盐和温度如何驱动 Aβ40 的回流冷凝。

IF 2.9 3区 生物学 Q3 BIOCHEMISTRY & MOLECULAR BIOLOGY Biochemistry Biochemistry Pub Date : 2024-10-28 DOI:10.1021/acs.biochem.4c00412
Susmita Sarkar, Jagannath Mondal
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引用次数: 0

摘要

在液-液相分离(LLPS)的框架内,生物分子凝结协调着重要的细胞过程,其失调与严重的病理状况有关。最近的研究强调了内在无序蛋白(IDPs)在液液相分离中的作用,但微环境因素的影响仍然是一个令人困惑的因素。在这里,通过计算模拟溶液条件对神经致病性 IDP Aβ40 的 LLPS 行为的影响,我们偶然发现了盐驱动的回流凝聚现象,即 Aβ40 的聚集在低盐浓度(25-50 mM)下增加,随后随着盐浓度的进一步增加而下降。对反相缩聚的热力学和动力学特征的探索揭示了作为潜在驱动因素的蛋白质静电和离子强度之间微妙的相互作用。值得注意的是,N 端带电残基对盐筛选表现出一种非单调反应,这与疏水核诱导缩聚过程中反复出现的重入行为有着错综复杂的联系。耐人寻味的是,我们的发现还揭示了在不同温度条件下类似的重陷缩聚现象的再次出现。总之,我们的研究揭示了 Aβ40 的液-液相分离行为具有深刻的环境依赖性,超越了其固有的分子框架,微环境线索对其异常功能具有重大影响。
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How Salt and Temperature Drive Reentrant Condensation of Aβ40.

Within the framework of liquid-liquid phase separation (LLPS), biomolecular condensation orchestrates vital cellular processes, and its dysregulation is implicated in severe pathological conditions. Recent studies highlight the role of intrinsically disordered proteins (IDPs) in LLPS, yet the influence of microenvironmental factors has remained a puzzling factor. Here, via computational simulation of the impact of solution conditions on LLPS behavior of neurologically pathogenic IDP Aβ40, we chanced upon a salt-driven reentrant condensation phenomenon, wherein Aβ40 aggregation increases with low salt concentrations (25-50 mM), followed by a decline with further salt increments. An exploration of the thermodynamic and kinetic signatures of reentrant condensation unveils a nuanced interplay between protein electrostatics and ionic strength as potential drivers. Notably, the charged residues of the N-terminus exhibit a nonmonotonic response to salt screening, intricately linked to the recurrence of reentrant behavior in hydrophobic core-induced condensation. Intriguingly, our findings also unveil the reappearance of similar reentrant condensation phenomena under varying temperature conditions. Collectively, our study illuminates the profoundly context-dependent nature of Aβ40s liquid-liquid phase separation behavior, extending beyond its intrinsic molecular framework, where microenvironmental cues wield significant influence over its aberrant functionality.

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来源期刊
Biochemistry Biochemistry
Biochemistry Biochemistry 生物-生化与分子生物学
CiteScore
5.50
自引率
3.40%
发文量
336
审稿时长
1-2 weeks
期刊介绍: Biochemistry provides an international forum for publishing exceptional, rigorous, high-impact research across all of biological chemistry. This broad scope includes studies on the chemical, physical, mechanistic, and/or structural basis of biological or cell function, and encompasses the fields of chemical biology, synthetic biology, disease biology, cell biology, nucleic acid biology, neuroscience, structural biology, and biophysics. In addition to traditional Research Articles, Biochemistry also publishes Communications, Viewpoints, and Perspectives, as well as From the Bench articles that report new methods of particular interest to the biological chemistry community.
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