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.

中文翻译：

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Hsp70解聚酶协同淀粉样纤维结合和分解

尽管淀粉样蛋白纤维是高度稳定的蛋白质聚集体，但人类 Hsp70 系统伴侣的特定组合可以分解它们，包括由 α-突触核蛋白、亨廷顿蛋白或 Tau 形成的纤维。分解需要组成型表达的 Hsp70 家族成员 Hsc70 的 ATP 酶活性以及 J 域蛋白 DNAJB1 和核苷酸交换因子 Apg2。Hsc70 在原纤维上的聚集似乎是拆卸所必需的。在这里，我们使用原子力显微镜来显示体外片段组装好的 α-突触核蛋白原纤维首先被分子伴侣包被，然后经历快速的单向解体。冷冻电子断层扫描和全内反射荧光显微镜显示原纤维具有密集结合的伴侣区域，优先位于纤维的一端。Apg2 相对于 Hsc70 的亚化学计量量显着增加 Hsc70 向纤维的募集，产生局部活性区，然后以每秒约 4 个亚单位的速度快速分解。观察到的 Hsc70 加载和解开的单向爆发可以通过极性纤维结构两端之间的差异来解释。