{"doi":"10.1101/2022.03.28.485992","title":"Molecular basis of DNA recognition by the HMG-box-C1 module of Capicua","abstract":"Abstract The HMG-box protein Capicua (CIC) is an evolutionarily conserved transcriptional repressor with key functions in development and disease-associated processes. CIC binds DNA using an exclusive mechanism that requires both its HMG-box and a separate domain called C1, but how these domains cooperate to recognize specific DNA sequences is not known. Here we report the crystal structure of the human CIC HMG-box and C1 domains in complex with an 18-base-pair DNA oligomer containing a consensus octameric CIC binding site. We find that both protein domains adopt independent tri-helical structures that pack against opposite sides of the DNA helix. The C1 domain in particular folds into a helix-turn-helix (HTH) structure that resembles the FF phosphoprotein binding domain. It inserts into the major groove of the DNA and plays a direct role in enhancing both the affinity and sequence specificity of CIC DNA binding. Our results reveal a unique bipartite protein module, ensuring highly specific DNA recognition by CIC, and show how this mechanism is disrupted by cancer mutations affecting either the HMG-box or C1 domains.","journal":"bioRxiv (Cold Spring Harbor Laboratory)","year":2022,"id":298175,"datarank":0.0,"base_score":0.0,"endowment":0.0,"self_citation_contribution":0.0,"citation_network_contribution":0.0,"self_endowment_contribution":0.0,"citer_contribution":0.0,"corpus_percentile":null,"corpus_rank":null,"citation_count":6,"citer_count":0,"citers_with_citation_signal":0,"citers_with_endowment":0,"datacite_reuse_total":0,"is_dataset":false,"is_dataset_confidence":0.949,"is_data_producer":false,"deposit_databanks":null,"is_oa":true,"file_count":0,"downloads":0,"has_version_chain":false,"published_date":"2022-01-01","fair_score":null,"fair_percentile":null,"algorithm_id":"datarank_citation_only_1hop_v6","ranking_scope":"data_only","authors":[{"id":745860,"name":"Jeremy Liew","orcid":"0000-0002-9190-8772","position":1,"is_corresponding":false},{"id":955735,"name":"Andrew Gnann","orcid":"0000-0002-1404-5459","position":2,"is_corresponding":false},{"id":249655,"name":"MacKenzie Patterson","orcid":"0000-0001-9765-3507","position":3,"is_corresponding":false},{"id":986799,"name":"Sayantanee Paul","orcid":"0000-0003-4616-1216","position":4,"is_corresponding":false},{"id":987199,"name":"Marta Forés","orcid":null,"position":5,"is_corresponding":false},{"id":569729,"name":"Gerardo Jiménez","orcid":"0000-0003-2765-9289","position":6,"is_corresponding":false},{"id":829500,"name":"Alexey Veraksa","orcid":"0000-0003-2920-080X","position":7,"is_corresponding":false},{"id":63443,"name":"Daniel Dowling","orcid":"0000-0002-2536-0905","position":8,"is_corresponding":false},{"id":986798,"name":"Jonathan Webb","orcid":"0000-0003-4169-6342","position":0,"is_corresponding":true}],"reference_count":57,"raw_metadata":null,"created_at":"2026-07-19T00:31:31.270564Z","pmid":null,"pmcid":null,"fwci":null,"citation_percentile":null,"influential_citations":0,"oa_status":null,"license":null,"views":0,"total_file_size_bytes":0,"version_count":0,"fair_f":null,"fair_a":null,"fair_i":null,"fair_r":null,"fair_zscore":null,"fair_rationale":null,"fair_model":null,"fair_agent_version":null,"fair_fulltext_source":null,"fair_has_llm":null,"fair_computed_at":null,"clinical_trials":[],"software_tools":[],"db_accessions":[],"linked_datasets":[],"topics":[]}