Center for Computational Biology and Bioinformatics, College of Engineering, Koc University, Rumelifeneri Yolu, Sariyer, Istanbul, Turkey.
Semin Cancer Biol. 2013 Aug;23(4):243-51. doi: 10.1016/j.semcancer.2013.05.003. Epub 2013 May 24.
Inflammation, the first line of defense against pathogens can contribute to all phases of tumorigenesis, including tumor initiation, promotion and metastasis. Within this framework, the Toll-like receptor (TLR) pathway plays a central role in inflammation and cancer. Although extremely useful, the classical representation of this, and other pathways in the cellular network in terms of nodes (proteins) and edges (interactions) is incomplete. Structural pathways can help complete missing parts of such diagrams: they demonstrate in detail how signals coming from different upstream pathways merge and propagate downstream, how parallel pathways compensate each other in drug resistant mutants, how multi-subunit signaling complexes form and in particular why they are needed and how they work, how allosteric events can control these proteins and their pathways, and intricate details of feedback loops and how kick in. They can also explain the mechanisms of some oncogenic SNP mutations. Constructing structural pathways is a challenging task. Here, our goal is to provide an overview of inflammation and cancer from the structural standpoint, focusing on the TLR pathway. We use the powerful PRISM (PRotein Interactions by Structural Matching) tool to reveal important structural information of interactions in and within key orchestrators of the TLR pathway, such as MyD88.
炎症是抵御病原体的第一道防线，它可以促进肿瘤发生的所有阶段，包括肿瘤起始、促进和转移。在这个框架内，Toll 样受体 (TLR) 途径在炎症和癌症中起着核心作用。尽管非常有用，但这种途径以及细胞网络中的其他途径在节点（蛋白质）和边（相互作用）方面的经典表示并不完整。结构途径可以帮助完成这些图中缺失的部分：它们详细展示了来自不同上游途径的信号如何在下游合并和传播，平行途径如何在耐药突变体中相互补偿，多亚基信号复合物如何形成，特别是它们为什么需要以及如何工作，变构事件如何控制这些蛋白质及其途径，以及反馈回路的复杂细节以及它们是如何启动的。它们还可以解释一些致癌 SNP 突变的机制。构建结构途径是一项具有挑战性的任务。在这里，我们的目标是从结构角度概述炎症和癌症，重点介绍 TLR 途径。我们使用强大的 PRISM（基于结构匹配的蛋白质相互作用）工具来揭示 TLR 途径中关键协调因子（如 MyD88）内和内的相互作用的重要结构信息。
