Pathways to Parkinson's disease: a spotlight on 14-3-3 proteins.
Pathways to Parkinson's disease: a spotlight on 14-3-3 proteins.
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DOI：
10.1038/s41531-021-00230-6
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发表时间：
2021-09-21
期刊：
影响因子：
--
通讯作者：
Civiero L
中科院分区：
文献类型：
--
作者：
Giusto E;Yacoubian TA;Greggio E;Civiero L
14-3-3s代表高度保守的30 kDa酸性蛋白家族。14-3-3s识别并结合客户伙伴上的特定磷酸序列，并作为分子枢纽来调节其活性、定位、折叠、降解和蛋白质-蛋白质相互作用。14-3-3s还与几种疾病的发病机制有关，其中包括帕金森病（PD）。14-3- 3在PD患者的路易体（LB）中被发现，并且它们的神经保护作用已经在几种PD动物模型中得到证实。值得注意的是，14-3-3s与已知参与PD发病机制的一些主要蛋白质相互作用。在这里，我们首先提供了一个详细的概述14-3-3s的分子组成和结构特征，重点放在其独特的目标结合机制。然后，我们简要描述了14-3-3s在中枢神经系统中的意义，并重点介绍了它们与LRRK 2，α-突触核蛋白和Parkin的相互作用，这三个是PD发病和进展的主要参与者。我们最后讨论了不同类型的小分子如何干扰14-3-3s相互作用组，从而代表了未来药物发现的有效策略。
14-3-3s represent a family of highly conserved 30 kDa acidic proteins. 14-3-3s recognize and bind specific phospho-sequences on client partners and operate as molecular hubs to regulate their activity, localization, folding, degradation, and protein–protein interactions. 14-3-3s are also associated with the pathogenesis of several diseases, among which Parkinson’s disease (PD). 14-3-3s are found within Lewy bodies (LBs) in PD patients, and their neuroprotective effects have been demonstrated in several animal models of PD. Notably, 14-3-3s interact with some of the major proteins known to be involved in the pathogenesis of PD. Here we first provide a detailed overview of the molecular composition and structural features of 14-3-3s, laying significant emphasis on their peculiar target-binding mechanisms. We then briefly describe the implication of 14-3-3s in the central nervous system and focus on their interaction with LRRK2, α-Synuclein, and Parkin, three of the major players in PD onset and progression. We finally discuss how different types of small molecules may interfere with 14-3-3s interactome, thus representing a valid strategy in the future of drug discovery.
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影响因子：
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通讯作者：
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