{"doi":"10.1016/j.celrep.2022.111007","title":"Recognition of the TDP-43 nuclear localization signal by importin α1/β","abstract":"Cytoplasmic mislocalization of the TAR-DNA binding protein of 43 kDa (TDP-43) leads to large, insoluble aggregates that are a hallmark of amyotrophic lateral sclerosis and frontotemporal dementia. Here, we study how importin α1/β recognizes TDP-43 bipartite nuclear localization signal (NLS). We find that the NLS makes extensive contacts with importin α1, especially at the minor NLS-binding site. NLS binding results in steric clashes with the C terminus of importin α1 that disrupts the TDP-43 N-terminal domain (NTD) dimerization interface. A putative phosphorylation site in the proximity of TDP-43 R83 at the minor NLS site destabilizes binding to importins by reducing the NLS backbone dynamics. Based on these data, we explain the pathogenic role of several post-translational modifications and mutations in the proximity of TDP-43 minor NLS site that are linked to disease and shed light on the chaperone activity of importin α1/β.","journal":"Cell Reports","year":2022,"id":236844,"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":65,"citer_count":0,"citers_with_citation_signal":0,"citers_with_endowment":0,"datacite_reuse_total":0,"is_dataset":false,"is_dataset_confidence":0.9502,"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":857916,"name":"Hamed Meshkin","orcid":"0000-0001-7269-4687","position":1,"is_corresponding":false},{"id":298281,"name":"Alexander J. Bryer","orcid":"0000-0002-2039-4778","position":2,"is_corresponding":false},{"id":663582,"name":"Fenglin Li","orcid":"0000-0001-7932-0071","position":3,"is_corresponding":false},{"id":513836,"name":"Ying‐Hui Ko","orcid":"0000-0003-4240-9923","position":4,"is_corresponding":false},{"id":367464,"name":"Ravi K. Lokareddy","orcid":"0000-0002-5357-1857","position":5,"is_corresponding":false},{"id":367466,"name":"Richard E. Gillilan","orcid":"0000-0002-7636-3188","position":6,"is_corresponding":false},{"id":361197,"name":"Kushol Gupta","orcid":"0000-0002-7006-2667","position":7,"is_corresponding":false},{"id":298286,"name":"Juan R. Perilla","orcid":"0000-0003-1171-6816","position":8,"is_corresponding":false},{"id":367467,"name":"Gino Cingolani","orcid":"0000-0002-9206-9640","position":9,"is_corresponding":false},{"id":513838,"name":"Steven G. Doll","orcid":"0000-0002-2860-2092","position":0,"is_corresponding":true}],"reference_count":102,"raw_metadata":null,"created_at":"2026-07-19T00:22:03.686498Z","pmid":"35767952","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":[]}