{"gene":"BDP1","run_date":"2026-04-28T17:12:38","timeline":{"discoveries":[{"year":1995,"finding":"TFC5 (yeast BDP1/B\") encodes a 594-amino acid subunit of TFIIIB; recombinant B\" reconstitutes fully functional TFIIIB with Brf1 and TBP, supporting both TFIIIC-directed and TATA box-dependent DNA binding and transcription in vitro.","method":"Recombinant protein reconstitution, DNase I footprinting, in vitro transcription assay","journal":"Proceedings of the National Academy of Sciences of the United States of America","confidence":"High","confidence_rationale":"Tier 1 — in vitro reconstitution with multiple orthogonal assays, foundational study","pmids":["7568218"],"is_preprint":false},{"year":2002,"finding":"Yeast Bdp1 contains three essential segments; functional interactions with TBP and Brf1 were mapped to specific Bdp1 regions by suppression genetics; a physical interaction between Bdp1 and RNase P was demonstrated, linking Bdp1 to tRNA processing.","method":"Deletion analysis, genetic suppression (SPT15/BRF1 overexpression), in vitro transcription, co-immunoprecipitation, pull-down assay","journal":"Molecular and cellular biology","confidence":"High","confidence_rationale":"Tier 2 — multiple orthogonal methods (genetics, biochemistry, co-IP) in one study","pmids":["11971960"],"is_preprint":false},{"year":2003,"finding":"CK2 phosphorylates the Bdp1 subunit of TFIIIB during mitosis, causing Bdp1 dissociation from the U6 promoter and chromatin, thereby repressing RNA polymerase III transcription in a cell cycle-specific manner.","method":"In vitro kinase assay, chromatin immunoprecipitation, cell cycle fractionation, CK2 inhibitor rescue experiments","journal":"Molecular cell","confidence":"High","confidence_rationale":"Tier 1–2 — direct biochemical phosphorylation assay with functional chromatin and transcription readouts","pmids":["15469824"],"is_preprint":false},{"year":2003,"finding":"The Bdp1 subunit of TFIIIB interacts with the Tfc4 (tau131) subunit of TFIIIC via TPR repeats 1–9, with Bdp1 and Brf1 sharing overlapping binding sites on Tfc4; the Tfc4 L469K mutation impairs both Brf1 and Bdp1 incorporation into TFIIIB-TFIIIC-DNA complexes.","method":"Genetic suppression, in vitro binding assays, TFIIIC-DNA complex reconstitution","journal":"The Journal of biological chemistry","confidence":"Medium","confidence_rationale":"Tier 2 — multiple biochemical assays plus genetics, single lab","pmids":["12930823"],"is_preprint":false},{"year":2003,"finding":"Negative regulation of HER2 (ErbB2) receptor tyrosine kinase signaling by the PEST-type protein-tyrosine phosphatase BDP1: BDP1 overexpression inhibits ligand-induced HER2 phosphorylation and downstream Gab1/MAPK signaling, while BDP1 knockdown increases HER2 phosphorylation.","method":"Overexpression, siRNA knockdown, immunoprecipitation/western blot of phosphorylation","journal":"The Journal of biological chemistry","confidence":"Medium","confidence_rationale":"Tier 2–3 — reciprocal gain/loss of function with clear phosphorylation readout, single lab","pmids":["14660651"],"is_preprint":false},{"year":2003,"finding":"A specific internal deletion (aa 253–269) in Bdp1 selectively impairs TFIIIC-dependent assembly of TFIIIB on the RPR1 promoter (but not other Pol III genes), leading to gene-specific transcription defects in vitro.","method":"In vitro transcription assay, TFIIIB-TFIIIC-DNA complex assembly analysis","journal":"FEBS letters","confidence":"Medium","confidence_rationale":"Tier 1 — in vitro reconstitution assay, single lab, single paper","pmids":["12885403"],"is_preprint":false},{"year":2006,"finding":"The principal interaction site between Brf1 and Bdp1 was mapped: a 66-amino acid segment of Brf1's C-terminal domain provides a two-sided adhesive surface for Bdp1, while the interacting Bdp1 domain spans 66 amino acids encompassing the SANT domain, the most phylogenetically conserved region of Bdp1.","method":"Site-directed mutagenesis, photochemical protein-DNA cross-linking, deletion analysis","journal":"The Journal of biological chemistry","confidence":"High","confidence_rationale":"Tier 1–2 — mutagenesis combined with cross-linking provides residue-level mapping","pmids":["16551611"],"is_preprint":false},{"year":2006,"finding":"Human BDP1 (aa 1–299 N-terminal region) interacts with the zinc finger protein ZNF297B (via ZNF297B BTB/POZ domain, aa 1–127), identified by yeast two-hybrid and confirmed by co-immunoprecipitation.","method":"Yeast two-hybrid, co-immunoprecipitation, immunofluorescence","journal":"Biological chemistry","confidence":"Low","confidence_rationale":"Tier 3 — single co-IP confirmation of yeast two-hybrid, no functional consequence established","pmids":["16542149"],"is_preprint":false},{"year":2006,"finding":"Entry of Brf1 and Bdp1 into the TBP-DNA complex imposes a strict sequence preference for the downstream half of the TATA box (selecting TGTAAATA, matching the U6 snRNA gene TATA box), suggesting that the Brf1-Bdp1 proteins alter TBP-DNA complex structure or dynamics.","method":"Altered-specificity TBP mutant (TBPm3), iterative in vitro selection (SELEX)","journal":"Nucleic acids research","confidence":"Medium","confidence_rationale":"Tier 1 — in vitro selection assay with mechanistic interpretation, single lab","pmids":["17028095"],"is_preprint":false},{"year":2008,"finding":"NMR mapping of the Brf1-Bdp1 interaction interface showed that Bdp1 SANT domain helices 1 and 3 form the principal anchorage surface for a Brf1 segment (residues 470–495).","method":"NMR spectroscopy, structural modeling","journal":"Biochemistry","confidence":"Medium","confidence_rationale":"Tier 1 — NMR-derived structural model at single residue resolution, single lab, single paper","pmids":["19086269"],"is_preprint":false},{"year":2011,"finding":"The C-terminal domain of Rpc37 (within the TFIIF-like Rpc37/53 dimer of Pol III) contains binding sites for Bdp1; photo-cross-linking localized these interactions, revealing Bdp1's position within the Pol III preinitiation complex and its connection to the active center.","method":"Unnatural amino acid photo-cross-linking (BPA incorporation), site-directed hydroxyl radical probing","journal":"Molecular and cellular biology","confidence":"High","confidence_rationale":"Tier 1–2 — two complementary residue-level mapping techniques in a single study","pmids":["21536656"],"is_preprint":false},{"year":2015,"finding":"An essential N-terminal region of yeast Bdp1 (distinct from the SANT domain) cross-links to the Pol III catalytic subunit C128 (N-terminal region) and the C-terminal domain of C37 subunit, positioning this Bdp1 region within the Pol III active site cleft and showing it is necessary for transcription initiation.","method":"Photoreactive unnatural amino acid (BPA) incorporation, photo-cross-linking, functional mutagenesis","journal":"Molecular and cellular biology","confidence":"High","confidence_rationale":"Tier 1–2 — residue-level cross-linking combined with functional assays","pmids":["26055328"],"is_preprint":false},{"year":2017,"finding":"Crystal structure of the Brf2-TBP-Bdp1 complex bound to DNA at 2.7 Å resolution, combined with single-molecule FRET and in vitro biochemical assays, reveals how Bdp1 assembles into TFIIIB, its structural and functional similarities to Pol II factors TFIIA and TFIIF, essential DNA contacts, interactions with SNAPc, and its role in driving the closed-to-open pre-initiation complex transition.","method":"X-ray crystallography (2.7 Å), single-molecule FRET, in vitro biochemical assays","journal":"Nature communications","confidence":"High","confidence_rationale":"Tier 1 — crystal structure with single-molecule FRET and functional biochemical validation, multiple orthogonal methods","pmids":["28743884"],"is_preprint":false},{"year":2018,"finding":"In Drosophila, DmSNAPc bound to the U6 PSE (but not U1 PSE) directly recruits Bdp1 to the U6 promoter via a specific 87-residue region of Bdp1, establishing that SNAPc conformation dictates selective Bdp1 recruitment for Pol III (versus Pol II) gene transcription.","method":"In vitro binding assays, promoter specificity assays (U6 vs. U1 PSE), deletion mapping","journal":"FEBS letters","confidence":"Medium","confidence_rationale":"Tier 2 — direct binding experiments with domain mapping and promoter specificity controls, single lab","pmids":["29932462"],"is_preprint":false},{"year":2020,"finding":"In Drosophila, DmSNAPc-Bdp1 recruits TBP to the U6 promoter; a specific region of Bdp1 is sufficient for TBP recruitment and cross-links to nucleotides within the U6 PSE; cross-linking mass spectrometry identified interactions of specific DmSNAPc subunits with Bdp1 and TBP.","method":"Functional domain mapping, UV cross-linking, cross-linking mass spectrometry","journal":"Molecular and cellular biology","confidence":"Medium","confidence_rationale":"Tier 2 — cross-linking MS with functional domain mapping, single lab","pmids":["32253345"],"is_preprint":false}],"current_model":"BDP1 (human/mammalian) is an essential subunit of the RNA Pol III transcription factor TFIIIB that assembles with Brf1/Brf2 and TBP on Pol III promoters; structurally, its SANT domain docks on Brf1 while an essential N-terminal region inserts into the Pol III active site cleft to drive the closed-to-open pre-initiation complex transition; it is recruited to U6 promoters via direct interaction with SNAPc; its activity is cell cycle-regulated by CK2-mediated phosphorylation during mitosis, causing Bdp1 dissociation from chromatin and transcription repression; additionally, a distinct non-TFIIIB isoform/paralog functions as a PEST-type protein-tyrosine phosphatase that negatively regulates HER2 receptor signaling."},"narrative":{"teleology":[{"year":1995,"claim":"Identification of TFC5/B\" as the gene encoding the third TFIIIB subunit resolved a longstanding gap in understanding how this minimal factor reconstitutes Pol III transcription together with TBP and Brf1.","evidence":"Recombinant protein reconstitution with DNase I footprinting and in vitro transcription in yeast","pmids":["7568218"],"confidence":"High","gaps":["No structural information on how Bdp1 integrates into the TFIIIB complex","Mammalian ortholog not yet characterized"]},{"year":2002,"claim":"Systematic deletion analysis defined three essential segments within Bdp1 and revealed functional interactions with both TBP and Brf1, establishing that Bdp1 makes multiple contacts within TFIIIB rather than acting through a single interaction surface.","evidence":"Deletion analysis, genetic suppression with SPT15/BRF1 overexpression, co-immunoprecipitation in yeast","pmids":["11971960"],"confidence":"High","gaps":["Residue-level mapping of Bdp1-TBP and Bdp1-Brf1 interfaces not achieved","Functional significance of the Bdp1-RNase P interaction unclear"]},{"year":2003,"claim":"Discovery that CK2 phosphorylates Bdp1 during mitosis, causing its release from chromatin and Pol III transcription repression, established the first mechanism for cell-cycle regulation of TFIIIB activity.","evidence":"In vitro kinase assay, ChIP, cell cycle fractionation, CK2 inhibitor rescue in human cells","pmids":["15469824"],"confidence":"High","gaps":["Specific phosphorylation sites on Bdp1 not fully mapped","Whether other kinases or phosphatases reverse this regulation in G1"]},{"year":2003,"claim":"Mapping the Bdp1-Tfc4 (TFIIIC subunit) interaction via TPR repeats and showing overlap with the Brf1 binding site clarified how TFIIIC hands off promoter-bound DNA to TFIIIB during complex assembly.","evidence":"Genetic suppression and in vitro binding/complex reconstitution assays in yeast","pmids":["12930823"],"confidence":"Medium","gaps":["Sequential order of Brf1 vs Bdp1 entry into the TFIIIC-DNA complex not resolved","No structural detail of the TFIIIC-TFIIIB handoff"]},{"year":2006,"claim":"Residue-level mapping revealed that the SANT domain of Bdp1 (helices 1 and 3) provides the principal docking surface for a 66-amino acid segment of the Brf1 C-terminal domain, establishing the structural basis of the core Brf1-Bdp1 interaction.","evidence":"Site-directed mutagenesis, photochemical cross-linking, and NMR spectroscopy in yeast","pmids":["16551611","19086269"],"confidence":"High","gaps":["Full atomic structure of the Brf1-Bdp1-TBP-DNA complex not yet available","Whether SANT domain contacts DNA directly was unclear"]},{"year":2006,"claim":"Demonstration that Brf1-Bdp1 entry into the TBP-DNA complex imposes strict TATA-box sequence selectivity revealed that TFIIIB subunits actively reshape the promoter DNA contact, not merely passively bind it.","evidence":"SELEX with altered-specificity TBP mutant in yeast","pmids":["17028095"],"confidence":"Medium","gaps":["Structural mechanism by which Bdp1 alters TBP-DNA contacts not determined"]},{"year":2011,"claim":"Photo-cross-linking placed Bdp1 at the Rpc37/53 (TFIIF-like) dimer within the Pol III pre-initiation complex, revealing for the first time that Bdp1 bridges TFIIIB to the polymerase active center.","evidence":"BPA incorporation photo-cross-linking and hydroxyl radical probing in yeast Pol III PIC","pmids":["21536656"],"confidence":"High","gaps":["Functional consequence of disrupting the Bdp1-Rpc37 contact not fully tested"]},{"year":2015,"claim":"An essential N-terminal region of Bdp1 was shown to insert into the Pol III active site cleft by cross-linking to the C128 catalytic subunit, establishing a direct mechanism by which Bdp1 participates in transcription initiation beyond promoter recognition.","evidence":"BPA photo-cross-linking combined with functional mutagenesis in yeast","pmids":["26055328"],"confidence":"High","gaps":["Whether this N-terminal insertion triggers DNA melting or stabilizes the open complex was not distinguished"]},{"year":2017,"claim":"The 2.7 Å crystal structure of Brf2-TBP-Bdp1 on DNA, validated by single-molecule FRET, revealed that Bdp1 makes essential DNA contacts, structurally resembles TFIIA/TFIIF, and drives the closed-to-open PIC transition, providing the definitive structural framework for TFIIIB function.","evidence":"X-ray crystallography, single-molecule FRET, in vitro biochemistry on human TFIIIB","pmids":["28743884"],"confidence":"High","gaps":["Full Pol III PIC structure with Bdp1 at atomic resolution not yet achieved","How Bdp1 structural changes couple to DNA strand separation remains incompletely resolved"]},{"year":2018,"claim":"Selective recruitment of Bdp1 to U6 promoters by SNAPc bound to the PSE (but not U1 PSE) established the molecular basis for how a single promoter-recognition factor discriminates Pol III from Pol II transcription at snRNA genes.","evidence":"In vitro binding and promoter specificity assays with domain mapping in Drosophila","pmids":["29932462"],"confidence":"Medium","gaps":["Whether the same SNAPc-Bdp1 recruitment logic operates in mammalian cells with distinct SNAPc architecture"]},{"year":2020,"claim":"Cross-linking mass spectrometry and functional mapping showed that the SNAPc-Bdp1 complex recruits TBP to U6 promoters, defining Bdp1 as an active participant in TFIIIB assembly at type III promoters rather than a passively recruited subunit.","evidence":"UV cross-linking, cross-linking mass spectrometry, functional domain mapping in Drosophila","pmids":["32253345"],"confidence":"Medium","gaps":["Order and kinetics of TBP vs Bdp1 loading on type III promoters in vivo not established"]},{"year":null,"claim":"A complete atomic-resolution structure of the full Pol III pre-initiation complex incorporating Bdp1 is still lacking, and the mechanism by which Bdp1's N-terminal insertion into the active site cleft couples to promoter DNA melting remains unresolved.","evidence":"","pmids":[],"confidence":"High","gaps":["No full Pol III PIC structure with Bdp1 at atomic resolution","Mechanism coupling Bdp1 cleft insertion to DNA strand separation unknown","Role of Bdp1 phosphorylation sites in fine-tuning gene-specific Pol III transcription not mapped"]}],"mechanism_profile":{"molecular_activity":[{"term_id":"GO:0003677","term_label":"DNA binding","supporting_discovery_ids":[0,8,12]},{"term_id":"GO:0140110","term_label":"transcription regulator activity","supporting_discovery_ids":[0,2,12]},{"term_id":"GO:0005198","term_label":"structural molecule activity","supporting_discovery_ids":[6,9,12]}],"localization":[{"term_id":"GO:0005634","term_label":"nucleus","supporting_discovery_ids":[2,12]},{"term_id":"GO:0000228","term_label":"nuclear chromosome","supporting_discovery_ids":[2]}],"pathway":[{"term_id":"R-HSA-74160","term_label":"Gene expression (Transcription)","supporting_discovery_ids":[0,2,12]},{"term_id":"R-HSA-1640170","term_label":"Cell Cycle","supporting_discovery_ids":[2]}],"complexes":["TFIIIB"],"partners":["BRF1","BRF2","TBP","POLR3B","RPC37","TFC4","SNAPC"],"other_free_text":[]},"mechanistic_narrative":"BDP1 is an essential subunit of the RNA polymerase III transcription factor TFIIIB that, together with TBP and Brf1/Brf2, assembles on Pol III promoters to drive transcription initiation of tRNAs, 5S rRNA, U6 snRNA, and other small non-coding RNAs. Its SANT domain anchors the Brf1 interaction interface, while a distinct essential N-terminal region inserts into the Pol III active site cleft—contacting the C128 catalytic subunit and the C37 subunit—to promote the closed-to-open pre-initiation complex transition required for transcription initiation [PMID:26055328, PMID:28743884]. At U6 snRNA promoters, Bdp1 is selectively recruited through direct interaction with SNAPc bound to the proximal sequence element, and it participates in subsequent TBP loading onto the TATA box [PMID:29932462, PMID:32253345]. BDP1 activity is cell-cycle regulated: CK2 phosphorylates Bdp1 during mitosis, causing its dissociation from chromatin and repression of Pol III transcription [PMID:15469824]."},"prefetch_data":{"uniprot":{"accession":"A6H8Y1","full_name":"Transcription factor TFIIIB component B'' homolog","aliases":["Transcription factor IIIB 150","TFIIIB150","Transcription factor-like nuclear regulator"],"length_aa":2624,"mass_kda":293.9,"function":"General activator of RNA polymerase III transcription. Requires for transcription from all three types of polymerase III promoters. Requires for transcription of genes with internal promoter elements and with promoter elements upstream of the initiation site","subcellular_location":"Nucleus","url":"https://www.uniprot.org/uniprotkb/A6H8Y1/entry"},"depmap":{"release":"DepMap","has_data":true,"is_common_essential":true,"resolved_as":"","url":"https://depmap.org/portal/gene/BDP1","classification":"Common Essential","n_dependent_lines":989,"n_total_lines":1208,"dependency_fraction":0.8187086092715232},"opencell":{"profiled":false,"resolved_as":"","ensg_id":"","cell_line_id":"","localizations":[],"interactors":[{"gene":"POLR1C","stoichiometry":0.2},{"gene":"POLR2E","stoichiometry":0.2},{"gene":"POLR2F","stoichiometry":0.2},{"gene":"POLR2H","stoichiometry":0.2},{"gene":"POLR2K","stoichiometry":0.2},{"gene":"POLR3A","stoichiometry":0.2},{"gene":"POLR3B","stoichiometry":0.2},{"gene":"POLR3D","stoichiometry":0.2},{"gene":"POLR3E","stoichiometry":0.2},{"gene":"POLR3F","stoichiometry":0.2}],"url":"https://opencell.sf.czbiohub.org/search/BDP1","total_profiled":1310},"omim":[{"mim_id":"618676","title":"ZINC FINGER- AND BTB DOMAIN-CONTAINING PROTEIN 43; ZBTB43","url":"https://www.omim.org/entry/618676"},{"mim_id":"618257","title":"DEAFNESS, AUTOSOMAL RECESSIVE 112; DFNB112","url":"https://www.omim.org/entry/618257"},{"mim_id":"613333","title":"MEMBRANE-ASSOCIATED RING-CH FINGER PROTEIN 3; MARCHF3","url":"https://www.omim.org/entry/613333"},{"mim_id":"607013","title":"BRF2 SUBUNIT OF RNA POLYMERASE III TRANSCRIPTION INITIATION FACTOR; BRF2","url":"https://www.omim.org/entry/607013"},{"mim_id":"607012","title":"B-DOUBLE PRIME 1, SUBUNIT OF RNA POLYMERASE III TRANSCRIPTION INITIATION FACTOR IIIB; BDP1","url":"https://www.omim.org/entry/607012"}],"hpa":{"profiled":true,"resolved_as":"","reliability":"Enhanced","locations":[{"location":"Nucleoplasm","reliability":"Enhanced"}],"tissue_specificity":"Low tissue specificity","tissue_distribution":"Detected in many","driving_tissues":[],"url":"https://www.proteinatlas.org/search/BDP1"},"hgnc":{"alias_symbol":["TFC5","KIAA1241","KIAA1689","HSA238520","TFIIIB150"],"prev_symbol":["TFNR","TAF3B1"]},"alphafold":{"accession":"A6H8Y1","domains":[{"cath_id":"-","chopping":"306-381","consensus_level":"medium","plddt":92.4438,"start":306,"end":381}],"viewer_url":"https://alphafold.ebi.ac.uk/entry/A6H8Y1","model_url":"https://alphafold.ebi.ac.uk/files/AF-A6H8Y1-F1-model_v6.cif","pae_url":"https://alphafold.ebi.ac.uk/files/AF-A6H8Y1-F1-predicted_aligned_error_v6.png","plddt_mean":36.97},"mouse_models":{"mgi_url":"https://www.informatics.jax.org/marker/summary?nomen=BDP1","jax_strain_url":"https://www.jax.org/strain/search?query=BDP1"},"sequence":{"accession":"A6H8Y1","fasta_url":"https://rest.uniprot.org/uniprotkb/A6H8Y1.fasta","uniprot_url":"https://www.uniprot.org/uniprotkb/A6H8Y1/entry","alphafold_viewer_url":"https://alphafold.ebi.ac.uk/entry/A6H8Y1"}},"corpus_meta":[{"pmid":"7568218","id":"PMC_7568218","title":"Cloning, expression, and function of TFC5, the gene encoding the B\" component of the Saccharomyces cerevisiae RNA polymerase III transcription factor TFIIIB.","date":"1995","source":"Proceedings of the National Academy of Sciences of the United States of America","url":"https://pubmed.ncbi.nlm.nih.gov/7568218","citation_count":93,"is_preprint":false},{"pmid":"21536656","id":"PMC_21536656","title":"The TFIIF-like Rpc37/53 dimer lies at the center of a protein network to connect TFIIIC, Bdp1, and the RNA polymerase III active center.","date":"2011","source":"Molecular and cellular biology","url":"https://pubmed.ncbi.nlm.nih.gov/21536656","citation_count":62,"is_preprint":false},{"pmid":"15469824","id":"PMC_15469824","title":"CK2 phosphorylation of Bdp1 executes cell cycle-specific RNA polymerase III transcription repression.","date":"2004","source":"Molecular 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roles of Bdp1, a subunit of RNA polymerase III initiation factor TFIIIB, in transcription and tRNA processing.","date":"2002","source":"Molecular and cellular biology","url":"https://pubmed.ncbi.nlm.nih.gov/11971960","citation_count":41,"is_preprint":false},{"pmid":"8950995","id":"PMC_8950995","title":"Characterization of the PEST family protein tyrosine phosphatase BDP1.","date":"1996","source":"Oncogene","url":"https://pubmed.ncbi.nlm.nih.gov/8950995","citation_count":23,"is_preprint":false},{"pmid":"16551611","id":"PMC_16551611","title":"Mapping the principal interaction site of the Brf1 and Bdp1 subunits of Saccharomyces cerevisiae TFIIIB.","date":"2006","source":"The Journal of biological chemistry","url":"https://pubmed.ncbi.nlm.nih.gov/16551611","citation_count":20,"is_preprint":false},{"pmid":"12930823","id":"PMC_12930823","title":"The Brf1 and Bdp1 subunits of transcription factor TFIIIB bind to overlapping sites in the tetratricopeptide repeats of Tfc4.","date":"2003","source":"The Journal of biological chemistry","url":"https://pubmed.ncbi.nlm.nih.gov/12930823","citation_count":17,"is_preprint":false},{"pmid":"26055328","id":"PMC_26055328","title":"A Region of Bdp1 Necessary for Transcription Initiation That Is Located within the RNA Polymerase III Active Site Cleft.","date":"2015","source":"Molecular and cellular biology","url":"https://pubmed.ncbi.nlm.nih.gov/26055328","citation_count":15,"is_preprint":false},{"pmid":"36328269","id":"PMC_36328269","title":"Structural insights into acetylated histone ligand recognition by the BDP1 bromodomain of Plasmodium falciparum.","date":"2022","source":"International journal of biological macromolecules","url":"https://pubmed.ncbi.nlm.nih.gov/36328269","citation_count":9,"is_preprint":false},{"pmid":"19086269","id":"PMC_19086269","title":"Structural characterization of the interaction between TFIIIB components Bdp1 and 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bromodomain <i>Pf</i> BDP1 of the malaria pathogen <i>Plasmodium falciparum</i>","date":"2025-01-16","source":"bioRxiv","url":"https://doi.org/10.1101/2025.01.16.633141","citation_count":0,"is_preprint":true}],"cost":{"stage1":{"model":"claude-sonnet-4-6","input_tokens":11275,"output_tokens":3314,"usd":0.041767},"stage2":{"model":"claude-opus-4-6","input_tokens":6741,"output_tokens":2702,"usd":0.151883},"total_usd":0.19365,"stage1_batch_id":"msgbatch_01TqNM6p6FsoMBT2jzQTwKBr","stage2_batch_id":"msgbatch_01Ya473eco8sTHbvRymQaU8o","note":"batch pricing = 50% of standard"},"stage1_raw":"```json\n{\n  \"discoveries\": [\n    {\n      \"year\": 1995,\n      \"finding\": \"TFC5 (yeast BDP1/B\\\") encodes a 594-amino acid subunit of TFIIIB; recombinant B\\\" reconstitutes fully functional TFIIIB with Brf1 and TBP, supporting both TFIIIC-directed and TATA box-dependent DNA binding and transcription in vitro.\",\n      \"method\": \"Recombinant protein reconstitution, DNase I footprinting, in vitro transcription assay\",\n      \"journal\": \"Proceedings of the National Academy of Sciences of the United States of America\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 — in vitro reconstitution with multiple orthogonal assays, foundational study\",\n      \"pmids\": [\"7568218\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2002,\n      \"finding\": \"Yeast Bdp1 contains three essential segments; functional interactions with TBP and Brf1 were mapped to specific Bdp1 regions by suppression genetics; a physical interaction between Bdp1 and RNase P was demonstrated, linking Bdp1 to tRNA processing.\",\n      \"method\": \"Deletion analysis, genetic suppression (SPT15/BRF1 overexpression), in vitro transcription, co-immunoprecipitation, pull-down assay\",\n      \"journal\": \"Molecular and cellular biology\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 — multiple orthogonal methods (genetics, biochemistry, co-IP) in one study\",\n      \"pmids\": [\"11971960\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2003,\n      \"finding\": \"CK2 phosphorylates the Bdp1 subunit of TFIIIB during mitosis, causing Bdp1 dissociation from the U6 promoter and chromatin, thereby repressing RNA polymerase III transcription in a cell cycle-specific manner.\",\n      \"method\": \"In vitro kinase assay, chromatin immunoprecipitation, cell cycle fractionation, CK2 inhibitor rescue experiments\",\n      \"journal\": \"Molecular cell\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1–2 — direct biochemical phosphorylation assay with functional chromatin and transcription readouts\",\n      \"pmids\": [\"15469824\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2003,\n      \"finding\": \"The Bdp1 subunit of TFIIIB interacts with the Tfc4 (tau131) subunit of TFIIIC via TPR repeats 1–9, with Bdp1 and Brf1 sharing overlapping binding sites on Tfc4; the Tfc4 L469K mutation impairs both Brf1 and Bdp1 incorporation into TFIIIB-TFIIIC-DNA complexes.\",\n      \"method\": \"Genetic suppression, in vitro binding assays, TFIIIC-DNA complex reconstitution\",\n      \"journal\": \"The Journal of biological chemistry\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 — multiple biochemical assays plus genetics, single lab\",\n      \"pmids\": [\"12930823\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2003,\n      \"finding\": \"Negative regulation of HER2 (ErbB2) receptor tyrosine kinase signaling by the PEST-type protein-tyrosine phosphatase BDP1: BDP1 overexpression inhibits ligand-induced HER2 phosphorylation and downstream Gab1/MAPK signaling, while BDP1 knockdown increases HER2 phosphorylation.\",\n      \"method\": \"Overexpression, siRNA knockdown, immunoprecipitation/western blot of phosphorylation\",\n      \"journal\": \"The Journal of biological chemistry\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2–3 — reciprocal gain/loss of function with clear phosphorylation readout, single lab\",\n      \"pmids\": [\"14660651\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2003,\n      \"finding\": \"A specific internal deletion (aa 253–269) in Bdp1 selectively impairs TFIIIC-dependent assembly of TFIIIB on the RPR1 promoter (but not other Pol III genes), leading to gene-specific transcription defects in vitro.\",\n      \"method\": \"In vitro transcription assay, TFIIIB-TFIIIC-DNA complex assembly analysis\",\n      \"journal\": \"FEBS letters\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 1 — in vitro reconstitution assay, single lab, single paper\",\n      \"pmids\": [\"12885403\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2006,\n      \"finding\": \"The principal interaction site between Brf1 and Bdp1 was mapped: a 66-amino acid segment of Brf1's C-terminal domain provides a two-sided adhesive surface for Bdp1, while the interacting Bdp1 domain spans 66 amino acids encompassing the SANT domain, the most phylogenetically conserved region of Bdp1.\",\n      \"method\": \"Site-directed mutagenesis, photochemical protein-DNA cross-linking, deletion analysis\",\n      \"journal\": \"The Journal of biological chemistry\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1–2 — mutagenesis combined with cross-linking provides residue-level mapping\",\n      \"pmids\": [\"16551611\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2006,\n      \"finding\": \"Human BDP1 (aa 1–299 N-terminal region) interacts with the zinc finger protein ZNF297B (via ZNF297B BTB/POZ domain, aa 1–127), identified by yeast two-hybrid and confirmed by co-immunoprecipitation.\",\n      \"method\": \"Yeast two-hybrid, co-immunoprecipitation, immunofluorescence\",\n      \"journal\": \"Biological chemistry\",\n      \"confidence\": \"Low\",\n      \"confidence_rationale\": \"Tier 3 — single co-IP confirmation of yeast two-hybrid, no functional consequence established\",\n      \"pmids\": [\"16542149\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2006,\n      \"finding\": \"Entry of Brf1 and Bdp1 into the TBP-DNA complex imposes a strict sequence preference for the downstream half of the TATA box (selecting TGTAAATA, matching the U6 snRNA gene TATA box), suggesting that the Brf1-Bdp1 proteins alter TBP-DNA complex structure or dynamics.\",\n      \"method\": \"Altered-specificity TBP mutant (TBPm3), iterative in vitro selection (SELEX)\",\n      \"journal\": \"Nucleic acids research\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 1 — in vitro selection assay with mechanistic interpretation, single lab\",\n      \"pmids\": [\"17028095\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2008,\n      \"finding\": \"NMR mapping of the Brf1-Bdp1 interaction interface showed that Bdp1 SANT domain helices 1 and 3 form the principal anchorage surface for a Brf1 segment (residues 470–495).\",\n      \"method\": \"NMR spectroscopy, structural modeling\",\n      \"journal\": \"Biochemistry\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 1 — NMR-derived structural model at single residue resolution, single lab, single paper\",\n      \"pmids\": [\"19086269\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2011,\n      \"finding\": \"The C-terminal domain of Rpc37 (within the TFIIF-like Rpc37/53 dimer of Pol III) contains binding sites for Bdp1; photo-cross-linking localized these interactions, revealing Bdp1's position within the Pol III preinitiation complex and its connection to the active center.\",\n      \"method\": \"Unnatural amino acid photo-cross-linking (BPA incorporation), site-directed hydroxyl radical probing\",\n      \"journal\": \"Molecular and cellular biology\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1–2 — two complementary residue-level mapping techniques in a single study\",\n      \"pmids\": [\"21536656\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2015,\n      \"finding\": \"An essential N-terminal region of yeast Bdp1 (distinct from the SANT domain) cross-links to the Pol III catalytic subunit C128 (N-terminal region) and the C-terminal domain of C37 subunit, positioning this Bdp1 region within the Pol III active site cleft and showing it is necessary for transcription initiation.\",\n      \"method\": \"Photoreactive unnatural amino acid (BPA) incorporation, photo-cross-linking, functional mutagenesis\",\n      \"journal\": \"Molecular and cellular biology\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1–2 — residue-level cross-linking combined with functional assays\",\n      \"pmids\": [\"26055328\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2017,\n      \"finding\": \"Crystal structure of the Brf2-TBP-Bdp1 complex bound to DNA at 2.7 Å resolution, combined with single-molecule FRET and in vitro biochemical assays, reveals how Bdp1 assembles into TFIIIB, its structural and functional similarities to Pol II factors TFIIA and TFIIF, essential DNA contacts, interactions with SNAPc, and its role in driving the closed-to-open pre-initiation complex transition.\",\n      \"method\": \"X-ray crystallography (2.7 Å), single-molecule FRET, in vitro biochemical assays\",\n      \"journal\": \"Nature communications\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 — crystal structure with single-molecule FRET and functional biochemical validation, multiple orthogonal methods\",\n      \"pmids\": [\"28743884\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2018,\n      \"finding\": \"In Drosophila, DmSNAPc bound to the U6 PSE (but not U1 PSE) directly recruits Bdp1 to the U6 promoter via a specific 87-residue region of Bdp1, establishing that SNAPc conformation dictates selective Bdp1 recruitment for Pol III (versus Pol II) gene transcription.\",\n      \"method\": \"In vitro binding assays, promoter specificity assays (U6 vs. U1 PSE), deletion mapping\",\n      \"journal\": \"FEBS letters\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 — direct binding experiments with domain mapping and promoter specificity controls, single lab\",\n      \"pmids\": [\"29932462\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2020,\n      \"finding\": \"In Drosophila, DmSNAPc-Bdp1 recruits TBP to the U6 promoter; a specific region of Bdp1 is sufficient for TBP recruitment and cross-links to nucleotides within the U6 PSE; cross-linking mass spectrometry identified interactions of specific DmSNAPc subunits with Bdp1 and TBP.\",\n      \"method\": \"Functional domain mapping, UV cross-linking, cross-linking mass spectrometry\",\n      \"journal\": \"Molecular and cellular biology\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 — cross-linking MS with functional domain mapping, single lab\",\n      \"pmids\": [\"32253345\"],\n      \"is_preprint\": false\n    }\n  ],\n  \"current_model\": \"BDP1 (human/mammalian) is an essential subunit of the RNA Pol III transcription factor TFIIIB that assembles with Brf1/Brf2 and TBP on Pol III promoters; structurally, its SANT domain docks on Brf1 while an essential N-terminal region inserts into the Pol III active site cleft to drive the closed-to-open pre-initiation complex transition; it is recruited to U6 promoters via direct interaction with SNAPc; its activity is cell cycle-regulated by CK2-mediated phosphorylation during mitosis, causing Bdp1 dissociation from chromatin and transcription repression; additionally, a distinct non-TFIIIB isoform/paralog functions as a PEST-type protein-tyrosine phosphatase that negatively regulates HER2 receptor signaling.\"\n}\n```","stage2_raw":"```json\n{\n  \"mechanistic_narrative\": \"BDP1 is an essential subunit of the RNA polymerase III transcription factor TFIIIB that, together with TBP and Brf1/Brf2, assembles on Pol III promoters to drive transcription initiation of tRNAs, 5S rRNA, U6 snRNA, and other small non-coding RNAs. Its SANT domain anchors the Brf1 interaction interface, while a distinct essential N-terminal region inserts into the Pol III active site cleft—contacting the C128 catalytic subunit and the C37 subunit—to promote the closed-to-open pre-initiation complex transition required for transcription initiation [PMID:26055328, PMID:28743884]. At U6 snRNA promoters, Bdp1 is selectively recruited through direct interaction with SNAPc bound to the proximal sequence element, and it participates in subsequent TBP loading onto the TATA box [PMID:29932462, PMID:32253345]. BDP1 activity is cell-cycle regulated: CK2 phosphorylates Bdp1 during mitosis, causing its dissociation from chromatin and repression of Pol III transcription [PMID:15469824].\",\n  \"teleology\": [\n    {\n      \"year\": 1995,\n      \"claim\": \"Identification of TFC5/B\\\" as the gene encoding the third TFIIIB subunit resolved a longstanding gap in understanding how this minimal factor reconstitutes Pol III transcription together with TBP and Brf1.\",\n      \"evidence\": \"Recombinant protein reconstitution with DNase I footprinting and in vitro transcription in yeast\",\n      \"pmids\": [\"7568218\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"No structural information on how Bdp1 integrates into the TFIIIB complex\", \"Mammalian ortholog not yet characterized\"]\n    },\n    {\n      \"year\": 2002,\n      \"claim\": \"Systematic deletion analysis defined three essential segments within Bdp1 and revealed functional interactions with both TBP and Brf1, establishing that Bdp1 makes multiple contacts within TFIIIB rather than acting through a single interaction surface.\",\n      \"evidence\": \"Deletion analysis, genetic suppression with SPT15/BRF1 overexpression, co-immunoprecipitation in yeast\",\n      \"pmids\": [\"11971960\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Residue-level mapping of Bdp1-TBP and Bdp1-Brf1 interfaces not achieved\", \"Functional significance of the Bdp1-RNase P interaction unclear\"]\n    },\n    {\n      \"year\": 2003,\n      \"claim\": \"Discovery that CK2 phosphorylates Bdp1 during mitosis, causing its release from chromatin and Pol III transcription repression, established the first mechanism for cell-cycle regulation of TFIIIB activity.\",\n      \"evidence\": \"In vitro kinase assay, ChIP, cell cycle fractionation, CK2 inhibitor rescue in human cells\",\n      \"pmids\": [\"15469824\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Specific phosphorylation sites on Bdp1 not fully mapped\", \"Whether other kinases or phosphatases reverse this regulation in G1\"]\n    },\n    {\n      \"year\": 2003,\n      \"claim\": \"Mapping the Bdp1-Tfc4 (TFIIIC subunit) interaction via TPR repeats and showing overlap with the Brf1 binding site clarified how TFIIIC hands off promoter-bound DNA to TFIIIB during complex assembly.\",\n      \"evidence\": \"Genetic suppression and in vitro binding/complex reconstitution assays in yeast\",\n      \"pmids\": [\"12930823\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Sequential order of Brf1 vs Bdp1 entry into the TFIIIC-DNA complex not resolved\", \"No structural detail of the TFIIIC-TFIIIB handoff\"]\n    },\n    {\n      \"year\": 2006,\n      \"claim\": \"Residue-level mapping revealed that the SANT domain of Bdp1 (helices 1 and 3) provides the principal docking surface for a 66-amino acid segment of the Brf1 C-terminal domain, establishing the structural basis of the core Brf1-Bdp1 interaction.\",\n      \"evidence\": \"Site-directed mutagenesis, photochemical cross-linking, and NMR spectroscopy in yeast\",\n      \"pmids\": [\"16551611\", \"19086269\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Full atomic structure of the Brf1-Bdp1-TBP-DNA complex not yet available\", \"Whether SANT domain contacts DNA directly was unclear\"]\n    },\n    {\n      \"year\": 2006,\n      \"claim\": \"Demonstration that Brf1-Bdp1 entry into the TBP-DNA complex imposes strict TATA-box sequence selectivity revealed that TFIIIB subunits actively reshape the promoter DNA contact, not merely passively bind it.\",\n      \"evidence\": \"SELEX with altered-specificity TBP mutant in yeast\",\n      \"pmids\": [\"17028095\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Structural mechanism by which Bdp1 alters TBP-DNA contacts not determined\"]\n    },\n    {\n      \"year\": 2011,\n      \"claim\": \"Photo-cross-linking placed Bdp1 at the Rpc37/53 (TFIIF-like) dimer within the Pol III pre-initiation complex, revealing for the first time that Bdp1 bridges TFIIIB to the polymerase active center.\",\n      \"evidence\": \"BPA incorporation photo-cross-linking and hydroxyl radical probing in yeast Pol III PIC\",\n      \"pmids\": [\"21536656\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Functional consequence of disrupting the Bdp1-Rpc37 contact not fully tested\"]\n    },\n    {\n      \"year\": 2015,\n      \"claim\": \"An essential N-terminal region of Bdp1 was shown to insert into the Pol III active site cleft by cross-linking to the C128 catalytic subunit, establishing a direct mechanism by which Bdp1 participates in transcription initiation beyond promoter recognition.\",\n      \"evidence\": \"BPA photo-cross-linking combined with functional mutagenesis in yeast\",\n      \"pmids\": [\"26055328\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Whether this N-terminal insertion triggers DNA melting or stabilizes the open complex was not distinguished\"]\n    },\n    {\n      \"year\": 2017,\n      \"claim\": \"The 2.7 Å crystal structure of Brf2-TBP-Bdp1 on DNA, validated by single-molecule FRET, revealed that Bdp1 makes essential DNA contacts, structurally resembles TFIIA/TFIIF, and drives the closed-to-open PIC transition, providing the definitive structural framework for TFIIIB function.\",\n      \"evidence\": \"X-ray crystallography, single-molecule FRET, in vitro biochemistry on human TFIIIB\",\n      \"pmids\": [\"28743884\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Full Pol III PIC structure with Bdp1 at atomic resolution not yet achieved\", \"How Bdp1 structural changes couple to DNA strand separation remains incompletely resolved\"]\n    },\n    {\n      \"year\": 2018,\n      \"claim\": \"Selective recruitment of Bdp1 to U6 promoters by SNAPc bound to the PSE (but not U1 PSE) established the molecular basis for how a single promoter-recognition factor discriminates Pol III from Pol II transcription at snRNA genes.\",\n      \"evidence\": \"In vitro binding and promoter specificity assays with domain mapping in Drosophila\",\n      \"pmids\": [\"29932462\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Whether the same SNAPc-Bdp1 recruitment logic operates in mammalian cells with distinct SNAPc architecture\"]\n    },\n    {\n      \"year\": 2020,\n      \"claim\": \"Cross-linking mass spectrometry and functional mapping showed that the SNAPc-Bdp1 complex recruits TBP to U6 promoters, defining Bdp1 as an active participant in TFIIIB assembly at type III promoters rather than a passively recruited subunit.\",\n      \"evidence\": \"UV cross-linking, cross-linking mass spectrometry, functional domain mapping in Drosophila\",\n      \"pmids\": [\"32253345\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Order and kinetics of TBP vs Bdp1 loading on type III promoters in vivo not established\"]\n    },\n    {\n      \"year\": null,\n      \"claim\": \"A complete atomic-resolution structure of the full Pol III pre-initiation complex incorporating Bdp1 is still lacking, and the mechanism by which Bdp1's N-terminal insertion into the active site cleft couples to promoter DNA melting remains unresolved.\",\n      \"evidence\": \"\",\n      \"pmids\": [],\n      \"confidence\": \"High\",\n      \"gaps\": [\"No full Pol III PIC structure with Bdp1 at atomic resolution\", \"Mechanism coupling Bdp1 cleft insertion to DNA strand separation unknown\", \"Role of Bdp1 phosphorylation sites in fine-tuning gene-specific Pol III transcription not mapped\"]\n    }\n  ],\n  \"mechanism_profile\": {\n    \"molecular_activity\": [\n      {\"term_id\": \"GO:0003677\", \"supporting_discovery_ids\": [0, 8, 12]},\n      {\"term_id\": \"GO:0140110\", \"supporting_discovery_ids\": [0, 2, 12]},\n      {\"term_id\": \"GO:0005198\", \"supporting_discovery_ids\": [6, 9, 12]}\n    ],\n    \"localization\": [\n      {\"term_id\": \"GO:0005634\", \"supporting_discovery_ids\": [2, 12]},\n      {\"term_id\": \"GO:0000228\", \"supporting_discovery_ids\": [2]}\n    ],\n    \"pathway\": [\n      {\"term_id\": \"R-HSA-74160\", \"supporting_discovery_ids\": [0, 2, 12]},\n      {\"term_id\": \"R-HSA-1640170\", \"supporting_discovery_ids\": [2]}\n    ],\n    \"complexes\": [\n      \"TFIIIB\"\n    ],\n    \"partners\": [\n      \"BRF1\",\n      \"BRF2\",\n      \"TBP\",\n      \"POLR3B\",\n      \"RPC37\",\n      \"TFC4\",\n      \"SNAPc\"\n    ],\n    \"other_free_text\": []\n  }\n}\n```"}