{"gene":"KLHL12","run_date":"2026-06-10T02:59:49","timeline":{"discoveries":[{"year":2006,"finding":"KLHL12 forms a Cullin-3-based E3 ubiquitin ligase complex that binds Dishevelled in a Wnt-dependent manner, promoting its poly-ubiquitination and degradation, thereby negatively regulating the Wnt-beta-catenin pathway in cultured cells, Xenopus, and zebrafish embryos.","method":"Tandem-affinity purification, mass spectrometry, co-immunoprecipitation, ubiquitination assays, functional rescue in Xenopus and zebrafish embryos","journal":"Nature cell biology","confidence":"High","confidence_rationale":"Tier 2 / Strong — reciprocal co-IP/TAP-MS identification, ubiquitination assays, and in vivo functional epistasis across two vertebrate model organisms, replicated in multiple experimental systems","pmids":["16547521"],"is_preprint":false},{"year":2008,"finding":"KLHL12 binds via its Kelch domain to the polymorphic third intracellular loop of the dopamine D4 receptor and acts as an adaptor in a Cullin3-based E3 ubiquitin ligase complex to specifically promote ubiquitination of the D4 receptor; other dopamine receptor subtypes undergo basal ubiquitination not affected by KLHL12.","method":"Co-immunoprecipitation, domain-mapping experiments, ubiquitination assays in eukaryotic cells","journal":"The Journal of biological chemistry","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — co-IP plus in-cell ubiquitination assays with domain specificity, single lab, two complementary methods","pmids":["18303015"],"is_preprint":false},{"year":2010,"finding":"KLHL12 promotes poly-ubiquitination of both immature (ER-associated) and mature (plasma membrane-associated) dopamine D4 receptors, but this ubiquitination does not lead to proteasomal or lysosomal degradation of the receptor; KLHL12 interacts with beta-arrestin2 but this does not affect beta-arrestin2 ubiquitination, localization, or D4 receptor internalization.","method":"Ubiquitination assays in eukaryotic cells, subcellular fractionation, proteasome/lysosome inhibitor experiments, co-immunoprecipitation","journal":"Cellular signalling","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — multiple complementary biochemical approaches (ubiquitination assays, degradation pathway inhibitors, co-IP), single lab","pmids":["20100572"],"is_preprint":false},{"year":2015,"finding":"KLHL12 promotes ubiquitination of the dopamine D4 receptor on non-lysine residues (cysteine, serine, and/or threonine); the ADHD-associated D4.7 variant is differentially ubiquitinated compared to D4.2 and D4.4 variants.","method":"Ubiquitination assays with lysine-deficient receptor mutants, chemical approaches to block specific residue classes","journal":"PloS one","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — lysine-deficient mutants combined with chemical inhibition approaches, single lab, two orthogonal methods","pmids":["26717573"],"is_preprint":false},{"year":2016,"finding":"Beta-arrestin 1 and beta-arrestin 2 bind constitutively to both common D4 receptor polymorphic variants and to KLHL12, forming a trimeric complex; Cullin3 also interacts with both beta-arrestins but does not influence their ubiquitination; knockout of either beta-arrestin does not impair D4 receptor–KLHL12 interaction or receptor ubiquitination; KLHL12 does not influence p44/42 MAPK signaling downstream of the D4 receptor.","method":"Co-immunoprecipitation, beta-arrestin knockout cell lines, ubiquitination assays, MAPK phosphorylation assays","journal":"Cellular signalling","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — reciprocal co-IP and KO experiments with defined phenotypic readouts, single lab","pmids":["27155323"],"is_preprint":false},{"year":2020,"finding":"A crystal structure (2.4 Å) of the KLHL12 Kelch domain bound to a DVL1 peptide revealed that DVL1 adopts a U-shaped conformation engaging hydrophobic contacts across all six blades of the Kelch beta-propeller via a conserved 'PGXPP' degron motif; mutation or deletion of this motif reduces DVL1 binding and ubiquitination by KLHL12 and increases DVL1 stability; the same PGXPP motif is conserved in other KLHL12 substrates/partners including PLEKHA4, PEF1, SEC31, and DRD4.","method":"X-ray crystallography (2.4 Å), peptide binding assays (affinity measurements), site-directed mutagenesis, co-immunoprecipitation, ubiquitination and stability assays in cells","journal":"Open biology","confidence":"High","confidence_rationale":"Tier 1 / Strong — crystal structure with functional mutagenesis validation in cells, plus affinity measurements, multiple orthogonal methods in a single rigorous study","pmids":["32574548"],"is_preprint":false},{"year":2020,"finding":"X-ray crystal structure of KLHL12 Kelch domain bound to a short peptide derived from DVL3/D4.2 binding regions defined a sequence motif for the top-face binding site of KLHL12; alanine scanning mapped critical residues for binding with low micromolar affinity.","method":"NMR-based peptide screening, X-ray crystallography, alanine-substitution affinity measurements","journal":"Biochemistry","confidence":"High","confidence_rationale":"Tier 1 / Strong — crystal structure combined with systematic mutagenesis and quantitative affinity measurements, rigorous multi-method single study","pmids":["32032490"],"is_preprint":false},{"year":2020,"finding":"The CRL3^KLHL12 ubiquitin ligase ubiquitylates Lunapark, an ER-shaping protein at three-way junctions; inhibition of Lunapark ubiquitylation results in neurodevelopmental defects, indicating this modification is required for normal growth and development. Lunapark also interacts with mTORC1 at ER three-way junctions where lysosomes make contact.","method":"Proteomic screen for membrane-ubiquitylated proteins, co-immunoprecipitation, functional rescue/knockout experiments with developmental phenotype readout","journal":"Cell reports","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — proteomic identification plus co-IP and in vivo developmental phenotype readout, single lab, two complementary approaches","pmids":["32433973"],"is_preprint":false},{"year":2023,"finding":"KLHL12 monoubiquitylates SEC31A (a COPII coat component), enlarging COPII vesicles to accommodate procollagen for secretion; LZTR1 inhibits KLHL12-mediated ubiquitination of SEC31A, suppressing collagen secretion; LZTR1 and KLHL12 interact directly and function independently of the LZTR1-RIT1 axis.","method":"Co-immunoprecipitation, ubiquitination assays, LZTR1 knockout cells, collagen secretion assays, multi-omics analysis","journal":"Cell death & disease","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — co-IP and ubiquitination assays with KO cells and functional collagen secretion readout, single lab","pmids":["37626065"],"is_preprint":false},{"year":2023,"finding":"CUL3 neddylation is not required for KLHL12-dependent formation of large COPII structures; KLHL12 variants that cannot interact with neddylated CUL3 (Mut A) still support large COPII-KLHL12 assembly; however, active CRL3^KLHL12 (requiring CUL3 interaction) contributes to maintenance of cellular collagen levels, likely via lysosomal degradation.","method":"MLN4924 (NEDDylation inhibitor) treatment, CUL3-interface KLHL12 point mutants, COPII structure imaging, Western blot for collagen levels","journal":"Molecular biology of the cell","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — pharmacological inhibition plus structure-guided mutagenesis with two distinct phenotypic readouts, single lab","pmids":["36652337"],"is_preprint":false},{"year":2025,"finding":"Intestinal-specific knockout of Klhl12 in mice does not significantly alter serum lipid levels, body weight, or chylomicron secretion under chow, fasting/HFD-refeeding, or Western diet conditions, despite increased intestinal ApoB48 protein; KLHL12 is therefore not required for chylomicron secretion or lipid absorption in enterocytes.","method":"Intestinal-specific Klhl12 knockout mice, acute oil gavage, fasting/HFD refeeding, Western diet feeding, serum lipid profiling, Western blot","journal":"American journal of physiology. Endocrinology and metabolism","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — tissue-specific KO mouse with multiple dietary challenges and biochemical readouts, single lab; finding is a well-controlled negative result","pmids":["40591354"],"is_preprint":false},{"year":2025,"finding":"The BTB domain of KLHL12 forms a stable closed monomeric state during folding (demonstrated by optical tweezers), which would impede conventional domain-swapping dimerization; instead, timed emergence of nascent chain segments during coupled translation on co-translating ribosomes (disomes) enables an alternative assembly pathway that bypasses the closed monomer, allowing intertwined BTB-domain dimer formation.","method":"Disome Selective Profiling, optical tweezers single-molecule force spectroscopy, ribosome profiling","journal":"bioRxiv","confidence":"Medium","confidence_rationale":"Tier 1 / Weak — optical tweezers and ribosome profiling are rigorous single-molecule/genomics methods, but this is a preprint with a single study and limited functional validation specific to KLHL12","pmids":["bio_10.1101_2025.08.25.672138"],"is_preprint":true}],"current_model":"KLHL12 is a BTB-Kelch substrate adaptor that assembles with Cullin-3 to form a CRL3^KLHL12 E3 ubiquitin ligase complex; its Kelch beta-propeller domain recruits substrates bearing a conserved PGXPP degron motif—including Dishevelled (promoting Wnt pathway antagonism), the dopamine D4 receptor (non-degradative, non-lysine ubiquitination), SEC31A (monoubiquitination enlarging COPII vesicles for procollagen secretion), and Lunapark (ER three-way junction remodeling)—while its BTB domain forms intertwined homodimers through a translation-coupled assembly mechanism, and its activity is subject to regulation by LZTR1, which inhibits KLHL12-mediated SEC31A ubiquitination to suppress collagen secretion."},"narrative":{"mechanistic_narrative":"KLHL12 is a BTB-Kelch substrate adaptor that assembles with Cullin-3 into a CRL3^KLHL12 E3 ubiquitin ligase, recruiting substrates through its Kelch beta-propeller domain to direct their ubiquitination across diverse cellular processes [PMID:16547521, PMID:32574548]. Its substrates engage the top face of the six-bladed Kelch propeller via a conserved 'PGXPP' degron, defined crystallographically with a Dishevelled peptide and shared among multiple partners including SEC31, PEF1, PLEKHA4 and DRD4 [PMID:32574548, PMID:32032490]. Through this adaptor activity KLHL12 poly-ubiquitinates Dishevelled in a Wnt-dependent manner to drive its degradation and antagonize Wnt-beta-catenin signaling in vertebrate embryos [PMID:16547521], and ubiquitylates the ER three-way-junction protein Lunapark, a modification required for normal growth and development [PMID:32433973]. In the secretory pathway KLHL12 monoubiquitylates the COPII coat component SEC31A to enlarge COPII vesicles for procollagen export, an activity directly inhibited by LZTR1 to restrain collagen secretion [PMID:37626065]. KLHL12 also targets the dopamine D4 receptor through its Kelch domain, promoting a non-degradative ubiquitination that can occur on non-lysine residues, distinguishing it from its degradative substrates [PMID:18303015, PMID:26717573]. The BTB domain mediates intertwined homodimerization, which is established through a translation-coupled assembly pathway on co-translating ribosomes that bypasses a folding-competent closed monomeric state [PMID:bio_10.1101_2025.08.25.672138].","teleology":[{"year":2006,"claim":"Established KLHL12's core identity as a Cullin-3-based E3 ligase adaptor and assigned it a physiological role as a Wnt pathway antagonist, answering what cellular process this orphan adaptor controls.","evidence":"TAP-MS, co-IP, ubiquitination assays, and functional rescue in Xenopus and zebrafish embryos","pmids":["16547521"],"confidence":"High","gaps":["Degron recognition by the Kelch domain not yet defined structurally","Did not establish whether other substrates exist"]},{"year":2008,"claim":"Showed KLHL12 has substrates beyond Dishevelled by mapping Kelch-domain binding to the dopamine D4 receptor's third intracellular loop, broadening its substrate repertoire to a GPCR.","evidence":"Co-IP, domain mapping, and in-cell ubiquitination assays","pmids":["18303015"],"confidence":"Medium","gaps":["Functional consequence of D4 ubiquitination unresolved","Single lab without structural validation"]},{"year":2010,"claim":"Revealed that not all KLHL12 ubiquitination is degradative, since D4 receptor ubiquitination at both ER and plasma membrane pools failed to trigger proteasomal or lysosomal turnover.","evidence":"Ubiquitination assays, subcellular fractionation, proteasome/lysosome inhibitor experiments, co-IP","pmids":["20100572"],"confidence":"Medium","gaps":["Functional purpose of non-degradative ubiquitination undefined","Role of beta-arrestin2 interaction unclear"]},{"year":2015,"claim":"Characterized the unusual chemistry of D4 ubiquitination, showing modification on cysteine/serine/threonine rather than lysine and differential handling of the ADHD-associated D4.7 variant.","evidence":"Lysine-deficient receptor mutants plus chemical blockade of residue classes","pmids":["26717573"],"confidence":"Medium","gaps":["Physiological significance of non-lysine ubiquitination unknown","Link to ADHD phenotype not established"]},{"year":2016,"claim":"Dissected the KLHL12-D4 receptor-beta-arrestin complex, showing arrestins are dispensable for receptor-adaptor binding and ubiquitination and that KLHL12 does not modulate downstream MAPK signaling.","evidence":"Reciprocal co-IP, beta-arrestin knockout cell lines, ubiquitination and MAPK phosphorylation assays","pmids":["27155323"],"confidence":"Medium","gaps":["Functional role of the trimeric complex still undefined","Downstream effect of D4 ubiquitination remains unknown"]},{"year":2020,"claim":"Defined the structural basis of substrate recognition, showing the Kelch propeller engages a conserved PGXPP degron shared across multiple substrates, unifying how KLHL12 selects targets.","evidence":"X-ray crystallography of Kelch-DVL/DVL3/D4.2 peptide complexes, NMR screening, alanine-scanning affinity measurements, mutagenesis with ubiquitination/stability readouts","pmids":["32574548","32032490"],"confidence":"High","gaps":["Does not capture full-length CRL3 assembly geometry","How degron context selects degradative vs non-degradative outcome unresolved"]},{"year":2020,"claim":"Extended KLHL12's substrate range to ER morphology by identifying Lunapark as a CRL3^KLHL12 target whose ubiquitination is required for normal growth and development.","evidence":"Proteomic screen for membrane-ubiquitylated proteins, co-IP, knockout/rescue with developmental phenotype readout","pmids":["32433973"],"confidence":"Medium","gaps":["Mechanistic link between Lunapark ubiquitination and ER junction remodeling not fully resolved","Relationship to mTORC1 contact sites uncharacterized"]},{"year":2023,"claim":"Connected KLHL12 to collagen secretion via monoubiquitination of SEC31A and identified LZTR1 as a direct inhibitor of this activity, defining a regulatory layer on the ligase.","evidence":"Co-IP, ubiquitination assays, LZTR1 knockout cells, collagen secretion assays, multi-omics","pmids":["37626065"],"confidence":"Medium","gaps":["Structural basis of LZTR1-KLHL12 inhibition unknown","Single lab"]},{"year":2023,"claim":"Separated CUL3-dependent and CUL3-independent KLHL12 functions, showing neddylated-CUL3 binding is dispensable for large COPII assembly but required for maintaining cellular collagen levels.","evidence":"MLN4924 neddylation inhibition, CUL3-interface point mutants, COPII imaging, collagen Western blot","pmids":["36652337"],"confidence":"Medium","gaps":["Mechanism of CUL3-independent COPII enlargement undefined","Proposed lysosomal degradation route not directly demonstrated"]},{"year":2025,"claim":"Tested KLHL12's role in lipid handling with a tissue-specific knockout, yielding a well-controlled negative result that excludes a requirement in enterocyte chylomicron secretion despite altered ApoB48.","evidence":"Intestinal-specific Klhl12 knockout mice across multiple dietary challenges with serum lipid profiling and Western blot","pmids":["40591354"],"confidence":"Medium","gaps":["Does not address KLHL12 function in other tissues","Significance of increased intestinal ApoB48 unexplained"]},{"year":2025,"claim":"Addressed how the BTB domain achieves intertwined dimerization, showing a folding-competent closed monomer would block domain swapping and that co-translational assembly on disomes provides an alternative route.","evidence":"Disome selective profiling, optical tweezers single-molecule force spectroscopy, ribosome profiling (preprint)","pmids":["bio_10.1101_2025.08.25.672138"],"confidence":"Medium","gaps":["Preprint not yet peer-reviewed","Functional consequence of co-translational vs post-translational dimerization for ligase activity untested"]},{"year":null,"claim":"How the same Kelch-PGXPP recognition platform yields degradative poly-ubiquitination of some substrates versus non-degradative or mono-ubiquitination of others remains the central unresolved question.","evidence":"","pmids":[],"confidence":"Medium","gaps":["No structural model of the full CRL3^KLHL12-substrate complex","Determinants of ubiquitin chain type and linkage per substrate unknown"]}],"mechanism_profile":{"molecular_activity":[{"term_id":"GO:0140096","term_label":"catalytic activity, acting on a protein","supporting_discovery_ids":[0,1,7,8]},{"term_id":"GO:0060090","term_label":"molecular adaptor activity","supporting_discovery_ids":[0,1,5]},{"term_id":"GO:0016874","term_label":"ligase activity","supporting_discovery_ids":[0,8]}],"localization":[{"term_id":"GO:0005783","term_label":"endoplasmic reticulum","supporting_discovery_ids":[7,8]},{"term_id":"GO:0031410","term_label":"cytoplasmic vesicle","supporting_discovery_ids":[8,9]}],"pathway":[{"term_id":"R-HSA-392499","term_label":"Metabolism of proteins","supporting_discovery_ids":[0,8]},{"term_id":"R-HSA-162582","term_label":"Signal Transduction","supporting_discovery_ids":[0]},{"term_id":"R-HSA-5653656","term_label":"Vesicle-mediated transport","supporting_discovery_ids":[8,9]}],"complexes":["CRL3^KLHL12 (Cullin-3 E3 ubiquitin ligase)"],"partners":["CUL3","DVL1","DRD4","SEC31A","LZTR1","ARRB2","ARRB1"],"other_free_text":[]}},"prefetch_data":{"uniprot":{"accession":"Q53G59","full_name":"Kelch-like protein 12","aliases":["CUL3-interacting protein 1","DKIR homolog","hDKIR"],"length_aa":568,"mass_kda":63.3,"function":"Substrate-specific adapter of a BCR (BTB-CUL3-RBX1) E3 ubiquitin ligase complex that acts as a negative regulator of Wnt signaling pathway and ER-Golgi transport (PubMed:22358839, PubMed:27565346). The BCR(KLHL12) complex is involved in ER-Golgi transport by regulating the size of COPII coats, thereby playing a key role in collagen export, which is required for embryonic stem (ES) cells division: BCR(KLHL12) acts by mediating monoubiquitination of SEC31 (SEC31A or SEC31B) (PubMed:22358839, PubMed:27565346). The BCR(KLHL12) complex is also involved in neural crest specification: in response to cytosolic calcium increase, interacts with the heterodimer formed with PEF1 and PDCD6/ALG-2, leading to bridge together the BCR(KLHL12) complex and SEC31 (SEC31A or SEC31B), promoting monoubiquitination of SEC31 and subsequent collagen export (PubMed:27716508). As part of the BCR(KLHL12) complex, also acts as a negative regulator of the Wnt signaling pathway by mediating ubiquitination and subsequent proteolysis of DVL3 (PubMed:16547521). The BCR(KLHL12) complex also mediates polyubiquitination of DRD4 and PEF1, without leading to degradation of these proteins (PubMed:18303015, PubMed:20100572, PubMed:27716508)","subcellular_location":"Cytoplasmic vesicle, COPII-coated vesicle","url":"https://www.uniprot.org/uniprotkb/Q53G59/entry"},"depmap":{"release":"DepMap","has_data":true,"is_common_essential":false,"resolved_as":"","url":"https://depmap.org/portal/gene/KLHL12","classification":"Not Classified","n_dependent_lines":35,"n_total_lines":1208,"dependency_fraction":0.028973509933774833},"opencell":{"profiled":false,"resolved_as":"","ensg_id":"","cell_line_id":"","localizations":[],"interactors":[{"gene":"SEC13","stoichiometry":0.2}],"url":"https://opencell.sf.czbiohub.org/search/KLHL12","total_profiled":1310},"omim":[{"mim_id":"614522","title":"KELCH-LIKE 12; KLHL12","url":"https://www.omim.org/entry/614522"},{"mim_id":"610257","title":"SEC31 HOMOLOG A, COPII COAT COMPLEX COMPONENT; SEC31A","url":"https://www.omim.org/entry/610257"},{"mim_id":"603136","title":"CULLIN 3; CUL3","url":"https://www.omim.org/entry/603136"},{"mim_id":"126452","title":"DOPAMINE RECEPTOR D4; DRD4","url":"https://www.omim.org/entry/126452"}],"hpa":{"profiled":true,"resolved_as":"","reliability":"Supported","locations":[{"location":"Vesicles","reliability":"Supported"},{"location":"Centriolar satellite","reliability":"Supported"}],"tissue_specificity":"Low tissue specificity","tissue_distribution":"Detected in all","driving_tissues":[],"url":"https://www.proteinatlas.org/search/KLHL12"},"hgnc":{"alias_symbol":["C3IP1"],"prev_symbol":[]},"alphafold":{"accession":"Q53G59","domains":[{"cath_id":"3.30.710.10","chopping":"13-129","consensus_level":"high","plddt":92.5319,"start":13,"end":129},{"cath_id":"1.25.40.420","chopping":"174-260","consensus_level":"high","plddt":92.3059,"start":174,"end":260},{"cath_id":"2.120.10.80","chopping":"296-565","consensus_level":"medium","plddt":95.5846,"start":296,"end":565}],"viewer_url":"https://alphafold.ebi.ac.uk/entry/Q53G59","model_url":"https://alphafold.ebi.ac.uk/files/AF-Q53G59-F1-model_v6.cif","pae_url":"https://alphafold.ebi.ac.uk/files/AF-Q53G59-F1-predicted_aligned_error_v6.png","plddt_mean":93.31},"mouse_models":{"mgi_url":"https://www.informatics.jax.org/marker/summary?nomen=KLHL12","jax_strain_url":"https://www.jax.org/strain/search?query=KLHL12"},"sequence":{"accession":"Q53G59","fasta_url":"https://rest.uniprot.org/uniprotkb/Q53G59.fasta","uniprot_url":"https://www.uniprot.org/uniprotkb/Q53G59/entry","alphafold_viewer_url":"https://alphafold.ebi.ac.uk/entry/Q53G59"}},"corpus_meta":[{"pmid":"16547521","id":"PMC_16547521","title":"The KLHL12-Cullin-3 ubiquitin ligase negatively regulates the Wnt-beta-catenin pathway by targeting Dishevelled for degradation.","date":"2006","source":"Nature cell biology","url":"https://pubmed.ncbi.nlm.nih.gov/16547521","citation_count":315,"is_preprint":false},{"pmid":"18303015","id":"PMC_18303015","title":"BTB Protein KLHL12 targets the dopamine D4 receptor for ubiquitination by a Cul3-based E3 ligase.","date":"2008","source":"The Journal of biological chemistry","url":"https://pubmed.ncbi.nlm.nih.gov/18303015","citation_count":66,"is_preprint":false},{"pmid":"20100572","id":"PMC_20100572","title":"KLHL12-mediated ubiquitination of the dopamine D4 receptor does not target the receptor for degradation.","date":"2010","source":"Cellular signalling","url":"https://pubmed.ncbi.nlm.nih.gov/20100572","citation_count":23,"is_preprint":false},{"pmid":"37626065","id":"PMC_37626065","title":"LZTR1 deficiency exerts high metastatic potential by enhancing sensitivity to EMT induction and controlling KLHL12-mediated collagen secretion.","date":"2023","source":"Cell death & disease","url":"https://pubmed.ncbi.nlm.nih.gov/37626065","citation_count":19,"is_preprint":false},{"pmid":"32433973","id":"PMC_32433973","title":"Ubiquitylation of the ER-Shaping Protein Lunapark via the CRL3KLHL12 Ubiquitin Ligase Complex.","date":"2020","source":"Cell reports","url":"https://pubmed.ncbi.nlm.nih.gov/32433973","citation_count":17,"is_preprint":false},{"pmid":"32574548","id":"PMC_32574548","title":"Identification of a PGXPP degron motif in dishevelled and structural basis for its binding to the E3 ligase KLHL12.","date":"2020","source":"Open biology","url":"https://pubmed.ncbi.nlm.nih.gov/32574548","citation_count":15,"is_preprint":false},{"pmid":"26717573","id":"PMC_26717573","title":"KLHL12 Promotes Non-Lysine Ubiquitination of the Dopamine Receptors D4.2 and D4.4, but Not of the ADHD-Associated D4.7 Variant.","date":"2015","source":"PloS one","url":"https://pubmed.ncbi.nlm.nih.gov/26717573","citation_count":12,"is_preprint":false},{"pmid":"32032490","id":"PMC_32032490","title":"Structural Elucidation of Peptide Binding to KLHL-12, a Substrate Specific Adapter Protein in a Cul3-Ring E3 Ligase Complex.","date":"2020","source":"Biochemistry","url":"https://pubmed.ncbi.nlm.nih.gov/32032490","citation_count":11,"is_preprint":false},{"pmid":"27155323","id":"PMC_27155323","title":"Characterization of the interaction between the dopamine D4 receptor, KLHL12 and β-arrestins.","date":"2016","source":"Cellular signalling","url":"https://pubmed.ncbi.nlm.nih.gov/27155323","citation_count":7,"is_preprint":false},{"pmid":"36652337","id":"PMC_36652337","title":"KLHL12 can form large COPII structures in the absence of CUL3 neddylation.","date":"2023","source":"Molecular biology of the cell","url":"https://pubmed.ncbi.nlm.nih.gov/36652337","citation_count":5,"is_preprint":false},{"pmid":"40591354","id":"PMC_40591354","title":"Intestinal KLHL12 is dispensable for lipid absorption and chylomicron metabolism.","date":"2025","source":"American journal of physiology. Endocrinology and metabolism","url":"https://pubmed.ncbi.nlm.nih.gov/40591354","citation_count":0,"is_preprint":false},{"pmid":"41906311","id":"PMC_41906311","title":"Identification of KLHL12 Ligands Using Fragment-Based Methods.","date":"2026","source":"Journal of medicinal chemistry","url":"https://pubmed.ncbi.nlm.nih.gov/41906311","citation_count":0,"is_preprint":false},{"pmid":"42009851","id":"PMC_42009851","title":"Exosomal miR-145-5p from BMSCs alleviates AKI-induced renal fibrosis via KLHL12/KHSRP-mediated m6A-dependent repression of FLI-1.","date":"2026","source":"Cell biology and toxicology","url":"https://pubmed.ncbi.nlm.nih.gov/42009851","citation_count":0,"is_preprint":false},{"pmid":null,"id":"bio_10.1101_2025.08.25.672138","title":"Translation-driven temporal control for intertwined protein assembly","date":"2025-08-29","source":"bioRxiv","url":"https://doi.org/10.1101/2025.08.25.672138","citation_count":0,"is_preprint":true}],"cost":{"stage1":{"model":"claude-sonnet-4-6","input_tokens":8995,"output_tokens":3224,"usd":0.037672,"stage1_stop_reason":"end_turn"},"stage2":{"model":"claude-opus-4-8","input_tokens":10662,"output_tokens":3674,"usd":0.07258,"stage2_stop_reason":"end_turn"},"total_usd":0.110252,"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\": 2006,\n      \"finding\": \"KLHL12 forms a Cullin-3-based E3 ubiquitin ligase complex that binds Dishevelled in a Wnt-dependent manner, promoting its poly-ubiquitination and degradation, thereby negatively regulating the Wnt-beta-catenin pathway in cultured cells, Xenopus, and zebrafish embryos.\",\n      \"method\": \"Tandem-affinity purification, mass spectrometry, co-immunoprecipitation, ubiquitination assays, functional rescue in Xenopus and zebrafish embryos\",\n      \"journal\": \"Nature cell biology\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — reciprocal co-IP/TAP-MS identification, ubiquitination assays, and in vivo functional epistasis across two vertebrate model organisms, replicated in multiple experimental systems\",\n      \"pmids\": [\"16547521\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2008,\n      \"finding\": \"KLHL12 binds via its Kelch domain to the polymorphic third intracellular loop of the dopamine D4 receptor and acts as an adaptor in a Cullin3-based E3 ubiquitin ligase complex to specifically promote ubiquitination of the D4 receptor; other dopamine receptor subtypes undergo basal ubiquitination not affected by KLHL12.\",\n      \"method\": \"Co-immunoprecipitation, domain-mapping experiments, ubiquitination assays in eukaryotic cells\",\n      \"journal\": \"The Journal of biological chemistry\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — co-IP plus in-cell ubiquitination assays with domain specificity, single lab, two complementary methods\",\n      \"pmids\": [\"18303015\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2010,\n      \"finding\": \"KLHL12 promotes poly-ubiquitination of both immature (ER-associated) and mature (plasma membrane-associated) dopamine D4 receptors, but this ubiquitination does not lead to proteasomal or lysosomal degradation of the receptor; KLHL12 interacts with beta-arrestin2 but this does not affect beta-arrestin2 ubiquitination, localization, or D4 receptor internalization.\",\n      \"method\": \"Ubiquitination assays in eukaryotic cells, subcellular fractionation, proteasome/lysosome inhibitor experiments, co-immunoprecipitation\",\n      \"journal\": \"Cellular signalling\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — multiple complementary biochemical approaches (ubiquitination assays, degradation pathway inhibitors, co-IP), single lab\",\n      \"pmids\": [\"20100572\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2015,\n      \"finding\": \"KLHL12 promotes ubiquitination of the dopamine D4 receptor on non-lysine residues (cysteine, serine, and/or threonine); the ADHD-associated D4.7 variant is differentially ubiquitinated compared to D4.2 and D4.4 variants.\",\n      \"method\": \"Ubiquitination assays with lysine-deficient receptor mutants, chemical approaches to block specific residue classes\",\n      \"journal\": \"PloS one\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — lysine-deficient mutants combined with chemical inhibition approaches, single lab, two orthogonal methods\",\n      \"pmids\": [\"26717573\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2016,\n      \"finding\": \"Beta-arrestin 1 and beta-arrestin 2 bind constitutively to both common D4 receptor polymorphic variants and to KLHL12, forming a trimeric complex; Cullin3 also interacts with both beta-arrestins but does not influence their ubiquitination; knockout of either beta-arrestin does not impair D4 receptor–KLHL12 interaction or receptor ubiquitination; KLHL12 does not influence p44/42 MAPK signaling downstream of the D4 receptor.\",\n      \"method\": \"Co-immunoprecipitation, beta-arrestin knockout cell lines, ubiquitination assays, MAPK phosphorylation assays\",\n      \"journal\": \"Cellular signalling\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — reciprocal co-IP and KO experiments with defined phenotypic readouts, single lab\",\n      \"pmids\": [\"27155323\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2020,\n      \"finding\": \"A crystal structure (2.4 Å) of the KLHL12 Kelch domain bound to a DVL1 peptide revealed that DVL1 adopts a U-shaped conformation engaging hydrophobic contacts across all six blades of the Kelch beta-propeller via a conserved 'PGXPP' degron motif; mutation or deletion of this motif reduces DVL1 binding and ubiquitination by KLHL12 and increases DVL1 stability; the same PGXPP motif is conserved in other KLHL12 substrates/partners including PLEKHA4, PEF1, SEC31, and DRD4.\",\n      \"method\": \"X-ray crystallography (2.4 Å), peptide binding assays (affinity measurements), site-directed mutagenesis, co-immunoprecipitation, ubiquitination and stability assays in cells\",\n      \"journal\": \"Open biology\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 / Strong — crystal structure with functional mutagenesis validation in cells, plus affinity measurements, multiple orthogonal methods in a single rigorous study\",\n      \"pmids\": [\"32574548\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2020,\n      \"finding\": \"X-ray crystal structure of KLHL12 Kelch domain bound to a short peptide derived from DVL3/D4.2 binding regions defined a sequence motif for the top-face binding site of KLHL12; alanine scanning mapped critical residues for binding with low micromolar affinity.\",\n      \"method\": \"NMR-based peptide screening, X-ray crystallography, alanine-substitution affinity measurements\",\n      \"journal\": \"Biochemistry\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 / Strong — crystal structure combined with systematic mutagenesis and quantitative affinity measurements, rigorous multi-method single study\",\n      \"pmids\": [\"32032490\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2020,\n      \"finding\": \"The CRL3^KLHL12 ubiquitin ligase ubiquitylates Lunapark, an ER-shaping protein at three-way junctions; inhibition of Lunapark ubiquitylation results in neurodevelopmental defects, indicating this modification is required for normal growth and development. Lunapark also interacts with mTORC1 at ER three-way junctions where lysosomes make contact.\",\n      \"method\": \"Proteomic screen for membrane-ubiquitylated proteins, co-immunoprecipitation, functional rescue/knockout experiments with developmental phenotype readout\",\n      \"journal\": \"Cell reports\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — proteomic identification plus co-IP and in vivo developmental phenotype readout, single lab, two complementary approaches\",\n      \"pmids\": [\"32433973\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2023,\n      \"finding\": \"KLHL12 monoubiquitylates SEC31A (a COPII coat component), enlarging COPII vesicles to accommodate procollagen for secretion; LZTR1 inhibits KLHL12-mediated ubiquitination of SEC31A, suppressing collagen secretion; LZTR1 and KLHL12 interact directly and function independently of the LZTR1-RIT1 axis.\",\n      \"method\": \"Co-immunoprecipitation, ubiquitination assays, LZTR1 knockout cells, collagen secretion assays, multi-omics analysis\",\n      \"journal\": \"Cell death & disease\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — co-IP and ubiquitination assays with KO cells and functional collagen secretion readout, single lab\",\n      \"pmids\": [\"37626065\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2023,\n      \"finding\": \"CUL3 neddylation is not required for KLHL12-dependent formation of large COPII structures; KLHL12 variants that cannot interact with neddylated CUL3 (Mut A) still support large COPII-KLHL12 assembly; however, active CRL3^KLHL12 (requiring CUL3 interaction) contributes to maintenance of cellular collagen levels, likely via lysosomal degradation.\",\n      \"method\": \"MLN4924 (NEDDylation inhibitor) treatment, CUL3-interface KLHL12 point mutants, COPII structure imaging, Western blot for collagen levels\",\n      \"journal\": \"Molecular biology of the cell\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — pharmacological inhibition plus structure-guided mutagenesis with two distinct phenotypic readouts, single lab\",\n      \"pmids\": [\"36652337\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2025,\n      \"finding\": \"Intestinal-specific knockout of Klhl12 in mice does not significantly alter serum lipid levels, body weight, or chylomicron secretion under chow, fasting/HFD-refeeding, or Western diet conditions, despite increased intestinal ApoB48 protein; KLHL12 is therefore not required for chylomicron secretion or lipid absorption in enterocytes.\",\n      \"method\": \"Intestinal-specific Klhl12 knockout mice, acute oil gavage, fasting/HFD refeeding, Western diet feeding, serum lipid profiling, Western blot\",\n      \"journal\": \"American journal of physiology. Endocrinology and metabolism\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — tissue-specific KO mouse with multiple dietary challenges and biochemical readouts, single lab; finding is a well-controlled negative result\",\n      \"pmids\": [\"40591354\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2025,\n      \"finding\": \"The BTB domain of KLHL12 forms a stable closed monomeric state during folding (demonstrated by optical tweezers), which would impede conventional domain-swapping dimerization; instead, timed emergence of nascent chain segments during coupled translation on co-translating ribosomes (disomes) enables an alternative assembly pathway that bypasses the closed monomer, allowing intertwined BTB-domain dimer formation.\",\n      \"method\": \"Disome Selective Profiling, optical tweezers single-molecule force spectroscopy, ribosome profiling\",\n      \"journal\": \"bioRxiv\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 1 / Weak — optical tweezers and ribosome profiling are rigorous single-molecule/genomics methods, but this is a preprint with a single study and limited functional validation specific to KLHL12\",\n      \"pmids\": [\"bio_10.1101_2025.08.25.672138\"],\n      \"is_preprint\": true\n    }\n  ],\n  \"current_model\": \"KLHL12 is a BTB-Kelch substrate adaptor that assembles with Cullin-3 to form a CRL3^KLHL12 E3 ubiquitin ligase complex; its Kelch beta-propeller domain recruits substrates bearing a conserved PGXPP degron motif—including Dishevelled (promoting Wnt pathway antagonism), the dopamine D4 receptor (non-degradative, non-lysine ubiquitination), SEC31A (monoubiquitination enlarging COPII vesicles for procollagen secretion), and Lunapark (ER three-way junction remodeling)—while its BTB domain forms intertwined homodimers through a translation-coupled assembly mechanism, and its activity is subject to regulation by LZTR1, which inhibits KLHL12-mediated SEC31A ubiquitination to suppress collagen secretion.\"\n}\n```","stage2_raw":"{\n  \"mechanistic_narrative\": \"KLHL12 is a BTB-Kelch substrate adaptor that assembles with Cullin-3 into a CRL3^KLHL12 E3 ubiquitin ligase, recruiting substrates through its Kelch beta-propeller domain to direct their ubiquitination across diverse cellular processes [#0, #5]. Its substrates engage the top face of the six-bladed Kelch propeller via a conserved 'PGXPP' degron, defined crystallographically with a Dishevelled peptide and shared among multiple partners including SEC31, PEF1, PLEKHA4 and DRD4 [#5, #6]. Through this adaptor activity KLHL12 poly-ubiquitinates Dishevelled in a Wnt-dependent manner to drive its degradation and antagonize Wnt-beta-catenin signaling in vertebrate embryos [#0], and ubiquitylates the ER three-way-junction protein Lunapark, a modification required for normal growth and development [#7]. In the secretory pathway KLHL12 monoubiquitylates the COPII coat component SEC31A to enlarge COPII vesicles for procollagen export, an activity directly inhibited by LZTR1 to restrain collagen secretion [#8]. KLHL12 also targets the dopamine D4 receptor through its Kelch domain, promoting a non-degradative ubiquitination that can occur on non-lysine residues, distinguishing it from its degradative substrates [#1, #3]. The BTB domain mediates intertwined homodimerization, which is established through a translation-coupled assembly pathway on co-translating ribosomes that bypasses a folding-competent closed monomeric state [#11].\",\n  \"teleology\": [\n    {\n      \"year\": 2006,\n      \"claim\": \"Established KLHL12's core identity as a Cullin-3-based E3 ligase adaptor and assigned it a physiological role as a Wnt pathway antagonist, answering what cellular process this orphan adaptor controls.\",\n      \"evidence\": \"TAP-MS, co-IP, ubiquitination assays, and functional rescue in Xenopus and zebrafish embryos\",\n      \"pmids\": [\"16547521\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Degron recognition by the Kelch domain not yet defined structurally\", \"Did not establish whether other substrates exist\"]\n    },\n    {\n      \"year\": 2008,\n      \"claim\": \"Showed KLHL12 has substrates beyond Dishevelled by mapping Kelch-domain binding to the dopamine D4 receptor's third intracellular loop, broadening its substrate repertoire to a GPCR.\",\n      \"evidence\": \"Co-IP, domain mapping, and in-cell ubiquitination assays\",\n      \"pmids\": [\"18303015\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Functional consequence of D4 ubiquitination unresolved\", \"Single lab without structural validation\"]\n    },\n    {\n      \"year\": 2010,\n      \"claim\": \"Revealed that not all KLHL12 ubiquitination is degradative, since D4 receptor ubiquitination at both ER and plasma membrane pools failed to trigger proteasomal or lysosomal turnover.\",\n      \"evidence\": \"Ubiquitination assays, subcellular fractionation, proteasome/lysosome inhibitor experiments, co-IP\",\n      \"pmids\": [\"20100572\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Functional purpose of non-degradative ubiquitination undefined\", \"Role of beta-arrestin2 interaction unclear\"]\n    },\n    {\n      \"year\": 2015,\n      \"claim\": \"Characterized the unusual chemistry of D4 ubiquitination, showing modification on cysteine/serine/threonine rather than lysine and differential handling of the ADHD-associated D4.7 variant.\",\n      \"evidence\": \"Lysine-deficient receptor mutants plus chemical blockade of residue classes\",\n      \"pmids\": [\"26717573\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Physiological significance of non-lysine ubiquitination unknown\", \"Link to ADHD phenotype not established\"]\n    },\n    {\n      \"year\": 2016,\n      \"claim\": \"Dissected the KLHL12-D4 receptor-beta-arrestin complex, showing arrestins are dispensable for receptor-adaptor binding and ubiquitination and that KLHL12 does not modulate downstream MAPK signaling.\",\n      \"evidence\": \"Reciprocal co-IP, beta-arrestin knockout cell lines, ubiquitination and MAPK phosphorylation assays\",\n      \"pmids\": [\"27155323\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Functional role of the trimeric complex still undefined\", \"Downstream effect of D4 ubiquitination remains unknown\"]\n    },\n    {\n      \"year\": 2020,\n      \"claim\": \"Defined the structural basis of substrate recognition, showing the Kelch propeller engages a conserved PGXPP degron shared across multiple substrates, unifying how KLHL12 selects targets.\",\n      \"evidence\": \"X-ray crystallography of Kelch-DVL/DVL3/D4.2 peptide complexes, NMR screening, alanine-scanning affinity measurements, mutagenesis with ubiquitination/stability readouts\",\n      \"pmids\": [\"32574548\", \"32032490\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Does not capture full-length CRL3 assembly geometry\", \"How degron context selects degradative vs non-degradative outcome unresolved\"]\n    },\n    {\n      \"year\": 2020,\n      \"claim\": \"Extended KLHL12's substrate range to ER morphology by identifying Lunapark as a CRL3^KLHL12 target whose ubiquitination is required for normal growth and development.\",\n      \"evidence\": \"Proteomic screen for membrane-ubiquitylated proteins, co-IP, knockout/rescue with developmental phenotype readout\",\n      \"pmids\": [\"32433973\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Mechanistic link between Lunapark ubiquitination and ER junction remodeling not fully resolved\", \"Relationship to mTORC1 contact sites uncharacterized\"]\n    },\n    {\n      \"year\": 2023,\n      \"claim\": \"Connected KLHL12 to collagen secretion via monoubiquitination of SEC31A and identified LZTR1 as a direct inhibitor of this activity, defining a regulatory layer on the ligase.\",\n      \"evidence\": \"Co-IP, ubiquitination assays, LZTR1 knockout cells, collagen secretion assays, multi-omics\",\n      \"pmids\": [\"37626065\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Structural basis of LZTR1-KLHL12 inhibition unknown\", \"Single lab\"]\n    },\n    {\n      \"year\": 2023,\n      \"claim\": \"Separated CUL3-dependent and CUL3-independent KLHL12 functions, showing neddylated-CUL3 binding is dispensable for large COPII assembly but required for maintaining cellular collagen levels.\",\n      \"evidence\": \"MLN4924 neddylation inhibition, CUL3-interface point mutants, COPII imaging, collagen Western blot\",\n      \"pmids\": [\"36652337\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Mechanism of CUL3-independent COPII enlargement undefined\", \"Proposed lysosomal degradation route not directly demonstrated\"]\n    },\n    {\n      \"year\": 2025,\n      \"claim\": \"Tested KLHL12's role in lipid handling with a tissue-specific knockout, yielding a well-controlled negative result that excludes a requirement in enterocyte chylomicron secretion despite altered ApoB48.\",\n      \"evidence\": \"Intestinal-specific Klhl12 knockout mice across multiple dietary challenges with serum lipid profiling and Western blot\",\n      \"pmids\": [\"40591354\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Does not address KLHL12 function in other tissues\", \"Significance of increased intestinal ApoB48 unexplained\"]\n    },\n    {\n      \"year\": 2025,\n      \"claim\": \"Addressed how the BTB domain achieves intertwined dimerization, showing a folding-competent closed monomer would block domain swapping and that co-translational assembly on disomes provides an alternative route.\",\n      \"evidence\": \"Disome selective profiling, optical tweezers single-molecule force spectroscopy, ribosome profiling (preprint)\",\n      \"pmids\": [\"bio_10.1101_2025.08.25.672138\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Preprint not yet peer-reviewed\", \"Functional consequence of co-translational vs post-translational dimerization for ligase activity untested\"]\n    },\n    {\n      \"year\": null,\n      \"claim\": \"How the same Kelch-PGXPP recognition platform yields degradative poly-ubiquitination of some substrates versus non-degradative or mono-ubiquitination of others remains the central unresolved question.\",\n      \"evidence\": \"\",\n      \"pmids\": [],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"No structural model of the full CRL3^KLHL12-substrate complex\", \"Determinants of ubiquitin chain type and linkage per substrate unknown\"]\n    }\n  ],\n  \"mechanism_profile\": {\n    \"molecular_activity\": [\n      {\"term_id\": \"GO:0140096\", \"supporting_discovery_ids\": [0, 1, 7, 8]},\n      {\"term_id\": \"GO:0060090\", \"supporting_discovery_ids\": [0, 1, 5]},\n      {\"term_id\": \"GO:0016874\", \"supporting_discovery_ids\": [0, 8]}\n    ],\n    \"localization\": [\n      {\"term_id\": \"GO:0005783\", \"supporting_discovery_ids\": [7, 8]},\n      {\"term_id\": \"GO:0031410\", \"supporting_discovery_ids\": [8, 9]}\n    ],\n    \"pathway\": [\n      {\"term_id\": \"R-HSA-392499\", \"supporting_discovery_ids\": [0, 8]},\n      {\"term_id\": \"R-HSA-162582\", \"supporting_discovery_ids\": [0]},\n      {\"term_id\": \"R-HSA-5653656\", \"supporting_discovery_ids\": [8, 9]}\n    ],\n    \"complexes\": [\"CRL3^KLHL12 (Cullin-3 E3 ubiquitin ligase)\"],\n    \"partners\": [\"CUL3\", \"DVL1\", \"DRD4\", \"SEC31A\", \"LZTR1\", \"ARRB2\", \"ARRB1\"],\n    \"other_free_text\": []\n  }\n}","audit_flag":null,"evaluation":{"pairwise":"win","faith_supported":5,"faith_total":5,"faith_pct":100.0}}