Topology of protein interaction network shapes protein abundances and strengths of their functional and nonspecific interactions
Topology of protein interaction network shapes protein abundances and strengths of their functional and nonspecific interactions
复制标题
DOI：
10.1073/pnas.1009392108
复制
发表时间：
2011-03-08
影响因子：
11.1
通讯作者：
Shakhnovich, Eugene
中科院分区：
文献类型：
--
作者：
Heo, Muyoung;Maslov, Sergei;Shakhnovich, Eugene
活细胞是如何获得足够丰富的功能性蛋白质复合物，同时最大限度地减少混杂的非功能性相互作用的？在这里，我们研究这个问题，使用第一原理模型的细胞，其表型性状直接从其基因组通过生物物理特性的蛋白质结构和结合在拥挤的细胞环境中的相互作用。模型细胞包括三个独立的原型通路，其蛋白质-蛋白质相互作用（PPI）子网络的拓扑结构不同，但其对细胞适应度的贡献是相等的。模型细胞通过基因型突变和表型蛋白质拷贝数变化进化。我们发现蛋白质相互作用的进化物理化学性质与其丰度之间存在很强的关系，这是由于“挫折”效应：功能相互作用的加强带来了疏水界面，这使得蛋白质易于混杂结合。平衡作用通过降低中心蛋白的浓度同时提高功能单体的溶解度和丰度来实现。在这些原则的基础上，我们生成并分析了一个可能实现的蛋白质组范围的PPI网络在酵母中。在这个模拟中，我们发现，高通量亲和捕获质谱实验可以检测功能的相互作用，只有高丰度的蛋白质，而低丰度的蛋白质的大部分相互作用的高保真度。
How do living cells achieve sufficient abundances of functional protein complexes while minimizing promiscuous nonfunctional interactions? Here we study this problem using a first-principle model of the cell whose phenotypic traits are directly determined from its genome through biophysical properties of protein structures and binding interactions in a crowded cellular environment. The model cell includes three independent prototypical pathways, whose topologies of protein-protein interaction (PPI) subnetworks are different, but whose contributions to the cell fitness are equal. Model cells evolve through genotypic mutations and phenotypic protein copy number variations. We found a strong relationship between evolved physical-chemical properties of protein interactions and their abundances due to a "frustration" effect: Strengthening of functional interactions brings about hydrophobic interfaces, which make proteins prone to promiscuous binding. The balancing act is achieved by lowering concentrations of hub proteins while raising solubilities and abundances of functional monomers. On the basis of these principles we generated and analyzed a possible realization of the proteome-wide PPI network in yeast. In this simulation we found that high-throughput affinity capture-mass spectroscopy experiments can detect functional interactions with high fidelity only for high-abundance proteins while missing most interactions for low-abundance proteins.