生命系统复杂性最重要的特征不仅在于其组成成分的复杂性，更在于各组成成分之间的关系，而在所有的这些关系中，蛋白质之间的相互作用在形成几乎所有生命系统、调控各种生理/病理进程中发挥至关重要的作用。近来，人们发展了许多高通量的实验方法，并以此发现、建立了越来越多的蛋白质相互作用网络。但是，现有的蛋白质相互作用网络只能反映蛋白质之间存在连接关系，而真实生命体系中大部分的蛋白质相互作用具有信号转导、转录激活/抑制等明显的信号流方向性。准确、高效、大规模预测蛋白质相互作用网络中相互作用的信号流方向、发现潜在的信号转导通路，为众多领域的生物科学工作者所期待，但一直是未能破解的世界性难题。
北京蛋白质组研究中心朱云平研究员、贺福初院士课题组刘伟博士等第一次提出蛋白质间结构域的相互作用在一定程度上决定了它们之间的信号流走向的假设；进而基于这个假设发展了一种新的理论方法来预测蛋白质组网络中信号流的方向性，并被成功地用于网络中未知信号转导通路的规模化挖掘。该方法不需要其它任何先验知识，仅根据蛋白质中包含的结构域就可以快速地推断出相互作用蛋白质间的信号流方向、系统地发掘出蛋白质组网络中潜在的大量信号通路。该方法应用范围广泛，其预测结果可为实验研究提供重要的研究线索。该方法已被成功地用于大规模预测和揭示人类蛋白质组成员间相互作用的信号流方向，并构建第一个具有明确作用方向的人蛋白质组相互作用网络，揭示了大量未知的信号转导通路。它们将为人们理解生命系统中的信息网络等重要理论问题提供全新的视野。相关工作近期在线发表于《分子与细胞蛋白质组学》。（生物谷Bioon.com）
生物谷推荐原始出处：
Mol. Cell. Proteomics, Jun 2009; doi:10.1074/mcp.M800354-MCP200
Proteome-wide prediction of signal flow direction in protein interaction networks based on interacting domains
Wei Liu, Dong Li, Jian Wang, Hongwei Xie, Yunping Zhu, and Fuchu He
1 the State Key Laboratory of Proteomics, Beijing Proteome Research Center, Beijing Institute of Radiation Medicine, Beijing, Changping 102206
Signal flow direction is one of the most important features of the protein-protein interactions (PPIs) in signalling networks. However, almost all the outcomes of current high-throughout techniques for PPI mapping are usually supposed to be non-directional. Based on the pairwise interaction domains, here we defined a novel parameter Protein Interaction Directional Score (PIDS) and then used it to predict the direction of signal flow between proteins in proteome-wide signaling networks. Using 5-fold cross-validation, our approach obtained a satisfied performance with the accuracy 89.79%, coverage 48.08% and error ratio 16.91%. As an application, we established an integrated human Directional Protein Interaction Network (DPIN), including 2,237 proteins and 5,530 interactions, and inferred a large amount of novel signaling pathways. DPIN was strongly supported by the known signaling pathways literature (with the 87.5% accuracy), and further analyses on the biological annotation, subcellular localization and network topology property. Thus, this study provided an effective method to define the upstream/downstream relations of interacting protein pairs, and a powerful tool to unravel the unknown signaling pathways.
