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首页> 美国卫生研究院文献>Frontiers in Physiology >Research Topic: From structural to molecular systems biology: experimental and computational approaches to unravel mechanisms of kinase activity regulation in cancer and neurodegeneration: A comparative study of Whi5 and retinoblastoma proteins: from sequence and structure analysis to intracellular networks
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Research Topic: From structural to molecular systems biology: experimental and computational approaches to unravel mechanisms of kinase activity regulation in cancer and neurodegeneration: A comparative study of Whi5 and retinoblastoma proteins: from sequence and structure analysis to intracellular networks

机译：研究主题：从结构生物学到分子生物学：揭示癌症和神经变性中激酶活性调节机制的实验和计算方法：Whi5和成视网膜细胞瘤蛋白的比较研究：从序列和结构分析到细胞内网络

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Cell growth and proliferation require a complex series of tight-regulated and well-orchestrated events. Accordingly, proteins governing such events are evolutionary conserved, even among distant organisms. By contrast, it is more singular the case of “core functions” exerted by functional analogous proteins that are not homologous and do not share any kind of structural similarity. This is the case of proteins regulating the G1/S transition in higher eukaryotes–i.e., the retinoblastoma (Rb) tumor suppressor Rb—and budding yeast, i.e., Whi5. The interaction landscape of Rb and Whi5 is quite large, with more than one hundred proteins interacting either genetically or physically with each protein. The Whi5 interactome has been used to construct a concept map of Whi5 function and regulation. Comparison of physical and genetic interactors of Rb and Whi5 allows highlighting a significant core of conserved, common functionalities associated with the interactors indicating that structure and function of the network—rather than individual proteins—are conserved during evolution. A combined bioinformatics and biochemical approach has shown that the whole Whi5 protein is highly disordered, except for a small region containing the protein family signature. The comparison with Whi5 homologs from Saccharomycetales has prompted the hypothesis of a modular organization of structural disorder, with most evolutionary conserved regions alternating with highly variable ones. The finding of a consensus sequence points to the conservation of a specific phosphorylation rhythm along with two disordered sequence motifs, probably acting as phosphorylation-dependent seeds in Whi5 folding/unfolding. Thus, the widely disordered Whi5 appears to act as a hierarchical, “date hub” that has evolutionary assayed an original way of modular organization before being supplanted by the globular, multi-domain structured Rb, more suitable to cover the role of a “party hub”.
机译：细胞生长和增殖需要一系列严格调控和精心策划的事件。因此，即使在遥远的生物体中，控制此类事件的蛋白质在进化上也是保守的。相比之下，功能相似的蛋白质所发挥的“核心功能”更为单一，这些功能相似的蛋白质不具有同源性且不具有任何类型的结构相似性。这种情况是蛋白质调节高等真核生物（即成视网膜细胞瘤（Rb）肿瘤抑制因子Rb）和发芽酵母（即Whi5）中G1 / S过渡的情况。 Rb和Whi5的相互作用非常大，有一百多种蛋白质通过遗传或物理方式与每种蛋白质相互作用。 Whi5交互基因组已用于构建Whi5功能和调控的概念图。比较Rb和Whi5的物理和遗传相互作用因子可以突出显示与相互作用因子相关的保守，共有功能的重要核心，表明进化过程中网络的结构和功能（而不是单个蛋白质）是保守的。生物信息学和生化方法相结合的结果表明，整个Whi5蛋白高度杂乱，只有一个小区域含有该蛋白家族的标志。与来自酿酒酵母的Whi5同源物的比较提出了结构紊乱的模块化组织的假说，大多数进化保守区与高度可变区交替出现。共有序列的发现指出特定的磷酸化节奏以及两个无序的序列基序的保守，这可能是Whi5折叠/展开中依赖于磷酸化的种子。因此，无序分布的Whi5似乎起着分层的“数据中心”的作用，在被球形，多域结构的Rb取代之前，已经进化了一种原始的模块化组织方式，该方法更适合于覆盖“派对”的角色。毂”。

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