ArticleCommunications biology2025
Stepwise recruitment of chaperone Hsc70 by DNAJB1 produces ordered arrays primed for bursts of amyloid fibril disassembly.
Article in Communications biology, 2025. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 9 papers.
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Who cites it
9 citing papers in PubMed.
- Human Hsp70 paralogs display selective J-domain interactions tuning proteostasis under stress.Proceedings of the National Academy of Sciences of the United States of America · 2026Article
- Wiring of cellular proteostasis by J-domain proteins.Cell stress & chaperones · 2026Review
- Phosphorylation of α‑Synuclein Fibrils at S129 Changes DNAJB1 Binding as Probed by Solid-State NMR.JACS Au · 2026Article
- Cardiolipin and mitochondrial membrane integrity in neurodegeneration: insights from α-synuclein-driven Parkinson's disease.Acta neuropathologica communications · 2025Review
- Structural polymorphism of α-synuclein fibrils alters the pathway of Hsc70-mediated disaggregation.The EMBO journal · 2025Article
- DnaJB1 chaperone inhibits tau aggregation by recognizing its N-terminus.bioRxiv : the preprint server for biology · 2025Article
- Effects of solution conditions on the self-assembly of the chaperone protein DNAJB6b.Communications chemistry · 2025Article
- Alpha-synuclein fibril structures cluster into distinct classes.Biophysical journal · 2025Review
- Ligands for Protein Fibrils of Amyloid-β, α-Synuclein, and Tau.Chemical reviews · 2025Review
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Authors and funding
6 authors.
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Abstract
The Hsp70 chaperone system is capable of disassembling pathological aggregates such as amyloid fibres associated with serious degenerative diseases. Here we examine the role of the J-domain protein co-factor in amyloid disaggregation by the Hsc70 system. We used cryo-EM and tomography to compare the assemblies with wild-type DNAJB1 or inactive mutants. We show that DNAJB1 binds regularly along α-synuclein amyloid fibrils and acts in a 2-step recruitment of Hsc70, releasing DNAJB1 auto-inhibition before activating Hsc70 ATPase. The wild-type DNAJB1:Hsc70:Apg2 complex forms dense arrays of chaperones on the fibrils, with Hsc70 on the outer surface. When the auto-inhibition is removed by mutating DNAJB1 (ΔH5 DNAJB1), Hsc70 is recruited to the fibrils at a similar level, but the ΔH5 DNAJB1:Ηsc70:Apg2 complex is inactive, binds less regularly to the fibrils and lacks the ordered clusters. Therefore, we propose that 2-step activation of DNAJB1 regulates the ordered assembly of Hsc70 on the fibril. The localised, dense packing of chaperones could trigger a cascade of recruitment and activation to give coordinated, sequential binding and disaggregation from an exposed fibril end, as previously observed in AFM videos. This mechanism is likely to be important in maintaining a healthy cellular proteome into old age.
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