{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"institution":[{"name":"bioRxiv"}],"indexed":{"date-parts":[[2026,6,24]],"date-time":"2026-06-24T05:52:12Z","timestamp":1782280332238,"version":"3.54.5"},"posted":{"date-parts":[[2025,5,3]]},"group-title":"Biochemistry","reference-count":77,"publisher":"openRxiv","license":[{"start":{"date-parts":[[2025,5,3]],"date-time":"2025-05-03T00:00:00Z","timestamp":1746230400000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/www.biorxiv.org\/about\/FAQ#license"}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":[],"accepted":{"date-parts":[[2025,5,3]]},"abstract":"<jats:p>Limb-girdle muscular dystrophy D1 (LGMDD1) is a rare, dominantly inherited neuromuscular disorder caused by mutations in the HSP40 co-chaperone DNAJB6, primarily in the GF or J-domains. Currently, no treatments are available, and a challenge in understanding the disease is identifying a specific client protein for DNAJB6 in skeletal muscle. Our previous research indicated that LGMDD1 GF domain mutants in Sis1 exhibit substrate-specific effects, influenced by HSP70 activity. Herein, we found that novel mutations in the J-domain similarly affected chaperone function. The J-domain mutants exhibited variable substrate processing, reduced binding affinity to client-substrate, and decreased stimulation of Ssa1 ATP hydrolysis, with these effects being substrate-conformer-specific. Our simulation studies noted differences in inter-domain interactions linked to the mutants, which influence the Hsp40-Hsp70 ATPase cycle. These mechanistic insights enhance our understanding of LGMDD1 myopathy and help to identify potential treatment strategies in the future.<\/jats:p>\n                <jats:sec>\n                  <jats:title>Teaser<\/jats:title>\n                  <jats:p>Recalibrating the inter-domain interface of the mutant protein could potentially serve as a key therapeutic strategy for LGMDD1 myopathy.<\/jats:p>\n                <\/jats:sec>","DOI":"10.1101\/2025.05.02.651952","type":"posted-content","created":{"date-parts":[[2025,5,3]],"date-time":"2025-05-03T22:35:12Z","timestamp":1746311712000},"source":"Crossref","is-referenced-by-count":0,"title":["Mutations in Hsp40 co-chaperone change the unique canonical inter-domain interactions stimulating LGMDD1 myopathy"],"prefix":"10.64898","author":[{"ORCID":"https:\/\/orcid.org\/0000-0002-8679-0984","authenticated-orcid":false,"given":"Ankan K.","family":"Bhadra","sequence":"first","affiliation":[{"name":"Department of Cell Biology and Physiology, Washington University School of Medicine, 660 South Euclid Avenue, Campus Box 8228, St. Louis, MO 63110, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-1848-5056","authenticated-orcid":false,"given":"Geetika","family":"Aggarwal","sequence":"additional","affiliation":[{"name":"Division of Geriatric Medicine, Department of Internal Medicine, Department of Pharmacology and Physiology, Saint Louis University School of Medicine, St Louis, Missouri, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-8110-077X","authenticated-orcid":false,"given":"Anshuman","family":"Jaysingh","sequence":"additional","affiliation":[{"name":"Department of Biochemistry and Molecular Biophysics, Washington University School of Medicine, St. Louis, MO, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0009-0004-8020-0738","authenticated-orcid":false,"given":"Daniel","family":"Chen","sequence":"additional","affiliation":[{"name":"Department of Cell Biology and Physiology, Washington University School of Medicine, 660 South Euclid Avenue, Campus Box 8228, St. Louis, MO 63110, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Jil","family":"Daw","sequence":"additional","affiliation":[{"name":"Department of Neurology, Hope Center for Neurological Diseases, Washington University School of Medicine, St. Louis, MO, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-3816-6124","authenticated-orcid":false,"given":"Conrad C.","family":"Weihl","sequence":"additional","affiliation":[{"name":"Department of Neurology, Hope Center for Neurological Diseases, Washington University School of Medicine, St. Louis, MO, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-4824-9529","authenticated-orcid":false,"given":"Heather L.","family":"True","sequence":"additional","affiliation":[{"name":"Department of Cell Biology and Physiology, Washington University School of Medicine, 660 South Euclid Avenue, Campus Box 8228, St. Louis, MO 63110, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"54368","reference":[{"key":"2026041209454734000_2025.05.02.651952v1.1","doi-asserted-by":"crossref","unstructured":"D. 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