{"doi":"10.1093/nar/gkaf035","title":"Inhibition of HMGA2 binding to AT-rich DNA by its negatively charged C-terminus","abstract":"The mammalian high mobility group protein AT-hook 2 (HMGA2) is a small DNA-binding protein that specifically targets AT-rich DNA sequences. Structurally, HMGA2 is an intrinsically disordered protein (IDP), comprising three positively charged 'AT-hooks' and a negatively charged C-terminus. HMGA2 can form homodimers through electrostatic interactions between its 'AT-hooks' and C-terminus. This suggests that the negatively charged C-terminus may inhibit DNA binding by interacting with the positively charged 'AT-hooks.' In this paper, we demonstrate that the C-terminus significantly influences HMGA2's DNA-binding properties. For example, the C-terminal deletion mutant HMGA2Δ95-108 binds more tightly to the AT-rich DNA oligomer FL814 than wild-type HMGA2. Additionally, a synthetic peptide derived from the C-terminus (the C-terminal motif peptide or CTMP) strongly inhibits HMGA2's binding to FL814, likely by interacting with the 'AT-hooks,' as shown by various biochemical and biophysical assays. Molecular modeling demonstrates that electrostatic interactions and hydrogen bonding are the primary forces driving CTMP's binding to the 'AT-hooks.' Intriguingly, we found that hydration does not play a role in HMGA2-DNA binding. These results suggest that the highly negatively charged C-terminus of HMGA2 plays a critical role in regulating its DNA-binding capacity through autoinhibition, likely facilitating the target search process for AT-rich DNA sequences.","journal":"Nucleic Acids Research","year":2025,"id":530314,"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":5,"citer_count":0,"citers_with_citation_signal":0,"citers_with_endowment":0,"datacite_reuse_total":0,"is_dataset":false,"is_dataset_confidence":0.9544,"is_data_producer":false,"deposit_databanks":null,"is_oa":true,"file_count":0,"downloads":0,"has_version_chain":false,"published_date":"2025-01-01","fair_score":null,"fair_percentile":null,"algorithm_id":"datarank_citation_only_1hop_v6","ranking_scope":"data_only","authors":[{"id":472483,"name":"Zifang Deng","orcid":null,"position":1,"is_corresponding":false},{"id":1410036,"name":"Miguel Santos-Fernandez","orcid":"0000-0003-4233-0203","position":2,"is_corresponding":false},{"id":947162,"name":"Kévin Jeanne Dit Fouque","orcid":"0000-0002-2974-1350","position":3,"is_corresponding":false},{"id":291399,"name":"Prem P. Chapagain","orcid":"0000-0002-0999-4975","position":4,"is_corresponding":false},{"id":489895,"name":"Jeremy W. Chambers","orcid":"0000-0002-6143-3091","position":5,"is_corresponding":false},{"id":334166,"name":"Francisco Fernandez‐Lima","orcid":"0000-0002-1283-4390","position":6,"is_corresponding":false},{"id":471718,"name":"Fenfei Leng","orcid":"0000-0002-9024-1216","position":7,"is_corresponding":false},{"id":471717,"name":"Linjia Su","orcid":"0000-0001-5227-6605","position":0,"is_corresponding":true}],"reference_count":64,"raw_metadata":null,"created_at":"2026-07-19T02:51:05.836974Z","pmid":"39873271","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":[]}