{"database":"biostudies-literature","file_versions":[],"scores":null,"additional":{"omics_type":["Unknown"],"submitter":["Lin J"],"funding":["NIGMS NIH HHS"],"pubmed_abstract":["The hexameric AAA+ disaggregase, Hsp104, collaborates with Hsp70 and Hsp40 via its autoregulatory middle domain (MD) to solubilize aggregated protein conformers. 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: (a) reduce Hsp70 collaboration without enhancing activity; (b) generate Hsp104 hypomorphs that collaborate selectively with class B Hsp40s; (c) produce Hsp70-independent potentiated variants; or (d) create species barriers between Hsp104 and Hsp70. Conversely, ADP-specific intraprotomer contacts between MD helix L2 and NBD1 restrict activity,"],"journal":["bioRxiv : the preprint server for biology"],"pagination":["2024.04.26.591398"],"full_dataset_link":["https://www.ebi.ac.uk/biostudies/studies/S-EPMC11071516"],"repository":["biostudies-literature"],"pubmed_title":["Design principles to tailor Hsp104 therapeutics."],"pmcid":["PMC11071516"],"funding_grant_id":["T32 GM008076","R01 GM099836","R01 GM110001"],"pubmed_authors":["Rizo AN","Gates SN","Gambogi CW","Chuang E","Yokom AL","Lin J","Southworth DR","Shorter J","Carman PJ","Kendsersky NM"],"additional_accession":[]},"is_claimable":false,"name":"Design principles to tailor Hsp104 therapeutics.","description":"The hexameric AAA+ disaggregase, Hsp104, collaborates with Hsp70 and Hsp40 via its autoregulatory middle domain (MD) to solubilize aggregated protein conformers. 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: (a) reduce Hsp70 collaboration without enhancing activity; (b) generate Hsp104 hypomorphs that collaborate selectively with class B Hsp40s; (c) produce Hsp70-independent potentiated variants; or (d) create species barriers between Hsp104 and Hsp70. Conversely, ADP-specific intraprotomer contacts between MD helix L2 and NBD1 restrict activity,","dates":{"release":"2024-01-01T00:00:00Z","publication":"2024 Apr","modification":"2026-04-15T03:26:04.994Z","creation":"2025-08-14T03:05:50.954Z"},"accession":"S-EPMC11071516","cross_references":{"pubmed":["38712168"],"doi":["10.1101/2024.04.26.591398"]}}