迄今为止，已列出了 650 多种可逆和不可逆的蛋白质翻译后修饰 (PTM)。蛋白质的典型 PTM 包括在目标主链氨基酸上共价添加功能或化学基团或蛋白质本身的裂解，从而产生在稳定性、溶解度、细胞分布、活性或相互作用方面具有特定性质的修饰蛋白质与其他生物分子。蛋白质的 PTM 有助于细胞稳态过程，实现基础细胞功能，使细胞能够响应和适应环境的变化，并在全球范围内维持内部环境（人体的内部环境）的恒定性，以维持人类健康。然而，异常蛋白质 PTM 与多种疾病状态有关，例如癌症、代谢紊乱或神经退行性疾病。异常的 PTM 会改变蛋白质的功能特性，甚至导致蛋白质功能丧失。引人注目的 PTM 的一个例子涉及细胞朊病毒蛋白 (PrPC)，这是一种锚定在质膜上的 GPI 信号分子，其不可逆的翻译后构象转化 (PTCC) 为致病性朊病毒 (PrPSc)，从而引发神经变性。 PrPC PTCC 转化为 PrPSc 是另一种类型的 PTM，它影响 PrPC 的三维结构和生理功能，并产生具有神经毒性特性的蛋白质构象异构体。神经元中的 PrPC PTCC 转化为 PrPSc 是影响人类（最具代表性的克雅氏病）和动物（绵羊瘙痒症、牛海绵状脑病）的一组神经退行性疾病的根源的一系列有害事件的第一步。牛，以及麋鹿和鹿的慢性消耗性疾病）。目前尚无疗法可以阻止 PrPC PTCC 转化为 PrPSc 并阻止朊病毒疾病中的神经变性。在这里，我们回顾了影响 PrPC 转化为 PrPSc 的已知 PrPC PTM。我们总结了 PrPC PTCC 转化为 PrPSc 如何影响质膜上的 PrPC 相互作用组和下游细胞内控制的蛋白质效应器，其由 PTM 改变引起的异常激活或运输会促进神经变性。我们讨论了这些效应子作为朊病毒疾病和可能的其他神经退行性疾病的候选药物靶点。版权所有 © 2024 Bizingre、Bianchi、Baudry、Alleaume-Butaux、Schneider 和 Pietri。

More than 650 reversible and irreversible post-translational modifications (PTMs) of proteins have been listed so far. Canonical PTMs of proteins consist of the covalent addition of functional or chemical groups on target backbone amino-acids or the cleavage of the protein itself, giving rise to modified proteins with specific properties in terms of stability, solubility, cell distribution, activity, or interactions with other biomolecules. PTMs of protein contribute to cell homeostatic processes, enabling basal cell functions, allowing the cell to respond and adapt to variations of its environment, and globally maintaining the constancy of the milieu interieur (the body's inner environment) to sustain human health. Abnormal protein PTMs are, however, associated with several disease states, such as cancers, metabolic disorders, or neurodegenerative diseases. Abnormal PTMs alter the functional properties of the protein or even cause a loss of protein function. One example of dramatic PTMs concerns the cellular prion protein (PrPC), a GPI-anchored signaling molecule at the plasma membrane, whose irreversible post-translational conformational conversion (PTCC) into pathogenic prions (PrPSc) provokes neurodegeneration. PrPC PTCC into PrPSc is an additional type of PTM that affects the tridimensional structure and physiological function of PrPC and generates a protein conformer with neurotoxic properties. PrPC PTCC into PrPSc in neurons is the first step of a deleterious sequence of events at the root of a group of neurodegenerative disorders affecting both humans (Creutzfeldt-Jakob diseases for the most representative diseases) and animals (scrapie in sheep, bovine spongiform encephalopathy in cow, and chronic wasting disease in elk and deer). There are currently no therapies to block PrPC PTCC into PrPSc and stop neurodegeneration in prion diseases. Here, we review known PrPC PTMs that influence PrPC conversion into PrPSc. We summarized how PrPC PTCC into PrPSc impacts the PrPC interactome at the plasma membrane and the downstream intracellular controlled protein effectors, whose abnormal activation or trafficking caused by altered PTMs promotes neurodegeneration. We discussed these effectors as candidate drug targets for prion diseases and possibly other neurodegenerative diseases.Copyright © 2024 Bizingre, Bianchi, Baudry, Alleaume-Butaux, Schneider and Pietri.