{"doi":"10.1016/j.celrep.2024.115005","title":"Design principles to tailor Hsp104 therapeutics","abstract":"The hexameric AAA+ disaggregase, Hsp104, collaborates with Hsp70 and Hsp40 via its autoregulatory middle domain (MD) to solubilize aggregated proteins. However, how ATP- or ADP-specific MD configurations regulate Hsp104 hexamers remains poorly understood. Here, we define an ATP-specific network of interprotomer contacts between nucleotide-binding domain 1 (NBD1) and MD helix L1, which tunes Hsp70 collaboration. Manipulating this network can (1) reduce Hsp70 collaboration without enhancing activity, (2) generate Hsp104 hypomorphs that collaborate selectively with class B Hsp40s, (3) produce Hsp70-independent potentiated variants, or (4) create species barriers between Hsp104 and Hsp70. Conversely, ADP-specific intraprotomer contacts between MD helix L2 and NBD1 restrict activity, and their perturbation frequently potentiates Hsp104. Importantly, adjusting an NBD1:MD helix L1 rheostat via rational design enables finely tuned collaboration with Hsp70 to safely potentiate Hsp104, minimize off-target toxicity, and counteract FUS and TDP-43 proteinopathies in human cells. Thus, we establish design principles to tailor Hsp104 therapeutics.","journal":"Cell Reports","year":2024,"id":472697,"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":2,"citer_count":0,"citers_with_citation_signal":0,"citers_with_endowment":0,"datacite_reuse_total":0,"is_dataset":false,"is_dataset_confidence":0.9562,"is_data_producer":false,"deposit_databanks":null,"is_oa":true,"file_count":0,"downloads":0,"has_version_chain":false,"published_date":"2024-01-01","fair_score":null,"fair_percentile":null,"algorithm_id":"datarank_citation_only_1hop_v6","ranking_scope":"data_only","authors":[{"id":460715,"name":"Peter J. Carman","orcid":"0000-0002-6120-5507","position":1,"is_corresponding":false},{"id":245815,"name":"Craig W. Gambogi","orcid":"0000-0001-7118-8942","position":2,"is_corresponding":false},{"id":550693,"name":"Nathan M. Kendsersky","orcid":"0000-0003-0132-8748","position":3,"is_corresponding":false},{"id":492659,"name":"Edward Chuang","orcid":"0000-0002-6380-7317","position":4,"is_corresponding":false},{"id":582770,"name":"Stephanie N. Gates","orcid":"0000-0002-4312-2900","position":5,"is_corresponding":false},{"id":281833,"name":"Adam L. Yokom","orcid":"0000-0002-3746-7961","position":6,"is_corresponding":false},{"id":108134,"name":"Alexandrea N. Rizo","orcid":"0000-0003-4813-6348","position":7,"is_corresponding":false},{"id":565763,"name":"Daniel R. Southworth","orcid":"0000-0001-7108-9389","position":8,"is_corresponding":false},{"id":268287,"name":"James Shorter","orcid":"0000-0001-5269-8533","position":9,"is_corresponding":false},{"id":480604,"name":"JiaBei Lin","orcid":"0000-0001-8863-1859","position":0,"is_corresponding":true}],"reference_count":142,"raw_metadata":null,"created_at":"2026-07-19T02:05:57.032095Z","pmid":"39671291","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":[]}