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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\u2010domain, essential for Hsp70 activation, and three TPR domains, which serve as protein\u2013protein binding interfaces. Here, we investigate the structural and functional consequences of the ALS\u2010associated E425K mutation located within the conserved J\u2010domain. Using NMR spectroscopy, we show that although the E425K mutation does not alter the structure of the protein, it significantly disrupts the conserved J\u2010domain\u2013Hsp70 interaction. We further identify a second Hsp70\u2010binding interface within the TPR domains, which interacts with the C\u2010terminal EEVD motif of Hsp70. This TPR\u2013EEVD interaction is preserved in the E425K mutant but cannot compensate for the loss of J\u2010domain binding or restore DNAJC7\u2010dependent Hsp70 activation. Functionally, we show that the TPR domains of DNAJC7 directly bind TDP\u201043 and prevent its aggregation and that this holdase activity is retained in the E425K mutant. However, the mutant fails to support client transfer to Hsp70 and the subsequent Hsp70\u2010mediated substrate refolding. Together, these findings demonstrate that DNAJC7 requires coordinated action of both J\u2010domain and TPRs to regulate Hsp70 function and that disruption of J\u2010domain\u2010mediated activation uncouples DNAJC7 from the Hsp70 cycle, providing a mechanistic basis for its dysfunction in ALS.<\/jats:p>","DOI":"10.1111\/febs.70395","type":"journal-article","created":{"date-parts":[[2026,1,14]],"date-time":"2026-01-14T08:15:58Z","timestamp":1768378558000},"page":"3485-3501","update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":2,"title":["The\n                    <scp>ALS<\/scp>\n                    \u2010associated\n                    <scp>E425K<\/scp>\n                    mutation uncouples\n                    <scp>DNAJC7<\/scp>\n                    from the Hsp70 chaperone cycle"],"prefix":"10.1111","volume":"293","author":[{"given":"Bar","family":"Elmaleh","sequence":"first","affiliation":[{"name":"Department of Chemical and Structural Biology Weizmann Institute of Science  Rehovot Israel"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Ofrah","family":"Faust","sequence":"additional","affiliation":[{"name":"Department of Chemical and Structural Biology Weizmann Institute of Science  Rehovot Israel"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-4019-5135","authenticated-orcid":false,"given":"Rina","family":"Rosenzweig","sequence":"additional","affiliation":[{"name":"Department of Chemical and Structural Biology Weizmann Institute of Science  Rehovot 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