The ALS‐associated E425K mutation uncouples DNAJC7 from the Hsp70 chaperone cycle

Abstract DNAJC7, a member of the J‐domain protein (JDP/Hsp40) family, plays a key role in protein homeostasis by regulating Hsp70 activity and preventing protein aggregation. Mutations in DNAJC7 have been linked to amyotrophic lateral sclerosis (ALS); yet, the molecular mechanisms by which these variants impair chaperone function remain poorly understood. DNAJC7 is a conserved chaperone featuring both a canonical J‐domain, essential for Hsp70 activation, and three TPR domains, which serve as protein–protein binding interfaces. Here, we investigate the structural and