Small heat shock proteins potentiate amyloid dissolution by protein disaggregases from yeast and humans.
Small heat shock proteins potentiate amyloid dissolution by protein disaggregases from yeast and humans.
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DOI：
10.1371/journal.pbio.1001346
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发表时间：
2012
期刊：
影响因子：
9.8
通讯作者：
Shorter J
中科院分区：
文献类型：
--
作者：
Duennwald ML;Echeverria A;Shorter J
作者定义了小型热冲蛋白如何协同调节有益的王室的组装和拆卸，然后利用这种知识来识别人淀粉样蛋白脱聚合酶。
小型热休克蛋白（SHSP）如何使蛋白质的网络能够控制有益的prions或拆卸病理淀粉样蛋白，我们确定酵母SHSPS，HSP26和HSP42抑制[PSI +] PRION PROTIEN PROTIEN，SUP35的元素，并抑制PRIONIGES的prionefients suergigents protinations。 Prionogenation并与HSP70合作相比之下，HSP26抑制了自我策略，在结合的prions上抑制了SHSP的结合。 4过表达。出乎意料的是，在没有HSP104的情况下，SHSP促进了HSP110，HSP70和HSP40的空前的Sup35 prions的分级沉积。 ，HSP70和HSP40。我们阐明了迄今未识别的人淀粉样蛋白 - 蛋白酶系统，该系统可能在各种神经退行性疾病中应用。
淀粉样蛋白纤维是蛋白质聚集体，包括帕金森氏病在内的许多神经退行性疾病，它们也可以在酵母中发挥有益的作用。纳米结构的多才多艺。 Ans。值得注意的是，人类的小热休克蛋白HSPB5刺激HSP110，HSP70和HSP40伴侣逐渐使α-突触核蛋白形成的淀粉样蛋白纤维（在帕金森氏病中隐含的淀粉样蛋白纤维（在帕金森氏病中）在生物学上的各种系统上都可以识别出各种系统范围。生成障碍。
The authors define how small heat-shock proteins synergize to regulate the assembly and disassembly of a beneficial prion, and then they exploit this knowledge to identify the human amyloid depolymerase. How small heat shock proteins (sHsps) might empower proteostasis networks to control beneficial prions or disassemble pathological amyloid is unknown. Here, we establish that yeast sHsps, Hsp26 and Hsp42, inhibit prionogenesis by the [PSI +] prion protein, Sup35, via distinct and synergistic mechanisms. Hsp42 prevents conformational rearrangements within molten oligomers that enable de novo prionogenesis and collaborates with Hsp70 to attenuate self-templating. By contrast, Hsp26 inhibits self-templating upon binding assembled prions. sHsp binding destabilizes Sup35 prions and promotes their disaggregation by Hsp104, Hsp70, and Hsp40. In yeast, Hsp26 or Hsp42 overexpression prevents [PSI+] induction, cures [PSI+], and potentiates [PSI+]-curing by Hsp104 overexpression. In vitro, sHsps enhance Hsp104-catalyzed disaggregation of pathological amyloid forms of α-synuclein and polyglutamine. Unexpectedly, in the absence of Hsp104, sHsps promote an unprecedented, gradual depolymerization of Sup35 prions by Hsp110, Hsp70, and Hsp40. This unanticipated amyloid-depolymerase activity is conserved from yeast to humans, which lack Hsp104 orthologues. A human sHsp, HspB5, stimulates depolymerization of α-synuclein amyloid by human Hsp110, Hsp70, and Hsp40. Thus, we elucidate a heretofore-unrecognized human amyloid-depolymerase system that could have applications in various neurodegenerative disorders. Amyloid fibers are protein aggregates that are associated with numerous neurodegenerative diseases, including Parkinson's disease, for which there are no effective treatments. They can also play beneficial roles; in yeast, for example, they are associated with increased survival and the evolution of new traits. Amyloid fibers are also central to many revolutionary concepts and important questions in biology and nanotechnology, including long-term memory formation and versatile self-organizing nanostructures. Thus, there is an urgent need to understand how we can promote beneficial amyloid assembly, or reverse pathogenic assembly, at will. In this study, we define the mechanisms by which small heat-shock proteins synergize to regulate the assembly and disassembly of a beneficial yeast prion. We then exploit this knowledge to discover an amyloid depolymerase machinery that is conserved from yeast to humans. Remarkably, the human small heat shock protein, HspB5, stimulates Hsp110, Hsp70, and Hsp40 chaperones to gradually depolymerize amyloid fibers formed by α-synuclein (which are implicated in Parkinson's disease) from their ends on a biologically relevant timescale. This newly identified and highly conserved amyloid-depolymerase system could have important therapeutic applications for various neurodegenerative disorders.