Lessons in Protein Design from Combined Evolution and Conformational Dynamics.
Lessons in Protein Design from Combined Evolution and Conformational Dynamics.
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DOI：
10.1038/srep14259
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发表时间：
2015-09-21
影响因子：
4.6
通讯作者：
Liu Y
中科院分区：
文献类型：
--
作者：
Tripathi S;Waxham MN;Cheung MS;Liu Y
蛋白质与蛋白质之间的相互作用在控制每一个细胞过程中起着重要的作用。自然选择如何优化蛋白质设计以产生能够与许多伴侣蛋白质结合的分子是一个令人着迷的问题，但尚未得到很好的理解。在这里，我们进行了蛋白质序列进化和构象动力学的组合分析，以研究钙调蛋白（CaM）是如何适应与大量伴侣蛋白结合的，CaM在钙信号通路中起重要作用。我们发现CaM中的氨基酸残基可以根据它们的进化保守程度和局部稳定性划分成独特的类。总体而言，CaM残基的分类揭示了与不同靶标结合所需的丰富的物理化学相互作用，平衡了保持CaM的折叠和结构模块化以实现其整体功能的需要。CaM的序列-结构-功能关系为蛋白质设计的一般原理提供了一个具体的例子。我们已经证明了分子进化和蛋白质生物物理学领域之间的协同作用，并创建了一个广泛适用于蛋白质-蛋白质相互作用研究的可推广框架。
Protein-protein interactions play important roles in the control of every cellular process. How natural selection has optimized protein design to produce molecules capable of binding to many partner proteins is a fascinating problem but not well understood. Here, we performed a combinatorial analysis of protein sequence evolution and conformational dynamics to study how calmodulin (CaM), which plays essential roles in calcium signaling pathways, has adapted to bind to a large number of partner proteins. We discovered that amino acid residues in CaM can be partitioned into unique classes according to their degree of evolutionary conservation and local stability. Holistically, categorization of CaM residues into these classes reveals enriched physico-chemical interactions required for binding to diverse targets, balanced against the need to maintain the folding and structural modularity of CaM to achieve its overall function. The sequence-structure-function relationship of CaM provides a concrete example of the general principle of protein design. We have demonstrated the synergy between the fields of molecular evolution and protein biophysics and created a generalizable framework broadly applicable to the study of protein-protein interactions.