A.N. Bach Institute of Biochemistry, Federal Research Center "Fundamentals of Biotechnology" of the Russian Academy of Sciences, Moscow, Russian Federation.
Adv Protein Chem Struct Biol. 2022;130:289-324. doi: 10.1016/bs.apcsb.2021.12.004. Epub 2022 Feb 9.
Being phosphopeptide-binding hubs, 14-3-3 proteins coordinate multiple cellular processes in eukaryotes, including the regulation of apoptosis, cell cycle, ion channels trafficking, transcription, signal transduction, and hormone biosynthesis. Forming constitutive α-helical dimers, 14-3-3 proteins predominantly recognize specifically phosphorylated Ser/Thr sites within their partners; this generally stabilizes phosphotarget conformation and affects its activity, intracellular distribution, dephosphorylation, degradation and interactions with other proteins. Not surprisingly, 14-3-3 complexes are involved in the development of a range of diseases and are considered promising drug targets. The wide interactome of 14-3-3 proteins encompasses hundreds of different phosphoproteins, for many of which the interaction is well-documented in vitro and in vivo but lack the structural data that would help better understand underlying regulatory mechanisms and develop new drugs. Despite obtaining structural information on 14-3-3 complexes is still lagging behind the research of 14-3-3 interactions on a proteome-wide scale, recent works provided some advances, including methodological improvements and accumulation of new interesting structural data, that are discussed in this review.
作为磷酸肽结合枢纽，14-3-3 蛋白在真核生物中协调多种细胞过程，包括细胞凋亡、细胞周期、离子通道运输、转录、信号转导和激素生物合成的调控。14-3-3 蛋白形成组成型 α-螺旋二聚体，主要识别其伴侣中特定的磷酸化 Ser/Thr 位点；这通常稳定磷酸化靶标构象并影响其活性、细胞内分布、去磷酸化、降解以及与其他蛋白的相互作用。毫不奇怪，14-3-3 复合物参与了一系列疾病的发展，被认为是有前途的药物靶点。14-3-3 蛋白的广泛互作组包含数百种不同的磷酸化蛋白，其中许多蛋白在体外和体内的相互作用都有很好的记录，但缺乏有助于更好地理解潜在调节机制和开发新药的结构数据。尽管在获取 14-3-3 复合物的结构信息方面仍落后于在全蛋白质组范围内研究 14-3-3 相互作用的研究，但最近的工作提供了一些进展，包括方法学的改进和新的有趣结构数据的积累，这些都在本综述中进行了讨论。
