蛋白质翻译后修饰在蛋白质-蛋白质相互作用中的调控作用
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摘要
蛋白质-蛋白质相互作用是蛋白质发挥功能的主要机制之一,在DNA损伤修复、自噬和代谢等过程中都扮演着非常重要的角色,蛋白相互作用异常便会导致肿瘤等疾病的发生.在蛋白质的赖氨酸、丝氨酸和苏氨酸等氨基酸残基上,可发生甲基化、乙酰化、磷酸化和泛素化等200多种翻译后修饰,这些修饰通常能改变蛋白质的电性、疏水性和空间结构等属性,为与之结合的蛋白提供结合的锚定或产生位阻效应,像一把开关在时空上精确调控蛋白质-蛋白质相互作用的发生以及动态变化.结构研究表明,蛋白质之间的相互作用通常由临近的几个氨基酸残基直接结合,替换该区域的氨基酸残基,通常能破坏结合,使其失去部分功能或酶活性,可以针对性地开发和设计抑制剂或激活剂,用于肿瘤等疾病的治疗.本文简要介绍了蛋白质翻译后修饰在蛋白质-蛋白质相互作用中的调控作用,以及发挥的重要生理功能.
Cellular processes are tightly regulated by functional protein networks, which are composed of numerous protein-protein interactions(PPIs). Proteins interact with their binding partners through distinct mechanisms, while defects of these machineries have been consequently implicated in the development of various diseases, such as cancer, neurodegeneration and immunological disorders. Interactions between proteins contribute to a complicated network involving many signaling pathways, and these interactions are either permanent or transient depending on the circumstances. Stable interactions assemble relatively stable complexes, which are mainly responsible for cellular functions under unstressed conditions, such as the proteasome complex, nuclear pore complex and histone octamer. On the other hand, transient proteins interactions allow cells to respond to both intracellular signals and extracellular stimuli timely and efficiently. To understand how PPIs are precisely regulated, it is critical to know how proteins and their binding partners interact in precise orientations. It is now well accepted that post-translational modifications(PTMs) of certain amino acid residues can be recognized and bound by specific motifs. PTMs such as methylation, acetylation, phosphorylation or ubiquitination on certain protein amino acid residues located on or around the interaction surfaces may interfere the electrical property, hydrophobicity, structure of proteins and provide anchors or obstacles for intermolecular binding. This is of great importance in regulating both permanent and transient interactions, which are indispensable for the coordination of temporal and spatial adaption. Abnormal PTMs can result in aberrant protein interaction network, cause systematic dysfunctions and ultimately lead to diseases such as cancer. Therefore, inhibitors design based on PTMs regulated PPIs may have good therapeutic prospects for cancer treatment. Recent studies have begun to show that, with the right tools, certain classes of PTMs regulated PPI can yield to the efforts to develop inhibitors to disrupt the interactions between proteins and their partners, and the first PTMs regulated PPI inhibitors have reached clinical development. In this review, we described the research leading to these breakthroughs, briefly summarize the vital roles played by several common PTMs in PPIs regulation and highlight the existence of mechanisms and structural basis, and explore their roles in deciding whether the PPIs are specific or not. Besides, we also explore and discuss emerging effective research strategies for PTMs in PPIs regulation.
Cellular processes are tightly regulated by functional protein networks, which are composed of numerous protein-protein interactions(PPIs). Proteins interact with their binding partners through distinct mechanisms, while defects of these machineries have been consequently implicated in the development of various diseases, such as cancer, neurodegeneration and immunological disorders. Interactions between proteins contribute to a complicated network involving many signaling pathways, and these interactions are either permanent or transient depending on the circumstances. Stable interactions assemble relatively stable complexes, which are mainly responsible for cellular functions under unstressed conditions, such as the proteasome complex, nuclear pore complex and histone octamer. On the other hand, transient proteins interactions allow cells to respond to both intracellular signals and extracellular stimuli timely and efficiently. To understand how PPIs are precisely regulated, it is critical to know how proteins and their binding partners interact in precise orientations. It is now well accepted that post-translational modifications(PTMs) of certain amino acid residues can be recognized and bound by specific motifs. PTMs such as methylation, acetylation, phosphorylation or ubiquitination on certain protein amino acid residues located on or around the interaction surfaces may interfere the electrical property, hydrophobicity, structure of proteins and provide anchors or obstacles for intermolecular binding. This is of great importance in regulating both permanent and transient interactions, which are indispensable for the coordination of temporal and spatial adaption. Abnormal PTMs can result in aberrant protein interaction network, cause systematic dysfunctions and ultimately lead to diseases such as cancer. Therefore, inhibitors design based on PTMs regulated PPIs may have good therapeutic prospects for cancer treatment. Recent studies have begun to show that, with the right tools, certain classes of PTMs regulated PPI can yield to the efforts to develop inhibitors to disrupt the interactions between proteins and their partners, and the first PTMs regulated PPI inhibitors have reached clinical development. In this review, we described the research leading to these breakthroughs, briefly summarize the vital roles played by several common PTMs in PPIs regulation and highlight the existence of mechanisms and structural basis, and explore their roles in deciding whether the PPIs are specific or not. Besides, we also explore and discuss emerging effective research strategies for PTMs in PPIs regulation.
引文
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13 Cai J,Zuo Y,Wang T,et al.A crucial role of SUMOylation in modulating Sirt6 deacetylation of H3 at lysine 56 and its tumor suppressive activity.Oncogene,2016,35:4949-4956
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23 Cheng Z,Cheung P,Kuo A J,et al.A molecular threading mechanism underlies Jumonji lysine demethylase KDM2A regulation of methylated H3K36.Genes Dev,2014,28:1758-1771
24 Huang Y,Fang J,Bedford M T,et al.Recognition of histone H3 lysine-4 methylation by the double tudor domain of JMJD2A.Science,2006,312:748-751
25 Lee J,Thompson J R,Botuyan M V,et al.Distinct binding modes specify the recognition of methylated histones H3K4 and H4K20 by JMJD2A-tudor.Nat Struct Mol Biol,2008,15:109-111
26 Sankaran S M,Wilkinson A W,Elias J E,et al.A PWWP domain of histone-lysine N-methyltransferase NSD2 binds to dimethylated Lys-36 of histone H3 and regulates NSD2 function at chromatin.J Biol Chem,2016,291:8465-8474
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28 Dhayalan A,Rajavelu A,Rathert P,et al.The Dnmt3a PWWP domain reads histone 3 lysine 36 trimethylation and guides DNA methylation.J Biol Chem,2010,285:26114-26120
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32 Cao L L,Wei F,Du Y,et al.ATM-mediated KDM2A phosphorylation is required for the DNA damage repair.Oncogene,2016,35:402
33 Huyen Y,Zgheib O,Ditullio R J,et al.Methylated lysine 79 of histone H3 targets 53BP1 to DNA double-strand breaks.Nature,2004,432:406-411
34 Zhang Y,Jurkowska R,Soeroes S,et al.Chromatin methylation activity of Dnmt3a and Dnmt3a/3L is guided by interaction of the add domain with the histone H3 tail.Nucleic Acids Res,2010,38:4246-4253
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