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HSP70降解淀粉样蛋白的分子机制
2020-11-14 23:34

海德堡大学(ZMBH)和德国癌症研究中心(DKFZ)Bernd Bukau及其团队揭示了人HSP70降解淀粉样蛋白的分子机制。相关论文在线发表在2020年11月11日出版的《自然》杂志上。

研究人员利用生化和核磁共振波谱确定了淀粉样蛋白原纤维分解过程的关键步骤。研究人员发现DNAJB1通过多价相互作用特异性识别α-突触核蛋白的寡聚形式,并选择性地将HSP70靶向原纤维。HSP70和DNAJB1通过暴露于α-突触核蛋白柔性末端的氨基和羧基与原纤维相互作用,而不是通过与淀粉样蛋白核心本身相互作用。

DNAJB1和HSP110的协同作用通过招募多个HSP70分子在原纤维表面的密集堆积从而大大加速其分解,这对于产生“熵拉力”是有利的。DNAJB1和HSP110在淀粉样蛋白分解中的协调作用超过了HSP70伴侣蛋白的经典底物靶向和再利用功能,并为淀粉样物底物的重构做出了积极而重要的贡献。这些对淀粉样蛋白分解机制的理解可能为神经变性新的治疗和干预手段提供基础。

据了解,高度有序的原纤维型聚集体沉积到包涵体中是神经退行性疾病(如帕金森氏病)的标志。这种淀粉样蛋白原纤维聚集体的高稳定性使其成为细胞内蛋白质质量控制细胞器难降解的底物。但是,人伴侣蛋白HSP70及其伴侣分子DNAJB1和HSP110可以在体外降解与帕金森氏病相关突触前蛋白α-突触核蛋白的原纤维。但对这种独特降解的潜在机制了解甚少。

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

Nature:《自然》,创刊于1869年。隶属于施普林格·自然出版集团,最新IF:43.07
官方网址:http://www.nature.com/
投稿链接:http://www.nature.com/authors/submit_manuscript.html


本期文章:《自然》:Online/在线发表

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