HSP70降解澱粉樣蛋白的分子機制
作者：
小柯機器人發布時間：2020/11/14 23:34:31
海德堡大學（ZMBH）和德國癌症研究中心（DKFZ）Bernd Bukau及其團隊揭示了人HSP70降解澱粉樣蛋白的分子機制。相關論文在線發表在2020年11月11日出版的《自然》雜誌上。
研究人員利用生化和核磁共振波譜確定了澱粉樣蛋白原纖維分解過程的關鍵步驟。研究人員發現DNAJB1通過多價相互作用特異性識別α-突觸核蛋白的寡聚形式，並選擇性地將HSP70靶向原纖維。HSP70和DNAJB1通過暴露於α-突觸核蛋白柔性末端的氨基和羧基與原纖維相互作用，而不是通過與澱粉樣蛋白核心本身相互作用。
DNAJB1和HSP110的協同作用通過招募多個HSP70分子在原纖維表面的密集堆積從而大大加速其分解，這對於產生「熵拉力」是有利的。DNAJB1和HSP110在澱粉樣蛋白分解中的協調作用超過了HSP70伴侶蛋白的經典底物靶向和再利用功能，並為澱粉樣物底物的重構做出了積極而重要的貢獻。這些對澱粉樣蛋白分解機制的理解可能為神經變性新的治療和幹預手段提供基礎。
據了解，高度有序的原纖維型聚集體沉積到包涵體中是神經退行性疾病（如帕金森氏病）的標誌。這種澱粉樣蛋白原纖維聚集體的高穩定性使其成為細胞內蛋白質質量控制細胞器難降解的底物。但是，人伴侶蛋白HSP70及其伴侶分子DNAJB1和HSP110可以在體外降解與帕金森氏病相關突觸前蛋白α-突觸核蛋白的原纖維。但對這種獨特降解的潛在機制了解甚少。
附：英文原文
Title: Molecular dissection of amyloid disaggregation by human HSP70
Author: Anne S. Wentink, Nadinath B. Nillegoda, Jennifer Feufel, Gabriel Ubartait, Carolyn P. Schneider, Paolo De Los Rios, Janosch Hennig, Alessandro Barducci, Bernd Bukau
Issue&Volume: 2020-11-11
Abstract: The deposition of highly ordered fibrillar-type aggregates into inclusion bodies is a hallmark of neurodegenerative diseases such as Parkinson’s disease. The high stability of such amyloid fibril aggregates makes them challenging substrates for the cellular protein quality-control machinery1,2. However, the human HSP70 chaperone and its co-chaperones DNAJB1 and HSP110 can dissolve preformed fibrils of the Parkinson’s disease-linked presynaptic protein α-synuclein in vitro3,4. The underlying mechanisms of this unique activity remain poorly understood. Here we use biochemical tools and nuclear magnetic resonance spectroscopy to determine the crucial steps of the disaggregation process of amyloid fibrils. We find that DNAJB1 specifically recognizes the oligomeric form of α-synuclein via multivalent interactions, and selectively targets HSP70 to fibrils. HSP70 and DNAJB1 interact with the fibril through exposed, flexible amino and carboxy termini of α-synuclein rather than the amyloid core itself. The synergistic action of DNAJB1 and HSP110 strongly accelerates disaggregation by facilitating the loading of several HSP70 molecules in a densely packed arrangement at the fibril surface, which is ideal for the generation of 『entropic pulling』 forces. The cooperation of DNAJB1 and HSP110 in amyloid disaggregation goes beyond the classical substrate targeting and recycling functions that are attributed to these HSP70 co-chaperones and constitutes an active and essential contribution to the remodelling of the amyloid substrate. These mechanistic insights into the essential prerequisites for amyloid disaggregation may provide a basis for new therapeutic interventions in neurodegeneration.
DOI: 10.1038/s41586-020-2904-6
Source: https://www.nature.com/articles/s41586-020-2904-6