Shu Jianping, Li Juelin, Wang Shaozhou, Lin Jing, Wen Li, Ye Haiyang, Zhou Peng
Center for Informational Biology, School of Life Science and Technology, University of Electronic Science and Technology of China (UESTC), Chengdu, China.
J Mol Recognit. 2023 Mar;36(3):e3006. doi: 10.1002/jmr.3006. Epub 2023 Jan 17.
Protein-peptide interactions (PpIs) play an important role in cell signaling networks and have been exploited as new and attractive therapeutic targets. The affinity and specificity are two unity-of-opposite aspects of PpIs (and other biomolecular interactions); the former indicates the absolute binding strength between the peptide ligand and its cognate protein receptor in a PpI, while the latter represents the relative recognition selectivity of the peptide ligand for its cognate protein receptor in a PpI over those noncognate decoys that could be potentially encountered by the peptide in cell. Although the PpI binding affinity has been widely investigated over the past decades, the peptide recognition specificity (and selectivity) still remains largely unexplored to date. In this study, we classified PpI specificity into three types: (i) class-I specificity: peptide selectivity for its cognate wild-type protein receptor over the noncognate mutant decoys of this receptor, (ii) class-II specificity: peptide selectivity for its cognate protein receptor over other noncognate decoys that are homologous with this receptor, and (iii) class-III specificity: peptide selectivity for its cognate protein receptor over other noncognate decoys that are the cognate receptors of other peptides. We performed affinity and selectivity analysis for the three types of PpI specificity and revealed that the PpIs generally exhibit a moderate or modest specificity; peptide selectivity increases in the order: class-I < class-II < class-III. All the three types of PpI specificity were observed to have no statistically significant correlation with peptide length and hydrophobicity, but the class-I and class-II specificities can be influenced considerably by peptide secondary structures; the high specificity is preferentially associated with ordered structure types as compared to undefined structure types. In addition, the mutation distribution (for class-I specificity), sequence conservation (for class-II specificity), and structural similarity (for class-III specificity) seem also to address effects on peptide selectivity.
蛋白质 - 肽相互作用（PpIs）在细胞信号网络中发挥着重要作用，并且已被开发为新的、具有吸引力的治疗靶点。亲和力和特异性是PpIs（以及其他生物分子相互作用）的两个对立统一的方面；前者表示肽配体与其在PpI中的同源蛋白受体之间的绝对结合强度，而后者表示肽配体在PpI中对其同源蛋白受体相对于该肽在细胞中可能遇到的那些非同源诱饵的相对识别选择性。尽管在过去几十年中对PpI结合亲和力进行了广泛研究，但肽识别特异性（和选择性）迄今为止在很大程度上仍未得到探索。在本研究中，我们将PpI特异性分为三种类型：（i）I类特异性：肽对其同源野生型蛋白受体相对于该受体的非同源突变诱饵的选择性，（ii）II类特异性：肽对其同源蛋白受体相对于与该受体同源的其他非同源诱饵的选择性，以及（iii）III类特异性：肽对其同源蛋白受体相对于其他肽的同源受体的其他非同源诱饵的选择性。我们对三种类型的PpI特异性进行了亲和力和选择性分析，结果表明PpIs通常表现出中等或适度的特异性；肽选择性按以下顺序增加：I类 < II类 < III类。观察到所有三种类型的PpI特异性与肽长度和疏水性均无统计学上的显著相关性，但I类和II类特异性会受到肽二级结构的显著影响；与未定义结构类型相比, 高特异性优先与有序结构类型相关。此外，突变分布（对于I类特异性）、序列保守性（对于II类特异性）和结构相似性（对于III类特异性）似乎也对肽选择性有影响。
