Grigoryan Gevorg, Reinke Aaron W, Keating Amy E
MIT Department of Biology, 77 Massachusetts Avenue, Cambridge, Massachusetts 02139, USA.
Nature. 2009 Apr 16;458(7240):859-64. doi: 10.1038/nature07885.
Interaction specificity is a required feature of biological networks and a necessary characteristic of protein or small-molecule reagents and therapeutics. The ability to alter or inhibit protein interactions selectively would advance basic and applied molecular science. Assessing or modelling interaction specificity requires treating multiple competing complexes, which presents computational and experimental challenges. Here we present a computational framework for designing protein-interaction specificity and use it to identify specific peptide partners for human basic-region leucine zipper (bZIP) transcription factors. Protein microarrays were used to characterize designed, synthetic ligands for all but one of 20 bZIP families. The bZIP proteins share strong sequence and structural similarities and thus are challenging targets to bind specifically. Nevertheless, many of the designs, including examples that bind the oncoproteins c-Jun, c-Fos and c-Maf (also called JUN, FOS and MAF, respectively), were selective for their targets over all 19 other families. Collectively, the designs exhibit a wide range of interaction profiles and demonstrate that human bZIPs have only sparsely sampled the possible interaction space accessible to them. Our computational method provides a way to systematically analyse trade-offs between stability and specificity and is suitable for use with many types of structure-scoring functions; thus, it may prove broadly useful as a tool for protein design.
相互作用特异性是生物网络的一个必要特征,也是蛋白质或小分子试剂及治疗药物的一个必备特性。选择性改变或抑制蛋白质相互作用的能力将推动基础和应用分子科学的发展。评估或模拟相互作用特异性需要处理多个相互竞争的复合物,这带来了计算和实验方面的挑战。在此,我们提出了一个用于设计蛋白质相互作用特异性的计算框架,并利用它来识别人类碱性区域亮氨酸拉链(bZIP)转录因子的特异性肽伴侣。蛋白质微阵列被用于表征20个bZIP家族中除一个家族外的所有设计合成配体。bZIP蛋白具有很强的序列和结构相似性,因此是特异性结合的挑战性靶点。尽管如此,许多设计,包括那些与癌蛋白c-Jun、c-Fos和c-Maf(分别也称为JUN、FOS和MAF)结合的例子,对其靶点的选择性高于所有其他19个家族。总体而言,这些设计展现出广泛的相互作用谱,并表明人类bZIP蛋白仅稀疏地占据了它们可及的可能相互作用空间。我们的计算方法提供了一种系统分析稳定性和特异性之间权衡的方法,适用于多种类型的结构评分函数;因此,它可能被证明是一种广泛有用的蛋白质设计工具。