Department of Bioengineering, McGill University, Montreal, Canada.
PLoS Comput Biol. 2022 Apr 11;18(4):e1010013. doi: 10.1371/journal.pcbi.1010013. eCollection 2022 Apr.
Protein-protein interactions (PPIs) are key drivers of cell function and evolution. While it is widely assumed that most permanent PPIs are important for cellular function, it remains unclear whether transient PPIs are equally important. Here, we estimate and compare dispensable content among transient PPIs and permanent PPIs in human. Starting with a human reference interactome mapped by experiments, we construct a human structural interactome by building three-dimensional structural models for PPIs, and then distinguish transient PPIs from permanent PPIs using several structural and biophysical properties. We map common mutations from healthy individuals and disease-causing mutations onto the structural interactome, and perform structure-based calculations of the probabilities for common mutations (assumed to be neutral) and disease mutations (assumed to be mildly deleterious) to disrupt transient PPIs and permanent PPIs. Using Bayes' theorem we estimate that a similarly small fraction (<~20%) of both transient and permanent PPIs are completely dispensable, i.e., effectively neutral upon disruption. Hence, transient and permanent interactions are subject to similarly strong selective constraints in the human interactome.
蛋白质-蛋白质相互作用（PPIs）是细胞功能和进化的关键驱动因素。虽然人们普遍认为大多数永久性 PPI 对于细胞功能很重要，但目前尚不清楚瞬时 PPI 是否同样重要。在这里，我们估计并比较了人类中瞬时 PPI 和永久性 PPI 之间的可分配内容。从实验映射的人类参考相互作用组开始，我们通过构建 PPI 的三维结构模型构建人类结构相互作用组，然后使用几种结构和生物物理特性将瞬时 PPI 与永久性 PPI 区分开来。我们将来自健康个体的常见突变和致病突变映射到结构相互作用组上，并对常见突变（假定为中性）和疾病突变（假定为轻度有害）破坏瞬时 PPI 和永久性 PPI 的概率进行基于结构的计算。使用贝叶斯定理，我们估计瞬时 PPI 和永久性 PPI 中同样很小的一部分（<~20%）是完全可分配的，即破坏后实际上是中性的。因此，瞬时和永久性相互作用在人类相互作用组中受到类似的强选择约束。
