Why do hubs tend to be essential in protein networks?
Why do hubs tend to be essential in protein networks?
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DOI：
10.1371/journal.pgen.0020088
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发表时间：
2006-06-02
期刊：
影响因子：
4.5
通讯作者：
Zhang J
中科院分区：
文献类型：
--
作者：
He X;Zhang J
蛋白质-蛋白质相互作用（PPI）网络有少量高度连接的蛋白质节点（称为枢纽）和许多连接不良的节点。全基因组研究表明，中心蛋白的缺失比非中心蛋白的缺失更有可能是致命的，这种现象被称为中心致死规则。人们普遍认为这一规则反映了枢纽在组织网络中的特殊重要性，这反过来又表明了网络结构的生物学意义，这是系统生物学的一个关键概念。尽管这一解释很受欢迎，但中心性-致命性规则的根本原因从未被批判性地研究过。我们在这里提出了必需PPI的概念，即生物体生存或繁殖所必需的PPI。我们的网络分析表明，中心性-致命性规则与网络架构无关，但可以用一个简单的事实来解释，即枢纽节点有大量的PPI，因此参与基本PPI的概率很高。我们估计约3%的PPI是酵母中必需的，约占必需基因的43%。正如预期的那样，必需PPI在进化上比非必需PPI更保守。考虑到必需PPI在确定基因重要性方面的作用，我们发现酵母PPI网络在功能上比随机网络更强大，但远不如潜在的最佳。这些发现和其他发现为网络结构和鲁棒性的生物相关性提供了新的视角。蛋白质及其相互作用形成蛋白质-蛋白质相互作用网络，其中蛋白质是节点，相互作用是边缘。基因组研究表明，删除一个高度连接的蛋白质节点（枢纽）比删除一个低连接的节点（非枢纽）更有可能对生物体造成致命影响，这种现象被称为中心性-致命性规则。由于枢纽在组织全球网络结构方面比非枢纽更重要，因此中心性-致命性规则被广泛认为反映了网络结构在决定网络功能方面的重要性，这是系统生物学的一个关键概念。在这项工作中，作者提出了一小部分随机分布的基本相互作用，每一种相互作用在被破坏时对生物体都是致命的。在这种情况下，枢纽比非枢纽更有可能是必不可少的，因为枢纽有更多的交互，因此参与必不可少的交互的机会更高。因此，在没有网络架构的参与下解释了中心性-致命性规则。使用酵母数据，作者提供了支持他们假设的经验证据。他们的建议和结果挑战了系统生物学的主流观点，并为网络结构在生物学中的作用提供了新的视角。
The protein–protein interaction (PPI) network has a small number of highly connected protein nodes (known as hubs) and many poorly connected nodes. Genome-wide studies show that deletion of a hub protein is more likely to be lethal than deletion of a non-hub protein, a phenomenon known as the centrality-lethality rule. This rule is widely believed to reflect the special importance of hubs in organizing the network, which in turn suggests the biological significance of network architectures, a key notion of systems biology. Despite the popularity of this explanation, the underlying cause of the centrality-lethality rule has never been critically examined. We here propose the concept of essential PPIs, which are PPIs that are indispensable for the survival or reproduction of an organism. Our network analysis suggests that the centrality-lethality rule is unrelated to the network architecture, but is explained by the simple fact that hubs have large numbers of PPIs, therefore high probabilities of engaging in essential PPIs. We estimate that ~ 3% of PPIs are essential in the yeast, accounting for ~ 43% of essential genes. As expected, essential PPIs are evolutionarily more conserved than nonessential PPIs. Considering the role of essential PPIs in determining gene essentiality, we find the yeast PPI network functionally more robust than random networks, yet far less robust than the potential optimum. These and other findings provide new perspectives on the biological relevance of network structure and robustness. Proteins and their interactions form a protein–protein interaction network, where the proteins are the nodes and the interactions are the edges. Genomic studies show that deleting a highly connected protein node (hub) is more likely to be lethal to an organism than deleting a lowly connected node (non-hub), a phenomenon known as the centrality-lethality rule. Because hubs are more important than non-hubs in organizing the global network structure, the centrality-lethality rule is widely believed to reflect the significance of network architecture in determining network function, a key notion of systems biology. In this work, the authors proposed a small fraction of randomly distributed essential interactions, each of which is lethal to an organism when disrupted. Under this scenario, a hub is more likely to be essential than a non-hub simply because the hub has more interactions and thus a higher chance to engage in an essential interaction. Hence, the centrality-lethality rule is explained without the involvement of network architecture. Using yeast data, the authors provided empirical evidence supporting their hypothesis. Their proposal and results challenge a prevailing view in systems biology and provide a new perspective on the role of network structures in biology.
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