{"gene":"DNAAF4","run_date":"2026-06-09T23:54:42","timeline":{"discoveries":[{"year":2013,"finding":"DYX1C1/DNAAF4 localizes to the cytoplasm of respiratory epithelial cells and its interactome is enriched for molecular chaperones; it physically interacts with the cytoplasmic ODA and IDA assembly factor DNAAF2 (KTU), establishing it as a dynein axonemal assembly factor required for outer and inner dynein arm assembly in motile cilia.","method":"Immunofluorescence, co-immunoprecipitation, mouse knockout (exon 2-4 deletion and ENU c.T2A start-codon mutation), zebrafish morpholino knockdown, human loss-of-function mutations, ultrastructural (electron microscopy) analysis of cilia","journal":"Nature genetics","confidence":"High","confidence_rationale":"Tier 2 / Strong — multiple orthogonal methods (Co-IP, IF, genetic knockouts in two mouse alleles, zebrafish morpholino, human patient mutations) across multiple organisms, replicated independently","pmids":["23872636"],"is_preprint":false},{"year":2006,"finding":"The C-terminal TPR domains of DYX1C1 determine its intracellular localization to cytoplasm and nucleus, and this C-terminal region is necessary and sufficient for DYX1C1's function in neuronal migration in the developing rat neocortex.","method":"In utero RNAi (shRNA), overexpression of C- and N-terminal truncation constructs, RNAi rescue experiments in rat neocortex","journal":"Neuroscience","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — domain deletion analysis with rescue experiments in vivo, single lab with two orthogonal approaches (localization and functional rescue)","pmids":["16989952"],"is_preprint":false},{"year":2009,"finding":"DYX1C1 physically interacts with both estrogen receptor alpha (ERα) and estrogen receptor beta (ERβ) in the presence of 17β-estradiol, and overexpression of DYX1C1 reduces protein levels of ERα and ERβ, resulting in decreased transcriptional responses to 17β-estradiol.","method":"Co-immunoprecipitation, co-localization, proximity ligation assay, overexpression studies in cell lines and primary rat hippocampal neurons","journal":"Human molecular genetics","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — reciprocal Co-IP plus proximity ligation assay and functional transcriptional readout, single lab with multiple orthogonal methods","pmids":["19423554"],"is_preprint":false},{"year":2009,"finding":"DYX1C1 functions as a co-chaperone that interacts with both Hsp70 and Hsp90 via its C-terminal EEVD residues, as demonstrated by GST pull-down and yeast two-hybrid assays.","method":"GST pull-down, yeast two-hybrid system, site-directed mutagenesis","journal":"Journal of cancer research and clinical oncology","confidence":"Medium","confidence_rationale":"Tier 1–2 / Moderate — GST pull-down and yeast two-hybrid with mutagenesis identifying the EEVD motif, single lab with two orthogonal binding methods","pmids":["19277710"],"is_preprint":false},{"year":2008,"finding":"A complex of TFII-I, PARP1, and SFPQ proteins binds the DYX1C1 promoter at the rs3743205 SNP and regulates DYX1C1 transcription; allelic differences at rs16787 and rs3743205 affect factor binding and promoter activity.","method":"Electrophoretic mobility shift assay (EMSA), affinity purification followed by mass spectrometry and protein sequencing, luciferase reporter assays, competition assays","journal":"FASEB journal","confidence":"Medium","confidence_rationale":"Tier 1–2 / Moderate — EMSA, mass spectrometry identification of complex components, and functional luciferase assay, single lab with multiple orthogonal methods","pmids":["18445785"],"is_preprint":false},{"year":2013,"finding":"Zebrafish dyx1c1 knockdown causes loss of both outer and inner dynein arms in cilia (as shown by electron microscopy) and reduces cilia length in multiple organs, establishing DYX1C1 as essential for cilia growth and dynein arm assembly in vivo.","method":"Morpholino knockdown in zebrafish, transmission electron microscopy, in situ hybridization, quantitative real-time PCR","journal":"PloS one","confidence":"High","confidence_rationale":"Tier 2 / Strong — morpholino knockdown with ultrastructural EM validation of ODA/IDA loss across multiple organs, independently corroborates findings in PMID:23872636","pmids":["23650548"],"is_preprint":false},{"year":2017,"finding":"In Chlamydomonas, DYX1C1/PF23 is required for preassembly of cytoplasmic dynein complexes (particularly inner dynein arms and a fraction of outer dynein arms); pf23 mutants lacking most IDAs show reduced preassembled dynein in cytoplasmic sucrose gradients, and a C-terminal truncation of DYX1C1 reduces a subset of ciliary IDAs, suggesting DYX1C1 provides a scaffold for macromolecular dynein assembly.","method":"Cryo-electron tomography (cryo-ET), spectral counting, sucrose gradient fractionation of cytoplasmic extracts, C-terminal truncation analysis","journal":"PLoS genetics","confidence":"High","confidence_rationale":"Tier 1 / Moderate — cryo-ET structural analysis combined with biochemical sucrose gradients and domain truncation mutants in a genetically defined mutant, single lab but multiple rigorous orthogonal methods","pmids":["28892495"],"is_preprint":false},{"year":2012,"finding":"DYX1C1 regulates cell migration of a human neuroblastoma cell line in a manner dependent on both its tetratricopeptide repeat (TPR) domain and a newly identified DYX1 domain; it also associates with cytoskeletal proteins and modulates expression of neuronal migration genes including RELN.","method":"Live cell imaging, gene expression profiling, protein interaction profiling, domain deletion constructs","journal":"Biological psychiatry","confidence":"Medium","confidence_rationale":"Tier 2–3 / Moderate — live-cell imaging with domain-specific constructs plus protein interaction and gene expression profiling, single lab with multiple approaches","pmids":["23036959"],"is_preprint":false},{"year":2012,"finding":"ERβ (not ERα) binds to a cis-regulatory region upstream of the DYX1C1 transcriptional start site and enhances DYX1C1 expression in response to 17β-estradiol; this regulation requires TFII-I and liganded ERβ, and the dyslexia-associated SNP rs3743205 in this region can alter epigenetic and endocrine regulation of DYX1C1.","method":"Reporter gene assays, chromatin immunoprecipitation (ChIP), expression analysis in neuroblastoma cell line","journal":"Molecular endocrinology","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — ChIP and reporter assays with specific receptor knockdown, single lab with multiple orthogonal methods","pmids":["22383464"],"is_preprint":false},{"year":2016,"finding":"RFX transcription factors (RFX1, RFX2, RFX3) bind conserved X-box motifs in the DYX1C1 promoter and significantly regulate endogenous DYX1C1 expression; endogenous DYX1C1 protein localizes to the base of the cilium (not along the axoneme).","method":"Reporter gene assays, electrophoretic mobility shift assay (EMSA), immunofluorescence of endogenous protein, RFX transcription factor overexpression in hTERT-RPE1 cells","journal":"FASEB journal","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — EMSA plus reporter assay and endogenous protein localization by IF, single lab with multiple orthogonal approaches","pmids":["27451412"],"is_preprint":false},{"year":2022,"finding":"DNAAF4 (DYX1C1) and DNAAF6 (PIH1D3) form an R2TP-like co-chaperone complex in Drosophila; flies lacking Dnaaf4 or Dnaaf6 lack motile sperm and have impaired chordotonal neuron function, with loss of outer dynein arms and a subset of inner dynein arms, demonstrating a conserved role in dynein assembly despite Drosophila Dnaaf4 lacking the TPR domain.","method":"Drosophila genetic knockouts, protein co-association assays, immunofluorescence, electron microscopy, behavioral/functional assays of mechanosensory neurons and sperm motility","journal":"Frontiers in genetics","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — genetic knockout with multiple functional readouts and protein interaction evidence, single lab","pmids":["35873488"],"is_preprint":false},{"year":2022,"finding":"A missense DNAAF4 variant (p.G373E) reduces stability of the DNAAF4 protein but does not affect its expression or interaction with downstream DNAAF2 protein, causing PCD by destabilizing DNAAF4 rather than abolishing its binding to DNAAF2.","method":"Whole-exome sequencing, plasmid transfection, co-immunoprecipitation, immunofluorescence, transmission electron microscopy","journal":"Frontiers in genetics","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — Co-IP with mutagenesis confirming protein stability effects vs interaction, single lab","pmids":["36583018"],"is_preprint":false},{"year":2023,"finding":"DYX1C1 (DNAAF4) physically interacts with DCDC2 and both proteins independently interact with the centrosomal protein CPAP (CENPJ); dyx1c1 and dcdc2b show synergistic genetic interaction in zebrafish exacerbating the ciliary phenotype, and they mutually affect each other's transcriptional regulation.","method":"Co-immunoprecipitation of exogenous and endogenous proteins, zebrafish double-knockdown epistasis, transcriptional regulation assays, brain organoid cell models","journal":"BMC molecular and cell biology","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — reciprocal Co-IP plus genetic epistasis in zebrafish with multiple cell models including brain organoids, single lab","pmids":["37237337"],"is_preprint":false}],"current_model":"DNAAF4 (DYX1C1) is a cytoplasmic dynein axonemal assembly factor that localizes to the base of motile cilia and functions as a co-chaperone scaffold—interacting with Hsp70/Hsp90 via its C-terminal EEVD motif and with DNAAF2 (KTU)—to preassemble outer and inner dynein arm complexes before their transport into the ciliary axoneme; its TPR domain governs subcellular localization and chaperone recruitment, its DYX1 domain contributes to cell migration, and it is also regulated transcriptionally by RFX factors and ERβ/TFII-I at X-box and estrogen-responsive promoter elements."},"narrative":{"mechanistic_narrative":"DNAAF4 (DYX1C1) is a cytoplasmic dynein axonemal assembly factor that preassembles outer and inner dynein arm (ODA/IDA) complexes required for motile cilia, with its loss causing primary ciliary dyskinesia in humans [PMID:23872636]. It localizes to the base of the cilium rather than along the axoneme [PMID:27451412] and functions as a co-chaperone scaffold: it engages Hsp70 and Hsp90 through a C-terminal EEVD motif [PMID:19277710] and physically partners with the dynein assembly factor DNAAF2/KTU [PMID:23872636], so that cytoplasmic dynein complexes are matured before transport into the axoneme. Cross-species genetics establish this role as conserved and essential—zebrafish knockdown abolishes both ODAs and IDAs and shortens cilia [PMID:23650548], the Chlamydomonas ortholog PF23 is needed for cytoplasmic preassembly of dynein with its C-terminus governing a subset of IDAs [PMID:28892495], and in Drosophila DNAAF4 acts with DNAAF6/PIH1D3 in an R2TP-like co-chaperone complex for sperm and chordotonal-neuron dynein assembly [PMID:35873488]. The C-terminal TPR domains direct subcellular localization and chaperone recruitment, while a separate DYX1 domain and TPR contribute to neuronal cell migration [PMID:16989952, PMID:23036959]. DNAAF4 also interacts with DCDC2, both proteins binding the centrosomal protein CPAP/CENPJ and acting synergistically in ciliogenesis [PMID:37237337]. Its transcription is controlled by RFX factors at X-box promoter motifs [PMID:27451412] and by liganded ERβ together with a TFII-I/PARP1/SFPQ complex at estrogen-responsive and SNP-containing promoter elements [PMID:19423554, PMID:18445785, PMID:22383464].","teleology":[{"year":2006,"claim":"Established that the C-terminal TPR region dictates DYX1C1 localization and is necessary and sufficient for its function, defining a structure-function map before the protein's molecular role was known.","evidence":"In utero RNAi with truncation constructs and rescue in rat neocortex","pmids":["16989952"],"confidence":"Medium","gaps":["Molecular partners recruited by the TPR domain not identified here","Neuronal migration role not connected to ciliary function","No biochemical activity assigned"]},{"year":2008,"claim":"Identified the transcriptional control of DYX1C1, showing a TFII-I/PARP1/SFPQ complex binds the promoter at disease-associated SNPs and modulates expression.","evidence":"EMSA, affinity-purification mass spectrometry, and luciferase reporter assays","pmids":["18445785"],"confidence":"Medium","gaps":["Physiological signals driving this regulation unclear","Connection to DNAAF4 protein function not addressed"]},{"year":2009,"claim":"Defined DYX1C1 biochemically as an Hsp70/Hsp90 co-chaperone via a C-terminal EEVD motif, providing the molecular basis for its later scaffold role.","evidence":"GST pull-down and yeast two-hybrid with site-directed mutagenesis","pmids":["19277710"],"confidence":"Medium","gaps":["Client proteins of the chaperone complex not identified","Not linked to dynein assembly at this stage"]},{"year":2009,"claim":"Showed DYX1C1 interacts with estrogen receptors and downregulates their levels, implicating it in steroid-hormone signaling beyond its ciliary role.","evidence":"Reciprocal Co-IP, proximity ligation assay, and transcriptional readout in cell lines and rat neurons","pmids":["19423554"],"confidence":"Medium","gaps":["Mechanism of ER destabilization unknown","Relevance to motile cilia unclear"]},{"year":2012,"claim":"Mapped DYX1C1 cell-migration activity to its TPR and a newly defined DYX1 domain and linked it to cytoskeletal proteins and migration-gene expression.","evidence":"Live-cell imaging, domain-deletion constructs, and interaction/expression profiling in neuroblastoma cells","pmids":["23036959"],"confidence":"Medium","gaps":["DYX1 domain biochemical activity undefined","Direct cytoskeletal binding partners not resolved"]},{"year":2012,"claim":"Refined the hormonal regulation of DYX1C1, showing liganded ERβ (not ERα) and TFII-I enhance expression at a SNP-containing cis-element.","evidence":"ChIP, reporter assays, and receptor knockdown in neuroblastoma cells","pmids":["22383464"],"confidence":"Medium","gaps":["In vivo relevance of estrogen regulation untested","Epigenetic mechanism at the SNP not detailed"]},{"year":2013,"claim":"Established DNAAF4 as a cytoplasmic dynein axonemal assembly factor required for ODA/IDA assembly, connecting it to the chaperone machinery via DNAAF2 and to human disease.","evidence":"IF, Co-IP, two mouse knockout alleles, zebrafish morpholino, human LOF mutations, and ciliary EM","pmids":["23872636"],"confidence":"High","gaps":["Precise assembly step catalyzed not resolved","Full client repertoire of the chaperone complex unknown"]},{"year":2013,"claim":"Independently confirmed in zebrafish that DNAAF4 loss removes both dynein arms and shortens cilia, demonstrating an essential in vivo role in ciliogenesis.","evidence":"Morpholino knockdown with transmission EM across multiple organs","pmids":["23650548"],"confidence":"High","gaps":["Does not distinguish assembly from transport defects","Morpholino specificity caveats"]},{"year":2016,"claim":"Placed DNAAF4 transcriptionally within the ciliogenic program by showing RFX factors drive its expression, and localized endogenous protein to the ciliary base.","evidence":"Reporter assays, EMSA, RFX overexpression, and endogenous IF in hTERT-RPE1 cells","pmids":["27451412"],"confidence":"Medium","gaps":["Functional consequence of basal localization not dissected","Interplay between RFX and estrogen regulation unclear"]},{"year":2017,"claim":"Demonstrated that the ortholog acts in cytoplasmic preassembly of dynein, with the C-terminus governing a subset of IDAs, supporting a scaffold model for macromolecular dynein assembly.","evidence":"Cryo-ET, sucrose-gradient fractionation, and C-terminal truncation in Chlamydomonas pf23 mutants","pmids":["28892495"],"confidence":"High","gaps":["Atomic structure of the scaffold complex absent","Which dynein subunits directly contact DNAAF4 unknown"]},{"year":2022,"claim":"Showed DNAAF4 partners with DNAAF6/PIH1D3 in a conserved R2TP-like co-chaperone complex for dynein assembly, with conservation despite loss of the TPR domain in flies.","evidence":"Drosophila knockouts, co-association assays, EM, and sperm/neuron functional assays","pmids":["35873488"],"confidence":"Medium","gaps":["Stoichiometry and architecture of the R2TP-like complex undefined","TPR-independent recruitment mechanism unclear"]},{"year":2022,"claim":"Resolved a disease mechanism, showing a missense variant destabilizes DNAAF4 protein without disrupting DNAAF2 binding, separating stability from interaction defects in PCD.","evidence":"Whole-exome sequencing, transfection, Co-IP, IF, and EM","pmids":["36583018"],"confidence":"Medium","gaps":["Generalizability to other PCD variants untested","Degradation pathway of the unstable protein not identified"]},{"year":2023,"claim":"Connected DNAAF4 to a wider ciliary network by showing it and DCDC2 interact and both bind the centrosomal protein CPAP, acting synergistically in ciliogenesis.","evidence":"Reciprocal Co-IP, zebrafish double-knockdown epistasis, and brain organoid models","pmids":["37237337"],"confidence":"Medium","gaps":["Functional meaning of CPAP binding unresolved","Whether DCDC2 acts in dynein assembly unknown"]},{"year":null,"claim":"How DNAAF4's co-chaperone scaffold selects and folds specific dynein subunits, and how its ciliary, migration, and hormonal roles are mechanistically related, remains unresolved.","evidence":"","pmids":[],"confidence":"Medium","gaps":["No high-resolution structure of the DNAAF4-chaperone-dynein assembly intermediate","Direct dynein clients of DNAAF4 not enumerated","Relationship between TPR-dependent localization and substrate handoff unknown"]}],"mechanism_profile":{"molecular_activity":[{"term_id":"GO:0044183","term_label":"protein folding chaperone","supporting_discovery_ids":[0,3,6,10]},{"term_id":"GO:0140096","term_label":"catalytic activity, acting on a protein","supporting_discovery_ids":[0,3]}],"localization":[{"term_id":"GO:0005929","term_label":"cilium","supporting_discovery_ids":[9]},{"term_id":"GO:0005829","term_label":"cytosol","supporting_discovery_ids":[0,1]},{"term_id":"GO:0005634","term_label":"nucleus","supporting_discovery_ids":[1]},{"term_id":"GO:0005815","term_label":"microtubule organizing center","supporting_discovery_ids":[12]}],"pathway":[{"term_id":"R-HSA-1852241","term_label":"Organelle biogenesis and maintenance","supporting_discovery_ids":[0,5,6]},{"term_id":"R-HSA-392499","term_label":"Metabolism of proteins","supporting_discovery_ids":[0,3]}],"complexes":["R2TP-like co-chaperone complex (DNAAF4-DNAAF6/PIH1D3)"],"partners":["DNAAF2","HSPA8","HSP90","DNAAF6","DCDC2","CENPJ","ESR1","ESR2"],"other_free_text":[]}},"prefetch_data":{"uniprot":{"accession":"Q8WXU2","full_name":"Dynein axonemal assembly factor 4","aliases":["Dyslexia susceptibility 1 candidate gene 1 protein"],"length_aa":420,"mass_kda":48.5,"function":"Axonemal dynein assembly factor required for ciliary motility. Involved in neuronal migration during development of the cerebral neocortex. May regulate the stability and proteasomal degradation of the estrogen receptors that play an important role in neuronal differentiation, survival and plasticity","subcellular_location":"Nucleus; Cytoplasm; Dynein axonemal particle; Cell projection, neuron projection","url":"https://www.uniprot.org/uniprotkb/Q8WXU2/entry"},"depmap":{"release":"DepMap","has_data":true,"is_common_essential":false,"resolved_as":"","url":"https://depmap.org/portal/gene/DNAAF4","classification":"Not Classified","n_dependent_lines":0,"n_total_lines":1208,"dependency_fraction":0.0},"opencell":{"profiled":false,"resolved_as":"","ensg_id":"","cell_line_id":"","localizations":[],"interactors":[],"url":"https://opencell.sf.czbiohub.org/search/DNAAF4","total_profiled":1310},"omim":[{"mim_id":"615482","title":"CILIARY DYSKINESIA, PRIMARY, 25; CILD25","url":"https://www.omim.org/entry/615482"},{"mim_id":"608706","title":"DYNEIN, AXONEMAL, ASSEMBLY FACTOR 4; DNAAF4","url":"https://www.omim.org/entry/608706"},{"mim_id":"300933","title":"DYNEIN, AXONEMAL, ASSEMBLY FACTOR 6; DNAAF6","url":"https://www.omim.org/entry/300933"},{"mim_id":"127700","title":"DYSLEXIA, SUSCEPTIBILITY TO, 1; DYX1","url":"https://www.omim.org/entry/127700"}],"hpa":{"profiled":true,"resolved_as":"","reliability":"Supported","locations":[{"location":"Cytosol","reliability":"Supported"},{"location":"Mid piece","reliability":"Supported"},{"location":"Plasma membrane","reliability":"Additional"},{"location":"Connecting piece","reliability":"Additional"},{"location":"Principal piece","reliability":"Additional"}],"tissue_specificity":"Tissue enhanced","tissue_distribution":"Detected in many","driving_tissues":[{"tissue":"retina","ntpm":27.4}],"url":"https://www.proteinatlas.org/search/DNAAF4"},"hgnc":{"alias_symbol":["EKN1","FLJ37882","CILD25","pf23"],"prev_symbol":["DYX1C1"]},"alphafold":{"accession":"Q8WXU2","domains":[{"cath_id":"2.60.40.790","chopping":"4-92","consensus_level":"high","plddt":89.4597,"start":4,"end":92},{"cath_id":"1.25.40.10","chopping":"289-415","consensus_level":"high","plddt":93.509,"start":289,"end":415},{"cath_id":"1.20.5","chopping":"116-193","consensus_level":"medium","plddt":90.571,"start":116,"end":193}],"viewer_url":"https://alphafold.ebi.ac.uk/entry/Q8WXU2","model_url":"https://alphafold.ebi.ac.uk/files/AF-Q8WXU2-F1-model_v6.cif","pae_url":"https://alphafold.ebi.ac.uk/files/AF-Q8WXU2-F1-predicted_aligned_error_v6.png","plddt_mean":83.88},"mouse_models":{"mgi_url":"https://www.informatics.jax.org/marker/summary?nomen=DNAAF4","jax_strain_url":"https://www.jax.org/strain/search?query=DNAAF4"},"sequence":{"accession":"Q8WXU2","fasta_url":"https://rest.uniprot.org/uniprotkb/Q8WXU2.fasta","uniprot_url":"https://www.uniprot.org/uniprotkb/Q8WXU2/entry","alphafold_viewer_url":"https://alphafold.ebi.ac.uk/entry/Q8WXU2"}},"corpus_meta":[{"pmid":"23872636","id":"PMC_23872636","title":"DYX1C1 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Part B, Neuropsychiatric genetics : the official publication of the International Society of Psychiatric Genetics","url":"https://pubmed.ncbi.nlm.nih.gov/23341075","citation_count":15,"is_preprint":false},{"pmid":"25989970","id":"PMC_25989970","title":"Deficits in learning and memory in mice with a mutation of the candidate dyslexia susceptibility gene Dyx1c1.","date":"2015","source":"Brain and language","url":"https://pubmed.ncbi.nlm.nih.gov/25989970","citation_count":15,"is_preprint":false},{"pmid":"18618141","id":"PMC_18618141","title":"Molecular characterization of the DYX1C1 gene and its application as a cancer biomarker.","date":"2008","source":"Journal of cancer research and clinical oncology","url":"https://pubmed.ncbi.nlm.nih.gov/18618141","citation_count":14,"is_preprint":false},{"pmid":"15470369","id":"PMC_15470369","title":"Family-based association study of DYX1C1 variants in autism.","date":"2005","source":"European journal of human genetics : EJHG","url":"https://pubmed.ncbi.nlm.nih.gov/15470369","citation_count":12,"is_preprint":false},{"pmid":"20300304","id":"PMC_20300304","title":"Allelic variants of DYX1C1 are not associated with dyslexia in India.","date":"2008","source":"Indian journal of human genetics","url":"https://pubmed.ncbi.nlm.nih.gov/20300304","citation_count":10,"is_preprint":false},{"pmid":"29201552","id":"PMC_29201552","title":"ATP2C2 and DYX1C1 are putative modulators of dyslexia-related MMR.","date":"2017","source":"Brain and behavior","url":"https://pubmed.ncbi.nlm.nih.gov/29201552","citation_count":9,"is_preprint":false},{"pmid":"35903363","id":"PMC_35903363","title":"Case Report: DNAAF4 Variants Cause Primary Ciliary Dyskinesia and Infertility in Two Han Chinese Families.","date":"2022","source":"Frontiers in genetics","url":"https://pubmed.ncbi.nlm.nih.gov/35903363","citation_count":8,"is_preprint":false},{"pmid":"35873488","id":"PMC_35873488","title":"Strongly Truncated Dnaaf4 Plays a Conserved Role in Drosophila Ciliary Dynein Assembly as Part of an R2TP-Like Co-Chaperone Complex With Dnaaf6.","date":"2022","source":"Frontiers in genetics","url":"https://pubmed.ncbi.nlm.nih.gov/35873488","citation_count":6,"is_preprint":false},{"pmid":"37237337","id":"PMC_37237337","title":"Genetic and protein interaction studies between the ciliary dyslexia candidate genes DYX1C1 and DCDC2.","date":"2023","source":"BMC molecular and cell biology","url":"https://pubmed.ncbi.nlm.nih.gov/37237337","citation_count":4,"is_preprint":false},{"pmid":"38610086","id":"PMC_38610086","title":"Developmental dyslexia susceptibility genes DNAAF4, DCDC2, and NRSN1 are associated with brain function in fluently reading adolescents and young adults.","date":"2024","source":"Cerebral cortex (New York, N.Y. : 1991)","url":"https://pubmed.ncbi.nlm.nih.gov/38610086","citation_count":4,"is_preprint":false},{"pmid":"37147940","id":"PMC_37147940","title":"Identification of a novel splice site mutation in the DNAAF4 gene of a Chinese patient with primary ciliary dyskinesia.","date":"2023","source":"Asian journal of andrology","url":"https://pubmed.ncbi.nlm.nih.gov/37147940","citation_count":4,"is_preprint":false},{"pmid":"36583018","id":"PMC_36583018","title":"Homozygous mutation in DNAAF4 causes primary ciliary dyskinesia in a Chinese family.","date":"2022","source":"Frontiers in genetics","url":"https://pubmed.ncbi.nlm.nih.gov/36583018","citation_count":3,"is_preprint":false},{"pmid":"39542997","id":"PMC_39542997","title":"Investigation of Association Between Expression of DYX1C1, KIAA0319, and ROBO1 Genes and Specific Learning Disorder in Children and Adolescents.","date":"2024","source":"Journal of molecular neuroscience : MN","url":"https://pubmed.ncbi.nlm.nih.gov/39542997","citation_count":3,"is_preprint":false},{"pmid":"22214596","id":"PMC_22214596","title":"Evolutionary diversification of DYX1C1 transcripts via an HERV-H LTR integration event.","date":"2011","source":"Genes & genetic 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Switzerland)","url":"https://pubmed.ncbi.nlm.nih.gov/37998638","citation_count":0,"is_preprint":false}],"cost":{"stage1":{"model":"claude-sonnet-4-6","input_tokens":21120,"output_tokens":3273,"usd":0.056227,"stage1_stop_reason":"end_turn"},"stage2":{"model":"claude-opus-4-8","input_tokens":10795,"output_tokens":3951,"usd":0.076375,"stage2_stop_reason":"end_turn"},"total_usd":0.132602,"stage1_batch_id":"msgbatch_01AsR7g8dGTEiEw9U83bJeWn","stage2_batch_id":"msgbatch_01YV5ZyxtFNUZEjxRcpd9jzb","note":"batch pricing = 50% of standard"},"stage1_raw":"```json\n{\n  \"discoveries\": [\n    {\n      \"year\": 2013,\n      \"finding\": \"DYX1C1/DNAAF4 localizes to the cytoplasm of respiratory epithelial cells and its interactome is enriched for molecular chaperones; it physically interacts with the cytoplasmic ODA and IDA assembly factor DNAAF2 (KTU), establishing it as a dynein axonemal assembly factor required for outer and inner dynein arm assembly in motile cilia.\",\n      \"method\": \"Immunofluorescence, co-immunoprecipitation, mouse knockout (exon 2-4 deletion and ENU c.T2A start-codon mutation), zebrafish morpholino knockdown, human loss-of-function mutations, ultrastructural (electron microscopy) analysis of cilia\",\n      \"journal\": \"Nature genetics\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — multiple orthogonal methods (Co-IP, IF, genetic knockouts in two mouse alleles, zebrafish morpholino, human patient mutations) across multiple organisms, replicated independently\",\n      \"pmids\": [\"23872636\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2006,\n      \"finding\": \"The C-terminal TPR domains of DYX1C1 determine its intracellular localization to cytoplasm and nucleus, and this C-terminal region is necessary and sufficient for DYX1C1's function in neuronal migration in the developing rat neocortex.\",\n      \"method\": \"In utero RNAi (shRNA), overexpression of C- and N-terminal truncation constructs, RNAi rescue experiments in rat neocortex\",\n      \"journal\": \"Neuroscience\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — domain deletion analysis with rescue experiments in vivo, single lab with two orthogonal approaches (localization and functional rescue)\",\n      \"pmids\": [\"16989952\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2009,\n      \"finding\": \"DYX1C1 physically interacts with both estrogen receptor alpha (ERα) and estrogen receptor beta (ERβ) in the presence of 17β-estradiol, and overexpression of DYX1C1 reduces protein levels of ERα and ERβ, resulting in decreased transcriptional responses to 17β-estradiol.\",\n      \"method\": \"Co-immunoprecipitation, co-localization, proximity ligation assay, overexpression studies in cell lines and primary rat hippocampal neurons\",\n      \"journal\": \"Human molecular genetics\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — reciprocal Co-IP plus proximity ligation assay and functional transcriptional readout, single lab with multiple orthogonal methods\",\n      \"pmids\": [\"19423554\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2009,\n      \"finding\": \"DYX1C1 functions as a co-chaperone that interacts with both Hsp70 and Hsp90 via its C-terminal EEVD residues, as demonstrated by GST pull-down and yeast two-hybrid assays.\",\n      \"method\": \"GST pull-down, yeast two-hybrid system, site-directed mutagenesis\",\n      \"journal\": \"Journal of cancer research and clinical oncology\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 1–2 / Moderate — GST pull-down and yeast two-hybrid with mutagenesis identifying the EEVD motif, single lab with two orthogonal binding methods\",\n      \"pmids\": [\"19277710\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2008,\n      \"finding\": \"A complex of TFII-I, PARP1, and SFPQ proteins binds the DYX1C1 promoter at the rs3743205 SNP and regulates DYX1C1 transcription; allelic differences at rs16787 and rs3743205 affect factor binding and promoter activity.\",\n      \"method\": \"Electrophoretic mobility shift assay (EMSA), affinity purification followed by mass spectrometry and protein sequencing, luciferase reporter assays, competition assays\",\n      \"journal\": \"FASEB journal\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 1–2 / Moderate — EMSA, mass spectrometry identification of complex components, and functional luciferase assay, single lab with multiple orthogonal methods\",\n      \"pmids\": [\"18445785\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2013,\n      \"finding\": \"Zebrafish dyx1c1 knockdown causes loss of both outer and inner dynein arms in cilia (as shown by electron microscopy) and reduces cilia length in multiple organs, establishing DYX1C1 as essential for cilia growth and dynein arm assembly in vivo.\",\n      \"method\": \"Morpholino knockdown in zebrafish, transmission electron microscopy, in situ hybridization, quantitative real-time PCR\",\n      \"journal\": \"PloS one\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — morpholino knockdown with ultrastructural EM validation of ODA/IDA loss across multiple organs, independently corroborates findings in PMID:23872636\",\n      \"pmids\": [\"23650548\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2017,\n      \"finding\": \"In Chlamydomonas, DYX1C1/PF23 is required for preassembly of cytoplasmic dynein complexes (particularly inner dynein arms and a fraction of outer dynein arms); pf23 mutants lacking most IDAs show reduced preassembled dynein in cytoplasmic sucrose gradients, and a C-terminal truncation of DYX1C1 reduces a subset of ciliary IDAs, suggesting DYX1C1 provides a scaffold for macromolecular dynein assembly.\",\n      \"method\": \"Cryo-electron tomography (cryo-ET), spectral counting, sucrose gradient fractionation of cytoplasmic extracts, C-terminal truncation analysis\",\n      \"journal\": \"PLoS genetics\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 / Moderate — cryo-ET structural analysis combined with biochemical sucrose gradients and domain truncation mutants in a genetically defined mutant, single lab but multiple rigorous orthogonal methods\",\n      \"pmids\": [\"28892495\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2012,\n      \"finding\": \"DYX1C1 regulates cell migration of a human neuroblastoma cell line in a manner dependent on both its tetratricopeptide repeat (TPR) domain and a newly identified DYX1 domain; it also associates with cytoskeletal proteins and modulates expression of neuronal migration genes including RELN.\",\n      \"method\": \"Live cell imaging, gene expression profiling, protein interaction profiling, domain deletion constructs\",\n      \"journal\": \"Biological psychiatry\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2–3 / Moderate — live-cell imaging with domain-specific constructs plus protein interaction and gene expression profiling, single lab with multiple approaches\",\n      \"pmids\": [\"23036959\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2012,\n      \"finding\": \"ERβ (not ERα) binds to a cis-regulatory region upstream of the DYX1C1 transcriptional start site and enhances DYX1C1 expression in response to 17β-estradiol; this regulation requires TFII-I and liganded ERβ, and the dyslexia-associated SNP rs3743205 in this region can alter epigenetic and endocrine regulation of DYX1C1.\",\n      \"method\": \"Reporter gene assays, chromatin immunoprecipitation (ChIP), expression analysis in neuroblastoma cell line\",\n      \"journal\": \"Molecular endocrinology\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — ChIP and reporter assays with specific receptor knockdown, single lab with multiple orthogonal methods\",\n      \"pmids\": [\"22383464\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2016,\n      \"finding\": \"RFX transcription factors (RFX1, RFX2, RFX3) bind conserved X-box motifs in the DYX1C1 promoter and significantly regulate endogenous DYX1C1 expression; endogenous DYX1C1 protein localizes to the base of the cilium (not along the axoneme).\",\n      \"method\": \"Reporter gene assays, electrophoretic mobility shift assay (EMSA), immunofluorescence of endogenous protein, RFX transcription factor overexpression in hTERT-RPE1 cells\",\n      \"journal\": \"FASEB journal\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — EMSA plus reporter assay and endogenous protein localization by IF, single lab with multiple orthogonal approaches\",\n      \"pmids\": [\"27451412\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2022,\n      \"finding\": \"DNAAF4 (DYX1C1) and DNAAF6 (PIH1D3) form an R2TP-like co-chaperone complex in Drosophila; flies lacking Dnaaf4 or Dnaaf6 lack motile sperm and have impaired chordotonal neuron function, with loss of outer dynein arms and a subset of inner dynein arms, demonstrating a conserved role in dynein assembly despite Drosophila Dnaaf4 lacking the TPR domain.\",\n      \"method\": \"Drosophila genetic knockouts, protein co-association assays, immunofluorescence, electron microscopy, behavioral/functional assays of mechanosensory neurons and sperm motility\",\n      \"journal\": \"Frontiers in genetics\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — genetic knockout with multiple functional readouts and protein interaction evidence, single lab\",\n      \"pmids\": [\"35873488\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2022,\n      \"finding\": \"A missense DNAAF4 variant (p.G373E) reduces stability of the DNAAF4 protein but does not affect its expression or interaction with downstream DNAAF2 protein, causing PCD by destabilizing DNAAF4 rather than abolishing its binding to DNAAF2.\",\n      \"method\": \"Whole-exome sequencing, plasmid transfection, co-immunoprecipitation, immunofluorescence, transmission electron microscopy\",\n      \"journal\": \"Frontiers in genetics\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — Co-IP with mutagenesis confirming protein stability effects vs interaction, single lab\",\n      \"pmids\": [\"36583018\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2023,\n      \"finding\": \"DYX1C1 (DNAAF4) physically interacts with DCDC2 and both proteins independently interact with the centrosomal protein CPAP (CENPJ); dyx1c1 and dcdc2b show synergistic genetic interaction in zebrafish exacerbating the ciliary phenotype, and they mutually affect each other's transcriptional regulation.\",\n      \"method\": \"Co-immunoprecipitation of exogenous and endogenous proteins, zebrafish double-knockdown epistasis, transcriptional regulation assays, brain organoid cell models\",\n      \"journal\": \"BMC molecular and cell biology\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — reciprocal Co-IP plus genetic epistasis in zebrafish with multiple cell models including brain organoids, single lab\",\n      \"pmids\": [\"37237337\"],\n      \"is_preprint\": false\n    }\n  ],\n  \"current_model\": \"DNAAF4 (DYX1C1) is a cytoplasmic dynein axonemal assembly factor that localizes to the base of motile cilia and functions as a co-chaperone scaffold—interacting with Hsp70/Hsp90 via its C-terminal EEVD motif and with DNAAF2 (KTU)—to preassemble outer and inner dynein arm complexes before their transport into the ciliary axoneme; its TPR domain governs subcellular localization and chaperone recruitment, its DYX1 domain contributes to cell migration, and it is also regulated transcriptionally by RFX factors and ERβ/TFII-I at X-box and estrogen-responsive promoter elements.\"\n}\n```","stage2_raw":"{\n  \"mechanistic_narrative\": \"DNAAF4 (DYX1C1) is a cytoplasmic dynein axonemal assembly factor that preassembles outer and inner dynein arm (ODA/IDA) complexes required for motile cilia, with its loss causing primary ciliary dyskinesia in humans [#0]. It localizes to the base of the cilium rather than along the axoneme [#9] and functions as a co-chaperone scaffold: it engages Hsp70 and Hsp90 through a C-terminal EEVD motif [#3] and physically partners with the dynein assembly factor DNAAF2/KTU [#0], so that cytoplasmic dynein complexes are matured before transport into the axoneme. Cross-species genetics establish this role as conserved and essential\\u2014zebrafish knockdown abolishes both ODAs and IDAs and shortens cilia [#5], the Chlamydomonas ortholog PF23 is needed for cytoplasmic preassembly of dynein with its C-terminus governing a subset of IDAs [#6], and in Drosophila DNAAF4 acts with DNAAF6/PIH1D3 in an R2TP-like co-chaperone complex for sperm and chordotonal-neuron dynein assembly [#10]. The C-terminal TPR domains direct subcellular localization and chaperone recruitment, while a separate DYX1 domain and TPR contribute to neuronal cell migration [#1, #7]. DNAAF4 also interacts with DCDC2, both proteins binding the centrosomal protein CPAP/CENPJ and acting synergistically in ciliogenesis [#12]. Its transcription is controlled by RFX factors at X-box promoter motifs [#9] and by liganded ER\\u03b2 together with a TFII-I/PARP1/SFPQ complex at estrogen-responsive and SNP-containing promoter elements [#2, #4, #8].\",\n  \"teleology\": [\n    {\n      \"year\": 2006,\n      \"claim\": \"Established that the C-terminal TPR region dictates DYX1C1 localization and is necessary and sufficient for its function, defining a structure-function map before the protein's molecular role was known.\",\n      \"evidence\": \"In utero RNAi with truncation constructs and rescue in rat neocortex\",\n      \"pmids\": [\"16989952\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Molecular partners recruited by the TPR domain not identified here\", \"Neuronal migration role not connected to ciliary function\", \"No biochemical activity assigned\"]\n    },\n    {\n      \"year\": 2008,\n      \"claim\": \"Identified the transcriptional control of DYX1C1, showing a TFII-I/PARP1/SFPQ complex binds the promoter at disease-associated SNPs and modulates expression.\",\n      \"evidence\": \"EMSA, affinity-purification mass spectrometry, and luciferase reporter assays\",\n      \"pmids\": [\"18445785\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Physiological signals driving this regulation unclear\", \"Connection to DNAAF4 protein function not addressed\"]\n    },\n    {\n      \"year\": 2009,\n      \"claim\": \"Defined DYX1C1 biochemically as an Hsp70/Hsp90 co-chaperone via a C-terminal EEVD motif, providing the molecular basis for its later scaffold role.\",\n      \"evidence\": \"GST pull-down and yeast two-hybrid with site-directed mutagenesis\",\n      \"pmids\": [\"19277710\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Client proteins of the chaperone complex not identified\", \"Not linked to dynein assembly at this stage\"]\n    },\n    {\n      \"year\": 2009,\n      \"claim\": \"Showed DYX1C1 interacts with estrogen receptors and downregulates their levels, implicating it in steroid-hormone signaling beyond its ciliary role.\",\n      \"evidence\": \"Reciprocal Co-IP, proximity ligation assay, and transcriptional readout in cell lines and rat neurons\",\n      \"pmids\": [\"19423554\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Mechanism of ER destabilization unknown\", \"Relevance to motile cilia unclear\"]\n    },\n    {\n      \"year\": 2012,\n      \"claim\": \"Mapped DYX1C1 cell-migration activity to its TPR and a newly defined DYX1 domain and linked it to cytoskeletal proteins and migration-gene expression.\",\n      \"evidence\": \"Live-cell imaging, domain-deletion constructs, and interaction/expression profiling in neuroblastoma cells\",\n      \"pmids\": [\"23036959\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"DYX1 domain biochemical activity undefined\", \"Direct cytoskeletal binding partners not resolved\"]\n    },\n    {\n      \"year\": 2012,\n      \"claim\": \"Refined the hormonal regulation of DYX1C1, showing liganded ER\\u03b2 (not ER\\u03b1) and TFII-I enhance expression at a SNP-containing cis-element.\",\n      \"evidence\": \"ChIP, reporter assays, and receptor knockdown in neuroblastoma cells\",\n      \"pmids\": [\"22383464\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"In vivo relevance of estrogen regulation untested\", \"Epigenetic mechanism at the SNP not detailed\"]\n    },\n    {\n      \"year\": 2013,\n      \"claim\": \"Established DNAAF4 as a cytoplasmic dynein axonemal assembly factor required for ODA/IDA assembly, connecting it to the chaperone machinery via DNAAF2 and to human disease.\",\n      \"evidence\": \"IF, Co-IP, two mouse knockout alleles, zebrafish morpholino, human LOF mutations, and ciliary EM\",\n      \"pmids\": [\"23872636\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Precise assembly step catalyzed not resolved\", \"Full client repertoire of the chaperone complex unknown\"]\n    },\n    {\n      \"year\": 2013,\n      \"claim\": \"Independently confirmed in zebrafish that DNAAF4 loss removes both dynein arms and shortens cilia, demonstrating an essential in vivo role in ciliogenesis.\",\n      \"evidence\": \"Morpholino knockdown with transmission EM across multiple organs\",\n      \"pmids\": [\"23650548\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Does not distinguish assembly from transport defects\", \"Morpholino specificity caveats\"]\n    },\n    {\n      \"year\": 2016,\n      \"claim\": \"Placed DNAAF4 transcriptionally within the ciliogenic program by showing RFX factors drive its expression, and localized endogenous protein to the ciliary base.\",\n      \"evidence\": \"Reporter assays, EMSA, RFX overexpression, and endogenous IF in hTERT-RPE1 cells\",\n      \"pmids\": [\"27451412\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Functional consequence of basal localization not dissected\", \"Interplay between RFX and estrogen regulation unclear\"]\n    },\n    {\n      \"year\": 2017,\n      \"claim\": \"Demonstrated that the ortholog acts in cytoplasmic preassembly of dynein, with the C-terminus governing a subset of IDAs, supporting a scaffold model for macromolecular dynein assembly.\",\n      \"evidence\": \"Cryo-ET, sucrose-gradient fractionation, and C-terminal truncation in Chlamydomonas pf23 mutants\",\n      \"pmids\": [\"28892495\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Atomic structure of the scaffold complex absent\", \"Which dynein subunits directly contact DNAAF4 unknown\"]\n    },\n    {\n      \"year\": 2022,\n      \"claim\": \"Showed DNAAF4 partners with DNAAF6/PIH1D3 in a conserved R2TP-like co-chaperone complex for dynein assembly, with conservation despite loss of the TPR domain in flies.\",\n      \"evidence\": \"Drosophila knockouts, co-association assays, EM, and sperm/neuron functional assays\",\n      \"pmids\": [\"35873488\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Stoichiometry and architecture of the R2TP-like complex undefined\", \"TPR-independent recruitment mechanism unclear\"]\n    },\n    {\n      \"year\": 2022,\n      \"claim\": \"Resolved a disease mechanism, showing a missense variant destabilizes DNAAF4 protein without disrupting DNAAF2 binding, separating stability from interaction defects in PCD.\",\n      \"evidence\": \"Whole-exome sequencing, transfection, Co-IP, IF, and EM\",\n      \"pmids\": [\"36583018\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Generalizability to other PCD variants untested\", \"Degradation pathway of the unstable protein not identified\"]\n    },\n    {\n      \"year\": 2023,\n      \"claim\": \"Connected DNAAF4 to a wider ciliary network by showing it and DCDC2 interact and both bind the centrosomal protein CPAP, acting synergistically in ciliogenesis.\",\n      \"evidence\": \"Reciprocal Co-IP, zebrafish double-knockdown epistasis, and brain organoid models\",\n      \"pmids\": [\"37237337\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Functional meaning of CPAP binding unresolved\", \"Whether DCDC2 acts in dynein assembly unknown\"]\n    },\n    {\n      \"year\": null,\n      \"claim\": \"How DNAAF4's co-chaperone scaffold selects and folds specific dynein subunits, and how its ciliary, migration, and hormonal roles are mechanistically related, remains unresolved.\",\n      \"evidence\": \"\",\n      \"pmids\": [],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"No high-resolution structure of the DNAAF4-chaperone-dynein assembly intermediate\", \"Direct dynein clients of DNAAF4 not enumerated\", \"Relationship between TPR-dependent localization and substrate handoff unknown\"]\n    }\n  ],\n  \"mechanism_profile\": {\n    \"molecular_activity\": [\n      {\"term_id\": \"GO:0044183\", \"supporting_discovery_ids\": [0, 3, 6, 10]},\n      {\"term_id\": \"GO:0140096\", \"supporting_discovery_ids\": [0, 3]}\n    ],\n    \"localization\": [\n      {\"term_id\": \"GO:0005929\", \"supporting_discovery_ids\": [9]},\n      {\"term_id\": \"GO:0005829\", \"supporting_discovery_ids\": [0, 1]},\n      {\"term_id\": \"GO:0005634\", \"supporting_discovery_ids\": [1]},\n      {\"term_id\": \"GO:0005815\", \"supporting_discovery_ids\": [12]}\n    ],\n    \"pathway\": [\n      {\"term_id\": \"R-HSA-1852241\", \"supporting_discovery_ids\": [0, 5, 6]},\n      {\"term_id\": \"R-HSA-392499\", \"supporting_discovery_ids\": [0, 3]}\n    ],\n    \"complexes\": [\"R2TP-like co-chaperone complex (DNAAF4-DNAAF6/PIH1D3)\"],\n    \"partners\": [\"DNAAF2\", \"HSPA8\", \"HSP90\", \"DNAAF6\", \"DCDC2\", \"CENPJ\", \"ESR1\", \"ESR2\"]\n  }\n}","audit_flag":null,"evaluation":{"pairwise":"win","faith_supported":6,"faith_total":6,"faith_pct":100.0}}