Amyloid-Driven Allostery

IF 3.3 3区 生物学 Q2 BIOCHEMISTRY & MOLECULAR BIOLOGY Biophysical chemistry Pub Date : 2024-08-30 DOI:10.1016/j.bpc.2024.107320
Jaskiran Garcha , Jinfeng Huang , Karla Martinez Pomier , Giuseppe Melacini
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Abstract

The fields of allostery and amyloid-related pathologies, such as Parkinson's disease (PD), have been extensively explored individually, but less is known about how amyloids control allostery. Recent advancements have revealed that amyloids can drive allosteric effects in both intrinsically disordered proteins, such as alpha-synuclein (αS), and multi-domain signaling proteins, such as protein kinase A (PKA). Amyloid-driven allostery plays a central role in explaining the mechanisms of gain-of-pathological-function mutations in αS (e.g. E46K, which causes early PD onset) and loss-of-physiological-function mutations in PKA (e.g. A211D, which predisposes to tumors). This review highlights allosteric effects of disease-related mutations and how they can cause exposure of amyloidogenic regions, leading to amyloids that are either toxic or cause aberrant signaling. We also discuss multiple potential modulators of these allosteric effects, such as MgATP and kinase substrates, opening future opportunities to improve current pharmacological interventions against αS and PKA-related pathologies. Overall, we show that amyloid-driven allosteric models are useful to explain the mechanisms underlying disease-related mutations.

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淀粉样蛋白驱动的异构体
人们已对异构和淀粉样蛋白相关病症(如帕金森病)进行了广泛的探讨,但对淀粉样蛋白如何控制异构却知之甚少。最近的研究进展表明,淀粉样蛋白既能驱动α-突触核蛋白(αS)等内在无序蛋白的异构效应,也能驱动蛋白激酶A(PKA)等多域信号转导蛋白的异构效应。淀粉样蛋白驱动的异构作用在解释αS的病理功能增益突变(如E46K,导致帕金森病早期发病)和PKA的生理功能缺失突变(如A211D,易患肿瘤)的机制方面发挥着核心作用。本综述强调了疾病相关突变的异构效应,以及这些突变如何导致淀粉样蛋白生成区暴露,从而产生具有毒性或导致信号传递异常的淀粉样蛋白。我们还讨论了这些异构效应的多种潜在调节剂,如 MgATP 和激酶底物,为改善目前针对 αS 和 PKA 相关病症的药物干预开辟了未来的机会。总之,我们的研究表明,淀粉样蛋白驱动的异构模型有助于解释疾病相关突变的内在机制。
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来源期刊
Biophysical chemistry
Biophysical chemistry 生物-生化与分子生物学
CiteScore
6.10
自引率
10.50%
发文量
121
审稿时长
20 days
期刊介绍: Biophysical Chemistry publishes original work and reviews in the areas of chemistry and physics directly impacting biological phenomena. Quantitative analysis of the properties of biological macromolecules, biologically active molecules, macromolecular assemblies and cell components in terms of kinetics, thermodynamics, spatio-temporal organization, NMR and X-ray structural biology, as well as single-molecule detection represent a major focus of the journal. Theoretical and computational treatments of biomacromolecular systems, macromolecular interactions, regulatory control and systems biology are also of interest to the journal.
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