{"gene":"SEPSECS","run_date":"2026-06-10T07:46:30","timeline":{"discoveries":[{"year":2009,"finding":"Crystal structure of human SepSecS in complex with tRNA(Sec), phosphoserine, and thiophosphate revealed that SepSecS catalyzes the final step of selenocysteine formation via a pyridoxal phosphate (PLP)-dependent mechanism. Two tRNA(Sec) molecules bind to each SepSecS tetramer through their 13-base-pair acceptor-TψC arm. tRNA binding induces a conformational change in the active site that allows phosphoserine covalently attached to tRNA(Sec) — but not free phosphoserine — to be properly oriented for the reaction.","method":"X-ray crystallography (SepSecS–tRNA(Sec) complex structure), in vivo and in vitro enzyme assays, active-site analysis","journal":"Science","confidence":"High","confidence_rationale":"Tier 1 / Strong — crystal structure with bound substrates/analogs combined with in vivo and in vitro enzymatic validation, single rigorous study with multiple orthogonal methods","pmids":["19608919"],"is_preprint":false},{"year":2000,"finding":"Expression cloning and absorption experiments identified SEPSECS (SLA/LP) as the sole target antigen of soluble liver antigen (SLA) and liver-pancreas (LP) autoantibodies in autoimmune hepatitis. The protein is 422 amino acids (present in two splice variants) and amino acids 371–409 were mapped as critical for immune recognition.","method":"Immunoscreening of cDNA expression libraries, inhibition ELISA, deletion mutant epitope mapping, absorption experiments","journal":"Lancet","confidence":"High","confidence_rationale":"Tier 2 / Strong — expression cloning with deletion-mutant epitope mapping and absorption experiments; replicated across subsequent independent studies","pmids":["10801173"],"is_preprint":false},{"year":2001,"finding":"A truncated 35-kDa recombinant SLA/LP protein (SLA-p35) was isolated by immunoscreening and shown by preabsorption to block reactivity to native SLA antigen, confirming it encodes a major (but not sole) antigenic component of the SLA/LP autoantigen. It showed strong homology to a UGA serine tRNA-protein complex-related protein.","method":"cDNA library immunoscreening, preabsorption/inhibition ELISA, immunoblot with recombinant protein expressed in E. coli","journal":"Hepatology","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — reciprocal inhibition assay and immunoblot in single lab; independently corroborated by Wies et al. 2000","pmids":["11230739"],"is_preprint":false},{"year":2009,"finding":"The native SepSecS/SLA/LP/tRNP(Ser)Sec autoantigen was purified from human hepatic cell extract by immune affinity chromatography and identified by mass spectrometry as a 52 kDa protein, confirming the identity of the recombinant antigen with its endogenous counterpart.","method":"Immune affinity chromatography, ion exchange chromatography, mass spectrometry, monoclonal antibody validation","journal":"Journal of autoimmunity","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — protein purification from native source plus mass spectrometry identification and mAb validation, single lab","pmids":["19683415"],"is_preprint":false},{"year":2017,"finding":"SEPSECS forms oligomers in eukaryotic cells and interacts with SECp43, SEPHS1, and SEPHS2 as part of the selenocysteine biosynthesis and incorporation machinery. The SEPSECS–SEPHS2 and SEPSECS–SEPHS1 interactions were confirmed by co-immunoprecipitation.","method":"Bioluminescence resonance energy transfer (BRET) in mammalian cells, co-immunoprecipitation","journal":"Biochemistry","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — two orthogonal methods (BRET and Co-IP) in single lab confirming protein–protein interactions","pmids":["28414460"],"is_preprint":false},{"year":2013,"finding":"Knockdown of SEPSECS in human trophoblast JEG-3 cells inhibited cell proliferation and induced apoptosis (increased caspase-3 activation), while overexpression promoted proliferation. Both knockdown and overexpression altered secretion of progesterone and hCG, establishing a functional role for SEPSECS in trophoblast cell proliferation, survival, and hormone production.","method":"siRNA knockdown and plasmid overexpression in JEG-3 cells; MTT assay, colony formation assay, Annexin V/PI apoptosis assay, caspase-3 activation assay, ELISA for hormones","journal":"Placenta","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — loss- and gain-of-function with multiple cellular readouts in single lab","pmids":["23966103"],"is_preprint":false},{"year":2024,"finding":"Human SEPSECS binds no more than two tRNA(Sec) molecules per tetramer despite having four equivalent active sites. A C-terminal acidic α-helical extension (helix 16), present exclusively in vertebrates, precludes tRNA binding in two of the four monomers and stabilizes the SEPSECS•tRNA(Sec) complex. Absence of this helix causes aggregation at low tRNA concentrations. Mammalian SEPSECS, unlike its archaeal ortholog, can bind unacylated tRNA(Sec) without requiring an aminoacyl group, reflecting an evolutionary innovation in the tRNA-binding mechanism.","method":"Comparative structural analysis, phylogenetic analysis, biochemical binding assays (acylated vs. unacylated tRNA), mutagenesis/deletion of C-terminal helix","journal":"Nucleic Acids Research","confidence":"High","confidence_rationale":"Tier 1 / Moderate — structural and biochemical reconstitution with comparative species analysis and mutagenesis in a single rigorous study","pmids":["39385655"],"is_preprint":false},{"year":2025,"finding":"SepSecS-specific CD4+ T cell clones isolated from AIH patients produced IFN-γ, IL-4, and IL-10, recognized multiple SepSecS epitopes, and in one patient were clonally expanded in both blood and liver biopsy tissue. SepSecS-specific B cell clones (but not unrelated B cells) presented soluble SepSecS antigen to specific T cells, demonstrating antigen-specific B cell–T cell collaboration in AIH.","method":"High-throughput B/T cell screening, monoclonal antibody isolation, T cell clone generation, intracellular cytokine staining, B cell antigen-presentation assay, liver biopsy TCR clonotype analysis","journal":"The Journal of Clinical Investigation","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — multiple orthogonal methods in single study; clonal analysis directly linking SepSecS-specific lymphocytes to AIH pathology","pmids":["39817450"],"is_preprint":false},{"year":2012,"finding":"In chicken brain neurons, selenium altered SepSecS mRNA stability (half-life) rather than directly increasing transcription, suggesting SepSecS expression is post-transcriptionally regulated by selenium availability to maintain selenium homeostasis in the brain.","method":"Se supplementation in vivo and in primary cultured chicken neurons, RT-PCR, real-time qRT-PCR, mRNA stability/half-life assay","journal":"PLoS ONE","confidence":"Low","confidence_rationale":"Tier 3 / Weak — single lab, single model organism (chicken), mRNA-level readout with no direct protein-level mechanism established","pmids":["22536434"],"is_preprint":false},{"year":2025,"finding":"In yellow catfish, a FOXO1 binding site in the sepsecs promoter (-721 to -731 bp) was identified as functionally active; FOXO1 was confirmed to interact with this site by EMSA and ChIP, and selenium (selenomethionine) regulated this interaction, establishing FOXO1 as a transcriptional regulator of sepsecs expression.","method":"Promoter deletion and mutation analysis, EMSA, chromatin immunoprecipitation (ChIP), selenium treatment","journal":"Biochimica et Biophysica Acta – Gene Regulatory Mechanisms","confidence":"Low","confidence_rationale":"Tier 3 / Weak — conducted in fish (Pelteobagrus fulvidraco), single lab; functional transcription data established but relevance to human/mammalian SEPSECS regulation not directly demonstrated","pmids":["40618995"],"is_preprint":false}],"current_model":"SEPSECS (SLA/LP) is a pyridoxal phosphate-dependent enzyme that functions as a homotetramer to catalyze the final step of selenocysteine biosynthesis on tRNA(Sec), converting O-phosphoseryl-tRNA(Sec) to selenocysteinyl-tRNA(Sec); its active site requires tRNA-dependent substrate positioning, only two of its four active sites bind tRNA(Sec) simultaneously due to a vertebrate-specific C-terminal helical extension, it physically interacts with SECp43, SEPHS1, and SEPHS2 within the selenocysteine incorporation machinery, and its loss-of-function in trophoblast cells reduces proliferation and induces apoptosis, while in humans it is also the primary autoantigen targeted by disease-specific SLA/LP autoantibodies in autoimmune hepatitis."},"narrative":{"mechanistic_narrative":"SEPSECS (SLA/LP) is a pyridoxal phosphate (PLP)-dependent enzyme that catalyzes the terminal step of selenocysteine biosynthesis on tRNA(Sec), converting O-phosphoseryl-tRNA(Sec) to selenocysteinyl-tRNA(Sec) [PMID:19608919]. It assembles as a homotetramer that engages tRNA(Sec) through the 13-base-pair acceptor-TψC arm, and tRNA binding drives a conformational change in the active site that correctly orients the tRNA-attached phosphoserine substrate — free phosphoserine is not productively positioned, making catalysis strictly tRNA-dependent [PMID:19608919]. Although the tetramer carries four equivalent active sites, no more than two tRNA(Sec) molecules bind per tetramer: a vertebrate-specific C-terminal acidic α-helical extension (helix 16) occludes tRNA binding in two monomers and stabilizes the complex, and mammalian SEPSECS can bind unacylated tRNA(Sec) without an aminoacyl group, distinguishing it from its archaeal ortholog [PMID:39385655]. SEPSECS oligomerizes in cells and operates within the selenocysteine biosynthesis/incorporation machinery, physically interacting with SECp43, SEPHS1, and SEPHS2 [PMID:28414460]. Loss of SEPSECS in trophoblast cells reduces proliferation and induces caspase-3-dependent apoptosis, while altering progesterone and hCG secretion [PMID:23966103]. Independently, SEPSECS is the primary autoantigen recognized by disease-specific SLA/LP autoantibodies in autoimmune hepatitis, with autoantigen-specific CD4+ T cells and antigen-presenting B cells driving the autoimmune response [PMID:10801173, PMID:39817450].","teleology":[{"year":2000,"claim":"Before its enzymatic function was known, SEPSECS was identified molecularly as the sole target of the SLA/LP autoantibodies that define a serologic subgroup of autoimmune hepatitis, giving the protein a clinical identity.","evidence":"Immunoscreening of cDNA expression libraries with patient sera, inhibition ELISA, and deletion-mutant epitope mapping (residues 371–409)","pmids":["10801173"],"confidence":"High","gaps":["Did not establish the enzymatic or cellular function of the protein","Epitope mapping was antibody-based and did not address T cell recognition"]},{"year":2001,"claim":"A truncated recombinant SLA/LP protein was shown to block patient reactivity to native antigen, confirming the cloned cDNA encodes a major antigenic component and noting homology to a UGA serine tRNA-protein complex protein — the first hint of a tRNA-related function.","evidence":"cDNA library immunoscreening, preabsorption/inhibition ELISA, immunoblot of E. coli-expressed recombinant protein","pmids":["11230739"],"confidence":"Medium","gaps":["The tRNA-protein homology was sequence-based, not functionally demonstrated","Did not define the full antigenic determinant"]},{"year":2009,"claim":"The crystal structure of the human SepSecS–tRNA(Sec) complex resolved the catalytic mechanism, establishing SEPSECS as the PLP-dependent enzyme that performs the final step of selenocysteine formation only when phosphoserine is tRNA-attached.","evidence":"X-ray crystallography of the SepSecS–tRNA(Sec)–phosphoserine–thiophosphate complex with in vivo and in vitro enzyme assays","pmids":["19608919"],"confidence":"High","gaps":["Did not explain why only two of four active sites engage tRNA","Did not address the enzyme's interactions with the broader selenocysteine incorporation machinery"]},{"year":2009,"claim":"Purification of the native autoantigen from human hepatic extract and mass-spectrometric identification confirmed that the endogenous SLA/LP protein is identical to the recombinant SepSecS, unifying the autoimmune-antigen and enzyme identities.","evidence":"Immune affinity chromatography, ion exchange chromatography, mass spectrometry, monoclonal antibody validation","pmids":["19683415"],"confidence":"Medium","gaps":["Single-lab purification","Did not address why this enzyme becomes an autoimmune target"]},{"year":2013,"claim":"Loss- and gain-of-function in trophoblast cells assigned SEPSECS a cellular role beyond housekeeping selenoprotein synthesis, linking it to proliferation, survival, and hormone secretion.","evidence":"siRNA knockdown and overexpression in JEG-3 cells with proliferation, colony formation, Annexin V/caspase-3 apoptosis, and hormone ELISA readouts","pmids":["23966103"],"confidence":"Medium","gaps":["Single cell line and single lab","Did not determine whether the phenotype is mediated through selenocysteine biosynthesis or an independent activity"]},{"year":2017,"claim":"Defining SEPSECS's physical partners placed it within an assembled selenocysteine biosynthesis/incorporation complex rather than acting in isolation.","evidence":"BRET in mammalian cells and co-immunoprecipitation confirming oligomerization and interactions with SECp43, SEPHS1, and SEPHS2","pmids":["28414460"],"confidence":"Medium","gaps":["Interaction stoichiometry and architecture of the complex not resolved","Functional consequence of each interaction not tested"]},{"year":2024,"claim":"Comparative structural and biochemical analysis explained the long-standing half-site occupancy puzzle, attributing the two-tRNA-per-tetramer limit and complex stability to a vertebrate-specific C-terminal helix and revealing a mammalian-specific ability to bind unacylated tRNA(Sec).","evidence":"Comparative structural and phylogenetic analysis, acylated-vs-unacylated tRNA binding assays, and C-terminal helix mutagenesis/deletion","pmids":["39385655"],"confidence":"High","gaps":["Functional consequence of unacylated tRNA binding for cellular selenocysteine synthesis not established","Did not connect the structural innovation to disease relevance"]},{"year":2025,"claim":"Identification of SepSecS-specific CD4+ T cell clones and antigen-presenting B cells demonstrated antigen-specific B–T cell collaboration in autoimmune hepatitis, advancing the autoantigen from a serologic marker to a driver of cellular autoimmunity.","evidence":"B/T cell screening, monoclonal antibody and T cell clone isolation, intracellular cytokine staining, B cell antigen-presentation assay, and liver-biopsy TCR clonotype analysis","pmids":["39817450"],"confidence":"Medium","gaps":["Causal contribution of these clones to liver injury not demonstrated","Mechanism by which a metabolic enzyme breaks tolerance unknown"]},{"year":null,"claim":"How SEPSECS expression is controlled in human tissues and how its enzymatic role connects to its trophoblast and autoimmune phenotypes remain unresolved.","evidence":"Selenium-dependent regulation has only been shown at the mRNA-stability level in chicken neurons and via FOXO1 promoter binding in catfish, without direct human/mammalian confirmation","pmids":[],"confidence":"Low","gaps":["No mammalian transcriptional/post-transcriptional regulatory mechanism established","Link between catalytic function and disease/cellular phenotypes uncharacterized"]}],"mechanism_profile":{"molecular_activity":[{"term_id":"GO:0016740","term_label":"transferase activity","supporting_discovery_ids":[0]},{"term_id":"GO:0140098","term_label":"catalytic activity, acting on RNA","supporting_discovery_ids":[0]},{"term_id":"GO:0003723","term_label":"RNA binding","supporting_discovery_ids":[0,6]}],"localization":[],"pathway":[{"term_id":"R-HSA-392499","term_label":"Metabolism of proteins","supporting_discovery_ids":[0,4]}],"complexes":[],"partners":["SECP43","SEPHS1","SEPHS2"],"other_free_text":[]}},"prefetch_data":{"uniprot":{"accession":"Q9HD40","full_name":"O-phosphoseryl-tRNA(Sec) selenium transferase","aliases":["Liver-pancreas antigen","LP","SLA-p35","SLA/LP autoantigen","Selenocysteine synthase","Sec synthase","Selenocysteinyl-tRNA(Sec) synthase","Sep-tRNA:Sec-tRNA synthase","SepSecS","Soluble liver antigen","SLA","UGA suppressor tRNA-associated protein","tRNA(Ser/Sec)-associated antigenic protein"],"length_aa":501,"mass_kda":55.7,"function":"Converts O-phosphoseryl-tRNA(Sec) to selenocysteinyl-tRNA(Sec) required for selenoprotein biosynthesis","subcellular_location":"Cytoplasm","url":"https://www.uniprot.org/uniprotkb/Q9HD40/entry"},"depmap":{"release":"DepMap","has_data":true,"is_common_essential":false,"resolved_as":"","url":"https://depmap.org/portal/gene/SEPSECS","classification":"Not Classified","n_dependent_lines":690,"n_total_lines":1208,"dependency_fraction":0.5711920529801324},"opencell":{"profiled":false,"resolved_as":"","ensg_id":"","cell_line_id":"","localizations":[],"interactors":[],"url":"https://opencell.sf.czbiohub.org/search/SEPSECS","total_profiled":1310},"omim":[{"mim_id":"619597","title":"tRNA SELENOCYSTEINE 1-ASSOCIATED PROTEIN 1; TRNAU1AP","url":"https://www.omim.org/entry/619597"},{"mim_id":"613811","title":"PONTOCEREBELLAR HYPOPLASIA, TYPE 2D; PCH2D","url":"https://www.omim.org/entry/613811"},{"mim_id":"613009","title":"O-PHOSPHOSERINE tRNA-SELENOCYSTEINE tRNA SYNTHASE; SEPSECS","url":"https://www.omim.org/entry/613009"},{"mim_id":"607596","title":"PONTOCEREBELLAR HYPOPLASIA, TYPE 1A; PCH1A","url":"https://www.omim.org/entry/607596"},{"mim_id":"277470","title":"PONTOCEREBELLAR HYPOPLASIA, TYPE 2A; PCH2A","url":"https://www.omim.org/entry/277470"}],"hpa":{"profiled":true,"resolved_as":"","reliability":"Approved","locations":[{"location":"Vesicles","reliability":"Approved"}],"tissue_specificity":"Tissue enhanced","tissue_distribution":"Detected in many","driving_tissues":[{"tissue":"liver","ntpm":24.4}],"url":"https://www.proteinatlas.org/search/SEPSECS"},"hgnc":{"alias_symbol":["SLA/LP","SLA","SLA-p35","SecS"],"prev_symbol":[]},"alphafold":{"accession":"Q9HD40","domains":[{"cath_id":"1.10.10.2160","chopping":"4-67_79-89","consensus_level":"medium","plddt":96.4603,"start":4,"end":89},{"cath_id":"3.40.640.10","chopping":"110-331","consensus_level":"medium","plddt":98.545,"start":110,"end":331},{"cath_id":"3.90.1150.10","chopping":"335-468","consensus_level":"medium","plddt":94.5366,"start":335,"end":468}],"viewer_url":"https://alphafold.ebi.ac.uk/entry/Q9HD40","model_url":"https://alphafold.ebi.ac.uk/files/AF-Q9HD40-F1-model_v6.cif","pae_url":"https://alphafold.ebi.ac.uk/files/AF-Q9HD40-F1-predicted_aligned_error_v6.png","plddt_mean":92.81},"mouse_models":{"mgi_url":"https://www.informatics.jax.org/marker/summary?nomen=SEPSECS","jax_strain_url":"https://www.jax.org/strain/search?query=SEPSECS"},"sequence":{"accession":"Q9HD40","fasta_url":"https://rest.uniprot.org/uniprotkb/Q9HD40.fasta","uniprot_url":"https://www.uniprot.org/uniprotkb/Q9HD40/entry","alphafold_viewer_url":"https://alphafold.ebi.ac.uk/entry/Q9HD40"}},"corpus_meta":[{"pmid":"10801173","id":"PMC_10801173","title":"Identification of target antigen for SLA/LP autoantibodies in autoimmune hepatitis.","date":"2000","source":"Lancet (London, England)","url":"https://pubmed.ncbi.nlm.nih.gov/10801173","citation_count":223,"is_preprint":false},{"pmid":"29263911","id":"PMC_29263911","title":"Let's talk about Secs: Sec61, Sec62 and Sec63 in signal transduction, oncology and personalized medicine.","date":"2017","source":"Signal transduction and targeted therapy","url":"https://pubmed.ncbi.nlm.nih.gov/29263911","citation_count":140,"is_preprint":false},{"pmid":"12117891","id":"PMC_12117891","title":"Establishment of standardised SLA/LP immunoassays: specificity for autoimmune hepatitis, worldwide occurrence, and clinical characteristics.","date":"2002","source":"Gut","url":"https://pubmed.ncbi.nlm.nih.gov/12117891","citation_count":122,"is_preprint":false},{"pmid":"19608919","id":"PMC_19608919","title":"The human SepSecS-tRNASec complex reveals the mechanism of selenocysteine formation.","date":"2009","source":"Science (New York, N.Y.)","url":"https://pubmed.ncbi.nlm.nih.gov/19608919","citation_count":121,"is_preprint":false},{"pmid":"28293634","id":"PMC_28293634","title":"SECs (Sinusoidal Endothelial Cells), Liver Microenvironment, and Fibrosis.","date":"2017","source":"BioMed research international","url":"https://pubmed.ncbi.nlm.nih.gov/28293634","citation_count":69,"is_preprint":false},{"pmid":"24367103","id":"PMC_24367103","title":"AFF1 is a ubiquitous P-TEFb partner to enable Tat extraction of P-TEFb from 7SK snRNP and formation of SECs for HIV transactivation.","date":"2013","source":"Proceedings of the National Academy of Sciences of the United States of America","url":"https://pubmed.ncbi.nlm.nih.gov/24367103","citation_count":67,"is_preprint":false},{"pmid":"11230739","id":"PMC_11230739","title":"Soluble liver antigen: isolation of a 35-kd recombinant protein (SLA-p35) specifically recognizing sera from patients with autoimmune hepatitis.","date":"2001","source":"Hepatology (Baltimore, Md.)","url":"https://pubmed.ncbi.nlm.nih.gov/11230739","citation_count":55,"is_preprint":false},{"pmid":"25113420","id":"PMC_25113420","title":"Anti-SLA/LP alone or in combination with anti-Ro52 and fine specificity of anti-Ro52 antibodies in patients with autoimmune hepatitis.","date":"2014","source":"Liver international : official journal of the International Association for the Study of the Liver","url":"https://pubmed.ncbi.nlm.nih.gov/25113420","citation_count":43,"is_preprint":false},{"pmid":"12765473","id":"PMC_12765473","title":"Anti-soluble liver antigen/liver-pancreas (SLA/LP) antibodies in pediatric patients with autoimmune hepatitis.","date":"2002","source":"Autoimmunity","url":"https://pubmed.ncbi.nlm.nih.gov/12765473","citation_count":32,"is_preprint":false},{"pmid":"16202982","id":"PMC_16202982","title":"Rat sinusoidal liver endothelial cells (SECs) produce pro-fibrotic factors in response to adducts formed from the metabolites of 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Comparative study using in-house ELISA with a recombinant 48.8 kDa protein, immunoblot, and analysis of immunoprecipitated RNAs.","date":"2005","source":"Liver international : official journal of the International Association for the Study of the Liver","url":"https://pubmed.ncbi.nlm.nih.gov/15780067","citation_count":11,"is_preprint":false},{"pmid":"39817450","id":"PMC_39817450","title":"Clonal analysis of SepSecS-specific B and T cells in autoimmune hepatitis.","date":"2025","source":"The Journal of clinical investigation","url":"https://pubmed.ncbi.nlm.nih.gov/39817450","citation_count":10,"is_preprint":false},{"pmid":"16521218","id":"PMC_16521218","title":"Characterization of human gene encoding SLA/LP autoantigen and its conserved homologs in mouse, fish, fly, and worm.","date":"2006","source":"World journal of gastroenterology","url":"https://pubmed.ncbi.nlm.nih.gov/16521218","citation_count":7,"is_preprint":false},{"pmid":"22311084","id":"PMC_22311084","title":"The expression of chicken selenoprotein W, selenocysteine-synthase (SecS), and selenophosphate synthetase-1 (SPS-1) in CHO-K1 cells.","date":"2012","source":"Biological trace element research","url":"https://pubmed.ncbi.nlm.nih.gov/22311084","citation_count":5,"is_preprint":false},{"pmid":"9438261","id":"PMC_9438261","title":"Direct sequencing of unpurified PCR-amplified DNA by semi-exponential cycle sequencing (SECS).","date":"1997","source":"Molecular biotechnology","url":"https://pubmed.ncbi.nlm.nih.gov/9438261","citation_count":5,"is_preprint":false},{"pmid":"35155316","id":"PMC_35155316","title":"Case Report: A Relatively Mild Phenotype Produced by Novel Mutations in the SEPSECS Gene.","date":"2022","source":"Frontiers in pediatrics","url":"https://pubmed.ncbi.nlm.nih.gov/35155316","citation_count":4,"is_preprint":false},{"pmid":"35252561","id":"PMC_35252561","title":"Novel SEPSECS Pathogenic Variants Featuring Unusual Phenotype of Complex Movement Disorder With Thin Corpus Callosum: A Case Report.","date":"2021","source":"Neurology. Genetics","url":"https://pubmed.ncbi.nlm.nih.gov/35252561","citation_count":4,"is_preprint":false},{"pmid":"36085396","id":"PMC_36085396","title":"Analysis of the Clinical Features and Imaging Findings of Pontocerebellar Hypoplasia Type 2D Caused by Mutations in SEPSECS Gene.","date":"2022","source":"Cerebellum (London, England)","url":"https://pubmed.ncbi.nlm.nih.gov/36085396","citation_count":3,"is_preprint":false},{"pmid":"37761892","id":"PMC_37761892","title":"Integrative Analysis Unveils the Correlation of Aminoacyl-tRNA Biosynthesis Metabolites with the Methylation of the SEPSECS Gene in Huntington's Disease Brain Tissue.","date":"2023","source":"Genes","url":"https://pubmed.ncbi.nlm.nih.gov/37761892","citation_count":3,"is_preprint":false},{"pmid":"40402207","id":"PMC_40402207","title":"SECS, drugs, and Rac1&Rho: regulation of EnNaC in vascular endothelial cells.","date":"2025","source":"Pflugers Archiv : European journal of physiology","url":"https://pubmed.ncbi.nlm.nih.gov/40402207","citation_count":2,"is_preprint":false},{"pmid":"23966103","id":"PMC_23966103","title":"The role of Sep (O-phosphoserine) tRNA: Sec (selenocysteine) synthase (SEPSECS) in proliferation, apoptosis and hormone secretion of trophoblast cells.","date":"2013","source":"Placenta","url":"https://pubmed.ncbi.nlm.nih.gov/23966103","citation_count":2,"is_preprint":false},{"pmid":"35091508","id":"PMC_35091508","title":"Biallelic SEPSECS variants in two siblings with pontocerebellar hypoplasia type 2D underscore the relevance of splice-disrupting synonymous variants in disease.","date":"2022","source":"Cold Spring Harbor molecular case studies","url":"https://pubmed.ncbi.nlm.nih.gov/35091508","citation_count":2,"is_preprint":false},{"pmid":"12353148","id":"PMC_12353148","title":"Expression of intercellular adhesion molecule-1 (ICAM-1) during hypoxia-reoxygenation by sinusoidal endothelial cells (SECs) in an obstructive jaundice model.","date":"2002","source":"Journal of hepato-biliary-pancreatic surgery","url":"https://pubmed.ncbi.nlm.nih.gov/12353148","citation_count":2,"is_preprint":false},{"pmid":"40017499","id":"PMC_40017499","title":"Acute neurological regression following fever as presenting sign of pontocerebellar hypoplasia type 2D (SEPSECS mutation).","date":"2025","source":"Biomedical reports","url":"https://pubmed.ncbi.nlm.nih.gov/40017499","citation_count":1,"is_preprint":false},{"pmid":"39385655","id":"PMC_39385655","title":"Human selenocysteine synthase, SEPSECS, has evolved to optimize binding of a tRNA-based substrate.","date":"2024","source":"Nucleic acids research","url":"https://pubmed.ncbi.nlm.nih.gov/39385655","citation_count":0,"is_preprint":false},{"pmid":"41070650","id":"PMC_41070650","title":"[Pontocerebellar hypoplasia type 2D caused by compound heterozygous variants in the SEPSECS gene: A case report and literature review].","date":"2025","source":"Zhonghua yi xue yi chuan xue za zhi = Zhonghua yixue yichuanxue zazhi = Chinese journal of medical genetics","url":"https://pubmed.ncbi.nlm.nih.gov/41070650","citation_count":0,"is_preprint":false},{"pmid":"40618995","id":"PMC_40618995","title":"Functional characterization of promoter regions in selenoprotein synthesis-relevant genes (sbp2, eefsec and sepsecs) and their selenium-dependent regulation in yellow catfish Pelteobagrus fulvidraco.","date":"2025","source":"Biochimica et biophysica acta. Gene regulatory mechanisms","url":"https://pubmed.ncbi.nlm.nih.gov/40618995","citation_count":0,"is_preprint":false},{"pmid":"16381642","id":"PMC_16381642","title":"[Clinical and laboratory characteristics of anti-soluble liver antigen/liver-pancreas (SLA/LP) autoantibody positive liver disease patients].","date":"2005","source":"Zhonghua gan zang bing za zhi = Zhonghua ganzangbing zazhi = Chinese journal of hepatology","url":"https://pubmed.ncbi.nlm.nih.gov/16381642","citation_count":0,"is_preprint":false},{"pmid":null,"id":"bio_10.1101_2025.08.29.672943","title":"Clonal analysis of SepSecS-specific CD4 T cells reveals a new HLA-DPA1*02:01/HLA-DPB1*01:01-restricted immunodominant epitope in autoimmune hepatitis","date":"2025-09-03","source":"bioRxiv","url":"https://doi.org/10.1101/2025.08.29.672943","citation_count":0,"is_preprint":true},{"pmid":null,"id":"bio_10.1101_2025.07.28.667120","title":"Genomic Regions and Variant Analysis Reveal Candidate Genes Associated with Age at First Service in Chinese Holstein Heifers","date":"2025-07-29","source":"bioRxiv","url":"https://doi.org/10.1101/2025.07.28.667120","citation_count":0,"is_preprint":true},{"pmid":null,"id":"bio_10.1101_2025.07.02.662640","title":"Epidermal Stem Cells Control Periderm Injury Repair via Matrix-Driven Specialization of Intercellular Junctions","date":"2025-07-03","source":"bioRxiv","url":"https://doi.org/10.1101/2025.07.02.662640","citation_count":0,"is_preprint":true},{"pmid":null,"id":"bio_10.1101_2025.04.23.25325959","title":"Validation of Angular Indication Measurement (AIM) Stereoacuity","date":"2025-04-25","source":"bioRxiv","url":"https://doi.org/10.1101/2025.04.23.25325959","citation_count":0,"is_preprint":true},{"pmid":null,"id":"bio_10.1101_2024.12.12.24318960","title":"Collaterals influence oxygen metabolism on admission MRI in acute ischemic stroke","date":"2024-12-17","source":"bioRxiv","url":"https://doi.org/10.1101/2024.12.12.24318960","citation_count":0,"is_preprint":true},{"pmid":null,"id":"bio_10.1101_2024.11.08.622119","title":"Sex differences in the cardiopulmonary and neuromuscular response to high-intensity interval exercise","date":"2024-11-11","source":"bioRxiv","url":"https://doi.org/10.1101/2024.11.08.622119","citation_count":0,"is_preprint":true}],"cost":{"stage1":{"model":"claude-sonnet-4-6","input_tokens":23064,"output_tokens":2682,"usd":0.054711,"stage1_stop_reason":"end_turn"},"stage2":{"model":"claude-opus-4-8","input_tokens":10045,"output_tokens":3125,"usd":0.064175,"stage2_stop_reason":"end_turn"},"total_usd":0.118886,"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\": 2009,\n      \"finding\": \"Crystal structure of human SepSecS in complex with tRNA(Sec), phosphoserine, and thiophosphate revealed that SepSecS catalyzes the final step of selenocysteine formation via a pyridoxal phosphate (PLP)-dependent mechanism. Two tRNA(Sec) molecules bind to each SepSecS tetramer through their 13-base-pair acceptor-TψC arm. tRNA binding induces a conformational change in the active site that allows phosphoserine covalently attached to tRNA(Sec) — but not free phosphoserine — to be properly oriented for the reaction.\",\n      \"method\": \"X-ray crystallography (SepSecS–tRNA(Sec) complex structure), in vivo and in vitro enzyme assays, active-site analysis\",\n      \"journal\": \"Science\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 / Strong — crystal structure with bound substrates/analogs combined with in vivo and in vitro enzymatic validation, single rigorous study with multiple orthogonal methods\",\n      \"pmids\": [\"19608919\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2000,\n      \"finding\": \"Expression cloning and absorption experiments identified SEPSECS (SLA/LP) as the sole target antigen of soluble liver antigen (SLA) and liver-pancreas (LP) autoantibodies in autoimmune hepatitis. The protein is 422 amino acids (present in two splice variants) and amino acids 371–409 were mapped as critical for immune recognition.\",\n      \"method\": \"Immunoscreening of cDNA expression libraries, inhibition ELISA, deletion mutant epitope mapping, absorption experiments\",\n      \"journal\": \"Lancet\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — expression cloning with deletion-mutant epitope mapping and absorption experiments; replicated across subsequent independent studies\",\n      \"pmids\": [\"10801173\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2001,\n      \"finding\": \"A truncated 35-kDa recombinant SLA/LP protein (SLA-p35) was isolated by immunoscreening and shown by preabsorption to block reactivity to native SLA antigen, confirming it encodes a major (but not sole) antigenic component of the SLA/LP autoantigen. It showed strong homology to a UGA serine tRNA-protein complex-related protein.\",\n      \"method\": \"cDNA library immunoscreening, preabsorption/inhibition ELISA, immunoblot with recombinant protein expressed in E. coli\",\n      \"journal\": \"Hepatology\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — reciprocal inhibition assay and immunoblot in single lab; independently corroborated by Wies et al. 2000\",\n      \"pmids\": [\"11230739\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2009,\n      \"finding\": \"The native SepSecS/SLA/LP/tRNP(Ser)Sec autoantigen was purified from human hepatic cell extract by immune affinity chromatography and identified by mass spectrometry as a 52 kDa protein, confirming the identity of the recombinant antigen with its endogenous counterpart.\",\n      \"method\": \"Immune affinity chromatography, ion exchange chromatography, mass spectrometry, monoclonal antibody validation\",\n      \"journal\": \"Journal of autoimmunity\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — protein purification from native source plus mass spectrometry identification and mAb validation, single lab\",\n      \"pmids\": [\"19683415\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2017,\n      \"finding\": \"SEPSECS forms oligomers in eukaryotic cells and interacts with SECp43, SEPHS1, and SEPHS2 as part of the selenocysteine biosynthesis and incorporation machinery. The SEPSECS–SEPHS2 and SEPSECS–SEPHS1 interactions were confirmed by co-immunoprecipitation.\",\n      \"method\": \"Bioluminescence resonance energy transfer (BRET) in mammalian cells, co-immunoprecipitation\",\n      \"journal\": \"Biochemistry\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — two orthogonal methods (BRET and Co-IP) in single lab confirming protein–protein interactions\",\n      \"pmids\": [\"28414460\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2013,\n      \"finding\": \"Knockdown of SEPSECS in human trophoblast JEG-3 cells inhibited cell proliferation and induced apoptosis (increased caspase-3 activation), while overexpression promoted proliferation. Both knockdown and overexpression altered secretion of progesterone and hCG, establishing a functional role for SEPSECS in trophoblast cell proliferation, survival, and hormone production.\",\n      \"method\": \"siRNA knockdown and plasmid overexpression in JEG-3 cells; MTT assay, colony formation assay, Annexin V/PI apoptosis assay, caspase-3 activation assay, ELISA for hormones\",\n      \"journal\": \"Placenta\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — loss- and gain-of-function with multiple cellular readouts in single lab\",\n      \"pmids\": [\"23966103\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2024,\n      \"finding\": \"Human SEPSECS binds no more than two tRNA(Sec) molecules per tetramer despite having four equivalent active sites. A C-terminal acidic α-helical extension (helix 16), present exclusively in vertebrates, precludes tRNA binding in two of the four monomers and stabilizes the SEPSECS•tRNA(Sec) complex. Absence of this helix causes aggregation at low tRNA concentrations. Mammalian SEPSECS, unlike its archaeal ortholog, can bind unacylated tRNA(Sec) without requiring an aminoacyl group, reflecting an evolutionary innovation in the tRNA-binding mechanism.\",\n      \"method\": \"Comparative structural analysis, phylogenetic analysis, biochemical binding assays (acylated vs. unacylated tRNA), mutagenesis/deletion of C-terminal helix\",\n      \"journal\": \"Nucleic Acids Research\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 / Moderate — structural and biochemical reconstitution with comparative species analysis and mutagenesis in a single rigorous study\",\n      \"pmids\": [\"39385655\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2025,\n      \"finding\": \"SepSecS-specific CD4+ T cell clones isolated from AIH patients produced IFN-γ, IL-4, and IL-10, recognized multiple SepSecS epitopes, and in one patient were clonally expanded in both blood and liver biopsy tissue. SepSecS-specific B cell clones (but not unrelated B cells) presented soluble SepSecS antigen to specific T cells, demonstrating antigen-specific B cell–T cell collaboration in AIH.\",\n      \"method\": \"High-throughput B/T cell screening, monoclonal antibody isolation, T cell clone generation, intracellular cytokine staining, B cell antigen-presentation assay, liver biopsy TCR clonotype analysis\",\n      \"journal\": \"The Journal of Clinical Investigation\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — multiple orthogonal methods in single study; clonal analysis directly linking SepSecS-specific lymphocytes to AIH pathology\",\n      \"pmids\": [\"39817450\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2012,\n      \"finding\": \"In chicken brain neurons, selenium altered SepSecS mRNA stability (half-life) rather than directly increasing transcription, suggesting SepSecS expression is post-transcriptionally regulated by selenium availability to maintain selenium homeostasis in the brain.\",\n      \"method\": \"Se supplementation in vivo and in primary cultured chicken neurons, RT-PCR, real-time qRT-PCR, mRNA stability/half-life assay\",\n      \"journal\": \"PLoS ONE\",\n      \"confidence\": \"Low\",\n      \"confidence_rationale\": \"Tier 3 / Weak — single lab, single model organism (chicken), mRNA-level readout with no direct protein-level mechanism established\",\n      \"pmids\": [\"22536434\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2025,\n      \"finding\": \"In yellow catfish, a FOXO1 binding site in the sepsecs promoter (-721 to -731 bp) was identified as functionally active; FOXO1 was confirmed to interact with this site by EMSA and ChIP, and selenium (selenomethionine) regulated this interaction, establishing FOXO1 as a transcriptional regulator of sepsecs expression.\",\n      \"method\": \"Promoter deletion and mutation analysis, EMSA, chromatin immunoprecipitation (ChIP), selenium treatment\",\n      \"journal\": \"Biochimica et Biophysica Acta – Gene Regulatory Mechanisms\",\n      \"confidence\": \"Low\",\n      \"confidence_rationale\": \"Tier 3 / Weak — conducted in fish (Pelteobagrus fulvidraco), single lab; functional transcription data established but relevance to human/mammalian SEPSECS regulation not directly demonstrated\",\n      \"pmids\": [\"40618995\"],\n      \"is_preprint\": false\n    }\n  ],\n  \"current_model\": \"SEPSECS (SLA/LP) is a pyridoxal phosphate-dependent enzyme that functions as a homotetramer to catalyze the final step of selenocysteine biosynthesis on tRNA(Sec), converting O-phosphoseryl-tRNA(Sec) to selenocysteinyl-tRNA(Sec); its active site requires tRNA-dependent substrate positioning, only two of its four active sites bind tRNA(Sec) simultaneously due to a vertebrate-specific C-terminal helical extension, it physically interacts with SECp43, SEPHS1, and SEPHS2 within the selenocysteine incorporation machinery, and its loss-of-function in trophoblast cells reduces proliferation and induces apoptosis, while in humans it is also the primary autoantigen targeted by disease-specific SLA/LP autoantibodies in autoimmune hepatitis.\"\n}\n```","stage2_raw":"{\n  \"mechanistic_narrative\": \"SEPSECS (SLA/LP) is a pyridoxal phosphate (PLP)-dependent enzyme that catalyzes the terminal step of selenocysteine biosynthesis on tRNA(Sec), converting O-phosphoseryl-tRNA(Sec) to selenocysteinyl-tRNA(Sec) [#0]. It assembles as a homotetramer that engages tRNA(Sec) through the 13-base-pair acceptor-TψC arm, and tRNA binding drives a conformational change in the active site that correctly orients the tRNA-attached phosphoserine substrate — free phosphoserine is not productively positioned, making catalysis strictly tRNA-dependent [#0]. Although the tetramer carries four equivalent active sites, no more than two tRNA(Sec) molecules bind per tetramer: a vertebrate-specific C-terminal acidic α-helical extension (helix 16) occludes tRNA binding in two monomers and stabilizes the complex, and mammalian SEPSECS can bind unacylated tRNA(Sec) without an aminoacyl group, distinguishing it from its archaeal ortholog [#6]. SEPSECS oligomerizes in cells and operates within the selenocysteine biosynthesis/incorporation machinery, physically interacting with SECp43, SEPHS1, and SEPHS2 [#4]. Loss of SEPSECS in trophoblast cells reduces proliferation and induces caspase-3-dependent apoptosis, while altering progesterone and hCG secretion [#5]. Independently, SEPSECS is the primary autoantigen recognized by disease-specific SLA/LP autoantibodies in autoimmune hepatitis, with autoantigen-specific CD4+ T cells and antigen-presenting B cells driving the autoimmune response [#1, #7].\",\n  \"teleology\": [\n    {\n      \"year\": 2000,\n      \"claim\": \"Before its enzymatic function was known, SEPSECS was identified molecularly as the sole target of the SLA/LP autoantibodies that define a serologic subgroup of autoimmune hepatitis, giving the protein a clinical identity.\",\n      \"evidence\": \"Immunoscreening of cDNA expression libraries with patient sera, inhibition ELISA, and deletion-mutant epitope mapping (residues 371–409)\",\n      \"pmids\": [\"10801173\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Did not establish the enzymatic or cellular function of the protein\", \"Epitope mapping was antibody-based and did not address T cell recognition\"]\n    },\n    {\n      \"year\": 2001,\n      \"claim\": \"A truncated recombinant SLA/LP protein was shown to block patient reactivity to native antigen, confirming the cloned cDNA encodes a major antigenic component and noting homology to a UGA serine tRNA-protein complex protein — the first hint of a tRNA-related function.\",\n      \"evidence\": \"cDNA library immunoscreening, preabsorption/inhibition ELISA, immunoblot of E. coli-expressed recombinant protein\",\n      \"pmids\": [\"11230739\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"The tRNA-protein homology was sequence-based, not functionally demonstrated\", \"Did not define the full antigenic determinant\"]\n    },\n    {\n      \"year\": 2009,\n      \"claim\": \"The crystal structure of the human SepSecS–tRNA(Sec) complex resolved the catalytic mechanism, establishing SEPSECS as the PLP-dependent enzyme that performs the final step of selenocysteine formation only when phosphoserine is tRNA-attached.\",\n      \"evidence\": \"X-ray crystallography of the SepSecS–tRNA(Sec)–phosphoserine–thiophosphate complex with in vivo and in vitro enzyme assays\",\n      \"pmids\": [\"19608919\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Did not explain why only two of four active sites engage tRNA\", \"Did not address the enzyme's interactions with the broader selenocysteine incorporation machinery\"]\n    },\n    {\n      \"year\": 2009,\n      \"claim\": \"Purification of the native autoantigen from human hepatic extract and mass-spectrometric identification confirmed that the endogenous SLA/LP protein is identical to the recombinant SepSecS, unifying the autoimmune-antigen and enzyme identities.\",\n      \"evidence\": \"Immune affinity chromatography, ion exchange chromatography, mass spectrometry, monoclonal antibody validation\",\n      \"pmids\": [\"19683415\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Single-lab purification\", \"Did not address why this enzyme becomes an autoimmune target\"]\n    },\n    {\n      \"year\": 2013,\n      \"claim\": \"Loss- and gain-of-function in trophoblast cells assigned SEPSECS a cellular role beyond housekeeping selenoprotein synthesis, linking it to proliferation, survival, and hormone secretion.\",\n      \"evidence\": \"siRNA knockdown and overexpression in JEG-3 cells with proliferation, colony formation, Annexin V/caspase-3 apoptosis, and hormone ELISA readouts\",\n      \"pmids\": [\"23966103\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Single cell line and single lab\", \"Did not determine whether the phenotype is mediated through selenocysteine biosynthesis or an independent activity\"]\n    },\n    {\n      \"year\": 2017,\n      \"claim\": \"Defining SEPSECS's physical partners placed it within an assembled selenocysteine biosynthesis/incorporation complex rather than acting in isolation.\",\n      \"evidence\": \"BRET in mammalian cells and co-immunoprecipitation confirming oligomerization and interactions with SECp43, SEPHS1, and SEPHS2\",\n      \"pmids\": [\"28414460\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Interaction stoichiometry and architecture of the complex not resolved\", \"Functional consequence of each interaction not tested\"]\n    },\n    {\n      \"year\": 2024,\n      \"claim\": \"Comparative structural and biochemical analysis explained the long-standing half-site occupancy puzzle, attributing the two-tRNA-per-tetramer limit and complex stability to a vertebrate-specific C-terminal helix and revealing a mammalian-specific ability to bind unacylated tRNA(Sec).\",\n      \"evidence\": \"Comparative structural and phylogenetic analysis, acylated-vs-unacylated tRNA binding assays, and C-terminal helix mutagenesis/deletion\",\n      \"pmids\": [\"39385655\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Functional consequence of unacylated tRNA binding for cellular selenocysteine synthesis not established\", \"Did not connect the structural innovation to disease relevance\"]\n    },\n    {\n      \"year\": 2025,\n      \"claim\": \"Identification of SepSecS-specific CD4+ T cell clones and antigen-presenting B cells demonstrated antigen-specific B–T cell collaboration in autoimmune hepatitis, advancing the autoantigen from a serologic marker to a driver of cellular autoimmunity.\",\n      \"evidence\": \"B/T cell screening, monoclonal antibody and T cell clone isolation, intracellular cytokine staining, B cell antigen-presentation assay, and liver-biopsy TCR clonotype analysis\",\n      \"pmids\": [\"39817450\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Causal contribution of these clones to liver injury not demonstrated\", \"Mechanism by which a metabolic enzyme breaks tolerance unknown\"]\n    },\n    {\n      \"year\": null,\n      \"claim\": \"How SEPSECS expression is controlled in human tissues and how its enzymatic role connects to its trophoblast and autoimmune phenotypes remain unresolved.\",\n      \"evidence\": \"Selenium-dependent regulation has only been shown at the mRNA-stability level in chicken neurons and via FOXO1 promoter binding in catfish, without direct human/mammalian confirmation\",\n      \"pmids\": [],\n      \"confidence\": \"Low\",\n      \"gaps\": [\"No mammalian transcriptional/post-transcriptional regulatory mechanism established\", \"Link between catalytic function and disease/cellular phenotypes uncharacterized\"]\n    }\n  ],\n  \"mechanism_profile\": {\n    \"molecular_activity\": [\n      {\"term_id\": \"GO:0016740\", \"supporting_discovery_ids\": [0]},\n      {\"term_id\": \"GO:0140098\", \"supporting_discovery_ids\": [0]},\n      {\"term_id\": \"GO:0003723\", \"supporting_discovery_ids\": [0, 6]}\n    ],\n    \"localization\": [],\n    \"pathway\": [\n      {\"term_id\": \"R-HSA-392499\", \"supporting_discovery_ids\": [0, 4]}\n    ],\n    \"complexes\": [],\n    \"partners\": [\"SECp43\", \"SEPHS1\", \"SEPHS2\"],\n    \"other_free_text\": []\n  }\n}","audit_flag":null,"evaluation":{"pairwise":"win","faith_supported":6,"faith_total":6,"faith_pct":100.0}}