{"doi":"10.1101/2025.05.02.651952","title":"Mutations in Hsp40 co-chaperone change the unique canonical inter-domain interactions stimulating LGMDD1 myopathy","abstract":"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. Teaser: Recalibrating the inter-domain interface of the mutant protein could potentially serve as a key therapeutic strategy for LGMDD1 myopathy.","journal":"bioRxiv (Cold Spring Harbor Laboratory)","year":2025,"id":565244,"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":0,"citer_count":0,"citers_with_citation_signal":0,"citers_with_endowment":0,"datacite_reuse_total":0,"is_dataset":false,"is_dataset_confidence":0.9546,"is_data_producer":false,"deposit_databanks":null,"is_oa":true,"file_count":0,"downloads":0,"has_version_chain":false,"published_date":"2025-01-01","fair_score":null,"fair_percentile":null,"algorithm_id":"datarank_citation_only_1hop_v6","ranking_scope":"data_only","authors":[{"id":402563,"name":"Geetika Aggarwal","orcid":"0000-0002-1848-5056","position":1,"is_corresponding":false},{"id":1468733,"name":"Mahapatra Anshuman Jaysingh","orcid":"0000-0002-8110-077X","position":2,"is_corresponding":false},{"id":1468994,"name":"Daniel C. Chen","orcid":null,"position":3,"is_corresponding":false},{"id":832903,"name":"Jil Daw","orcid":"0000-0002-8002-076X","position":4,"is_corresponding":false},{"id":420105,"name":"Conrad C. Weihl","orcid":"0000-0002-3816-6124","position":5,"is_corresponding":false},{"id":420106,"name":"Heather L. True","orcid":"0000-0003-4824-9529","position":6,"is_corresponding":false},{"id":488515,"name":"Ankan K. Bhadra","orcid":"0000-0002-8679-0984","position":0,"is_corresponding":true}],"reference_count":77,"raw_metadata":null,"created_at":"2026-07-19T02:56:28.709936Z","pmid":"40654958","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":[]}