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    Cooperative amyloid fibre binding and disassembly by the Hsp70 disaggregase

    Beton, J.G. and Monistrol, J. and Wentink, A. and Johnston, E.C. and Roberts, A.J. and Bukau, B.G. and Hoogenboom, B.W. and Saibil, Helen (2022) Cooperative amyloid fibre binding and disassembly by the Hsp70 disaggregase. The EMBO Journal 41 (16), e110410. ISSN 0261-4189.

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    Although amyloid fibres are highly stable protein aggregates, a specific combination of human Hsp70 system chaperones can disassemble them, including fibres formed of α-synuclein, huntingtin, or Tau. Disaggregation requires the ATPase activity of the constitutively expressed Hsp70 family member, Hsc70, together with the J domain protein DNAJB1 and the nucleotide exchange factor Apg2. Clustering of Hsc70 on the fibrils appears to be necessary for disassembly. Here we use atomic force microscopy to show that segments of in vitro assembled α-synuclein fibrils are first coated with chaperones and then undergo bursts of rapid, unidirectional disassembly. Cryo-electron tomography and total internal reflection fluorescence microscopy reveal fibrils with regions of densely bound chaperones, preferentially at one end of the fibre. Sub-stoichiometric amounts of Apg2 relative to Hsc70 dramatically increase recruitment of Hsc70 to the fibres, creating localised active zones that then undergo rapid disassembly at a rate of ~ 4 subunits per second. The observed unidirectional bursts of Hsc70 loading and unravelling may be explained by differences between the two ends of the polar fibre structure.


    Item Type: Article
    School: Birkbeck Faculties and Schools > Faculty of Science > School of Natural Sciences
    Depositing User: Administrator
    Date Deposited: 20 Jul 2022 06:12
    Last Modified: 02 Aug 2023 18:17


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