosolic tail is sufficient to engage the SNX3-retromer complex and drive membrane tubulation, a hallmark of retrograde trafficking; in AAVR-knockout HuH-7 cells, AAV2 particles are internalized but fail to reach the trans-Golgi network (TGN) and support transgene expression; Galectin-8 recruitment assays reveal no endosomal membrane rupture during productive AAV2 transduction; VP1u-deficient and PLA2-mutant AAV2 capsids accumulate at the TGN, indicating VP1u is dispensable for early AAVR-dependent trafficking but required for post-TGN progression.\",\n      \"method\": \"In vitro reconstitution assay (SNX3-retromer tubulation), AAVR-KO cells + live imaging of AAV trafficking, Galectin-8 recruitment assay, VP1u/PLA2-mutant capsid analysis\",\n      \"journal\": \"bioRxiv\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 1 / Moderate — reconstitution assay plus KO cell trafficking studies and multiple orthogonal assays, single lab, preprint not yet peer-reviewed\",\n      \"pmids\": [\"bio_10.1101_2025.11.22.689972\"],\n      \"is_preprint\": true\n    },\n    {\n      \"year\": 2025,\n      \"finding\": \"Human AAVR PKD2 domain sequence variation relative to mouse AAVR (four amino acid differences, with I426V having the greatest effect) is responsible for the species tropism of AAV-LK03; human AAVR supplementation rescues low murine transduction of AAV-LK03 in vitro and in vivo; the AAV-AM capsid 265G insertion is surface-exposed and facilitates binding to AAVR.\",\n      \"method\": \"Sequence swap experiments between human and mouse AAVR PKD2, human AAVR complementation in mouse cells/mice, in vitro and in vivo transduction assays\",\n      \"journal\": \"Research square\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — genetic complementation + domain swap experiments with functional readout in vitro and in vivo, single lab, preprint\",\n      \"pmids\": [\"41377965\"],\n      \"is_preprint\": true\n    },\n    {\n      \"year\": 2025,\n      \"finding\": \"Cryo-EM structures of engineered AAV capsid CAP-B10 alone (2.22 Å) and in complex with AAVR PKD2 (2.20 Å) reveal a structural motif that hinders AAVR binding; reduced AAVR affinity correlates with liver de-targeting; this motif is transferable to other capsids (AAV9-X1, AAV9-X1.1 structures solved), enabling rational design of AAV variants with reduced liver tropism.\",\n      \"method\": \"Cryo-EM structure determination of AAV-AAVR complex + affinity measurements + in vivo transduction assays\",\n      \"journal\": \"bioRxiv\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 1 / Moderate — atomic-resolution cryo-EM structures with functional validation in vivo, single lab, preprint\",\n      \"pmids\": [\"bio_10.1101_2025.06.02.655683\"],\n      \"is_preprint\": true\n    }\n  ],\n  \"current_model\": \"KIAA0319L/AAVR is a multi-domain cell-surface receptor (containing five PKD domains) that serves as the essential entry receptor for multiple AAV serotypes: PKD2 mediates binding for AAV1, AAV2, and most other serotypes at a conserved plateau region of the capsid, while PKD1 exclusively mediates binding for AAV5 and related serotypes at a structurally distinct site; upon internalization, AAVR's cytosolic tail engages the SNX3-retromer complex to direct AAV via retrograde trafficking through the trans-Golgi network (rather than direct endosomal escape) en route to productive transduction; AAVR expression levels directly determine transduction efficiency in polarized epithelia, sensory hair cells, and hippocampal neurons, and human genetic variants in KIAA0319L modulate AAV gene therapy efficacy in a serotype-specific manner.\"\n}\n```","stage2_raw":"{\n  \"mechanistic_narrative\": \"KIAA0319L (AAVR) is a multi-domain cell-surface receptor that serves as the essential entry receptor for adeno-associated virus (AAV) across multiple serotypes, with its PKD domains directly engaging the viral capsid to determine transduction efficiency [#0, #2]. Receptor engagement follows two divergent structural rules: the PKD2 domain binds at a conserved plateau region adjacent to the icosahedral three-fold axis for AAV1, AAV2, and most serotypes (via strands B/C/E and the BC loop), whereas the PKD1 domain uniquely binds AAV5 and the related goat AAVGo.1 at a structurally distinct site on the opposite side of the spike (via strands F/G and the CD loop) [#0, #2, #3, #4]. The AAVR footprint overlaps epitopes of several neutralizing antibodies, marking the receptor-binding surface as an immunodominant capsid site [#1, #3]. Beyond surface attachment, AAVR functions in intracellular trafficking: its cytosolic tail engages the SNX3-retromer complex to drive membrane tubulation and direct internalized AAV2 to the trans-Golgi network for productive transduction, a route that proceeds without endosomal membrane rupture [#11]. AAVR expression levels directly determine transduction in physiologically relevant cells, including basolaterally polarized airway epithelia and cochlear/vestibular sensory hair cells, where knockout abolishes and overexpression restores AAV transduction [#5, #7]. Human KIAA0319L sequence variants modulate AAV gene-transfer efficacy in a serotype-specific manner, and PKD2 sequence differences between human and mouse AAVR govern species tropism of engineered capsids [#10, #12]. Independent of its viral-receptor role, mouse knockout links Kiaa0319L to auditory brainstem function rather than to cortical neuronal migration [#8].\"\n,\n  \"teleology\": [\n    {\n      \"year\": 2017,\n      \"claim\": \"Established whether KIAA0319L contributes to neurodevelopment as had been hypothesized, distinguishing a neuronal-migration role from an auditory one.\",\n      \"evidence\": \"Knockout mouse cortical histology, auditory brainstem response recordings, and gap-in-noise behavior\",\n      \"pmids\": [\"29045729\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Molecular mechanism underlying the auditory deficit not defined\", \"No link drawn to AAVR's receptor or trafficking activities\", \"Single lab; effect partly emerges only in double KO with Kiaa0319\"]\n    },\n    {\n      \"year\": 2019,\n      \"claim\": \"Resolved the atomic basis of AAV-receptor engagement, showing the PKD2 domain binds the AAV2 capsid spike and that interface residues are required for infectivity.\",\n      \"evidence\": \"Cryo-EM at 2.8 Å with site-directed mutagenesis and infectivity assays; independently replicated by cryo-ET/cryo-EM/XL-MS at 2.4 Å\",\n      \"pmids\": [\"30742069\", \"31115336\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Did not address serotypes engaging a different PKD domain\", \"Post-binding internalization and trafficking steps not resolved structurally\"]\n    },\n    {\n      \"year\": 2019,\n      \"claim\": \"Demonstrated that AAVR expression and basolateral localization control AAV2 entry in a physiological epithelium and that AAVR-independent entry routes exist.\",\n      \"evidence\": \"Immunocytochemistry, anti-AAVR antibody blockade, and CRISPR knockout with transduction assays in polarized airway epithelia\",\n      \"pmids\": [\"30962536\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Molecular basis of AAVR-independent AAV2.5T entry not identified\", \"Mechanism of basolateral targeting unknown\"]\n    },\n    {\n      \"year\": 2019,\n      \"claim\": \"Defined divergent receptor-engagement rules, revealing PKD1 as the exclusive binding domain for AAV5 versus PKD2 for AAV1/AAV2.\",\n      \"evidence\": \"Cryo-EM structures of AAV1-AAVR and AAV5-AAVR complexes\",\n      \"pmids\": [\"31434885\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Functional consequence of two-site binding for trafficking not addressed\", \"Did not establish why some serotypes select PKD1 over PKD2\"]\n    },\n    {\n      \"year\": 2020,\n      \"claim\": \"Confirmed AAV5's exclusive PKD1 engagement at high resolution and mapped overlap with neutralizing-antibody epitopes.\",\n      \"evidence\": \"Cryo-EM at 2.5 Å with molecular modeling of antibody footprints\",\n      \"pmids\": [\"33218165\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Affinity and stoichiometry of PKD1 binding not quantified\", \"Trafficking fate after PKD1 binding not addressed\"]\n    },\n    {\n      \"year\": 2022,\n      \"claim\": \"Showed the PKD1-binding mode generalizes beyond AAV5 to a wider capsid class and quantified differential receptor affinity.\",\n      \"evidence\": \"Cryo-EM of goat AAVGo.1-AAVR PKD12 complex at 2.4 Å plus ELISA binding comparison\",\n      \"pmids\": [\"36453885\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Relationship between higher binding affinity and transduction outcome not tested\", \"Biological host range of AAVGo.1 via human AAVR unexplored\"]\n    },\n    {\n      \"year\": 2023,\n      \"claim\": \"Provided biophysical evidence that AAVR affinity is serotype-specific and pH-dependent, supporting a trafficking role beyond surface attachment.\",\n      \"evidence\": \"BLI, SEC-MALS, and SV-AUC binding measurements under varying pH\",\n      \"pmids\": [\"37441888\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Direct demonstration of pH-driven Golgi trafficking not provided here\", \"Single lab; cellular relevance of in vitro pH dependence not validated\"]\n    },\n    {\n      \"year\": 2025,\n      \"claim\": \"Established AAVR as a determinant of AAV transduction in sensory hair cells in vivo, linking receptor abundance to gene-therapy-relevant cell targeting.\",\n      \"evidence\": \"Immunocytochemistry, antibody blockade, AAVR knockout mice, and conditional overexpression with transduction assays in vivo and ex vivo\",\n      \"pmids\": [\"39776318\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Trafficking mechanism in hair cells not dissected\", \"Cause of developmental decline in AAVR expression unknown\"]\n    },\n    {\n      \"year\": 2025,\n      \"claim\": \"Defined the intracellular itinerary by showing AAVR's cytosolic tail recruits the SNX3-retromer to route AAV via retrograde trafficking to the TGN without endosomal rupture.\",\n      \"evidence\": \"In vitro SNX3-retromer tubulation reconstitution, AAVR-KO cell trafficking imaging, Galectin-8 recruitment, and VP1u/PLA2-mutant capsid analysis (preprint)\",\n      \"pmids\": [\"bio_10.1101_2025.11.22.689972\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Preprint not yet peer-reviewed\", \"Post-TGN steps requiring VP1u not mechanistically resolved\", \"Whether the same route applies to PKD1-engaging serotypes untested\"]\n    },\n    {\n      \"year\": 2025,\n      \"claim\": \"Identified the PKD2 sequence determinants of species tropism, with human-versus-mouse residue differences controlling engineered-capsid transduction.\",\n      \"evidence\": \"Human/mouse PKD2 domain swaps and human AAVR complementation with in vitro and in vivo transduction (preprint)\",\n      \"pmids\": [\"41377965\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Preprint; single lab\", \"Structural basis of the I426V effect not resolved\"]\n    },\n    {\n      \"year\": 2025,\n      \"claim\": \"Demonstrated that engineering capsid motifs to weaken AAVR binding rationally de-targets the liver, validating AAVR affinity as a tropism-tuning lever.\",\n      \"evidence\": \"Cryo-EM of CAP-B10-AAVR PKD2 complexes with affinity measurements and in vivo transduction (preprint)\",\n      \"pmids\": [\"bio_10.1101_2025.06.02.655683\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Preprint; not peer-reviewed\", \"Off-target effects of reduced AAVR binding on other tissues not fully mapped\"]\n    },\n    {\n      \"year\": 2026,\n      \"claim\": \"Systematically linked human KIAA0319L coding variants to serotype-specific changes in AAV transduction, including loss-of-function and gain-of-function alleles affecting trafficking.\",\n      \"evidence\": \"Transfection of AAVR variant constructs in AAVR-null cells with serotype-specific transduction, expression, binding, and nuclear trafficking assays\",\n      \"pmids\": [\"42137583\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Population frequency and clinical impact of variants not assessed\", \"Mechanism by which Ser1031Phe enhances nuclear trafficking only partly defined\"]\n    },\n    {\n      \"year\": null,\n      \"claim\": \"How AAVR's distinct PKD1- versus PKD2-engagement modes feed into a common or divergent retrograde trafficking pathway, and what its endogenous (non-viral) cellular ligand or function is, remain unresolved.\",\n      \"evidence\": \"\",\n      \"pmids\": [],\n      \"confidence\": \"Low\",\n      \"gaps\": [\"No endogenous ligand or native physiological function of AAVR identified\", \"Whether PKD1-binding serotypes use the SNX3-retromer route is untested\", \"Connection between auditory brainstem phenotype and AAVR's molecular activity unknown\"]\n    }\n  ],\n  \"mechanism_profile\": {\n    \"molecular_activity\": [\n      {\"term_id\": \"GO:0001618\", \"supporting_discovery_ids\": [0, 2, 5, 7]},\n      {\"term_id\": \"GO:0060089\", \"supporting_discovery_ids\": [0, 2]}\n    ],\n    \"localization\": [\n      {\"term_id\": \"GO:0005886\", \"supporting_discovery_ids\": [5]},\n      {\"term_id\": \"GO:0005794\", \"supporting_discovery_ids\": [11, 6]},\n      {\"term_id\": \"GO:0005768\", \"supporting_discovery_ids\": [11]}\n    ],\n    \"pathway\": [\n      {\"term_id\": \"R-HSA-5653656\", \"supporting_discovery_ids\": [11]},\n      {\"term_id\": \"R-HSA-9609507\", \"supporting_discovery_ids\": [11]}\n    ],\n    \"complexes\": [\"SNX3-retromer\"],\n    \"partners\": [\"SNX3\"],\n    \"other_free_text\": []\n  }\n}","audit_flag":null,"evaluation":{"pairwise":"win","faith_supported":6,"faith_total":6,"faith_pct":100.0}}