{"gene":"SECISBP2","run_date":"2026-04-28T20:42:07","timeline":{"discoveries":[{"year":2000,"finding":"SBP2 was purified and identified as a novel SECIS RNA-binding protein essential for co-translational selenocysteine incorporation. Immunodepletion of SBP2 from cell lysates abolished selenocysteine insertion, which was restored by adding recombinant SBP2, establishing its essential role in Sec incorporation in vitro.","method":"UV cross-linking, immunoprecipitation, in vitro translation with 75Se-labeled Sec-tRNA, immunodepletion and add-back reconstitution","journal":"The EMBO journal","confidence":"High","confidence_rationale":"Tier 1 — in vitro reconstitution with immunodepletion/add-back, multiple orthogonal methods, foundational paper","pmids":["10637234"],"is_preprint":false},{"year":2000,"finding":"SBP2 overexpression overcomes competition for selenoprotein synthesis caused by excess selenoprotein mRNA, and SBP2 once bound to SECIS elements does not readily exchange between them. SBP2 preferentially stimulates selenocysteine incorporation directed by selenoprotein P and PHGPx SECIS elements over those of other selenoproteins, establishing its role in determining a hierarchy of selenoprotein synthesis.","method":"Transfection-based competition assay, co-expression of SBP2 and selenoprotein mRNAs in cells","journal":"The EMBO journal","confidence":"High","confidence_rationale":"Tier 2 — functional cell-based competition assay with clear mechanistic outcome, replicated with multiple SECIS elements","pmids":["11118223"],"is_preprint":false},{"year":2001,"finding":"SBP2 binds the proximal part of SECIS hairpin, protecting both strands of the lower half of the upper helix containing the non-Watson-Crick G·A/A·G base-pair quartet; the G·A/A·G tandem and internal loop are critical for SBP2 binding. Phosphate modification along both strands of the non-Watson-Crick base-pair quartet prevents SBP2 binding.","method":"Enzymatic and hydroxyl radical footprinting, gel mobility shift assay, phosphate-ethylation binding interference","journal":"RNA (New York, N.Y.)","confidence":"High","confidence_rationale":"Tier 1 — multiple orthogonal biochemical methods defining binding site at nucleotide resolution","pmids":["11680849"],"is_preprint":false},{"year":2002,"finding":"SBP2 and the U4 snRNA-binding protein 15.5 kD/Snu13p share the same L7A/L30 family RNA binding domain. Structure-guided alanine substitution of 12 predicted residues identified four whose mutation severely diminished or abolished SECIS RNA binding, mapping critical amino acids for SECIS recognition by SBP2.","method":"Multiple sequence alignment, structure-guided mutagenesis, alanine substitution, gel shift assays","journal":"RNA (New York, N.Y.)","confidence":"High","confidence_rationale":"Tier 1 — structure-guided mutagenesis with functional validation of specific residues","pmids":["12403468"],"is_preprint":false},{"year":2007,"finding":"SBP2 exhibits strong preferential binding to some selenoprotein mRNAs over others in vivo, and knockdown of SBP2 expression leads to differential effects on selenoprotein mRNA levels and sensitivity to nonsense-mediated decay, establishing SBP2 as a major determinant of the hierarchy of selenoprotein synthesis.","method":"siRNA knockdown of SBP2, immunoprecipitation of SBP2 followed by quantitative RT-PCR of bound mRNAs","journal":"Molecular and cellular biology","confidence":"High","confidence_rationale":"Tier 2 — RIP-qPCR and KD with multiple selenoprotein mRNA readouts, mechanistic hierarchy established","pmids":["17846120"],"is_preprint":false},{"year":2008,"finding":"Alternative splicing of human SECISBP2 produces at least eight splice variants encoding five isoforms with varying N-terminal sequences. One isoform, mtSBP2, contains a mitochondrial targeting sequence and localizes to mitochondria. Full-length SBP2 and some splice variants are subject to coordinated transcriptional and translational regulation in response to UVA irradiation-induced stress.","method":"In silico analysis, minigene-based in vivo splicing assay, antisense oligonucleotide modulation, subcellular localization by fluorescence microscopy, UVA stress experiments","journal":"Nucleic acids research","confidence":"Medium","confidence_rationale":"Tier 2 — direct localization of mtSBP2 to mitochondria with functional context, single lab","pmids":["19004874"],"is_preprint":false},{"year":2014,"finding":"SBP2 contacts the human ribosome primarily through the 28S rRNA at helix ES7L-E in expansion segment 7 of the 60S subunit. SBP2 binding to ribosomes induces conformational changes in ES7L-E and the universally conserved helix H89 of 28S rRNA.","method":"Bifunctional reagent cross-linking, hydroxyl radical probing of 28S rRNA, diepoxybutane cross-linking, chemical probing","journal":"RNA (New York, N.Y.)","confidence":"High","confidence_rationale":"Tier 1 — direct biochemical mapping of ribosome contact sites with multiple orthogonal methods","pmids":["24850884"],"is_preprint":false},{"year":2017,"finding":"Ribosome profiling and RNA-Seq in mouse liver with conditional deletion of Secisbp2 or Trsp (tRNASec) revealed that Secisbp2 has two separable functions: facilitating Sec incorporation at UGA codons and stabilizing selenoprotein mRNAs. Loss of tRNASec uniformly abolished ribosome density downstream of UGA-Sec codons, while loss of Secisbp2 produced gene-specific variable effects. For several selenoproteins, Secisbp2 loss reduced mRNA levels without affecting translational activity on remaining mRNA, demonstrating a distinct mRNA stability role.","method":"Ribosome profiling, RNA-Seq, mRNA half-life measurements, conditional knockout mouse models (Secisbp2 and Trsp), genetic epistasis comparison","journal":"Nucleic acids research","confidence":"High","confidence_rationale":"Tier 1-2 — ribosome profiling with genetic epistasis using two conditional KO mouse models, multiple readouts","pmids":["27956496"],"is_preprint":false},{"year":2019,"finding":"Two pathogenic missense mutations in Secisbp2 were functionally dissected in mouse models: C696R in the RNA-binding domain abrogates SECIS binding and does not support selenoprotein translation above the null level; R543Q in the selenocysteine insertion domain causes residual activity but is thermally unstable in vitro and completely degraded in mouse liver while being partially functional in the brain, demonstrating that differential protein stability in individual cell types dictates tissue-specific phenotypes.","method":"Mouse knockin models with pathogenic mutations, ribosome profiling, in vitro thermal stability assay, Western blotting","journal":"The Journal of biological chemistry","confidence":"High","confidence_rationale":"Tier 1-2 — in vivo mouse models with ribosome profiling and in vitro biochemical validation of two distinct functional domains","pmids":["31350336"],"is_preprint":false},{"year":2005,"finding":"Homozygous or compound heterozygous missense mutations in SECISBP2 in humans cause decreased DIO2 enzymatic activity and generalized selenoprotein deficiency, establishing SBP2 as epistatic to selenoprotein synthesis in vivo. The phenotype includes abnormal thyroid hormone metabolism with reduced T3, elevated T4, and reduced glutathione peroxidase and selenoprotein P levels.","method":"Genetic linkage analysis, fibroblast DIO2 enzyme activity assay, sequencing of SECISBP2 gene, in vivo human studies","journal":"Nature genetics","confidence":"High","confidence_rationale":"Tier 2 — genetic epistasis in humans with biochemical validation of selenoprotein deficiency, foundational human disease paper","pmids":["16228000"],"is_preprint":false},{"year":2010,"finding":"The R770X truncation mutation in SBP2 specifically inhibits its binding to SECIS elements in vitro, as demonstrated by gel shift assay, while R120X disrupts all functional motifs. This establishes the C-terminal region (around residue 770) as required for SECIS RNA binding.","method":"Gel shift assay with mutant SBP2 proteins, DNA sequencing","journal":"The Journal of clinical endocrinology and metabolism","confidence":"Medium","confidence_rationale":"Tier 3 — single gel shift assay establishing functional domain requirement, single lab","pmids":["20501692"],"is_preprint":false},{"year":2009,"finding":"The R128X nonsense mutation in SBP2 allows synthesis of SBP2 isoforms from at least three downstream ATGs that contain all essential functional domains, explaining the relatively mild phenotype caused by an early stop codon. This demonstrates that internal translation initiation can produce functional SBP2 isoforms.","method":"Minigene construction, in vitro translation analysis, clinical phenotyping","journal":"The Journal of clinical endocrinology and metabolism","confidence":"Medium","confidence_rationale":"Tier 2 — in vitro minigene/translation experiments identifying downstream ATG-initiated isoforms, single lab","pmids":["19602558"],"is_preprint":false},{"year":2019,"finding":"SBP2 deficiency in adipose tissue macrophages (ATMs) promotes metabolic activation, increases intracellular reactive oxygen species and inflammasome activity, and promotes IL-1β-associated local proliferation and infiltration of proinflammatory macrophages. ATM-specific SBP2 knockdown in obese mice promoted insulin resistance, while reexpression of SBP2 improved insulin sensitivity.","method":"ATM-specific knockdown in vivo in obese mice, ROS measurement, inflammasome assays, metabolic phenotyping","journal":"Science advances","confidence":"Medium","confidence_rationale":"Tier 2 — tissue-specific KD with defined cellular and metabolic phenotype, single lab","pmids":["31453320"],"is_preprint":false},{"year":2025,"finding":"CRISPR-Cas9 knockout of SBP2 in HepG2 cells impairs selenoprotein mRNA and protein expression with a transcriptomic signature enriched for metabolic and ion transport processes, distinct from that of the paralog SECISBP2L. SBP2 targeting confirmed its canonical role in selenoprotein synthesis while demonstrating it does not regulate extracellular matrix or cell adhesion pathways (those are SECISBP2L-specific).","method":"CRISPR-Cas9 knockout, RNA-seq, mass spectrometry, immunoblotting","journal":"bioRxiv","confidence":"Medium","confidence_rationale":"Tier 2 — CRISPR KO with transcriptomics and proteomics, preprint not yet peer-reviewed","pmids":["bio_10.1101_2025.07.02.662884"],"is_preprint":true}],"current_model":"SECISBP2/SBP2 is an essential trans-acting factor for selenoprotein synthesis that binds the non-Watson-Crick base-pair quartet of SECIS RNA hairpin elements in the 3' UTR of selenoprotein mRNAs via its L7A/L30-family RNA-binding domain, recruits the selenocysteine-specific elongation factor to the ribosome by contacting helix ES7L-E of the 60S 28S rRNA, facilitates UGA-to-selenocysteine recoding in a gene-specific and hierarchical manner, and independently stabilizes selenoprotein mRNAs against nonsense-mediated decay; pathogenic mutations that disrupt either SECIS binding or the selenocysteine insertion domain reduce selenoprotein expression in a tissue-dependent manner determined partly by differential SBP2 protein stability."},"narrative":{"teleology":[{"year":2000,"claim":"Identifying SBP2 as the essential SECIS-binding factor resolved how the selenocysteine incorporation machinery is recruited to selenoprotein mRNAs during translation.","evidence":"UV cross-linking, immunodepletion/add-back reconstitution in rabbit reticulocyte lysate in vitro translation system","pmids":["10637234"],"confidence":"High","gaps":["Binding site on SECIS RNA not yet mapped at nucleotide resolution","Ribosome contact sites unknown","Mechanism of selenocysteine elongation factor recruitment not addressed"]},{"year":2000,"claim":"Demonstrating that SBP2 does not readily exchange between SECIS elements and preferentially stimulates certain selenoproteins established the concept of a hierarchy in selenoprotein synthesis governed by SBP2 availability.","evidence":"Transfection-based competition assay with multiple SECIS elements and SBP2 co-expression","pmids":["11118223"],"confidence":"High","gaps":["Molecular basis of differential SECIS affinity not defined","In vivo hierarchy not yet confirmed"]},{"year":2001,"claim":"Nucleotide-resolution mapping of the SBP2 footprint on SECIS RNA pinpointed the non-Watson–Crick G·A/A·G quartet as the critical recognition element, defining the RNA determinants of binding specificity.","evidence":"Enzymatic and hydroxyl radical footprinting, phosphate-ethylation interference, gel shift assays","pmids":["11680849"],"confidence":"High","gaps":["Structural basis of recognition not resolved at atomic level","How quartet differences among SECIS elements produce differential SBP2 affinity unclear"]},{"year":2002,"claim":"Identifying SBP2's RNA-binding domain as an L7Ae/L30 family fold and mapping critical residues by alanine scanning established the protein-side determinants of SECIS recognition.","evidence":"Structure-guided mutagenesis with gel shift assays for SECIS binding","pmids":["12403468"],"confidence":"High","gaps":["No co-crystal structure of SBP2-SECIS complex","How the same fold discriminates SECIS from other kink-turn RNAs not explained"]},{"year":2005,"claim":"Discovery of human SECISBP2 mutations causing generalized selenoprotein deficiency proved that SBP2 is epistatic to the entire selenoproteome in vivo and linked it to a Mendelian syndrome of abnormal thyroid hormone metabolism.","evidence":"Genetic linkage analysis, SECISBP2 sequencing, fibroblast DIO2 activity assay, serum selenoprotein measurements in affected individuals","pmids":["16228000"],"confidence":"High","gaps":["Genotype-phenotype correlations across tissues not established","Whether residual selenoprotein synthesis reflects alternative Sec insertion pathways unclear"]},{"year":2007,"claim":"In vivo RIP-qPCR and SBP2 knockdown showed that SBP2 binds selenoprotein mRNAs with widely varying affinity and that limiting SBP2 exposes some mRNAs to nonsense-mediated decay, confirming the selenoprotein synthesis hierarchy in mammalian cells.","evidence":"siRNA knockdown of SBP2, RIP-qPCR for bound selenoprotein mRNAs, mRNA level quantification","pmids":["17846120"],"confidence":"High","gaps":["Whether mRNA stabilization and Sec insertion are mechanistically coupled or fully separable not resolved","SECIS features determining NMD sensitivity unknown"]},{"year":2008,"claim":"Discovery of alternative splicing producing a mitochondrially targeted SBP2 isoform (mtSBP2) raised the possibility of compartmentalized selenoprotein synthesis regulation.","evidence":"Minigene splicing assay, fluorescence microscopy showing mitochondrial localization of mtSBP2","pmids":["19004874"],"confidence":"Medium","gaps":["Functional role of mtSBP2 in mitochondria not demonstrated","Whether mitochondrial selenoprotein synthesis requires SBP2 not tested","Findings from a single lab"]},{"year":2009,"claim":"Internal translation initiation from downstream ATGs in an early-truncation mutant allele explained how severe N-terminal mutations can produce mild phenotypes, revealing that functional SBP2 domains reside in the C-terminal half.","evidence":"Minigene construction and in vitro translation identifying downstream ATG-initiated isoforms","pmids":["19602558"],"confidence":"Medium","gaps":["In vivo contribution of each downstream ATG-initiated isoform not quantified","Single lab, single mutation context"]},{"year":2014,"claim":"Mapping SBP2's ribosome contact to expansion segment helix ES7L-E of the 28S rRNA, and showing it induces conformational changes in helix H89, revealed how SBP2 physically connects SECIS-bound mRNA to the ribosomal A-site where Sec-tRNA is delivered.","evidence":"Bifunctional cross-linking, hydroxyl radical probing, and chemical probing of 28S rRNA in SBP2-ribosome complexes","pmids":["24850884"],"confidence":"High","gaps":["No cryo-EM or crystal structure of the SBP2-ribosome complex","How H89 conformational change facilitates Sec-tRNA accommodation not mechanistically resolved"]},{"year":2017,"claim":"Genetic epistasis comparing Secisbp2 and tRNASec conditional knockouts by ribosome profiling formally demonstrated that SBP2 has two separable functions — facilitating Sec incorporation and stabilizing selenoprotein mRNAs — with gene-specific effects on each.","evidence":"Ribosome profiling and RNA-Seq in conditional knockout mouse livers (Secisbp2 vs. Trsp), mRNA half-life measurements","pmids":["27956496"],"confidence":"High","gaps":["Molecular mechanism of mRNA stabilization (e.g., which decay pathway is inhibited) not identified","Whether SBP2 directly shields mRNA or acts through NMD factor exclusion not resolved"]},{"year":2019,"claim":"Mouse knockin models of two pathogenic mutations showed that disruption of the RNA-binding domain (C696R) abolishes all function while disruption of the selenocysteine insertion domain (R543Q) produces a thermally unstable protein whose tissue-specific degradation rate dictates tissue-specific phenotype severity.","evidence":"Mouse knockin alleles, ribosome profiling, in vitro thermal stability assays, Western blots across tissues","pmids":["31350336"],"confidence":"High","gaps":["Proteostatic machinery responsible for differential SBP2 degradation across tissues not identified","Whether pharmacological stabilization of R543Q could rescue selenoprotein synthesis not tested"]},{"year":null,"claim":"Key unresolved questions include the atomic structure of the SBP2–SECIS–ribosome ternary complex, the molecular mechanism by which SBP2 stabilizes selenoprotein mRNAs independently of Sec insertion, and the functional significance of the mitochondrially targeted SBP2 isoform.","evidence":"","pmids":[],"confidence":"High","gaps":["No high-resolution structure of SBP2 bound to SECIS RNA or ribosome","Mechanism of mRNA stabilization (NMD shielding vs. direct decay pathway inhibition) unresolved","Functional role of mtSBP2 in mitochondria untested"]}],"mechanism_profile":{"molecular_activity":[{"term_id":"GO:0003723","term_label":"RNA binding","supporting_discovery_ids":[0,2,3,10]},{"term_id":"GO:0045182","term_label":"translation regulator activity","supporting_discovery_ids":[0,1,7,8]}],"localization":[{"term_id":"GO:0005829","term_label":"cytosol","supporting_discovery_ids":[0,1]},{"term_id":"GO:0005739","term_label":"mitochondrion","supporting_discovery_ids":[5]}],"pathway":[{"term_id":"R-HSA-392499","term_label":"Metabolism of proteins","supporting_discovery_ids":[0,1,7,8,9]},{"term_id":"R-HSA-8953854","term_label":"Metabolism of RNA","supporting_discovery_ids":[4,7]}],"complexes":[],"partners":["EEFSEC","28S RRNA (ES7L-E)"],"other_free_text":[]},"mechanistic_narrative":"SECISBP2 (SBP2) is an essential trans-acting factor for selenoprotein synthesis that binds SECIS RNA hairpin elements in the 3′ UTRs of selenoprotein mRNAs and recruits the selenocysteine incorporation machinery to the ribosome. SBP2 recognizes the non-Watson–Crick G·A/A·G base-pair quartet of the SECIS element through its L7Ae/L30-family RNA-binding domain and contacts the 60S ribosomal subunit at helix ES7L-E of the 28S rRNA, inducing conformational changes in universally conserved helix H89 [PMID:10637234, PMID:11680849, PMID:12403468, PMID:24850884]. Beyond facilitating UGA-to-selenocysteine recoding, SBP2 independently stabilizes selenoprotein mRNAs against nonsense-mediated decay in a gene-specific, hierarchical manner, with differential SECIS-binding affinity determining which selenoproteins are preferentially synthesized under limiting SBP2 conditions [PMID:17846120, PMID:27956496]. Homozygous or compound heterozygous loss-of-function mutations in SECISBP2 cause a multisystem selenoprotein deficiency syndrome characterized by abnormal thyroid hormone metabolism, and tissue-specific phenotypic severity is dictated by differential SBP2 protein stability across cell types [PMID:16228000, PMID:31350336]."},"prefetch_data":{"uniprot":{"accession":"Q96T21","full_name":"Selenocysteine insertion sequence-binding protein 2","aliases":[],"length_aa":854,"mass_kda":95.5,"function":"mRNA-binding protein that binds to the SECIS (selenocysteine insertion sequence) element present in the 3'-UTR of mRNAs encoding selenoproteins and facilitates the incorporation of the rare amino acid selenocysteine (PubMed:35709277). Insertion of selenocysteine at UGA codons is mediated by SECISBP2 and EEFSEC: SECISBP2 (1) specifically binds the SECIS sequence once the 80S ribosome encounters an in-frame UGA codon and (2) contacts the RPS27A/eS31 of the 40S ribosome before ribosome stalling (PubMed:35709277). (3) GTP-bound EEFSEC then delivers selenocysteinyl-tRNA(Sec) to the 80S ribosome and adopts a preaccommodated state conformation (PubMed:35709277). (4) After GTP hydrolysis, EEFSEC dissociates from the assembly, selenocysteinyl-tRNA(Sec) accommodates, and peptide bond synthesis and selenoprotein elongation occur (PubMed:35709277)","subcellular_location":"Mitochondrion","url":"https://www.uniprot.org/uniprotkb/Q96T21/entry"},"depmap":{"release":"DepMap","has_data":true,"is_common_essential":false,"resolved_as":"","url":"https://depmap.org/portal/gene/SECISBP2","classification":"Not Classified","n_dependent_lines":27,"n_total_lines":1208,"dependency_fraction":0.022350993377483443},"opencell":{"profiled":false,"resolved_as":"","ensg_id":"","cell_line_id":"","localizations":[],"interactors":[],"url":"https://opencell.sf.czbiohub.org/search/SECISBP2","total_profiled":1310},"omim":[{"mim_id":"620198","title":"THYROID HORMONE METABOLISM, ABNORMAL, 3; THMA3","url":"https://www.omim.org/entry/620198"},{"mim_id":"615756","title":"SELENOCYSTEINE INSERTION SEQUENCE-BINDING PROTEIN 2-LIKE; SECISBP2L","url":"https://www.omim.org/entry/615756"},{"mim_id":"609698","title":"THYROID HORMONE METABOLISM, ABNORMAL, 1; THMA1","url":"https://www.omim.org/entry/609698"},{"mim_id":"607693","title":"SELENOCYSTEINE INSERTION SEQUENCE-BINDING PROTEIN 2; SECISBP2","url":"https://www.omim.org/entry/607693"}],"hpa":{"profiled":true,"resolved_as":"","reliability":"Supported","locations":[{"location":"Nucleoplasm","reliability":"Supported"}],"tissue_specificity":"Low tissue specificity","tissue_distribution":"Detected in all","driving_tissues":[],"url":"https://www.proteinatlas.org/search/SECISBP2"},"hgnc":{"alias_symbol":["SBP2"],"prev_symbol":[]},"alphafold":{"accession":"Q96T21","domains":[{"cath_id":"3.30.1330.30","chopping":"625-782","consensus_level":"medium","plddt":95.0246,"start":625,"end":782}],"viewer_url":"https://alphafold.ebi.ac.uk/entry/Q96T21","model_url":"https://alphafold.ebi.ac.uk/files/AF-Q96T21-F1-model_v6.cif","pae_url":"https://alphafold.ebi.ac.uk/files/AF-Q96T21-F1-predicted_aligned_error_v6.png","plddt_mean":55.12},"mouse_models":{"mgi_url":"https://www.informatics.jax.org/marker/summary?nomen=SECISBP2","jax_strain_url":"https://www.jax.org/strain/search?query=SECISBP2"},"sequence":{"accession":"Q96T21","fasta_url":"https://rest.uniprot.org/uniprotkb/Q96T21.fasta","uniprot_url":"https://www.uniprot.org/uniprotkb/Q96T21/entry","alphafold_viewer_url":"https://alphafold.ebi.ac.uk/entry/Q96T21"}},"corpus_meta":[{"pmid":"10637234","id":"PMC_10637234","title":"A novel RNA binding 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metabolism","url":"https://pubmed.ncbi.nlm.nih.gov/19602558","citation_count":82,"is_preprint":false},{"pmid":"20501692","id":"PMC_20501692","title":"Selenoprotein-related disease in a young girl caused by nonsense mutations in the SBP2 gene.","date":"2010","source":"The Journal of clinical endocrinology and metabolism","url":"https://pubmed.ncbi.nlm.nih.gov/20501692","citation_count":73,"is_preprint":false},{"pmid":"12403468","id":"PMC_12403468","title":"The SBP2 and 15.5 kD/Snu13p proteins share the same RNA binding domain: identification of SBP2 amino acids important to SECIS RNA binding.","date":"2002","source":"RNA (New York, N.Y.)","url":"https://pubmed.ncbi.nlm.nih.gov/12403468","citation_count":55,"is_preprint":false},{"pmid":"22247018","id":"PMC_22247018","title":"Novel compound heterozygous mutations in the SBP2 gene: characteristic clinical manifestations and the implications of GH and triiodothyronine in longitudinal bone growth and 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mutation in a pediatric patient.","date":"2025","source":"Frontiers in pediatrics","url":"https://pubmed.ncbi.nlm.nih.gov/40918659","citation_count":1,"is_preprint":false},{"pmid":"40294688","id":"PMC_40294688","title":"Biophysical analysis of SECIS binding protein 2 (SBP2) from Naegleria gruberi.","date":"2025","source":"Biochimica et biophysica acta. 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Gene regulatory mechanisms","url":"https://pubmed.ncbi.nlm.nih.gov/40618995","citation_count":0,"is_preprint":false},{"pmid":null,"id":"bio_10.1101_2025.07.02.662884","title":"RNA Sequencing Reveals Divergent Transcriptome Changes in SBP2 and SECISBP2L Depleted Cell Lines","date":"2025-07-03","source":"bioRxiv","url":"https://doi.org/10.1101/2025.07.02.662884","citation_count":0,"is_preprint":true}],"cost":{"stage1":{"model":"claude-sonnet-4-6","input_tokens":19785,"output_tokens":3453,"usd":0.055575},"stage2":{"model":"claude-opus-4-6","input_tokens":6853,"output_tokens":2870,"usd":0.159023},"total_usd":0.214598,"stage1_batch_id":"msgbatch_011rkcQdVV1RaFq9XhcG6df6","stage2_batch_id":"msgbatch_01RzgrJafdF4EWHhj5mNi6dh","note":"batch pricing = 50% of standard"},"stage1_raw":"```json\n{\n  \"discoveries\": [\n    {\n      \"year\": 2000,\n      \"finding\": \"SBP2 was purified and identified as a novel SECIS RNA-binding protein essential for co-translational selenocysteine incorporation. Immunodepletion of SBP2 from cell lysates abolished selenocysteine insertion, which was restored by adding recombinant SBP2, establishing its essential role in Sec incorporation in vitro.\",\n      \"method\": \"UV cross-linking, immunoprecipitation, in vitro translation with 75Se-labeled Sec-tRNA, immunodepletion and add-back reconstitution\",\n      \"journal\": \"The EMBO journal\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 — in vitro reconstitution with immunodepletion/add-back, multiple orthogonal methods, foundational paper\",\n      \"pmids\": [\"10637234\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2000,\n      \"finding\": \"SBP2 overexpression overcomes competition for selenoprotein synthesis caused by excess selenoprotein mRNA, and SBP2 once bound to SECIS elements does not readily exchange between them. SBP2 preferentially stimulates selenocysteine incorporation directed by selenoprotein P and PHGPx SECIS elements over those of other selenoproteins, establishing its role in determining a hierarchy of selenoprotein synthesis.\",\n      \"method\": \"Transfection-based competition assay, co-expression of SBP2 and selenoprotein mRNAs in cells\",\n      \"journal\": \"The EMBO journal\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 — functional cell-based competition assay with clear mechanistic outcome, replicated with multiple SECIS elements\",\n      \"pmids\": [\"11118223\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2001,\n      \"finding\": \"SBP2 binds the proximal part of SECIS hairpin, protecting both strands of the lower half of the upper helix containing the non-Watson-Crick G·A/A·G base-pair quartet; the G·A/A·G tandem and internal loop are critical for SBP2 binding. Phosphate modification along both strands of the non-Watson-Crick base-pair quartet prevents SBP2 binding.\",\n      \"method\": \"Enzymatic and hydroxyl radical footprinting, gel mobility shift assay, phosphate-ethylation binding interference\",\n      \"journal\": \"RNA (New York, N.Y.)\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 — multiple orthogonal biochemical methods defining binding site at nucleotide resolution\",\n      \"pmids\": [\"11680849\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2002,\n      \"finding\": \"SBP2 and the U4 snRNA-binding protein 15.5 kD/Snu13p share the same L7A/L30 family RNA binding domain. Structure-guided alanine substitution of 12 predicted residues identified four whose mutation severely diminished or abolished SECIS RNA binding, mapping critical amino acids for SECIS recognition by SBP2.\",\n      \"method\": \"Multiple sequence alignment, structure-guided mutagenesis, alanine substitution, gel shift assays\",\n      \"journal\": \"RNA (New York, N.Y.)\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 — structure-guided mutagenesis with functional validation of specific residues\",\n      \"pmids\": [\"12403468\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2007,\n      \"finding\": \"SBP2 exhibits strong preferential binding to some selenoprotein mRNAs over others in vivo, and knockdown of SBP2 expression leads to differential effects on selenoprotein mRNA levels and sensitivity to nonsense-mediated decay, establishing SBP2 as a major determinant of the hierarchy of selenoprotein synthesis.\",\n      \"method\": \"siRNA knockdown of SBP2, immunoprecipitation of SBP2 followed by quantitative RT-PCR of bound mRNAs\",\n      \"journal\": \"Molecular and cellular biology\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 — RIP-qPCR and KD with multiple selenoprotein mRNA readouts, mechanistic hierarchy established\",\n      \"pmids\": [\"17846120\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2008,\n      \"finding\": \"Alternative splicing of human SECISBP2 produces at least eight splice variants encoding five isoforms with varying N-terminal sequences. One isoform, mtSBP2, contains a mitochondrial targeting sequence and localizes to mitochondria. Full-length SBP2 and some splice variants are subject to coordinated transcriptional and translational regulation in response to UVA irradiation-induced stress.\",\n      \"method\": \"In silico analysis, minigene-based in vivo splicing assay, antisense oligonucleotide modulation, subcellular localization by fluorescence microscopy, UVA stress experiments\",\n      \"journal\": \"Nucleic acids research\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 — direct localization of mtSBP2 to mitochondria with functional context, single lab\",\n      \"pmids\": [\"19004874\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2014,\n      \"finding\": \"SBP2 contacts the human ribosome primarily through the 28S rRNA at helix ES7L-E in expansion segment 7 of the 60S subunit. SBP2 binding to ribosomes induces conformational changes in ES7L-E and the universally conserved helix H89 of 28S rRNA.\",\n      \"method\": \"Bifunctional reagent cross-linking, hydroxyl radical probing of 28S rRNA, diepoxybutane cross-linking, chemical probing\",\n      \"journal\": \"RNA (New York, N.Y.)\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 — direct biochemical mapping of ribosome contact sites with multiple orthogonal methods\",\n      \"pmids\": [\"24850884\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2017,\n      \"finding\": \"Ribosome profiling and RNA-Seq in mouse liver with conditional deletion of Secisbp2 or Trsp (tRNASec) revealed that Secisbp2 has two separable functions: facilitating Sec incorporation at UGA codons and stabilizing selenoprotein mRNAs. Loss of tRNASec uniformly abolished ribosome density downstream of UGA-Sec codons, while loss of Secisbp2 produced gene-specific variable effects. For several selenoproteins, Secisbp2 loss reduced mRNA levels without affecting translational activity on remaining mRNA, demonstrating a distinct mRNA stability role.\",\n      \"method\": \"Ribosome profiling, RNA-Seq, mRNA half-life measurements, conditional knockout mouse models (Secisbp2 and Trsp), genetic epistasis comparison\",\n      \"journal\": \"Nucleic acids research\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1-2 — ribosome profiling with genetic epistasis using two conditional KO mouse models, multiple readouts\",\n      \"pmids\": [\"27956496\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2019,\n      \"finding\": \"Two pathogenic missense mutations in Secisbp2 were functionally dissected in mouse models: C696R in the RNA-binding domain abrogates SECIS binding and does not support selenoprotein translation above the null level; R543Q in the selenocysteine insertion domain causes residual activity but is thermally unstable in vitro and completely degraded in mouse liver while being partially functional in the brain, demonstrating that differential protein stability in individual cell types dictates tissue-specific phenotypes.\",\n      \"method\": \"Mouse knockin models with pathogenic mutations, ribosome profiling, in vitro thermal stability assay, Western blotting\",\n      \"journal\": \"The Journal of biological chemistry\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1-2 — in vivo mouse models with ribosome profiling and in vitro biochemical validation of two distinct functional domains\",\n      \"pmids\": [\"31350336\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2005,\n      \"finding\": \"Homozygous or compound heterozygous missense mutations in SECISBP2 in humans cause decreased DIO2 enzymatic activity and generalized selenoprotein deficiency, establishing SBP2 as epistatic to selenoprotein synthesis in vivo. The phenotype includes abnormal thyroid hormone metabolism with reduced T3, elevated T4, and reduced glutathione peroxidase and selenoprotein P levels.\",\n      \"method\": \"Genetic linkage analysis, fibroblast DIO2 enzyme activity assay, sequencing of SECISBP2 gene, in vivo human studies\",\n      \"journal\": \"Nature genetics\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 — genetic epistasis in humans with biochemical validation of selenoprotein deficiency, foundational human disease paper\",\n      \"pmids\": [\"16228000\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2010,\n      \"finding\": \"The R770X truncation mutation in SBP2 specifically inhibits its binding to SECIS elements in vitro, as demonstrated by gel shift assay, while R120X disrupts all functional motifs. This establishes the C-terminal region (around residue 770) as required for SECIS RNA binding.\",\n      \"method\": \"Gel shift assay with mutant SBP2 proteins, DNA sequencing\",\n      \"journal\": \"The Journal of clinical endocrinology and metabolism\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 3 — single gel shift assay establishing functional domain requirement, single lab\",\n      \"pmids\": [\"20501692\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2009,\n      \"finding\": \"The R128X nonsense mutation in SBP2 allows synthesis of SBP2 isoforms from at least three downstream ATGs that contain all essential functional domains, explaining the relatively mild phenotype caused by an early stop codon. This demonstrates that internal translation initiation can produce functional SBP2 isoforms.\",\n      \"method\": \"Minigene construction, in vitro translation analysis, clinical phenotyping\",\n      \"journal\": \"The Journal of clinical endocrinology and metabolism\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 — in vitro minigene/translation experiments identifying downstream ATG-initiated isoforms, single lab\",\n      \"pmids\": [\"19602558\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2019,\n      \"finding\": \"SBP2 deficiency in adipose tissue macrophages (ATMs) promotes metabolic activation, increases intracellular reactive oxygen species and inflammasome activity, and promotes IL-1β-associated local proliferation and infiltration of proinflammatory macrophages. ATM-specific SBP2 knockdown in obese mice promoted insulin resistance, while reexpression of SBP2 improved insulin sensitivity.\",\n      \"method\": \"ATM-specific knockdown in vivo in obese mice, ROS measurement, inflammasome assays, metabolic phenotyping\",\n      \"journal\": \"Science advances\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 — tissue-specific KD with defined cellular and metabolic phenotype, single lab\",\n      \"pmids\": [\"31453320\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2025,\n      \"finding\": \"CRISPR-Cas9 knockout of SBP2 in HepG2 cells impairs selenoprotein mRNA and protein expression with a transcriptomic signature enriched for metabolic and ion transport processes, distinct from that of the paralog SECISBP2L. SBP2 targeting confirmed its canonical role in selenoprotein synthesis while demonstrating it does not regulate extracellular matrix or cell adhesion pathways (those are SECISBP2L-specific).\",\n      \"method\": \"CRISPR-Cas9 knockout, RNA-seq, mass spectrometry, immunoblotting\",\n      \"journal\": \"bioRxiv\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 — CRISPR KO with transcriptomics and proteomics, preprint not yet peer-reviewed\",\n      \"pmids\": [\"bio_10.1101_2025.07.02.662884\"],\n      \"is_preprint\": true\n    }\n  ],\n  \"current_model\": \"SECISBP2/SBP2 is an essential trans-acting factor for selenoprotein synthesis that binds the non-Watson-Crick base-pair quartet of SECIS RNA hairpin elements in the 3' UTR of selenoprotein mRNAs via its L7A/L30-family RNA-binding domain, recruits the selenocysteine-specific elongation factor to the ribosome by contacting helix ES7L-E of the 60S 28S rRNA, facilitates UGA-to-selenocysteine recoding in a gene-specific and hierarchical manner, and independently stabilizes selenoprotein mRNAs against nonsense-mediated decay; pathogenic mutations that disrupt either SECIS binding or the selenocysteine insertion domain reduce selenoprotein expression in a tissue-dependent manner determined partly by differential SBP2 protein stability.\"\n}\n```","stage2_raw":"```json\n{\n  \"mechanistic_narrative\": \"SECISBP2 (SBP2) is an essential trans-acting factor for selenoprotein synthesis that binds SECIS RNA hairpin elements in the 3′ UTRs of selenoprotein mRNAs and recruits the selenocysteine incorporation machinery to the ribosome. SBP2 recognizes the non-Watson–Crick G·A/A·G base-pair quartet of the SECIS element through its L7Ae/L30-family RNA-binding domain and contacts the 60S ribosomal subunit at helix ES7L-E of the 28S rRNA, inducing conformational changes in universally conserved helix H89 [PMID:10637234, PMID:11680849, PMID:12403468, PMID:24850884]. Beyond facilitating UGA-to-selenocysteine recoding, SBP2 independently stabilizes selenoprotein mRNAs against nonsense-mediated decay in a gene-specific, hierarchical manner, with differential SECIS-binding affinity determining which selenoproteins are preferentially synthesized under limiting SBP2 conditions [PMID:17846120, PMID:27956496]. Homozygous or compound heterozygous loss-of-function mutations in SECISBP2 cause a multisystem selenoprotein deficiency syndrome characterized by abnormal thyroid hormone metabolism, and tissue-specific phenotypic severity is dictated by differential SBP2 protein stability across cell types [PMID:16228000, PMID:31350336].\",\n  \"teleology\": [\n    {\n      \"year\": 2000,\n      \"claim\": \"Identifying SBP2 as the essential SECIS-binding factor resolved how the selenocysteine incorporation machinery is recruited to selenoprotein mRNAs during translation.\",\n      \"evidence\": \"UV cross-linking, immunodepletion/add-back reconstitution in rabbit reticulocyte lysate in vitro translation system\",\n      \"pmids\": [\"10637234\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\n        \"Binding site on SECIS RNA not yet mapped at nucleotide resolution\",\n        \"Ribosome contact sites unknown\",\n        \"Mechanism of selenocysteine elongation factor recruitment not addressed\"\n      ]\n    },\n    {\n      \"year\": 2000,\n      \"claim\": \"Demonstrating that SBP2 does not readily exchange between SECIS elements and preferentially stimulates certain selenoproteins established the concept of a hierarchy in selenoprotein synthesis governed by SBP2 availability.\",\n      \"evidence\": \"Transfection-based competition assay with multiple SECIS elements and SBP2 co-expression\",\n      \"pmids\": [\"11118223\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\n        \"Molecular basis of differential SECIS affinity not defined\",\n        \"In vivo hierarchy not yet confirmed\"\n      ]\n    },\n    {\n      \"year\": 2001,\n      \"claim\": \"Nucleotide-resolution mapping of the SBP2 footprint on SECIS RNA pinpointed the non-Watson–Crick G·A/A·G quartet as the critical recognition element, defining the RNA determinants of binding specificity.\",\n      \"evidence\": \"Enzymatic and hydroxyl radical footprinting, phosphate-ethylation interference, gel shift assays\",\n      \"pmids\": [\"11680849\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\n        \"Structural basis of recognition not resolved at atomic level\",\n        \"How quartet differences among SECIS elements produce differential SBP2 affinity unclear\"\n      ]\n    },\n    {\n      \"year\": 2002,\n      \"claim\": \"Identifying SBP2's RNA-binding domain as an L7Ae/L30 family fold and mapping critical residues by alanine scanning established the protein-side determinants of SECIS recognition.\",\n      \"evidence\": \"Structure-guided mutagenesis with gel shift assays for SECIS binding\",\n      \"pmids\": [\"12403468\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\n        \"No co-crystal structure of SBP2-SECIS complex\",\n        \"How the same fold discriminates SECIS from other kink-turn RNAs not explained\"\n      ]\n    },\n    {\n      \"year\": 2005,\n      \"claim\": \"Discovery of human SECISBP2 mutations causing generalized selenoprotein deficiency proved that SBP2 is epistatic to the entire selenoproteome in vivo and linked it to a Mendelian syndrome of abnormal thyroid hormone metabolism.\",\n      \"evidence\": \"Genetic linkage analysis, SECISBP2 sequencing, fibroblast DIO2 activity assay, serum selenoprotein measurements in affected individuals\",\n      \"pmids\": [\"16228000\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\n        \"Genotype-phenotype correlations across tissues not established\",\n        \"Whether residual selenoprotein synthesis reflects alternative Sec insertion pathways unclear\"\n      ]\n    },\n    {\n      \"year\": 2007,\n      \"claim\": \"In vivo RIP-qPCR and SBP2 knockdown showed that SBP2 binds selenoprotein mRNAs with widely varying affinity and that limiting SBP2 exposes some mRNAs to nonsense-mediated decay, confirming the selenoprotein synthesis hierarchy in mammalian cells.\",\n      \"evidence\": \"siRNA knockdown of SBP2, RIP-qPCR for bound selenoprotein mRNAs, mRNA level quantification\",\n      \"pmids\": [\"17846120\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\n        \"Whether mRNA stabilization and Sec insertion are mechanistically coupled or fully separable not resolved\",\n        \"SECIS features determining NMD sensitivity unknown\"\n      ]\n    },\n    {\n      \"year\": 2008,\n      \"claim\": \"Discovery of alternative splicing producing a mitochondrially targeted SBP2 isoform (mtSBP2) raised the possibility of compartmentalized selenoprotein synthesis regulation.\",\n      \"evidence\": \"Minigene splicing assay, fluorescence microscopy showing mitochondrial localization of mtSBP2\",\n      \"pmids\": [\"19004874\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\n        \"Functional role of mtSBP2 in mitochondria not demonstrated\",\n        \"Whether mitochondrial selenoprotein synthesis requires SBP2 not tested\",\n        \"Findings from a single lab\"\n      ]\n    },\n    {\n      \"year\": 2009,\n      \"claim\": \"Internal translation initiation from downstream ATGs in an early-truncation mutant allele explained how severe N-terminal mutations can produce mild phenotypes, revealing that functional SBP2 domains reside in the C-terminal half.\",\n      \"evidence\": \"Minigene construction and in vitro translation identifying downstream ATG-initiated isoforms\",\n      \"pmids\": [\"19602558\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\n        \"In vivo contribution of each downstream ATG-initiated isoform not quantified\",\n        \"Single lab, single mutation context\"\n      ]\n    },\n    {\n      \"year\": 2014,\n      \"claim\": \"Mapping SBP2's ribosome contact to expansion segment helix ES7L-E of the 28S rRNA, and showing it induces conformational changes in helix H89, revealed how SBP2 physically connects SECIS-bound mRNA to the ribosomal A-site where Sec-tRNA is delivered.\",\n      \"evidence\": \"Bifunctional cross-linking, hydroxyl radical probing, and chemical probing of 28S rRNA in SBP2-ribosome complexes\",\n      \"pmids\": [\"24850884\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\n        \"No cryo-EM or crystal structure of the SBP2-ribosome complex\",\n        \"How H89 conformational change facilitates Sec-tRNA accommodation not mechanistically resolved\"\n      ]\n    },\n    {\n      \"year\": 2017,\n      \"claim\": \"Genetic epistasis comparing Secisbp2 and tRNASec conditional knockouts by ribosome profiling formally demonstrated that SBP2 has two separable functions — facilitating Sec incorporation and stabilizing selenoprotein mRNAs — with gene-specific effects on each.\",\n      \"evidence\": \"Ribosome profiling and RNA-Seq in conditional knockout mouse livers (Secisbp2 vs. Trsp), mRNA half-life measurements\",\n      \"pmids\": [\"27956496\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\n        \"Molecular mechanism of mRNA stabilization (e.g., which decay pathway is inhibited) not identified\",\n        \"Whether SBP2 directly shields mRNA or acts through NMD factor exclusion not resolved\"\n      ]\n    },\n    {\n      \"year\": 2019,\n      \"claim\": \"Mouse knockin models of two pathogenic mutations showed that disruption of the RNA-binding domain (C696R) abolishes all function while disruption of the selenocysteine insertion domain (R543Q) produces a thermally unstable protein whose tissue-specific degradation rate dictates tissue-specific phenotype severity.\",\n      \"evidence\": \"Mouse knockin alleles, ribosome profiling, in vitro thermal stability assays, Western blots across tissues\",\n      \"pmids\": [\"31350336\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\n        \"Proteostatic machinery responsible for differential SBP2 degradation across tissues not identified\",\n        \"Whether pharmacological stabilization of R543Q could rescue selenoprotein synthesis not tested\"\n      ]\n    },\n    {\n      \"year\": null,\n      \"claim\": \"Key unresolved questions include the atomic structure of the SBP2–SECIS–ribosome ternary complex, the molecular mechanism by which SBP2 stabilizes selenoprotein mRNAs independently of Sec insertion, and the functional significance of the mitochondrially targeted SBP2 isoform.\",\n      \"evidence\": \"\",\n      \"pmids\": [],\n      \"confidence\": \"High\",\n      \"gaps\": [\n        \"No high-resolution structure of SBP2 bound to SECIS RNA or ribosome\",\n        \"Mechanism of mRNA stabilization (NMD shielding vs. direct decay pathway inhibition) unresolved\",\n        \"Functional role of mtSBP2 in mitochondria untested\"\n      ]\n    }\n  ],\n  \"mechanism_profile\": {\n    \"molecular_activity\": [\n      {\"term_id\": \"GO:0003723\", \"supporting_discovery_ids\": [0, 2, 3, 10]},\n      {\"term_id\": \"GO:0045182\", \"supporting_discovery_ids\": [0, 1, 7, 8]}\n    ],\n    \"localization\": [\n      {\"term_id\": \"GO:0005829\", \"supporting_discovery_ids\": [0, 1]},\n      {\"term_id\": \"GO:0005739\", \"supporting_discovery_ids\": [5]}\n    ],\n    \"pathway\": [\n      {\"term_id\": \"R-HSA-392499\", \"supporting_discovery_ids\": [0, 1, 7, 8, 9]},\n      {\"term_id\": \"R-HSA-8953854\", \"supporting_discovery_ids\": [4, 7]}\n    ],\n    \"complexes\": [],\n    \"partners\": [\n      \"EEFSEC\",\n      \"28S rRNA (ES7L-E)\"\n    ],\n    \"other_free_text\": []\n  }\n}\n```"}