Home > Publications database > Stepwise recruitment of chaperone Hsc70 by DNAJB1 produces ordered arrays primed for bursts of amyloid fibril disassembly. > print

001     300235
005     20250819095112.0
024 7 _ |a 10.1038/s42003-025-07906-2
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100 1 _ |a Monistrol, Jim
|0 0000-0002-4634-818X
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245 _ _ |a Stepwise recruitment of chaperone Hsc70 by DNAJB1 produces ordered arrays primed for bursts of amyloid fibril disassembly.
260 _ _ |a London
|c 2025
|b Springer Nature
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520 _ _ |a 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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650 _ 7 |a HSP40 Heat-Shock Proteins
|2 NLM Chemicals
650 _ 7 |a HSC70 Heat-Shock Proteins
|2 NLM Chemicals
650 _ 7 |a Amyloid
|2 NLM Chemicals
650 _ 7 |a DNAJB1 protein, human
|2 NLM Chemicals
650 _ 7 |a alpha-Synuclein
|2 NLM Chemicals
650 _ 7 |a HSPA8 protein, human
|2 NLM Chemicals
650 _ 7 |a Molecular Chaperones
|2 NLM Chemicals
650 _ 2 |a HSP40 Heat-Shock Proteins: metabolism
|2 MeSH
650 _ 2 |a HSP40 Heat-Shock Proteins: genetics
|2 MeSH
650 _ 2 |a HSC70 Heat-Shock Proteins: metabolism
|2 MeSH
650 _ 2 |a HSC70 Heat-Shock Proteins: genetics
|2 MeSH
650 _ 2 |a Amyloid: metabolism
|2 MeSH
650 _ 2 |a Humans
|2 MeSH
650 _ 2 |a alpha-Synuclein: metabolism
|2 MeSH
650 _ 2 |a alpha-Synuclein: genetics
|2 MeSH
650 _ 2 |a alpha-Synuclein: chemistry
|2 MeSH
650 _ 2 |a Molecular Chaperones: metabolism
|2 MeSH
650 _ 2 |a Molecular Chaperones: genetics
|2 MeSH
650 _ 2 |a Protein Binding
|2 MeSH
650 _ 2 |a Cryoelectron Microscopy
|2 MeSH
700 1 _ |a Beton, Joseph G
|0 0000-0001-7499-3867
|b 1
700 1 _ |a Johnston, Erin C
|0 0000-0002-7616-0778
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700 1 _ |a Dang, Thi Lieu
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700 1 _ |a Bukau, Bernd
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700 1 _ |a Saibil, Helen R
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773 _ _ |a 10.1038/s42003-025-07906-2
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