{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,5,1]],"date-time":"2026-05-01T17:14:39Z","timestamp":1777655679428,"version":"3.51.4"},"reference-count":114,"publisher":"Wiley","issue":"5","license":[{"start":{"date-parts":[[2026,4,27]],"date-time":"2026-04-27T00:00:00Z","timestamp":1777248000000},"content-version":"vor","delay-in-days":0,"URL":"http:\/\/creativecommons.org\/licenses\/by-nc-nd\/4.0\/"},{"start":{"date-parts":[[2026,4,27]],"date-time":"2026-04-27T00:00:00Z","timestamp":1777248000000},"content-version":"tdm","delay-in-days":0,"URL":"http:\/\/doi.wiley.com\/10.1002\/tdm_license_1.1"}],"funder":[{"DOI":"10.13039\/100000002","name":"National Institutes of Health","doi-asserted-by":"publisher","award":["R01GM098592"],"award-info":[{"award-number":["R01GM098592"]}],"id":[{"id":"10.13039\/100000002","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/100006108","name":"National Center for Advancing Translational Sciences","doi-asserted-by":"publisher","award":["UL1TR002649"],"award-info":[{"award-number":["UL1TR002649"]}],"id":[{"id":"10.13039\/100006108","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/100009238","name":"Virginia Commonwealth University","doi-asserted-by":"publisher","id":[{"id":"10.13039\/100009238","id-type":"DOI","asserted-by":"publisher"}]}],"content-domain":{"domain":["onlinelibrary.wiley.com"],"crossmark-restriction":true},"short-container-title":["Protein Science"],"published-print":{"date-parts":[[2026,5]]},"abstract":"<jats:title>Abstract<\/jats:title>\n                  <jats:p>\n                    Heat shock proteins of the 70\u2010kDa family (Hsp70s) are highly abundant and conserved molecular chaperones that help preserve proteostasis primarily by facilitating proper protein folding. Heat shock protein of the 110\u2010kDa family (Hsp110s), a specialized branch of the Hsp70\/Hsp110 superfamily, function both as nucleotide exchange factor (NEF) cochaperones for Hsp70s and as independent \u201choldase\u201d chaperones that stabilize non\u2010native polypeptides to prevent aggregation and facilitate downstream refolding by Hsp70s. While Hsp110 NEF activity is well characterized, the consequences of adenosine 5\u2032\u2010triphosphate (ATP) binding for Hsp110 holdase behavior have remained largely unexplored. Although holdase activity is generally considered nucleotide\u2010independent, reports of ATP\u2010dependent effects have raised questions about the underlying mechanism. Here, we examined the biochemical properties of Multicopy Suppressor of\n                    <jats:italic>ira1<\/jats:italic>\n                    3 (Msi3), the sole Hsp110 in\n                    <jats:italic>Candida albicans<\/jats:italic>\n                    , to dissect the role of ATP in holdase function. We first identified an inhibitory effect of elevated Mg\n                    <jats:sup>2+<\/jats:sup>\n                    concentrations on Msi3 holdase activity. This inhibitory effect is counteracted by the intrinsically disordered C\u2010terminal segment, revealing a distinct stabilization role for this region, previously of unknown function. In addition, ATP alleviates inhibition by elevated Mg\n                    <jats:sup>2+<\/jats:sup>\n                    , providing an explanation for an apparent ATP\u2010dependence observed previously. Interestingly, although dispensable for aggregation suppression, ATP modulates Msi3 holdase activity for refolding competence by broadening the concentration range over which it remains productive. Increasing Msi3 concentration improved overall downstream refolding recovery but slowed refolding kinetics, and ATP alleviated this kinetic constraint. Analyses of Hsp105, the major human Hsp110, suggest that these biochemical properties are largely conserved. Together, these findings suggest that ATP modulates Hsp110 holdase activity by tuning the balance between substrate sequestration and engagement dynamics, revealing an ATP\u2010dependent regulatory dimension of Hsp110 holdase function that is mechanistically distinct from its NEF activity.\n                  <\/jats:p>","DOI":"10.1002\/pro.70575","type":"journal-article","created":{"date-parts":[[2026,4,27]],"date-time":"2026-04-27T13:40:27Z","timestamp":1777297227000},"update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":0,"title":["<scp>ATP<\/scp>\n                    modulates holdase activity of fungal and human 110\u2010kilodalton heat shock proteins to promote protein folding"],"prefix":"10.1002","volume":"35","author":[{"ORCID":"https:\/\/orcid.org\/0009-0009-1481-9379","authenticated-orcid":false,"given":"Justin M.","family":"Kidd","sequence":"first","affiliation":[{"name":"Department of Cellular, Molecular, and Genetic Medicine, School of Medicine Virginia Commonwealth University  Richmond Virginia USA"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-1040-6621","authenticated-orcid":false,"given":"Cancan","family":"Sun","sequence":"additional","affiliation":[{"name":"Department of Cellular, Molecular, and Genetic Medicine, School of Medicine Virginia Commonwealth University  Richmond Virginia USA"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Alissa","family":"Garay","sequence":"additional","affiliation":[{"name":"Department of Cellular, Molecular, and Genetic Medicine, School of Medicine Virginia Commonwealth University  Richmond Virginia USA"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Mitchell","family":"Keplinger","sequence":"additional","affiliation":[{"name":"Department of Cellular, Molecular, and Genetic Medicine, School of Medicine Virginia Commonwealth University  Richmond Virginia USA"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Colin","family":"Richter","sequence":"additional","affiliation":[{"name":"Department of Cellular, Molecular, and Genetic Medicine, School of Medicine Virginia Commonwealth University  Richmond Virginia USA"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Aaron E.","family":"May","sequence":"additional","affiliation":[{"name":"Department of Medicinal Chemistry, School of Pharmacy Virginia Commonwealth University  Richmond Virginia USA"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-5581-6993","authenticated-orcid":false,"given":"Qinglian","family":"Liu","sequence":"additional","affiliation":[{"name":"Department of Cellular, Molecular, and Genetic Medicine, School of Medicine Virginia Commonwealth University  Richmond Virginia USA"}],"role":[{"role":"author","vocabulary":"crossref"}]}],"member":"311","published-online":{"date-parts":[[2026,4,27]]},"reference":[{"key":"e_1_2_9_2_1","doi-asserted-by":"crossref","first-page":"75","DOI":"10.1016\/j.cell.2005.11.039","article-title":"Systems analyses reveal two chaperone networks with distinct functions in eukaryotic cells","volume":"124","author":"Albanese V","year":"2006","journal-title":"Cell"},{"key":"e_1_2_9_3_1","doi-asserted-by":"crossref","first-page":"16519","DOI":"10.1073\/pnas.0804187105","article-title":"Insights into the structural dynamics of the Hsp110\u2010Hsp70 interaction reveal the mechanism for nucleotide exchange activity","volume":"105","author":"Andreasson C","year":"2008","journal-title":"Proc Natl Acad Sci U S A"},{"key":"e_1_2_9_4_1","doi-asserted-by":"crossref","first-page":"8877","DOI":"10.1074\/jbc.M710063200","article-title":"Hsp110 is a nucleotide\u2010activated exchange factor for Hsp70","volume":"283","author":"Andreasson 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extension of Apg2","volume":"434","author":"Cabrera Y","year":"2022","journal-title":"J Mol Biol"},{"key":"e_1_2_9_13_1","doi-asserted-by":"crossref","DOI":"10.1016\/j.heliyon.2024.e29690","article-title":"Swapping the linkers of canonical Hsp70 and Hsp110 chaperones compromises both self\u2010association and client selection","volume":"10","author":"Chakafana G","year":"2024","journal-title":"Heliyon"},{"key":"e_1_2_9_14_1","doi-asserted-by":"crossref","first-page":"797","DOI":"10.1038\/s41580-023-00640-9","article-title":"Structural and functional complexity of HSP90 in cellular homeostasis and disease","volume":"24","author":"Chiosis G","year":"2023","journal-title":"Nat Rev Mol Cell Biol"},{"key":"e_1_2_9_15_1","doi-asserted-by":"crossref","first-page":"86","DOI":"10.1379\/CSC-99r.1","article-title":"Heat shock proteins in cancer: diagnostic, prognostic, predictive, and treatment implications","volume":"10","author":"Ciocca DR","year":"2005","journal-title":"Cell Stress 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