Abstract
Protein-protein interaction (PPI) networks (interactome networks) have successfully advanced our knowledge of molecular function, disease and evolution. While much progress has been made in quantifying errors and biases in experimental PPI datasets, it remains unknown what fraction of the error-free PPIs in the cell are completely dispensable, i.e., effectively neutral upon disruption. Here, we estimate dispensable content in the human interactome by calculating the fractions of PPIs disrupted by neutral and non-neutral mutations. Starting with the human reference interactome determined by experiments, we construct a human structural interactome by building homology-based three-dimensional structural models for PPIs. Next, we map common mutations from healthy individuals as well as Mendelian disease-causing mutations onto the human structural interactome, and perform structure-based calculations of how these mutations perturb the interactome. Using our predicted as well as experimentally-determined interactome perturbation patterns by common and disease mutations, we estimate that <~20% of the human interactome is completely dispensable.
Highlights
Protein-protein interaction (PPI) networks have successfully advanced our knowledge of molecular function, disease and evolution
We started with two high-quality, experimentally determined human reference interactomes: the HI-II-14 interactome[43] consisting of PPIs identified in yeast two-hybrid (Y2H) screens, and the IntAct interactome consisting of PPIs reported in the IntAct database[44] by at least two independent experiments in the literature
We obtained two high-resolution human structural interactomes: the HI-II-14 structural interactome (Y2H-SI) consisting of 486 PPIs among 573 proteins with their binding interfaces resolved at the residue level (Supplementary Data 1a and 2a), and the IntAct structural interactome (IntAct-SI) consisting of 3333 PPIs among 2654 proteins with their binding interfaces resolved at the residue level (Supplementary Data 1b and 2b)
Summary
Protein-protein interaction (PPI) networks (interactome networks) have successfully advanced our knowledge of molecular function, disease and evolution. While much progress has been made in quantifying errors and biases in experimental PPI datasets, it remains unknown what fraction of the error-free PPIs in the cell are completely dispensable, i.e., effectively neutral upon disruption. Significant progress has been made toward mapping interactome networks for several species including human[1,2] These networks have been highly successful in providing insights into molecular function[3,4], disease[1,5,6,7,8], and evolution[9,10,11,12,13]. While much work has been done in quantifying errors and biases in experimental PPI datasets[14,15,16], it remains unknown what fraction of the error-free PPIs in the cell are completely dispensable, i.e., effectively neutral upon disruption.
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