{"gene":"CUBN","run_date":"2026-06-09T22:57:19","timeline":{"discoveries":[{"year":1997,"finding":"Cubilin (gp280) was identified as the intrinsic factor-cobalamin (IF-Cbl) receptor: purified gp280 from rat kidney binds the IF-cobalamin complex with an association constant of 0.3×10⁹ M⁻¹, mediates its internalization, and antibodies to gp280 inhibit binding of IF-[57Co]Cbl to intestinal, renal, and yolk sac apical membranes. Immunoelectron microscopy showed gp280 and the previously characterized IFCR are colocalized in the kidney, establishing they are the same protein.","method":"Ligand binding assay (radiolabeled IF-[57Co]Cbl), internalization assay in yolk sac epithelial cells, immunoblotting, immunoprecipitation of [35S]methionine-labeled cells, immunoelectron microscopy","journal":"The Journal of clinical investigation","confidence":"High","confidence_rationale":"Tier 1–2 / Strong — multiple orthogonal methods (binding assay, internalization, immunoprecipitation, immunoelectron microscopy) in a single focused study establishing ligand identity and receptor function","pmids":["9153271"],"is_preprint":false},{"year":1998,"finding":"Human cubilin is a 3597-amino-acid peripheral membrane protein (69% identity to rat cubilin) that binds IF-cobalamin in a calcium- and cobalamin-dependent manner with high affinity, as shown by surface plasmon resonance on ligand-affinity-purified protein. The N-terminal signal sequence is cleaved by the trans-Golgi proteinase furin at a recognition site (Arg7-Glu8-Lys9-Arg), indicating proteolytic processing is part of its maturation.","method":"Surface plasmon resonance, complete cDNA cloning, N-terminal protein sequencing, fluorescence in situ hybridization, radiation hybrid mapping","journal":"Blood","confidence":"High","confidence_rationale":"Tier 1–2 / Strong — surface plasmon resonance binding assay with purified protein, full cDNA characterization, N-terminal sequencing to identify furin cleavage site; multiple orthogonal methods in one study","pmids":["9572993"],"is_preprint":false},{"year":1998,"finding":"Cubilin (gp280) functions as a receptor for myeloma immunoglobulin light chains in the kidney proximal tubule: light chains co-eluted during immunoaffinity purification of cubilin, anti-cubilin antibodies displaced light-chain binding from renal brush-border membranes, cubilin bound multiple light-chain species by surface plasmon resonance, and anti-cubilin antiserum partially inhibited light-chain endocytosis by yolk sac epithelial cells.","method":"Immunoaffinity purification co-elution, antibody displacement of ligand binding from brush-border membranes, surface plasmon resonance, endocytosis inhibition assay in yolk sac epithelial cells","journal":"The American journal of physiology","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — four orthogonal lines of evidence in a single lab, but inhibition was only partial and additional receptors were not excluded","pmids":["9691015"],"is_preprint":false},{"year":1999,"finding":"Loss-of-function mutations in CUBN cause hereditary megaloblastic anaemia 1 (MGA1/Imerslund-Gräsbeck syndrome), characterized by selective intestinal vitamin B12 malabsorption. Two independent disease-specific CUBN mutations were identified in 17 Finnish MGA1 families by linkage disequilibrium mapping and sequencing, establishing CUBN as the causative gene.","method":"Linkage disequilibrium mapping, mutation identification by sequencing, genetic association in patient cohorts","journal":"Nature genetics","confidence":"High","confidence_rationale":"Tier 2 / Strong — disease-causing mutations in multiple independent families, replication across Finnish and Norwegian cohorts, plus convergence with biochemical data on IF-B12 receptor","pmids":["10080186"],"is_preprint":false},{"year":1995,"finding":"Cubilin (gp280) is concentrated in clathrin-coated intermicrovillar membrane areas of yolk sac and proximal tubule epithelial cells. Antibodies to gp280 inhibited internalization of endocytic tracers ([14C]sucrose, peroxidase) and disrupted the early endocytic pathway morphology, establishing a direct role for cubilin in clathrin-mediated endocytosis.","method":"Indirect immunofluorescence, ultrastructural immunoelectron microscopy, endocytosis inhibition assays with antibodies, biosynthetic labeling","journal":"European journal of cell biology","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — localization by immunoelectron microscopy with functional consequence demonstrated by antibody-mediated inhibition of endocytosis; single lab, two orthogonal methods","pmids":["7664754"],"is_preprint":false},{"year":1995,"finding":"Cubilin (gp280) undergoes an unusual processing pathway: unlike gp330, which is fully processed by Golgi enzymes before plasma membrane delivery, gp280 is initially targeted to the plasma membrane in an endoglycosidase H-sensitive (immature, incompletely glycosylated) form and undergoes Golgi processing mainly by recycling through the Golgi apparatus.","method":"Endoglycosidase H sensitivity assay, biosynthetic labeling, subcellular fractionation of yolk sac epithelial cells in culture","journal":"Biochemical and biophysical research communications","confidence":"Medium","confidence_rationale":"Tier 2 / Weak — endoglycosidase H biochemistry clearly demonstrates the processing pathway; single lab, single method type","pmids":["7626048"],"is_preprint":false},{"year":2013,"finding":"A frameshift mutation in exon 53 of CUBN (single base deletion) reduces CUBN mRNA ~10-fold and protein ~20-fold in both ileum and kidney of affected Border Collies via nonsense-mediated mRNA decay, abrogating cubam receptor expression and causing cobalamin malabsorption plus proteinuria of CUBN ligands. Radiolabeled cobalamin uptake studies and SDS-PAGE of urine confirmed functional loss of the receptor.","method":"Whole-genome resequencing, CUBN mRNA/protein quantification, radiolabeled cobalamin uptake assay, SDS-PAGE of urine proteins, genetic segregation analysis","journal":"Molecular genetics and metabolism","confidence":"High","confidence_rationale":"Tier 1–2 / Strong — loss-of-function confirmed by both molecular quantification and functional cobalamin uptake assay, replicated across multiple kindreds","pmids":["23746554"],"is_preprint":false},{"year":2020,"finding":"C-terminal biallelic CUBN variants (located after the vitamin B12-binding domain, i.e., in the C-terminal half of cubilin) cause isolated chronic proteinuria with high albumin fraction and preserved renal function, without megaloblastic anaemia or vitamin B12 malabsorption. This establishes that the C-terminal CUB domains are specifically required for renal albumin reabsorption, functionally separable from the N-terminal IF-cobalamin binding function.","method":"Next-generation sequencing (kidney disease gene panel), bioinformatics, structural modeling, cohort clinical characterization, meta-analyses of population cohorts for albuminuria","journal":"The Journal of clinical investigation","confidence":"High","confidence_rationale":"Tier 2 / Strong — domain-specific genotype–phenotype dissection in 39 patients plus population-level replication; multiple independent families and cohorts","pmids":["31613795"],"is_preprint":false},{"year":2022,"finding":"Novel CUBN variants located after the vitamin B12-binding domain disrupt association of cubilin with its partner amnionless (AMN), causing AMN to mislocalize to the cell cytoplasm rather than the plasma membrane, thereby abolishing the cubam complex at the membrane and causing albuminuria with elevated urinary transferrin and α1-microglobulin but no glomerular filtration barrier impairment.","method":"Exome sequencing, Sanger sequencing, in vitro expression in HEK293T cells, co-immunoprecipitation to assess cubilin–AMN interaction, subcellular localization of AMN by immunofluorescence, mouse in vivo experiments","journal":"Journal of translational medicine","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — co-IP and localization experiments in cell lines plus in vivo validation; single lab with two orthogonal methods","pmids":["36266725"],"is_preprint":false},{"year":2025,"finding":"A novel truncated CUBN transcript (isoform) exists that is expressed in both kidney and small intestine, whereas full-length cubilin is expressed only in the kidney. Because only the truncated isoform is present in the intestine, C-terminal CUBN variants that truncate or modify the region absent from the intestinal isoform do not affect vitamin B12 absorption, explaining why patients with C-terminal biallelic CUBN variants have isolated proteinuria without cobalamin malabsorption.","method":"Targeted panel sequencing, cDNA transcript analysis to identify novel isoform, tissue expression profiling (kidney vs. small intestine), electron microscopy of renal biopsies","journal":"Kidney international reports","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — novel isoform identified by cDNA analysis with tissue expression profiling providing mechanistic explanation; single lab but strong internal consistency with clinical data from 52 patients","pmids":["41624452"],"is_preprint":false}],"current_model":"Cubilin (CUBN) is a large peripheral membrane endocytic receptor concentrated in clathrin-coated intermicrovillar domains of intestinal and renal proximal tubule epithelial cells; it forms a functional heteromeric complex (cubam) with amnionless (AMN) at the apical plasma membrane, where it binds intrinsic factor-cobalamin (via its N-terminal region), albumin, transferrin, light chains, and other ligands through its 27 CUB domains, mediating their endocytic uptake—with the C-terminal CUB domains specifically required for renal albumin reabsorption, as established by domain-specific loss-of-function mutations that disrupt cubilin–AMN interaction and cause isolated proteinuria without vitamin B12 malabsorption."},"narrative":{"mechanistic_narrative":"Cubilin (CUBN) is a large peripheral membrane endocytic receptor of intestinal and renal proximal tubule epithelia that mediates clathrin-dependent uptake of filtered and luminal ligands [PMID:9153271, PMID:7664754]. It was first identified as the intrinsic factor-cobalamin (IF-Cbl) receptor (gp280/IFCR), binding IF-cobalamin with high affinity in a calcium- and cobalamin-dependent manner and internalizing the complex at apical membranes of intestinal, renal, and yolk sac cells [PMID:9153271, PMID:9572993]. The mature protein is a ~3597-residue peripheral membrane protein whose N-terminal signal sequence is cleaved by the trans-Golgi protease furin during maturation, and which is targeted to the plasma membrane in an immature, endoglycosidase H-sensitive form that completes glycosylation by recycling through the Golgi [PMID:9572993, PMID:7626048]. Cubilin concentrates in clathrin-coated intermicrovillar membrane domains, where antibody-mediated blockade inhibits endocytic tracer uptake, establishing its direct role in receptor-mediated endocytosis [PMID:7664754]. Beyond IF-cobalamin, it serves as a receptor for myeloma immunoglobulin light chains in the proximal tubule [PMID:9691015] and for albumin and other proteins reabsorbed from the glomerular filtrate [PMID:31613795]. Membrane expression and ligand uptake require its partner amnionless (AMN), with which cubilin forms the apical cubam complex; variants that disrupt cubilin–AMN association cause AMN to mislocalize to the cytoplasm and abolish surface cubam [PMID:36266725]. Domain function is regionally separable: N-terminal regions mediate IF-cobalamin binding, while C-terminal CUB domains are specifically required for renal albumin reabsorption [PMID:31613795]. Loss-of-function CUBN mutations cause hereditary megaloblastic anaemia 1 (Imerslund-Gräsbeck syndrome) with selective intestinal B12 malabsorption [PMID:10080186], whereas C-terminal biallelic variants cause isolated chronic proteinuria without B12 malabsorption [PMID:31613795]; this dissociation is explained by a truncated CUBN isoform expressed in intestine that lacks the C-terminal region, sparing cobalamin absorption when C-terminal variants are present [PMID:41624452].","teleology":[{"year":1995,"claim":"Establishing where cubilin acts and whether it is functionally required for endocytosis defined its cellular role before its ligands were known.","evidence":"Immunofluorescence and immunoelectron microscopy with antibody-mediated endocytosis inhibition in yolk sac and proximal tubule epithelia","pmids":["7664754"],"confidence":"Medium","gaps":["Ligand identity not yet established","Did not define the molecular interactions driving clathrin recruitment"]},{"year":1995,"claim":"Characterizing cubilin's unusual maturation showed it reaches the plasma membrane in an immature form and completes processing by Golgi recycling, distinguishing its trafficking from related receptors.","evidence":"Endoglycosidase H sensitivity assay, biosynthetic labeling and subcellular fractionation of cultured yolk sac epithelial cells","pmids":["7626048"],"confidence":"Medium","gaps":["Single method type from one lab","Functional consequence of the recycling route not tested"]},{"year":1997,"claim":"Identifying gp280 as the IF-cobalamin receptor assigned cubilin its first defined ligand and physiological function.","evidence":"Radiolabeled IF-[57Co]Cbl binding and internalization assays, immunoprecipitation, and immunoelectron microscopy in rat kidney and yolk sac","pmids":["9153271"],"confidence":"High","gaps":["Did not define the binding domain","No partner protein for membrane anchoring identified"]},{"year":1998,"claim":"Cloning human cubilin and mapping its furin cleavage site defined the mature receptor and confirmed calcium/cobalamin-dependent high-affinity IF-Cbl binding.","evidence":"Surface plasmon resonance on affinity-purified protein, full cDNA cloning, N-terminal sequencing, FISH and radiation hybrid mapping","pmids":["9572993"],"confidence":"High","gaps":["No membrane anchor or transmembrane domain identified, leaving membrane association unexplained","Other ligands not yet defined"]},{"year":1998,"claim":"Demonstrating that cubilin binds myeloma immunoglobulin light chains broadened its role beyond cobalamin to proximal tubule protein reabsorption.","evidence":"Immunoaffinity co-elution, antibody displacement from brush-border membranes, surface plasmon resonance, and endocytosis inhibition in yolk sac cells","pmids":["9691015"],"confidence":"Medium","gaps":["Endocytosis inhibition was only partial","Additional light-chain receptors not excluded"]},{"year":1999,"claim":"Identifying disease-causing CUBN mutations established the gene as causative for hereditary megaloblastic anaemia 1, linking receptor loss to selective B12 malabsorption in humans.","evidence":"Linkage disequilibrium mapping and mutation sequencing in 17 Finnish MGA1 families","pmids":["10080186"],"confidence":"High","gaps":["Did not address renal protein-reabsorption phenotypes","Mechanism by which mutations impair receptor function not defined"]},{"year":2013,"claim":"An animal frameshift model showed that CUBN loss-of-function via nonsense-mediated decay abrogates cubam and causes both cobalamin malabsorption and proteinuria, linking the two functions to one receptor.","evidence":"Whole-genome resequencing, mRNA/protein quantification, radiolabeled cobalamin uptake and urine SDS-PAGE in Border Collies","pmids":["23746554"],"confidence":"High","gaps":["Did not separate cobalamin and albumin functions by domain","Mechanism of AMN dependence not addressed"]},{"year":2020,"claim":"Domain-specific genotype–phenotype dissection showed C-terminal CUB domains are required for renal albumin reabsorption independently of N-terminal IF-cobalamin binding.","evidence":"Kidney disease gene-panel sequencing, structural modeling, and clinical/population cohort analysis in 39 patients","pmids":["31613795"],"confidence":"High","gaps":["Did not demonstrate the molecular mechanism of C-terminal variant dysfunction","Why intestinal B12 uptake is spared not explained"]},{"year":2022,"claim":"Linking C-terminal variants to loss of cubilin–AMN association explained how they abolish surface cubam through AMN cytoplasmic mislocalization.","evidence":"Exome sequencing, HEK293T expression, co-immunoprecipitation, AMN immunofluorescence localization, and mouse in vivo experiments","pmids":["36266725"],"confidence":"Medium","gaps":["Single lab with co-IP not reciprocally validated","Quantitative contribution of AMN mislocalization to proteinuria not measured"]},{"year":2025,"claim":"Identifying a truncated, intestine-expressed CUBN isoform resolved why C-terminal variants cause renal proteinuria without affecting cobalamin absorption.","evidence":"Targeted panel sequencing, cDNA transcript analysis, tissue expression profiling (kidney vs intestine), and renal biopsy electron microscopy in 52 patients","pmids":["41624452"],"confidence":"Medium","gaps":["Isoform identified by cDNA analysis in one lab","Functional reconstitution of the truncated isoform not performed"]},{"year":null,"claim":"How cubilin, a protein lacking its own transmembrane anchor, couples ligand binding to clathrin-mediated internalization at the molecular level remains incompletely defined.","evidence":"","pmids":[],"confidence":"Medium","gaps":["No structural model of the full cubam endocytic complex in the corpus","Mechanism of clathrin recruitment and cargo handoff not defined","Binding sites for albumin and transferrin not mapped to specific CUB domains"]}],"mechanism_profile":{"molecular_activity":[{"term_id":"GO:0038024","term_label":"cargo receptor activity","supporting_discovery_ids":[0,2,7]},{"term_id":"GO:0140104","term_label":"molecular carrier activity","supporting_discovery_ids":[0,1]}],"localization":[{"term_id":"GO:0005886","term_label":"plasma membrane","supporting_discovery_ids":[4,8]},{"term_id":"GO:0031410","term_label":"cytoplasmic vesicle","supporting_discovery_ids":[4]},{"term_id":"GO:0005794","term_label":"Golgi apparatus","supporting_discovery_ids":[5]}],"pathway":[{"term_id":"R-HSA-5653656","term_label":"Vesicle-mediated transport","supporting_discovery_ids":[0,4]},{"term_id":"R-HSA-382551","term_label":"Transport of small molecules","supporting_discovery_ids":[0,7]}],"complexes":["cubam (cubilin-amnionless complex)"],"partners":["AMN"],"other_free_text":[]}},"prefetch_data":{"uniprot":{"accession":"O60494","full_name":"Cubilin","aliases":["460 kDa receptor","Intestinal intrinsic factor receptor","Intrinsic factor-cobalamin receptor","Intrinsic factor-vitamin B12 receptor"],"length_aa":3623,"mass_kda":398.7,"function":"Endocytic receptor which plays a role in lipoprotein, vitamin and iron metabolism by facilitating their uptake (PubMed:10371504, PubMed:11606717, PubMed:11717447, PubMed:14576052, PubMed:9572993). Acts together with LRP2 to mediate endocytosis of high-density lipoproteins, GC, hemoglobin, ALB, TF and SCGB1A1. Acts together with AMN to mediate endocytosis of the CBLIF-cobalamin complex (PubMed:14576052, PubMed:9572993). Binds to ALB, MB, Kappa and lambda-light chains, TF, hemoglobin, GC, SCGB1A1, APOA1, high density lipoprotein, and the CBLIF-cobalamin complex. Ligand binding requires calcium (PubMed:9572993). Serves as important transporter in several absorptive epithelia, including intestine, renal proximal tubules and embryonic yolk sac. May play an important role in the development of the peri-implantation embryo through internalization of APOA1 and cholesterol. Binds to LGALS3 at the maternal-fetal interface","subcellular_location":"Apical cell membrane; Cell membrane; Membrane, coated pit; Endosome; Lysosome membrane","url":"https://www.uniprot.org/uniprotkb/O60494/entry"},"depmap":{"release":"DepMap","has_data":true,"is_common_essential":false,"resolved_as":"","url":"https://depmap.org/portal/gene/CUBN","classification":"Not Classified","n_dependent_lines":2,"n_total_lines":1208,"dependency_fraction":0.0016556291390728477},"opencell":{"profiled":false,"resolved_as":"","ensg_id":"","cell_line_id":"","localizations":[],"interactors":[],"url":"https://opencell.sf.czbiohub.org/search/CUBN","total_profiled":1310},"omim":[{"mim_id":"619845","title":"RETINITIS PIGMENTOSA 93; RP93","url":"https://www.omim.org/entry/619845"},{"mim_id":"618884","title":"PROTEINURIA, CHRONIC BENIGN; PROCHOB","url":"https://www.omim.org/entry/618884"},{"mim_id":"618882","title":"IMERSLUND-GRASBECK SYNDROME 2; IGS2","url":"https://www.omim.org/entry/618882"},{"mim_id":"610528","title":"CHROMODOMAIN HELICASE DNA-BINDING PROTEIN 8; CHD8","url":"https://www.omim.org/entry/610528"},{"mim_id":"609342","title":"COBALAMIN-BINDING INTRINSIC FACTOR; CBLIF","url":"https://www.omim.org/entry/609342"}],"hpa":{"profiled":true,"resolved_as":"","reliability":"","locations":[],"tissue_specificity":"Tissue enriched","tissue_distribution":"Detected in many","driving_tissues":[{"tissue":"kidney","ntpm":131.1}],"url":"https://www.proteinatlas.org/search/CUBN"},"hgnc":{"alias_symbol":["IFCR","gp280"],"prev_symbol":["MGA1"]},"alphafold":{"accession":"O60494","domains":[],"viewer_url":"https://alphafold.ebi.ac.uk/entry/O60494","model_url":"","pae_url":"","plddt_mean":null},"mouse_models":{"mgi_url":"https://www.informatics.jax.org/marker/summary?nomen=CUBN","jax_strain_url":"https://www.jax.org/strain/search?query=CUBN"},"sequence":{"accession":"O60494","fasta_url":"https://rest.uniprot.org/uniprotkb/O60494.fasta","uniprot_url":"https://www.uniprot.org/uniprotkb/O60494/entry","alphafold_viewer_url":"https://alphafold.ebi.ac.uk/entry/O60494"}},"corpus_meta":[{"pmid":"10080186","id":"PMC_10080186","title":"Mutations in CUBN, encoding the intrinsic factor-vitamin B12 receptor, cubilin, cause hereditary megaloblastic anaemia 1.","date":"1999","source":"Nature genetics","url":"https://pubmed.ncbi.nlm.nih.gov/10080186","citation_count":195,"is_preprint":false},{"pmid":"21355061","id":"PMC_21355061","title":"CUBN is a gene locus for albuminuria.","date":"2011","source":"Journal of the American Society of Nephrology : JASN","url":"https://pubmed.ncbi.nlm.nih.gov/21355061","citation_count":191,"is_preprint":false},{"pmid":"9572993","id":"PMC_9572993","title":"The human intrinsic factor-vitamin B12 receptor, cubilin: molecular characterization and chromosomal mapping of the gene to 10p within the autosomal recessive megaloblastic anemia (MGA1) region.","date":"1998","source":"Blood","url":"https://pubmed.ncbi.nlm.nih.gov/9572993","citation_count":114,"is_preprint":false},{"pmid":"9153271","id":"PMC_9153271","title":"Identification of rat yolk sac target protein of teratogenic antibodies, gp280, as intrinsic factor-cobalamin receptor.","date":"1997","source":"The Journal of clinical investigation","url":"https://pubmed.ncbi.nlm.nih.gov/9153271","citation_count":95,"is_preprint":false},{"pmid":"9691015","id":"PMC_9691015","title":"Myeloma light chains are ligands for cubilin (gp280).","date":"1998","source":"The American journal of physiology","url":"https://pubmed.ncbi.nlm.nih.gov/9691015","citation_count":91,"is_preprint":false},{"pmid":"31613795","id":"PMC_31613795","title":"Human C-terminal CUBN variants associate with chronic proteinuria and normal renal function.","date":"2020","source":"The Journal of clinical investigation","url":"https://pubmed.ncbi.nlm.nih.gov/31613795","citation_count":73,"is_preprint":false},{"pmid":"19161160","id":"PMC_19161160","title":"An association study of 45 folate-related genes in spina bifida: Involvement of cubilin (CUBN) and tRNA aspartic acid methyltransferase 1 (TRDMT1).","date":"2009","source":"Birth defects research. Part A, Clinical and molecular teratology","url":"https://pubmed.ncbi.nlm.nih.gov/19161160","citation_count":62,"is_preprint":false},{"pmid":"7664754","id":"PMC_7664754","title":"Immunofunctional properties of a yolk sac epithelial cell line expressing two proteins gp280 and gp330 of the intermicrovillar area of proximal tubule cells: inhibition of endocytosis by the specific antibodies.","date":"1995","source":"European journal of cell biology","url":"https://pubmed.ncbi.nlm.nih.gov/7664754","citation_count":41,"is_preprint":false},{"pmid":"20500530","id":"PMC_20500530","title":"Identification of Mga1, a G-protein alpha-subunit gene involved in regulating citrinin and pigment production in Monascus ruber M7.","date":"2010","source":"FEMS microbiology letters","url":"https://pubmed.ncbi.nlm.nih.gov/20500530","citation_count":33,"is_preprint":false},{"pmid":"23613799","id":"PMC_23613799","title":"A frameshift mutation in the cubilin gene (CUBN) in Border Collies with Imerslund-Gräsbeck 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European Dialysis and Transplant Association - European Renal Association","url":"https://pubmed.ncbi.nlm.nih.gov/24052458","citation_count":5,"is_preprint":false},{"pmid":"37312928","id":"PMC_37312928","title":"Isolated benign persistent proteinuria with novel association of CUBN (cubilin) variants.","date":"2023","source":"Clinical case reports","url":"https://pubmed.ncbi.nlm.nih.gov/37312928","citation_count":5,"is_preprint":false},{"pmid":"39390623","id":"PMC_39390623","title":"To treat or not to treat: CUBN-associated persistent proteinuria.","date":"2024","source":"Kidney research and clinical practice","url":"https://pubmed.ncbi.nlm.nih.gov/39390623","citation_count":4,"is_preprint":false},{"pmid":"36926036","id":"PMC_36926036","title":"Four missense genetic variants in CUBN are associated with higher levels of eGFR in non-diabetes but not in diabetes mellitus or its subtypes: A genetic association study in Europeans.","date":"2023","source":"Frontiers in endocrinology","url":"https://pubmed.ncbi.nlm.nih.gov/36926036","citation_count":4,"is_preprint":false},{"pmid":"23390341","id":"PMC_23390341","title":"Phylogenetic analysis of cubilin (CUBN) gene.","date":"2013","source":"Bioinformation","url":"https://pubmed.ncbi.nlm.nih.gov/23390341","citation_count":4,"is_preprint":false},{"pmid":"17065800","id":"PMC_17065800","title":"Assignment of linkage groups to turkey chromosome 1 (MGA1).","date":"2006","source":"Cytogenetic and genome research","url":"https://pubmed.ncbi.nlm.nih.gov/17065800","citation_count":4,"is_preprint":false},{"pmid":"39698573","id":"PMC_39698573","title":"Depletion of intrinsic renal macrophages with moderate-to-high expression of CD163, MRC1, PTH2R, PDE4D, and CUBN in regulating podocyte injury in diabetic nephropathy: a single-cell RNA sequencing analysis.","date":"2024","source":"Translational andrology and urology","url":"https://pubmed.ncbi.nlm.nih.gov/39698573","citation_count":3,"is_preprint":false},{"pmid":"41624452","id":"PMC_41624452","title":"Clinical and Genetic Insights Into Isolated Proteinuria With CUBN Variants.","date":"2025","source":"Kidney international reports","url":"https://pubmed.ncbi.nlm.nih.gov/41624452","citation_count":3,"is_preprint":false},{"pmid":"38488435","id":"PMC_38488435","title":"Identification of novel pathogenic variants of CUBN in patients with isolated proteinuria.","date":"2024","source":"Molecular genetics & genomic medicine","url":"https://pubmed.ncbi.nlm.nih.gov/38488435","citation_count":2,"is_preprint":false},{"pmid":"32803705","id":"PMC_32803705","title":"Tuberculosis risk is associated with genetic polymorphisms in the LRP2, CUBN, and VDR genes.","date":"2020","source":"Genes & genomics","url":"https://pubmed.ncbi.nlm.nih.gov/32803705","citation_count":2,"is_preprint":false},{"pmid":"33031161","id":"PMC_33031161","title":"Novel CUBN Mutation in a Young Child With Megaloblastic Anemia.","date":"2021","source":"Journal of pediatric hematology/oncology","url":"https://pubmed.ncbi.nlm.nih.gov/33031161","citation_count":2,"is_preprint":false},{"pmid":"39187978","id":"PMC_39187978","title":"New findings on the genetic basis of feathered legs in chickens: association of CUBN gene mutations with feathered-leg phenotype.","date":"2024","source":"Journal of animal science","url":"https://pubmed.ncbi.nlm.nih.gov/39187978","citation_count":2,"is_preprint":false},{"pmid":"39102129","id":"PMC_39102129","title":"Identification of CUBN variants in triplets with a 20-year history of proteinuria.","date":"2024","source":"CEN case reports","url":"https://pubmed.ncbi.nlm.nih.gov/39102129","citation_count":2,"is_preprint":false},{"pmid":"39873481","id":"PMC_39873481","title":"Relationship between the CUBN and the MIA3 gene copy number variation and growth traits in different cattle breeds.","date":"2025","source":"Animal biotechnology","url":"https://pubmed.ncbi.nlm.nih.gov/39873481","citation_count":1,"is_preprint":false},{"pmid":"40461506","id":"PMC_40461506","title":"Genomic locus of lncRNA-Gm26793 forms an inter-chromosomal interaction with Cubn to ensure proper stem cell differentiation in vitro and in vivo.","date":"2025","source":"Cell discovery","url":"https://pubmed.ncbi.nlm.nih.gov/40461506","citation_count":0,"is_preprint":false},{"pmid":"39911140","id":"PMC_39911140","title":"Chronic Benign Tubular Albuminuria From Compound Heterozygous Variants in CUBN: A Case Report.","date":"2025","source":"Canadian journal of kidney health and disease","url":"https://pubmed.ncbi.nlm.nih.gov/39911140","citation_count":0,"is_preprint":false},{"pmid":"42161660","id":"PMC_42161660","title":"[Long-term outcomes of first-line iFCR regimen in chronic lymphocytic leukemia/small lymphocytic lymphoma and the role of MRD].","date":"2026","source":"Zhonghua xue ye xue za zhi = Zhonghua xueyexue zazhi","url":"https://pubmed.ncbi.nlm.nih.gov/42161660","citation_count":0,"is_preprint":false}],"cost":{"stage1":{"model":"claude-sonnet-4-6","input_tokens":26431,"output_tokens":2904,"usd":0.061427,"stage1_stop_reason":"end_turn"},"stage2":{"model":"claude-opus-4-8","input_tokens":10364,"output_tokens":3501,"usd":0.069672,"stage2_stop_reason":"end_turn"},"total_usd":0.131099,"stage1_batch_id":"msgbatch_01ACAxJQabDsht39JXeWG22d","stage2_batch_id":"msgbatch_01QEU22A9U5sbPTgsMzTmvSf","note":"batch pricing = 50% of standard"},"stage1_raw":"```json\n{\n  \"discoveries\": [\n    {\n      \"year\": 1997,\n      \"finding\": \"Cubilin (gp280) was identified as the intrinsic factor-cobalamin (IF-Cbl) receptor: purified gp280 from rat kidney binds the IF-cobalamin complex with an association constant of 0.3×10⁹ M⁻¹, mediates its internalization, and antibodies to gp280 inhibit binding of IF-[57Co]Cbl to intestinal, renal, and yolk sac apical membranes. Immunoelectron microscopy showed gp280 and the previously characterized IFCR are colocalized in the kidney, establishing they are the same protein.\",\n      \"method\": \"Ligand binding assay (radiolabeled IF-[57Co]Cbl), internalization assay in yolk sac epithelial cells, immunoblotting, immunoprecipitation of [35S]methionine-labeled cells, immunoelectron microscopy\",\n      \"journal\": \"The Journal of clinical investigation\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1–2 / Strong — multiple orthogonal methods (binding assay, internalization, immunoprecipitation, immunoelectron microscopy) in a single focused study establishing ligand identity and receptor function\",\n      \"pmids\": [\"9153271\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 1998,\n      \"finding\": \"Human cubilin is a 3597-amino-acid peripheral membrane protein (69% identity to rat cubilin) that binds IF-cobalamin in a calcium- and cobalamin-dependent manner with high affinity, as shown by surface plasmon resonance on ligand-affinity-purified protein. The N-terminal signal sequence is cleaved by the trans-Golgi proteinase furin at a recognition site (Arg7-Glu8-Lys9-Arg), indicating proteolytic processing is part of its maturation.\",\n      \"method\": \"Surface plasmon resonance, complete cDNA cloning, N-terminal protein sequencing, fluorescence in situ hybridization, radiation hybrid mapping\",\n      \"journal\": \"Blood\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1–2 / Strong — surface plasmon resonance binding assay with purified protein, full cDNA characterization, N-terminal sequencing to identify furin cleavage site; multiple orthogonal methods in one study\",\n      \"pmids\": [\"9572993\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 1998,\n      \"finding\": \"Cubilin (gp280) functions as a receptor for myeloma immunoglobulin light chains in the kidney proximal tubule: light chains co-eluted during immunoaffinity purification of cubilin, anti-cubilin antibodies displaced light-chain binding from renal brush-border membranes, cubilin bound multiple light-chain species by surface plasmon resonance, and anti-cubilin antiserum partially inhibited light-chain endocytosis by yolk sac epithelial cells.\",\n      \"method\": \"Immunoaffinity purification co-elution, antibody displacement of ligand binding from brush-border membranes, surface plasmon resonance, endocytosis inhibition assay in yolk sac epithelial cells\",\n      \"journal\": \"The American journal of physiology\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — four orthogonal lines of evidence in a single lab, but inhibition was only partial and additional receptors were not excluded\",\n      \"pmids\": [\"9691015\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 1999,\n      \"finding\": \"Loss-of-function mutations in CUBN cause hereditary megaloblastic anaemia 1 (MGA1/Imerslund-Gräsbeck syndrome), characterized by selective intestinal vitamin B12 malabsorption. Two independent disease-specific CUBN mutations were identified in 17 Finnish MGA1 families by linkage disequilibrium mapping and sequencing, establishing CUBN as the causative gene.\",\n      \"method\": \"Linkage disequilibrium mapping, mutation identification by sequencing, genetic association in patient cohorts\",\n      \"journal\": \"Nature genetics\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — disease-causing mutations in multiple independent families, replication across Finnish and Norwegian cohorts, plus convergence with biochemical data on IF-B12 receptor\",\n      \"pmids\": [\"10080186\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 1995,\n      \"finding\": \"Cubilin (gp280) is concentrated in clathrin-coated intermicrovillar membrane areas of yolk sac and proximal tubule epithelial cells. Antibodies to gp280 inhibited internalization of endocytic tracers ([14C]sucrose, peroxidase) and disrupted the early endocytic pathway morphology, establishing a direct role for cubilin in clathrin-mediated endocytosis.\",\n      \"method\": \"Indirect immunofluorescence, ultrastructural immunoelectron microscopy, endocytosis inhibition assays with antibodies, biosynthetic labeling\",\n      \"journal\": \"European journal of cell biology\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — localization by immunoelectron microscopy with functional consequence demonstrated by antibody-mediated inhibition of endocytosis; single lab, two orthogonal methods\",\n      \"pmids\": [\"7664754\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 1995,\n      \"finding\": \"Cubilin (gp280) undergoes an unusual processing pathway: unlike gp330, which is fully processed by Golgi enzymes before plasma membrane delivery, gp280 is initially targeted to the plasma membrane in an endoglycosidase H-sensitive (immature, incompletely glycosylated) form and undergoes Golgi processing mainly by recycling through the Golgi apparatus.\",\n      \"method\": \"Endoglycosidase H sensitivity assay, biosynthetic labeling, subcellular fractionation of yolk sac epithelial cells in culture\",\n      \"journal\": \"Biochemical and biophysical research communications\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Weak — endoglycosidase H biochemistry clearly demonstrates the processing pathway; single lab, single method type\",\n      \"pmids\": [\"7626048\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2013,\n      \"finding\": \"A frameshift mutation in exon 53 of CUBN (single base deletion) reduces CUBN mRNA ~10-fold and protein ~20-fold in both ileum and kidney of affected Border Collies via nonsense-mediated mRNA decay, abrogating cubam receptor expression and causing cobalamin malabsorption plus proteinuria of CUBN ligands. Radiolabeled cobalamin uptake studies and SDS-PAGE of urine confirmed functional loss of the receptor.\",\n      \"method\": \"Whole-genome resequencing, CUBN mRNA/protein quantification, radiolabeled cobalamin uptake assay, SDS-PAGE of urine proteins, genetic segregation analysis\",\n      \"journal\": \"Molecular genetics and metabolism\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1–2 / Strong — loss-of-function confirmed by both molecular quantification and functional cobalamin uptake assay, replicated across multiple kindreds\",\n      \"pmids\": [\"23746554\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2020,\n      \"finding\": \"C-terminal biallelic CUBN variants (located after the vitamin B12-binding domain, i.e., in the C-terminal half of cubilin) cause isolated chronic proteinuria with high albumin fraction and preserved renal function, without megaloblastic anaemia or vitamin B12 malabsorption. This establishes that the C-terminal CUB domains are specifically required for renal albumin reabsorption, functionally separable from the N-terminal IF-cobalamin binding function.\",\n      \"method\": \"Next-generation sequencing (kidney disease gene panel), bioinformatics, structural modeling, cohort clinical characterization, meta-analyses of population cohorts for albuminuria\",\n      \"journal\": \"The Journal of clinical investigation\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — domain-specific genotype–phenotype dissection in 39 patients plus population-level replication; multiple independent families and cohorts\",\n      \"pmids\": [\"31613795\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2022,\n      \"finding\": \"Novel CUBN variants located after the vitamin B12-binding domain disrupt association of cubilin with its partner amnionless (AMN), causing AMN to mislocalize to the cell cytoplasm rather than the plasma membrane, thereby abolishing the cubam complex at the membrane and causing albuminuria with elevated urinary transferrin and α1-microglobulin but no glomerular filtration barrier impairment.\",\n      \"method\": \"Exome sequencing, Sanger sequencing, in vitro expression in HEK293T cells, co-immunoprecipitation to assess cubilin–AMN interaction, subcellular localization of AMN by immunofluorescence, mouse in vivo experiments\",\n      \"journal\": \"Journal of translational medicine\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — co-IP and localization experiments in cell lines plus in vivo validation; single lab with two orthogonal methods\",\n      \"pmids\": [\"36266725\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2025,\n      \"finding\": \"A novel truncated CUBN transcript (isoform) exists that is expressed in both kidney and small intestine, whereas full-length cubilin is expressed only in the kidney. Because only the truncated isoform is present in the intestine, C-terminal CUBN variants that truncate or modify the region absent from the intestinal isoform do not affect vitamin B12 absorption, explaining why patients with C-terminal biallelic CUBN variants have isolated proteinuria without cobalamin malabsorption.\",\n      \"method\": \"Targeted panel sequencing, cDNA transcript analysis to identify novel isoform, tissue expression profiling (kidney vs. small intestine), electron microscopy of renal biopsies\",\n      \"journal\": \"Kidney international reports\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — novel isoform identified by cDNA analysis with tissue expression profiling providing mechanistic explanation; single lab but strong internal consistency with clinical data from 52 patients\",\n      \"pmids\": [\"41624452\"],\n      \"is_preprint\": false\n    }\n  ],\n  \"current_model\": \"Cubilin (CUBN) is a large peripheral membrane endocytic receptor concentrated in clathrin-coated intermicrovillar domains of intestinal and renal proximal tubule epithelial cells; it forms a functional heteromeric complex (cubam) with amnionless (AMN) at the apical plasma membrane, where it binds intrinsic factor-cobalamin (via its N-terminal region), albumin, transferrin, light chains, and other ligands through its 27 CUB domains, mediating their endocytic uptake—with the C-terminal CUB domains specifically required for renal albumin reabsorption, as established by domain-specific loss-of-function mutations that disrupt cubilin–AMN interaction and cause isolated proteinuria without vitamin B12 malabsorption.\"\n}\n```","stage2_raw":"{\n  \"mechanistic_narrative\": \"Cubilin (CUBN) is a large peripheral membrane endocytic receptor of intestinal and renal proximal tubule epithelia that mediates clathrin-dependent uptake of filtered and luminal ligands [#0, #4]. It was first identified as the intrinsic factor-cobalamin (IF-Cbl) receptor (gp280/IFCR), binding IF-cobalamin with high affinity in a calcium- and cobalamin-dependent manner and internalizing the complex at apical membranes of intestinal, renal, and yolk sac cells [#0, #1]. The mature protein is a ~3597-residue peripheral membrane protein whose N-terminal signal sequence is cleaved by the trans-Golgi protease furin during maturation, and which is targeted to the plasma membrane in an immature, endoglycosidase H-sensitive form that completes glycosylation by recycling through the Golgi [#1, #5]. Cubilin concentrates in clathrin-coated intermicrovillar membrane domains, where antibody-mediated blockade inhibits endocytic tracer uptake, establishing its direct role in receptor-mediated endocytosis [#4]. Beyond IF-cobalamin, it serves as a receptor for myeloma immunoglobulin light chains in the proximal tubule [#2] and for albumin and other proteins reabsorbed from the glomerular filtrate [#7]. Membrane expression and ligand uptake require its partner amnionless (AMN), with which cubilin forms the apical cubam complex; variants that disrupt cubilin–AMN association cause AMN to mislocalize to the cytoplasm and abolish surface cubam [#8]. Domain function is regionally separable: N-terminal regions mediate IF-cobalamin binding, while C-terminal CUB domains are specifically required for renal albumin reabsorption [#7]. Loss-of-function CUBN mutations cause hereditary megaloblastic anaemia 1 (Imerslund-Gräsbeck syndrome) with selective intestinal B12 malabsorption [#3], whereas C-terminal biallelic variants cause isolated chronic proteinuria without B12 malabsorption [#7]; this dissociation is explained by a truncated CUBN isoform expressed in intestine that lacks the C-terminal region, sparing cobalamin absorption when C-terminal variants are present [#9].\",\n  \"teleology\": [\n    {\n      \"year\": 1995,\n      \"claim\": \"Establishing where cubilin acts and whether it is functionally required for endocytosis defined its cellular role before its ligands were known.\",\n      \"evidence\": \"Immunofluorescence and immunoelectron microscopy with antibody-mediated endocytosis inhibition in yolk sac and proximal tubule epithelia\",\n      \"pmids\": [\"7664754\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Ligand identity not yet established\", \"Did not define the molecular interactions driving clathrin recruitment\"]\n    },\n    {\n      \"year\": 1995,\n      \"claim\": \"Characterizing cubilin's unusual maturation showed it reaches the plasma membrane in an immature form and completes processing by Golgi recycling, distinguishing its trafficking from related receptors.\",\n      \"evidence\": \"Endoglycosidase H sensitivity assay, biosynthetic labeling and subcellular fractionation of cultured yolk sac epithelial cells\",\n      \"pmids\": [\"7626048\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Single method type from one lab\", \"Functional consequence of the recycling route not tested\"]\n    },\n    {\n      \"year\": 1997,\n      \"claim\": \"Identifying gp280 as the IF-cobalamin receptor assigned cubilin its first defined ligand and physiological function.\",\n      \"evidence\": \"Radiolabeled IF-[57Co]Cbl binding and internalization assays, immunoprecipitation, and immunoelectron microscopy in rat kidney and yolk sac\",\n      \"pmids\": [\"9153271\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Did not define the binding domain\", \"No partner protein for membrane anchoring identified\"]\n    },\n    {\n      \"year\": 1998,\n      \"claim\": \"Cloning human cubilin and mapping its furin cleavage site defined the mature receptor and confirmed calcium/cobalamin-dependent high-affinity IF-Cbl binding.\",\n      \"evidence\": \"Surface plasmon resonance on affinity-purified protein, full cDNA cloning, N-terminal sequencing, FISH and radiation hybrid mapping\",\n      \"pmids\": [\"9572993\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"No membrane anchor or transmembrane domain identified, leaving membrane association unexplained\", \"Other ligands not yet defined\"]\n    },\n    {\n      \"year\": 1998,\n      \"claim\": \"Demonstrating that cubilin binds myeloma immunoglobulin light chains broadened its role beyond cobalamin to proximal tubule protein reabsorption.\",\n      \"evidence\": \"Immunoaffinity co-elution, antibody displacement from brush-border membranes, surface plasmon resonance, and endocytosis inhibition in yolk sac cells\",\n      \"pmids\": [\"9691015\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Endocytosis inhibition was only partial\", \"Additional light-chain receptors not excluded\"]\n    },\n    {\n      \"year\": 1999,\n      \"claim\": \"Identifying disease-causing CUBN mutations established the gene as causative for hereditary megaloblastic anaemia 1, linking receptor loss to selective B12 malabsorption in humans.\",\n      \"evidence\": \"Linkage disequilibrium mapping and mutation sequencing in 17 Finnish MGA1 families\",\n      \"pmids\": [\"10080186\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Did not address renal protein-reabsorption phenotypes\", \"Mechanism by which mutations impair receptor function not defined\"]\n    },\n    {\n      \"year\": 2013,\n      \"claim\": \"An animal frameshift model showed that CUBN loss-of-function via nonsense-mediated decay abrogates cubam and causes both cobalamin malabsorption and proteinuria, linking the two functions to one receptor.\",\n      \"evidence\": \"Whole-genome resequencing, mRNA/protein quantification, radiolabeled cobalamin uptake and urine SDS-PAGE in Border Collies\",\n      \"pmids\": [\"23746554\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Did not separate cobalamin and albumin functions by domain\", \"Mechanism of AMN dependence not addressed\"]\n    },\n    {\n      \"year\": 2020,\n      \"claim\": \"Domain-specific genotype–phenotype dissection showed C-terminal CUB domains are required for renal albumin reabsorption independently of N-terminal IF-cobalamin binding.\",\n      \"evidence\": \"Kidney disease gene-panel sequencing, structural modeling, and clinical/population cohort analysis in 39 patients\",\n      \"pmids\": [\"31613795\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Did not demonstrate the molecular mechanism of C-terminal variant dysfunction\", \"Why intestinal B12 uptake is spared not explained\"]\n    },\n    {\n      \"year\": 2022,\n      \"claim\": \"Linking C-terminal variants to loss of cubilin–AMN association explained how they abolish surface cubam through AMN cytoplasmic mislocalization.\",\n      \"evidence\": \"Exome sequencing, HEK293T expression, co-immunoprecipitation, AMN immunofluorescence localization, and mouse in vivo experiments\",\n      \"pmids\": [\"36266725\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Single lab with co-IP not reciprocally validated\", \"Quantitative contribution of AMN mislocalization to proteinuria not measured\"]\n    },\n    {\n      \"year\": 2025,\n      \"claim\": \"Identifying a truncated, intestine-expressed CUBN isoform resolved why C-terminal variants cause renal proteinuria without affecting cobalamin absorption.\",\n      \"evidence\": \"Targeted panel sequencing, cDNA transcript analysis, tissue expression profiling (kidney vs intestine), and renal biopsy electron microscopy in 52 patients\",\n      \"pmids\": [\"41624452\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Isoform identified by cDNA analysis in one lab\", \"Functional reconstitution of the truncated isoform not performed\"]\n    },\n    {\n      \"year\": null,\n      \"claim\": \"How cubilin, a protein lacking its own transmembrane anchor, couples ligand binding to clathrin-mediated internalization at the molecular level remains incompletely defined.\",\n      \"evidence\": \"\",\n      \"pmids\": [],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"No structural model of the full cubam endocytic complex in the corpus\", \"Mechanism of clathrin recruitment and cargo handoff not defined\", \"Binding sites for albumin and transferrin not mapped to specific CUB domains\"]\n    }\n  ],\n  \"mechanism_profile\": {\n    \"molecular_activity\": [\n      {\"term_id\": \"GO:0038024\", \"supporting_discovery_ids\": [0, 2, 7]},\n      {\"term_id\": \"GO:0140104\", \"supporting_discovery_ids\": [0, 1]}\n    ],\n    \"localization\": [\n      {\"term_id\": \"GO:0005886\", \"supporting_discovery_ids\": [4, 8]},\n      {\"term_id\": \"GO:0031410\", \"supporting_discovery_ids\": [4]},\n      {\"term_id\": \"GO:0005794\", \"supporting_discovery_ids\": [5]}\n    ],\n    \"pathway\": [\n      {\"term_id\": \"R-HSA-5653656\", \"supporting_discovery_ids\": [0, 4]},\n      {\"term_id\": \"R-HSA-382551\", \"supporting_discovery_ids\": [0, 7]}\n    ],\n    \"complexes\": [\"cubam (cubilin-amnionless complex)\"],\n    \"partners\": [\"AMN\"],\n    \"other_free_text\": []\n  }\n}","audit_flag":null,"evaluation":{"pairwise":"win","faith_supported":8,"faith_total":8,"faith_pct":100.0}}