{"gene":"SECISBP2","run_date":"2026-06-10T07:46:30","timeline":{"discoveries":[{"year":2000,"finding":"SBP2 was purified as a SECIS-binding protein and shown to be essential for co-translational selenocysteine insertion. Immunodepletion of SBP2 from cell lysates abolished selenocysteine incorporation into selenoprotein mRNAs in vitro, and this was rescued by adding back recombinant SBP2. The activity was both SBP2- and SECIS element-dependent.","method":"UV cross-linking, immunoprecipitation, in vitro Sec incorporation assay with 75Se-labeled Sec-tRNA, immunodepletion and recombinant protein rescue","journal":"The EMBO journal","confidence":"High","confidence_rationale":"Tier 1 / Strong — in vitro reconstitution with immunodepletion/rescue, multiple orthogonal methods in one study establishing essential catalytic role","pmids":["10637234"],"is_preprint":false},{"year":2000,"finding":"SBP2 recruits the selenocysteine-specific elongation factor (eEFSec) to selenoprotein mRNA via SECIS binding. Overexpression of SBP2 (but not selenocysteyl-tRNA or eEFSec) overcame competition from excess selenoprotein mRNAs, establishing SBP2 as the limiting trans-acting factor. SBP2, once bound to SECIS elements, does not readily exchange between them. SBP2 preferentially stimulates selenocysteine incorporation from selenoprotein P and PHGPx SECIS elements over others, establishing a hierarchy of selenoprotein synthesis.","method":"Transfection-based competition assay, co-expression of trans-acting factors, overexpression of selenoprotein mRNAs","journal":"The EMBO journal","confidence":"High","confidence_rationale":"Tier 2 / Strong — functional competition assay with multiple trans-acting factor comparisons, replicated finding of SBP2 limiting role","pmids":["11118223"],"is_preprint":false},{"year":2001,"finding":"SBP2 binds to a conserved site on SECIS RNA hairpins: it protects the proximal part of the hairpin and 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, the 5' strand of the lower helix, and part of the 5' strand of the internal loop prevented SBP2 binding.","method":"Enzymatic and hydroxyl radical footprinting, gel mobility shift analysis, phosphate-ethylation binding interference","journal":"RNA (New York, N.Y.)","confidence":"High","confidence_rationale":"Tier 1 / Strong — multiple orthogonal RNA-binding methods (footprinting, EMSA, chemical interference) defining precise binding site","pmids":["11680849"],"is_preprint":false},{"year":2002,"finding":"SBP2 shares an RNA-binding domain of the L7A/L30 family with the U4 snRNA-binding protein 15.5 kD/Snu13p. Structure-guided alanine scanning of 12 SBP2 residues predicted from alignment with the 15.5 kD–U4 snRNA crystal structure identified four residues whose mutation severely diminished or abolished SECIS RNA binding, with the other eight causing intermediate effects, defining the key amino acids for SECIS recognition.","method":"Multiple sequence alignment, structure-guided alanine mutagenesis, gel shift assays","journal":"RNA (New York, N.Y.)","confidence":"High","confidence_rationale":"Tier 1 / Moderate — active-site mutagenesis guided by crystal structure of homolog, functional validation by gel shift, single lab but multiple mutants","pmids":["12403468"],"is_preprint":false},{"year":2005,"finding":"Homozygous and compound heterozygous missense mutations in SECISBP2 in humans cause a global defect in selenoprotein synthesis, resulting in abnormal thyroid hormone metabolism. SBP2 is epistatic to selenoprotein synthesis, so its partial loss has a generalized effect on selenoproteins including deiodinase 2.","method":"Genetic linkage analysis, sequencing, fibroblast DIO2 enzymatic activity assay","journal":"Nature genetics","confidence":"High","confidence_rationale":"Tier 2 / Strong — human genetic epistasis combined with biochemical enzyme activity assay in patient fibroblasts, replicated in multiple families","pmids":["16228000"],"is_preprint":false},{"year":2007,"finding":"SBP2 exhibits strong preferential binding to some selenoprotein mRNAs over others in vivo (determined by immunoprecipitation and mRNA quantitation), whereas nucleolin exhibits minimal differences in binding. Knockdown of SBP2 confirmed that SBP2 binding affinity is a major determinant dictating the hierarchy of selenoprotein synthesis via differential mRNA translation and sensitivity to nonsense-mediated decay.","method":"SBP2 knockdown by siRNA, immunoprecipitation of SBP2 followed by mRNA quantitation, selenoprotein mRNA level measurement","journal":"Molecular and cellular biology","confidence":"High","confidence_rationale":"Tier 2 / Moderate — reciprocal Co-IP of endogenous SBP2 with mRNA quantitation plus functional knockdown, single lab but two orthogonal methods","pmids":["17846120"],"is_preprint":false},{"year":2008,"finding":"Alternative splicing of SECISBP2 produces at least 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 undergo 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 mitochondrial targeting sequence identification and localization","journal":"Nucleic acids research","confidence":"Medium","confidence_rationale":"Tier 3 / Moderate — direct localization experiments for mtSBP2 isoform plus functional splicing assays, single lab, not fully reconstituted in vitro","pmids":["19004874"],"is_preprint":false},{"year":2009,"finding":"A nonsense mutation R128X in SBP2 results in synthesis of shorter SBP2 isoforms from at least three downstream ATGs, all of which retain the essential functional domains for SECIS binding. This explains why a severe truncating mutation produces a relatively mild phenotype of partial SBP2 deficiency.","method":"Sequencing, minigene construction, in vitro translation analysis of mutant proteins","journal":"The Journal of clinical endocrinology and metabolism","confidence":"Medium","confidence_rationale":"Tier 2 / Weak — in vitro translation of minigene constructs showing downstream ATG usage; single lab, single method","pmids":["19602558"],"is_preprint":false},{"year":2010,"finding":"The SBP2 truncation mutation R770X (in the RNA-binding domain) inhibits binding of SBP2 to SECIS elements, as shown by gel shift assay, whereas R120X disrupts all functional motifs. Compound heterozygous R120X/R770X causes widespread selenoprotein deficiency including undetectable selenoprotein P.","method":"Gel shift assay of mutant SBP2 proteins, sequencing, selenoprotein P measurement","journal":"The Journal of clinical endocrinology and metabolism","confidence":"Medium","confidence_rationale":"Tier 2 / Weak — direct in vitro binding assay for SECIS-binding defect of R770X mutant; single lab, single method","pmids":["20501692"],"is_preprint":false},{"year":2014,"finding":"SBP2 contacts the human ribosome primarily through the 28S rRNA at expansion segment ES7L, specifically helix ES7L-E. SBP2 binding to 80S ribosomes or 60S subunits protects helix ES7L-E from hydroxyl radical cleavage and induces conformational changes in ES7L-E and the universally conserved helix H89 of the 28S rRNA.","method":"Cross-linking with bifunctional reagents (diepoxybutane), direct hydroxyl radical probing of 28S rRNA, chemical probing","journal":"RNA (New York, N.Y.)","confidence":"High","confidence_rationale":"Tier 1 / Moderate — multiple orthogonal structural probing methods (cross-linking, hydroxyl radical probing, chemical probing) mapping SBP2 contact site on ribosome","pmids":["24850884"],"is_preprint":false},{"year":2017,"finding":"Ribosome profiling and RNA-seq of conditional Secisbp2 and Trsp (tRNA-Sec) knockout mouse livers showed that Secisbp2 loss results in gene-specific (variable) effects on ribosome density downstream of UGA-Sec codons, distinct from the uniform loss seen with tRNA-Sec depletion. For several selenoproteins, Secisbp2 loss greatly reduced mRNA levels without affecting translational activity or Sec incorporation efficiency on remaining RNA. These data demonstrate that Secisbp2 has a distinct role in stabilizing selenoprotein mRNAs separable from its role in UGA redefinition, and that Secisbp2 is not strictly required for Sec incorporation.","method":"Ribosome profiling, RNA-seq, mRNA half-life measurements, conditional genetic knockout (Cre-lox) in mouse liver","journal":"Nucleic acids research","confidence":"High","confidence_rationale":"Tier 1 / Strong — ribosome profiling with genetic comparison of Secisbp2 vs tRNA-Sec knockouts, multiple orthogonal methods establishing separable functions","pmids":["27956496"],"is_preprint":false},{"year":2017,"finding":"Sbp2 conditional knockout mice have decreased deiodinase 1 expression and enzymatic activity in liver, decreased deiodinase 2 enzymatic activity and deiodinase 3 expression in cerebrum, and decreased expression of other selenoproteins in brain, liver, and serum, demonstrating that SBP2 deficiency causes global selenoprotein synthesis impairment with organ-specific effects on thyroid hormone metabolism.","method":"Tamoxifen-inducible conditional knockout mouse model, deiodinase enzymatic activity assays, selenoprotein expression analysis, serum thyroid hormone measurements","journal":"Endocrinology","confidence":"High","confidence_rationale":"Tier 2 / Moderate — clean in vivo conditional KO with specific enzymatic activity readouts for multiple selenoproteins across tissues","pmids":["29029094"],"is_preprint":false},{"year":2019,"finding":"Pathogenic missense mutation C696R in the RNA-binding domain of SECISBP2 abrogates SECIS binding and does not support selenoprotein translation above the level of a complete null mutation. The R543Q missense mutation in the selenocysteine insertion domain results in residual translational activity but causes thermally unstable protein that is completely degraded in mouse liver in vivo while being partially functional in brain, demonstrating that cell-type-specific protein stability dictates clinical phenotypes.","method":"Mouse knock-in models of patient mutations, ribosome profiling, in vitro thermal stability assay, immunoblot for protein levels in different tissues","journal":"The Journal of biological chemistry","confidence":"High","confidence_rationale":"Tier 1 / Moderate — ribosome profiling plus in vitro biochemical stability assay plus tissue-specific protein quantification in knock-in mouse models carrying patient mutations","pmids":["31350336"],"is_preprint":false},{"year":2019,"finding":"SBP2 deficiency in adipose tissue macrophages (ATMs) causes increased intracellular reactive oxygen species and inflammasome activation, leading to IL-1β-driven proinflammatory macrophage expansion. ATM-specific knockdown of SBP2 in obese mice promoted insulin resistance via increased fat tissue inflammation; re-expression of SBP2 improved insulin sensitivity.","method":"ATM-specific siRNA knockdown in obese mice, re-expression experiments, ROS and inflammasome measurements, insulin sensitivity assays","journal":"Science advances","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — in vivo cell-type-specific knockdown and rescue with defined molecular readouts (ROS, inflammasome, IL-1β), single lab","pmids":["31453320"],"is_preprint":false},{"year":2025,"finding":"SBP2 targeting in HepG2 cells (CRISPR-Cas9) impaired selenoprotein mRNA and protein expression, confirming its essential role in selenoprotein synthesis in human hepatocytes, while producing a transcriptomic signature enriched for metabolic and ion transport processes distinct from that of its paralog SECISBP2L.","method":"CRISPR-Cas9 gene editing, RNA-seq, mass spectrometry, immunoblot","journal":"bioRxiv","confidence":"Medium","confidence_rationale":"Tier 2 / Weak — CRISPR KO with transcriptomic and proteomic readouts in human cell line; preprint, single lab","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 SECIS RNA hairpin (specifically the non-Watson-Crick G·A/A·G quartet in the upper helix) via an L7A/L30-family RNA-binding domain, recruits the selenocysteine-specific elongation factor eEFSec to selenoprotein mRNAs, and contacts the 60S ribosome at expansion segment ES7L of the 28S rRNA; it functions as the rate-limiting determinant of selenoprotein synthesis hierarchy through differential SECIS binding affinity, and additionally stabilizes selenoprotein mRNAs independently of its role in UGA-Sec recoding, while alternative splicing produces a mitochondria-targeted isoform and protein stability varies by cell type to influence clinical phenotypes."},"narrative":{"mechanistic_narrative":"SECISBP2 (SBP2) is the essential, rate-limiting trans-acting factor that directs co-translational incorporation of selenocysteine into selenoproteins, recoding in-frame UGA codons during translation [PMID:10637234, PMID:11118223]. It recognizes the SECIS RNA hairpin in selenoprotein mRNA 3' UTRs through an L7A/L30-family RNA-binding domain, contacting the conserved non-Watson-Crick G·A/A·G base-pair quartet and internal loop of the upper helix [PMID:11680849, PMID:12403468]. Once bound to a SECIS element, SBP2 recruits the selenocysteine-specific elongation factor eEFSec and does not readily exchange between elements; because SBP2 is limiting and binds different SECIS elements with differing affinity, it establishes the hierarchy of selenoprotein synthesis, favoring mRNAs such as selenoprotein P and PHGPx [PMID:11118223, PMID:17846120]. SBP2 also contacts the 60S ribosome at expansion segment ES7L of the 28S rRNA, inducing conformational changes in ES7L-E and the conserved helix H89 [PMID:24850884]. Beyond UGA recoding, SBP2 has a separable function in stabilizing selenoprotein mRNAs, as its loss reduces mRNA levels for several selenoproteins without impairing Sec incorporation on remaining transcripts [PMID:27956496]. In vivo, SBP2 deficiency causes global selenoprotein synthesis impairment with organ-specific effects on thyroid hormone metabolism via the deiodinases [PMID:29029094]. Missense and truncating mutations in SECISBP2 cause a human disorder of abnormal thyroid hormone metabolism through generalized selenoprotein deficiency, with clinical severity modulated by cell-type-specific protein stability and by use of downstream initiation codons that preserve functional domains [PMID:16228000, PMID:19602558, PMID:31350336].","teleology":[{"year":2000,"claim":"Established that a dedicated SECIS-binding protein is required for selenocysteine insertion, answering whether selenoprotein synthesis needs a specific trans-acting factor beyond the SECIS element itself.","evidence":"UV cross-linking, immunodepletion/recombinant rescue, and in vitro Sec incorporation with 75Se-Sec-tRNA","pmids":["10637234"],"confidence":"High","gaps":["Did not define the SECIS recognition determinants at nucleotide resolution","Did not identify downstream factors recruited by SBP2"]},{"year":2000,"claim":"Showed how SBP2 acts mechanistically — recruiting eEFSec and acting as the limiting, non-exchanging factor that sets a synthesis hierarchy — answering why some selenoproteins are favored over others.","evidence":"Transfection competition assays comparing overexpressed trans-acting factors and selenoprotein mRNAs","pmids":["11118223"],"confidence":"High","gaps":["Quantitative SECIS affinity differences not measured","Did not establish whether hierarchy reflects translation, mRNA stability, or both"]},{"year":2001,"claim":"Defined the precise SBP2 footprint on SECIS RNA, answering which structural features of the hairpin are recognized.","evidence":"Enzymatic and hydroxyl radical footprinting, EMSA, and phosphate-ethylation interference","pmids":["11680849"],"confidence":"High","gaps":["No co-crystal or solution structure of the SBP2–SECIS complex","Protein residues mediating contacts not yet identified"]},{"year":2002,"claim":"Identified the SBP2 RNA-binding domain as L7A/L30-family and pinpointed residues required for SECIS recognition, linking SBP2 to a known RNA-binding fold.","evidence":"Structure-guided alanine scanning informed by the 15.5 kD–U4 snRNA crystal structure, with gel shift validation","pmids":["12403468"],"confidence":"High","gaps":["No direct SBP2 structure determined","Contributions of non-RBD regions to function not addressed"]},{"year":2005,"claim":"Connected SBP2 to human disease, answering whether SBP2 loss-of-function has physiological consequences, by linking mutations to abnormal thyroid hormone metabolism via generalized selenoprotein deficiency.","evidence":"Genetic linkage, sequencing, and DIO2 enzymatic activity in patient fibroblasts across multiple families","pmids":["16228000"],"confidence":"High","gaps":["Did not resolve why partial loss yields tissue-specific phenotypes","Molecular impact of individual mutations not biochemically dissected"]},{"year":2007,"claim":"Demonstrated that differential SBP2 binding affinity, not a generic SECIS-binder, dictates the selenoprotein hierarchy in vivo and links it to mRNA translation and NMD sensitivity.","evidence":"siRNA knockdown plus reciprocal Co-IP of endogenous SBP2 with mRNA quantitation","pmids":["17846120"],"confidence":"High","gaps":["Mechanism coupling SBP2 binding to NMD not detailed","Quantitative affinity ranking across the full selenoproteome incomplete"]},{"year":2008,"claim":"Revealed isoform diversity and a mitochondria-targeted variant, answering whether SBP2 function extends beyond cytoplasmic selenoprotein synthesis.","evidence":"Minigene splicing assays, antisense modulation, and mitochondrial localization of mtSBP2","pmids":["19004874"],"confidence":"Medium","gaps":["Function of mtSBP2 in mitochondria not established","Stress-regulated splicing not reconstituted mechanistically"]},{"year":2009,"claim":"Explained the mild phenotype of a severe truncating mutation through downstream ATG usage producing functional shorter isoforms.","evidence":"Minigene constructs and in vitro translation of R128X mutant","pmids":["19602558"],"confidence":"Medium","gaps":["Single method, single lab","In vivo abundance and activity of downstream-initiated isoforms not quantified"]},{"year":2010,"claim":"Mapped a disease mutation (R770X) directly to loss of SECIS binding, connecting genotype to a defined biochemical defect.","evidence":"Gel shift assays of mutant proteins and selenoprotein P measurement in compound heterozygotes","pmids":["20501692"],"confidence":"Medium","gaps":["Single binding method without reciprocal validation","Cellular consequences of partial binding loss not fully resolved"]},{"year":2014,"claim":"Located the SBP2–ribosome interface at 28S rRNA ES7L, answering how SBP2 physically engages the translation machinery.","evidence":"Bifunctional cross-linking, hydroxyl radical probing, and chemical probing of 28S rRNA","pmids":["24850884"],"confidence":"High","gaps":["High-resolution structure of the SBP2–ribosome complex lacking","Functional consequence of induced H89 conformational change unproven"]},{"year":2017,"claim":"Separated SBP2's mRNA-stabilizing function from UGA recoding and showed it is not strictly required for Sec incorporation, refining the model of SBP2 essentiality.","evidence":"Ribosome profiling and RNA-seq comparing conditional Secisbp2 vs Trsp knockout mouse livers, with mRNA half-life measurements","pmids":["27956496"],"confidence":"High","gaps":["Molecular mechanism of mRNA stabilization unknown","Why effects are gene-specific not explained"]},{"year":2017,"claim":"Quantified in vivo organ-specific selenoprotein and deiodinase deficits, linking SBP2 loss to tissue-differential thyroid hormone metabolism.","evidence":"Tamoxifen-inducible conditional knockout mouse with deiodinase activity assays and serum thyroid hormone measurements","pmids":["29029094"],"confidence":"High","gaps":["Basis of organ-specific severity not mechanistically resolved","Non-thyroidal selenoprotein consequences not fully characterized"]},{"year":2019,"claim":"Showed that cell-type-specific protein stability of mutant SBP2 dictates clinical phenotype, explaining tissue-differential disease severity.","evidence":"Knock-in mouse models of patient mutations with ribosome profiling, thermal stability assays, and tissue protein quantification","pmids":["31350336"],"confidence":"High","gaps":["Degradation pathway controlling tissue-specific stability not identified","Generalizability across other mutations untested"]},{"year":2019,"claim":"Extended SBP2 function to immunometabolism, showing its deficiency in adipose tissue macrophages drives ROS, inflammasome activation, and insulin resistance.","evidence":"ATM-specific siRNA knockdown and re-expression in obese mice with ROS, inflammasome, and insulin sensitivity readouts","pmids":["31453320"],"confidence":"Medium","gaps":["Which selenoproteins mediate the antioxidant/anti-inflammatory effect not identified","Single lab, not independently confirmed"]},{"year":2025,"claim":"Confirmed SBP2's essential role in human hepatocyte selenoprotein synthesis and distinguished its transcriptomic footprint from paralog SECISBP2L.","evidence":"CRISPR-Cas9 knockout in HepG2 with RNA-seq, mass spectrometry, and immunoblot (preprint)","pmids":["bio_10.1101_2025.07.02.662884"],"confidence":"Medium","gaps":["Preprint, single lab","Functional division of labor between SBP2 and SECISBP2L not mechanistically defined"]},{"year":null,"claim":"How SBP2 mechanistically stabilizes selenoprotein mRNAs and the high-resolution architecture of the SBP2–SECIS–eEFSec–ribosome assembly remain unresolved.","evidence":"","pmids":[],"confidence":"High","gaps":["No structure of SBP2 bound to SECIS or the ribosome","mRNA-stabilization mechanism uncharacterized","Mitochondrial mtSBP2 function unknown"]}],"mechanism_profile":{"molecular_activity":[{"term_id":"GO:0003723","term_label":"RNA binding","supporting_discovery_ids":[0,2,3,5]},{"term_id":"GO:0045182","term_label":"translation regulator activity","supporting_discovery_ids":[0,1,10]},{"term_id":"GO:0060090","term_label":"molecular adaptor activity","supporting_discovery_ids":[1,9]}],"localization":[{"term_id":"GO:0005840","term_label":"ribosome","supporting_discovery_ids":[9]},{"term_id":"GO:0005739","term_label":"mitochondrion","supporting_discovery_ids":[6]}],"pathway":[{"term_id":"R-HSA-392499","term_label":"Metabolism of proteins","supporting_discovery_ids":[0,1,10]},{"term_id":"R-HSA-8953854","term_label":"Metabolism of RNA","supporting_discovery_ids":[5,10]}],"complexes":[],"partners":["EEFSEC"],"other_free_text":[]}},"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 protein, SBP2, is required for the translation of mammalian selenoprotein mRNAs.","date":"2000","source":"The EMBO journal","url":"https://pubmed.ncbi.nlm.nih.gov/10637234","citation_count":303,"is_preprint":false},{"pmid":"16228000","id":"PMC_16228000","title":"Mutations in SECISBP2 result in abnormal thyroid hormone metabolism.","date":"2005","source":"Nature genetics","url":"https://pubmed.ncbi.nlm.nih.gov/16228000","citation_count":288,"is_preprint":false},{"pmid":"32745331","id":"PMC_32745331","title":"K2 Sb(P2 O7 )F: Cairo Pentagonal Layer with Bifunctional Genes Reveal Optical Performance.","date":"2020","source":"Angewandte Chemie (International ed. in English)","url":"https://pubmed.ncbi.nlm.nih.gov/32745331","citation_count":135,"is_preprint":false},{"pmid":"11118223","id":"PMC_11118223","title":"SECIS-SBP2 interactions dictate selenocysteine incorporation efficiency and selenoprotein hierarchy.","date":"2000","source":"The EMBO 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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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contribute to its vascular tissue-specific expression in different vegetative organs.","date":"2007","source":"Plant molecular biology","url":"https://pubmed.ncbi.nlm.nih.gov/17710554","citation_count":8,"is_preprint":false},{"pmid":"31826256","id":"PMC_31826256","title":"Role of the Thyroid Gland in Expression of the Thyroid Phenotype of Sbp2-Deficient Mice.","date":"2020","source":"Endocrinology","url":"https://pubmed.ncbi.nlm.nih.gov/31826256","citation_count":5,"is_preprint":false},{"pmid":"40123624","id":"PMC_40123624","title":"The First-Ever Investigation of SNP rs119461977 in SECISBP2/SBP2 Gene and its Implications for Hypothyroidism: A Novel Case-Control Research.","date":"2024","source":"Indian journal of clinical biochemistry : IJCB","url":"https://pubmed.ncbi.nlm.nih.gov/40123624","citation_count":1,"is_preprint":false},{"pmid":"40918659","id":"PMC_40918659","title":"Case Report: A homozygous selenocysteine insertion sequence-binding protein 2 (SECISBP2) gene mutation in a 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Gene regulatory mechanisms","url":"https://pubmed.ncbi.nlm.nih.gov/40618995","citation_count":0,"is_preprint":false},{"pmid":"42238688","id":"PMC_42238688","title":"A Rare Cause of Thyroid Hormone Abnormalities in an Adolescent: A Case Report of SBP2 (SECISBP2) Deficiency.","date":"2026","source":"Molecular syndromology","url":"https://pubmed.ncbi.nlm.nih.gov/42238688","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":21037,"output_tokens":4009,"usd":0.061623,"stage1_stop_reason":"end_turn"},"stage2":{"model":"claude-opus-4-8","input_tokens":11945,"output_tokens":4304,"usd":0.083663,"stage2_stop_reason":"end_turn"},"total_usd":0.145286,"stage1_batch_id":"msgbatch_013LWZZT6MWaqB9qyTSeQBmU","stage2_batch_id":"msgbatch_0194ZzQaTGNpruoNJBbEMbt3","note":"batch pricing = 50% of standard"},"stage1_raw":"```json\n{\n  \"discoveries\": [\n    {\n      \"year\": 2000,\n      \"finding\": \"SBP2 was purified as a SECIS-binding protein and shown to be essential for co-translational selenocysteine insertion. Immunodepletion of SBP2 from cell lysates abolished selenocysteine incorporation into selenoprotein mRNAs in vitro, and this was rescued by adding back recombinant SBP2. The activity was both SBP2- and SECIS element-dependent.\",\n      \"method\": \"UV cross-linking, immunoprecipitation, in vitro Sec incorporation assay with 75Se-labeled Sec-tRNA, immunodepletion and recombinant protein rescue\",\n      \"journal\": \"The EMBO journal\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 / Strong — in vitro reconstitution with immunodepletion/rescue, multiple orthogonal methods in one study establishing essential catalytic role\",\n      \"pmids\": [\"10637234\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2000,\n      \"finding\": \"SBP2 recruits the selenocysteine-specific elongation factor (eEFSec) to selenoprotein mRNA via SECIS binding. Overexpression of SBP2 (but not selenocysteyl-tRNA or eEFSec) overcame competition from excess selenoprotein mRNAs, establishing SBP2 as the limiting trans-acting factor. SBP2, once bound to SECIS elements, does not readily exchange between them. SBP2 preferentially stimulates selenocysteine incorporation from selenoprotein P and PHGPx SECIS elements over others, establishing a hierarchy of selenoprotein synthesis.\",\n      \"method\": \"Transfection-based competition assay, co-expression of trans-acting factors, overexpression of selenoprotein mRNAs\",\n      \"journal\": \"The EMBO journal\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — functional competition assay with multiple trans-acting factor comparisons, replicated finding of SBP2 limiting role\",\n      \"pmids\": [\"11118223\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2001,\n      \"finding\": \"SBP2 binds to a conserved site on SECIS RNA hairpins: it protects the proximal part of the hairpin and 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, the 5' strand of the lower helix, and part of the 5' strand of the internal loop prevented SBP2 binding.\",\n      \"method\": \"Enzymatic and hydroxyl radical footprinting, gel mobility shift analysis, phosphate-ethylation binding interference\",\n      \"journal\": \"RNA (New York, N.Y.)\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 / Strong — multiple orthogonal RNA-binding methods (footprinting, EMSA, chemical interference) defining precise binding site\",\n      \"pmids\": [\"11680849\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2002,\n      \"finding\": \"SBP2 shares an RNA-binding domain of the L7A/L30 family with the U4 snRNA-binding protein 15.5 kD/Snu13p. Structure-guided alanine scanning of 12 SBP2 residues predicted from alignment with the 15.5 kD–U4 snRNA crystal structure identified four residues whose mutation severely diminished or abolished SECIS RNA binding, with the other eight causing intermediate effects, defining the key amino acids for SECIS recognition.\",\n      \"method\": \"Multiple sequence alignment, structure-guided alanine mutagenesis, gel shift assays\",\n      \"journal\": \"RNA (New York, N.Y.)\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 / Moderate — active-site mutagenesis guided by crystal structure of homolog, functional validation by gel shift, single lab but multiple mutants\",\n      \"pmids\": [\"12403468\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2005,\n      \"finding\": \"Homozygous and compound heterozygous missense mutations in SECISBP2 in humans cause a global defect in selenoprotein synthesis, resulting in abnormal thyroid hormone metabolism. SBP2 is epistatic to selenoprotein synthesis, so its partial loss has a generalized effect on selenoproteins including deiodinase 2.\",\n      \"method\": \"Genetic linkage analysis, sequencing, fibroblast DIO2 enzymatic activity assay\",\n      \"journal\": \"Nature genetics\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — human genetic epistasis combined with biochemical enzyme activity assay in patient fibroblasts, replicated in multiple families\",\n      \"pmids\": [\"16228000\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2007,\n      \"finding\": \"SBP2 exhibits strong preferential binding to some selenoprotein mRNAs over others in vivo (determined by immunoprecipitation and mRNA quantitation), whereas nucleolin exhibits minimal differences in binding. Knockdown of SBP2 confirmed that SBP2 binding affinity is a major determinant dictating the hierarchy of selenoprotein synthesis via differential mRNA translation and sensitivity to nonsense-mediated decay.\",\n      \"method\": \"SBP2 knockdown by siRNA, immunoprecipitation of SBP2 followed by mRNA quantitation, selenoprotein mRNA level measurement\",\n      \"journal\": \"Molecular and cellular biology\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — reciprocal Co-IP of endogenous SBP2 with mRNA quantitation plus functional knockdown, single lab but two orthogonal methods\",\n      \"pmids\": [\"17846120\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2008,\n      \"finding\": \"Alternative splicing of SECISBP2 produces at least 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 undergo 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 mitochondrial targeting sequence identification and localization\",\n      \"journal\": \"Nucleic acids research\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 3 / Moderate — direct localization experiments for mtSBP2 isoform plus functional splicing assays, single lab, not fully reconstituted in vitro\",\n      \"pmids\": [\"19004874\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2009,\n      \"finding\": \"A nonsense mutation R128X in SBP2 results in synthesis of shorter SBP2 isoforms from at least three downstream ATGs, all of which retain the essential functional domains for SECIS binding. This explains why a severe truncating mutation produces a relatively mild phenotype of partial SBP2 deficiency.\",\n      \"method\": \"Sequencing, minigene construction, in vitro translation analysis of mutant proteins\",\n      \"journal\": \"The Journal of clinical endocrinology and metabolism\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Weak — in vitro translation of minigene constructs showing downstream ATG usage; single lab, single method\",\n      \"pmids\": [\"19602558\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2010,\n      \"finding\": \"The SBP2 truncation mutation R770X (in the RNA-binding domain) inhibits binding of SBP2 to SECIS elements, as shown by gel shift assay, whereas R120X disrupts all functional motifs. Compound heterozygous R120X/R770X causes widespread selenoprotein deficiency including undetectable selenoprotein P.\",\n      \"method\": \"Gel shift assay of mutant SBP2 proteins, sequencing, selenoprotein P measurement\",\n      \"journal\": \"The Journal of clinical endocrinology and metabolism\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Weak — direct in vitro binding assay for SECIS-binding defect of R770X mutant; single lab, single method\",\n      \"pmids\": [\"20501692\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2014,\n      \"finding\": \"SBP2 contacts the human ribosome primarily through the 28S rRNA at expansion segment ES7L, specifically helix ES7L-E. SBP2 binding to 80S ribosomes or 60S subunits protects helix ES7L-E from hydroxyl radical cleavage and induces conformational changes in ES7L-E and the universally conserved helix H89 of the 28S rRNA.\",\n      \"method\": \"Cross-linking with bifunctional reagents (diepoxybutane), direct hydroxyl radical probing of 28S rRNA, chemical probing\",\n      \"journal\": \"RNA (New York, N.Y.)\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 / Moderate — multiple orthogonal structural probing methods (cross-linking, hydroxyl radical probing, chemical probing) mapping SBP2 contact site on ribosome\",\n      \"pmids\": [\"24850884\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2017,\n      \"finding\": \"Ribosome profiling and RNA-seq of conditional Secisbp2 and Trsp (tRNA-Sec) knockout mouse livers showed that Secisbp2 loss results in gene-specific (variable) effects on ribosome density downstream of UGA-Sec codons, distinct from the uniform loss seen with tRNA-Sec depletion. For several selenoproteins, Secisbp2 loss greatly reduced mRNA levels without affecting translational activity or Sec incorporation efficiency on remaining RNA. These data demonstrate that Secisbp2 has a distinct role in stabilizing selenoprotein mRNAs separable from its role in UGA redefinition, and that Secisbp2 is not strictly required for Sec incorporation.\",\n      \"method\": \"Ribosome profiling, RNA-seq, mRNA half-life measurements, conditional genetic knockout (Cre-lox) in mouse liver\",\n      \"journal\": \"Nucleic acids research\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 / Strong — ribosome profiling with genetic comparison of Secisbp2 vs tRNA-Sec knockouts, multiple orthogonal methods establishing separable functions\",\n      \"pmids\": [\"27956496\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2017,\n      \"finding\": \"Sbp2 conditional knockout mice have decreased deiodinase 1 expression and enzymatic activity in liver, decreased deiodinase 2 enzymatic activity and deiodinase 3 expression in cerebrum, and decreased expression of other selenoproteins in brain, liver, and serum, demonstrating that SBP2 deficiency causes global selenoprotein synthesis impairment with organ-specific effects on thyroid hormone metabolism.\",\n      \"method\": \"Tamoxifen-inducible conditional knockout mouse model, deiodinase enzymatic activity assays, selenoprotein expression analysis, serum thyroid hormone measurements\",\n      \"journal\": \"Endocrinology\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — clean in vivo conditional KO with specific enzymatic activity readouts for multiple selenoproteins across tissues\",\n      \"pmids\": [\"29029094\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2019,\n      \"finding\": \"Pathogenic missense mutation C696R in the RNA-binding domain of SECISBP2 abrogates SECIS binding and does not support selenoprotein translation above the level of a complete null mutation. The R543Q missense mutation in the selenocysteine insertion domain results in residual translational activity but causes thermally unstable protein that is completely degraded in mouse liver in vivo while being partially functional in brain, demonstrating that cell-type-specific protein stability dictates clinical phenotypes.\",\n      \"method\": \"Mouse knock-in models of patient mutations, ribosome profiling, in vitro thermal stability assay, immunoblot for protein levels in different tissues\",\n      \"journal\": \"The Journal of biological chemistry\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 / Moderate — ribosome profiling plus in vitro biochemical stability assay plus tissue-specific protein quantification in knock-in mouse models carrying patient mutations\",\n      \"pmids\": [\"31350336\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2019,\n      \"finding\": \"SBP2 deficiency in adipose tissue macrophages (ATMs) causes increased intracellular reactive oxygen species and inflammasome activation, leading to IL-1β-driven proinflammatory macrophage expansion. ATM-specific knockdown of SBP2 in obese mice promoted insulin resistance via increased fat tissue inflammation; re-expression of SBP2 improved insulin sensitivity.\",\n      \"method\": \"ATM-specific siRNA knockdown in obese mice, re-expression experiments, ROS and inflammasome measurements, insulin sensitivity assays\",\n      \"journal\": \"Science advances\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — in vivo cell-type-specific knockdown and rescue with defined molecular readouts (ROS, inflammasome, IL-1β), single lab\",\n      \"pmids\": [\"31453320\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2025,\n      \"finding\": \"SBP2 targeting in HepG2 cells (CRISPR-Cas9) impaired selenoprotein mRNA and protein expression, confirming its essential role in selenoprotein synthesis in human hepatocytes, while producing a transcriptomic signature enriched for metabolic and ion transport processes distinct from that of its paralog SECISBP2L.\",\n      \"method\": \"CRISPR-Cas9 gene editing, RNA-seq, mass spectrometry, immunoblot\",\n      \"journal\": \"bioRxiv\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Weak — CRISPR KO with transcriptomic and proteomic readouts in human cell line; preprint, single lab\",\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 SECIS RNA hairpin (specifically the non-Watson-Crick G·A/A·G quartet in the upper helix) via an L7A/L30-family RNA-binding domain, recruits the selenocysteine-specific elongation factor eEFSec to selenoprotein mRNAs, and contacts the 60S ribosome at expansion segment ES7L of the 28S rRNA; it functions as the rate-limiting determinant of selenoprotein synthesis hierarchy through differential SECIS binding affinity, and additionally stabilizes selenoprotein mRNAs independently of its role in UGA-Sec recoding, while alternative splicing produces a mitochondria-targeted isoform and protein stability varies by cell type to influence clinical phenotypes.\"\n}\n```","stage2_raw":"{\n  \"mechanistic_narrative\": \"SECISBP2 (SBP2) is the essential, rate-limiting trans-acting factor that directs co-translational incorporation of selenocysteine into selenoproteins, recoding in-frame UGA codons during translation [#0, #1]. It recognizes the SECIS RNA hairpin in selenoprotein mRNA 3' UTRs through an L7A/L30-family RNA-binding domain, contacting the conserved non-Watson-Crick G·A/A·G base-pair quartet and internal loop of the upper helix [#2, #3]. Once bound to a SECIS element, SBP2 recruits the selenocysteine-specific elongation factor eEFSec and does not readily exchange between elements; because SBP2 is limiting and binds different SECIS elements with differing affinity, it establishes the hierarchy of selenoprotein synthesis, favoring mRNAs such as selenoprotein P and PHGPx [#1, #5]. SBP2 also contacts the 60S ribosome at expansion segment ES7L of the 28S rRNA, inducing conformational changes in ES7L-E and the conserved helix H89 [#9]. Beyond UGA recoding, SBP2 has a separable function in stabilizing selenoprotein mRNAs, as its loss reduces mRNA levels for several selenoproteins without impairing Sec incorporation on remaining transcripts [#10]. In vivo, SBP2 deficiency causes global selenoprotein synthesis impairment with organ-specific effects on thyroid hormone metabolism via the deiodinases [#11]. Missense and truncating mutations in SECISBP2 cause a human disorder of abnormal thyroid hormone metabolism through generalized selenoprotein deficiency, with clinical severity modulated by cell-type-specific protein stability and by use of downstream initiation codons that preserve functional domains [#4, #7, #12].\",\n  \"teleology\": [\n    {\n      \"year\": 2000,\n      \"claim\": \"Established that a dedicated SECIS-binding protein is required for selenocysteine insertion, answering whether selenoprotein synthesis needs a specific trans-acting factor beyond the SECIS element itself.\",\n      \"evidence\": \"UV cross-linking, immunodepletion/recombinant rescue, and in vitro Sec incorporation with 75Se-Sec-tRNA\",\n      \"pmids\": [\"10637234\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Did not define the SECIS recognition determinants at nucleotide resolution\", \"Did not identify downstream factors recruited by SBP2\"]\n    },\n    {\n      \"year\": 2000,\n      \"claim\": \"Showed how SBP2 acts mechanistically — recruiting eEFSec and acting as the limiting, non-exchanging factor that sets a synthesis hierarchy — answering why some selenoproteins are favored over others.\",\n      \"evidence\": \"Transfection competition assays comparing overexpressed trans-acting factors and selenoprotein mRNAs\",\n      \"pmids\": [\"11118223\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Quantitative SECIS affinity differences not measured\", \"Did not establish whether hierarchy reflects translation, mRNA stability, or both\"]\n    },\n    {\n      \"year\": 2001,\n      \"claim\": \"Defined the precise SBP2 footprint on SECIS RNA, answering which structural features of the hairpin are recognized.\",\n      \"evidence\": \"Enzymatic and hydroxyl radical footprinting, EMSA, and phosphate-ethylation interference\",\n      \"pmids\": [\"11680849\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"No co-crystal or solution structure of the SBP2–SECIS complex\", \"Protein residues mediating contacts not yet identified\"]\n    },\n    {\n      \"year\": 2002,\n      \"claim\": \"Identified the SBP2 RNA-binding domain as L7A/L30-family and pinpointed residues required for SECIS recognition, linking SBP2 to a known RNA-binding fold.\",\n      \"evidence\": \"Structure-guided alanine scanning informed by the 15.5 kD–U4 snRNA crystal structure, with gel shift validation\",\n      \"pmids\": [\"12403468\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"No direct SBP2 structure determined\", \"Contributions of non-RBD regions to function not addressed\"]\n    },\n    {\n      \"year\": 2005,\n      \"claim\": \"Connected SBP2 to human disease, answering whether SBP2 loss-of-function has physiological consequences, by linking mutations to abnormal thyroid hormone metabolism via generalized selenoprotein deficiency.\",\n      \"evidence\": \"Genetic linkage, sequencing, and DIO2 enzymatic activity in patient fibroblasts across multiple families\",\n      \"pmids\": [\"16228000\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Did not resolve why partial loss yields tissue-specific phenotypes\", \"Molecular impact of individual mutations not biochemically dissected\"]\n    },\n    {\n      \"year\": 2007,\n      \"claim\": \"Demonstrated that differential SBP2 binding affinity, not a generic SECIS-binder, dictates the selenoprotein hierarchy in vivo and links it to mRNA translation and NMD sensitivity.\",\n      \"evidence\": \"siRNA knockdown plus reciprocal Co-IP of endogenous SBP2 with mRNA quantitation\",\n      \"pmids\": [\"17846120\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Mechanism coupling SBP2 binding to NMD not detailed\", \"Quantitative affinity ranking across the full selenoproteome incomplete\"]\n    },\n    {\n      \"year\": 2008,\n      \"claim\": \"Revealed isoform diversity and a mitochondria-targeted variant, answering whether SBP2 function extends beyond cytoplasmic selenoprotein synthesis.\",\n      \"evidence\": \"Minigene splicing assays, antisense modulation, and mitochondrial localization of mtSBP2\",\n      \"pmids\": [\"19004874\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Function of mtSBP2 in mitochondria not established\", \"Stress-regulated splicing not reconstituted mechanistically\"]\n    },\n    {\n      \"year\": 2009,\n      \"claim\": \"Explained the mild phenotype of a severe truncating mutation through downstream ATG usage producing functional shorter isoforms.\",\n      \"evidence\": \"Minigene constructs and in vitro translation of R128X mutant\",\n      \"pmids\": [\"19602558\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Single method, single lab\", \"In vivo abundance and activity of downstream-initiated isoforms not quantified\"]\n    },\n    {\n      \"year\": 2010,\n      \"claim\": \"Mapped a disease mutation (R770X) directly to loss of SECIS binding, connecting genotype to a defined biochemical defect.\",\n      \"evidence\": \"Gel shift assays of mutant proteins and selenoprotein P measurement in compound heterozygotes\",\n      \"pmids\": [\"20501692\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Single binding method without reciprocal validation\", \"Cellular consequences of partial binding loss not fully resolved\"]\n    },\n    {\n      \"year\": 2014,\n      \"claim\": \"Located the SBP2–ribosome interface at 28S rRNA ES7L, answering how SBP2 physically engages the translation machinery.\",\n      \"evidence\": \"Bifunctional cross-linking, hydroxyl radical probing, and chemical probing of 28S rRNA\",\n      \"pmids\": [\"24850884\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"High-resolution structure of the SBP2–ribosome complex lacking\", \"Functional consequence of induced H89 conformational change unproven\"]\n    },\n    {\n      \"year\": 2017,\n      \"claim\": \"Separated SBP2's mRNA-stabilizing function from UGA recoding and showed it is not strictly required for Sec incorporation, refining the model of SBP2 essentiality.\",\n      \"evidence\": \"Ribosome profiling and RNA-seq comparing conditional Secisbp2 vs Trsp knockout mouse livers, with mRNA half-life measurements\",\n      \"pmids\": [\"27956496\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Molecular mechanism of mRNA stabilization unknown\", \"Why effects are gene-specific not explained\"]\n    },\n    {\n      \"year\": 2017,\n      \"claim\": \"Quantified in vivo organ-specific selenoprotein and deiodinase deficits, linking SBP2 loss to tissue-differential thyroid hormone metabolism.\",\n      \"evidence\": \"Tamoxifen-inducible conditional knockout mouse with deiodinase activity assays and serum thyroid hormone measurements\",\n      \"pmids\": [\"29029094\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Basis of organ-specific severity not mechanistically resolved\", \"Non-thyroidal selenoprotein consequences not fully characterized\"]\n    },\n    {\n      \"year\": 2019,\n      \"claim\": \"Showed that cell-type-specific protein stability of mutant SBP2 dictates clinical phenotype, explaining tissue-differential disease severity.\",\n      \"evidence\": \"Knock-in mouse models of patient mutations with ribosome profiling, thermal stability assays, and tissue protein quantification\",\n      \"pmids\": [\"31350336\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Degradation pathway controlling tissue-specific stability not identified\", \"Generalizability across other mutations untested\"]\n    },\n    {\n      \"year\": 2019,\n      \"claim\": \"Extended SBP2 function to immunometabolism, showing its deficiency in adipose tissue macrophages drives ROS, inflammasome activation, and insulin resistance.\",\n      \"evidence\": \"ATM-specific siRNA knockdown and re-expression in obese mice with ROS, inflammasome, and insulin sensitivity readouts\",\n      \"pmids\": [\"31453320\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Which selenoproteins mediate the antioxidant/anti-inflammatory effect not identified\", \"Single lab, not independently confirmed\"]\n    },\n    {\n      \"year\": 2025,\n      \"claim\": \"Confirmed SBP2's essential role in human hepatocyte selenoprotein synthesis and distinguished its transcriptomic footprint from paralog SECISBP2L.\",\n      \"evidence\": \"CRISPR-Cas9 knockout in HepG2 with RNA-seq, mass spectrometry, and immunoblot (preprint)\",\n      \"pmids\": [\"bio_10.1101_2025.07.02.662884\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Preprint, single lab\", \"Functional division of labor between SBP2 and SECISBP2L not mechanistically defined\"]\n    },\n    {\n      \"year\": null,\n      \"claim\": \"How SBP2 mechanistically stabilizes selenoprotein mRNAs and the high-resolution architecture of the SBP2–SECIS–eEFSec–ribosome assembly remain unresolved.\",\n      \"evidence\": \"\",\n      \"pmids\": [],\n      \"confidence\": \"High\",\n      \"gaps\": [\"No structure of SBP2 bound to SECIS or the ribosome\", \"mRNA-stabilization mechanism uncharacterized\", \"Mitochondrial mtSBP2 function unknown\"]\n    }\n  ],\n  \"mechanism_profile\": {\n    \"molecular_activity\": [\n      {\"term_id\": \"GO:0003723\", \"supporting_discovery_ids\": [0, 2, 3, 5]},\n      {\"term_id\": \"GO:0045182\", \"supporting_discovery_ids\": [0, 1, 10]},\n      {\"term_id\": \"GO:0060090\", \"supporting_discovery_ids\": [1, 9]}\n    ],\n    \"localization\": [\n      {\"term_id\": \"GO:0005840\", \"supporting_discovery_ids\": [9]},\n      {\"term_id\": \"GO:0005739\", \"supporting_discovery_ids\": [6]}\n    ],\n    \"pathway\": [\n      {\"term_id\": \"R-HSA-392499\", \"supporting_discovery_ids\": [0, 1, 10]},\n      {\"term_id\": \"R-HSA-8953854\", \"supporting_discovery_ids\": [5, 10]}\n    ],\n    \"complexes\": [],\n    \"partners\": [\"EEFSEC\"],\n    \"other_free_text\": []\n  }\n}","audit_flag":null,"evaluation":{"pairwise":"win","faith_supported":7,"faith_total":7,"faith_pct":100.0}}