Department of Chemistry and Chemical Biology, McMaster University, Hamilton, Ontario L8S 4L8, Canada.
Department of Chemistry and Chemical Biology, McMaster University, Hamilton, Ontario L8S 4L8, Canada; Department of Biochemistry and Biomedical Sciences, McMaster University, Hamilton, Ontario L8S 4L8, Canada.
Biophys Chem. 2024 Dec;315:107320. doi: 10.1016/j.bpc.2024.107320. Epub 2024 Aug 30.
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.
变构和淀粉样相关病理学领域，如帕金森病 (PD)，已经被广泛研究，但对于淀粉样蛋白如何控制变构作用知之甚少。最近的进展表明，淀粉样蛋白可以驱动包括无规卷曲蛋白（如α-突触核蛋白 (αS)）和多结构域信号蛋白（如蛋白激酶 A (PKA)）在内的多种蛋白质的变构效应。淀粉样蛋白驱动的变构作用在解释 αS 中获得病理性功能突变（例如导致早发性 PD 的 E46K）和 PKA 中丧失生理功能突变（例如易患肿瘤的 A211D）的机制中起着核心作用。本综述强调了与疾病相关的突变的变构效应，以及它们如何导致淀粉样蛋白形成区域的暴露，导致具有毒性或引起异常信号的淀粉样蛋白。我们还讨论了多种潜在的这些变构效应调节剂，如 MgATP 和激酶底物，为改善针对 αS 和 PKA 相关病理学的现有药物干预提供了未来的机会。总的来说，我们表明，淀粉样蛋白驱动的变构模型可用于解释与疾病相关的突变的机制。
