Department of Electrical and Computer Engineering, University of Alberta, Edmonton, Alberta, Canada.
Cell Death Differ. 2013 Sep;20(9):1257-67. doi: 10.1038/cdd.2013.65. Epub 2013 Jun 14.
It is recognized now that intrinsically disordered proteins (IDPs), which do not have unique 3D structures as a whole or in noticeable parts, constitute a significant fraction of any given proteome. IDPs are characterized by an astonishing structural and functional diversity that defines their ability to be universal regulators of various cellular pathways. Programmed cell death (PCD) is one of the most intricate cellular processes where the cell uses specialized cellular machinery and intracellular programs to kill itself. This cell-suicide mechanism enables metazoans to control cell numbers and to eliminate cells that threaten the animal's survival. PCD includes several specific modules, such as apoptosis, autophagy, and programmed necrosis (necroptosis). These modules are not only tightly regulated but also intimately interconnected and are jointly controlled via a complex set of protein-protein interactions. To understand the role of the intrinsic disorder in controlling and regulating the PCD, several large sets of PCD-related proteins across 28 species were analyzed using a wide array of modern bioinformatics tools. This study indicates that the intrinsic disorder phenomenon has to be taken into consideration to generate a complete picture of the interconnected processes, pathways, and modules that determine the essence of the PCD. We demonstrate that proteins involved in regulation and execution of PCD possess substantial amount of intrinsic disorder. We annotate functional roles of disorder across and within apoptosis, autophagy, and necroptosis processes. Disordered regions are shown to be implemented in a number of crucial functions, such as protein-protein interactions, interactions with other partners including nucleic acids and other ligands, are enriched in post-translational modification sites, and are characterized by specific evolutionary patterns. We mapped the disorder into an integrated network of PCD pathways and into the interactomes of selected proteins that are involved in the p53-mediated apoptotic signaling pathway.
现在人们已经认识到，没有独特的整体或明显部分三维结构的无规卷曲蛋白质（IDP）构成了任何给定蛋白质组的重要组成部分。IDP 的特点是结构和功能的惊人多样性，这定义了它们作为各种细胞途径通用调节剂的能力。程序性细胞死亡（PCD）是最复杂的细胞过程之一，其中细胞使用专门的细胞机制和细胞内程序来杀死自身。这种细胞自杀机制使后生动物能够控制细胞数量并消除威胁动物生存的细胞。PCD 包括几种特定的模块，如细胞凋亡、自噬和程序性细胞坏死（坏死性细胞死亡）。这些模块不仅受到严格的调节，而且还紧密相互关联，并通过一组复杂的蛋白质-蛋白质相互作用共同控制。为了了解内在无序在控制和调节 PCD 中的作用，使用各种现代生物信息学工具对来自 28 个物种的多个大的 PCD 相关蛋白组进行了分析。这项研究表明，为了生成决定 PCD 本质的相互关联的过程、途径和模块的完整图景，必须考虑内在无序现象。我们证明，参与 PCD 的调节和执行的蛋白质具有大量的内在无序。我们在细胞凋亡、自噬和坏死性细胞死亡过程中注释了无序的功能作用。无序区域被证明在许多关键功能中得到实施，例如蛋白质-蛋白质相互作用、与其他伙伴（包括核酸和其他配体）的相互作用、富含翻译后修饰位点，并具有特定的进化模式。我们将无序映射到 PCD 途径的综合网络中，并映射到参与 p53 介导的细胞凋亡信号通路的选定蛋白质的相互作用组中。
