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.

14-3-3s 代表高度保守的 30 kDa 酸性蛋白家族。14-3-3s 识别并结合客户合作伙伴的特定磷酸化序列，并作为分子中枢来调节它们的活动、定位、折叠、降解和蛋白质-蛋白质相互作用。14-3-3s 还与多种疾病的发病机制有关，其中包括帕金森病 (PD)。14-3-3s 存在于 PD 患者的路易体 (LB) 中，其神经保护作用已在几种 PD 动物模型中得到证实。值得注意的是，14-3-3s 与一些已知参与 PD 发病机制的主要蛋白质相互作用。在这里，我们首先详细概述了 14-3-3s 的分子组成和结构特征，着重强调了它们独特的靶标结合机制。然后，我们简要描述 14-3-3s 在中枢神经系统中的意义，并重点介绍它们与 LRRK2、α-突触核蛋白和帕金的相互作用，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。