Centre for High-Throughput Biology, University of British Columbia, East Mall, Vancouver, Canada.
PLoS Comput Biol. 2013;9(8):e1003192. doi: 10.1371/journal.pcbi.1003192. Epub 2013 Aug 22.
There is a growing recognition for the importance of proteins with large intrinsically disordered (ID) segments in cell signaling and regulation. ID segments in these proteins often harbor regions that mediate molecular recognition. Coupled folding and binding of the recognition regions has been proposed to confer high specificity to interactions involving ID segments. However, researchers recently questioned the origin of the interaction specificity of ID proteins because of the overrepresentation of hydrophobic residues in their interaction interfaces. Here, we focused on the role of polar and charged residues in interactions mediated by ID segments. Making use of the extended nature of most ID segments when in complex with globular proteins, we first identified large numbers of complexes between globular proteins and ID segments by using radius-of-gyration-based selection criteria. Consistent with previous studies, we found the interfaces of these complexes to be enriched in hydrophobic residues, and that these residues contribute significantly to the stability of the interaction interface. However, our analyses also show that polar interactions play a larger role in these complexes than in structured protein complexes. Computational alanine scanning and salt-bridge analysis indicate that interfaces in ID complexes are highly complementary with respect to electrostatics, more so than interfaces of globular proteins. Follow-up calculations of the electrostatic contributions to the free energy of binding uncovered significantly stronger Coulombic interactions in complexes harbouring ID segments than in structured protein complexes. However, they are counter-balanced by even higher polar-desolvation penalties. We propose that polar interactions are a key contributing factor to the observed high specificity of ID segment-mediated interactions.
越来越多的人认识到，具有大的固有无序（ID）片段的蛋白质在细胞信号转导和调控中非常重要。这些蛋白质中的 ID 片段通常包含介导分子识别的区域。折叠和结合识别区域的偶联被认为赋予了涉及 ID 片段的相互作用的高特异性。然而，由于 ID 蛋白质的相互作用界面中存在大量疏水性残基，研究人员最近对 ID 蛋白质相互作用特异性的起源提出了质疑。在这里，我们专注于 ID 片段介导的相互作用中极性和带电残基的作用。利用 ID 片段与球状蛋白质复合时的伸展性质，我们首先使用基于旋转半径的选择标准，确定了大量球状蛋白质和 ID 片段之间的复合物。与先前的研究一致，我们发现这些复合物的界面富含疏水性残基，这些残基对相互作用界面的稳定性有重要贡献。然而，我们的分析还表明，极性相互作用在这些复合物中比在结构蛋白复合物中起着更大的作用。计算性丙氨酸扫描和盐桥分析表明，ID 复合物的界面在静电方面非常互补，比球状蛋白质的界面更互补。对结合自由能的静电贡献的后续计算表明，含有 ID 片段的复合物比结构蛋白复合物具有更强的库仑相互作用。然而，它们被更高的极性去溶剂化惩罚所抵消。我们提出，极性相互作用是观察到的 ID 片段介导的相互作用高特异性的关键因素。
