Abstract
Missense mutations are known to perturb protein-protein interaction networks (known as interactome networks) in different ways. However, it remains unknown how different interactome perturbation patterns (“edgotypes”) impact organismal fitness. Here, we estimate the fitness effect of missense mutations with different interactome perturbation patterns in human, by calculating the fractions of neutral and deleterious mutations that do not disrupt PPIs (“quasi-wild-type”), or disrupt PPIs either by disrupting the binding interface (“edgetic”) or by disrupting overall protein stability (“quasi-null”). We first map pathogenic mutations and common non-pathogenic mutations onto homology-based three-dimensional structural models of proteins and protein-protein interactions in human. Next, we perform structure-based calculations to classify each mutation as either quasi-wild-type, edgetic, or quasi-null. Using our predicted as well as experimentally determined interactome perturbation patterns, we estimate that >∼40% of quasi-wild-type mutations are effectively neutral and the remaining are mostly mildly deleterious, that >∼75% of edgetic mutations are only mildly deleterious, and that up to ∼75% of quasi-null mutations may be strongly detrimental. These estimates are the first such estimates of fitness effect for different network perturbation patterns in any interactome. Our results suggest that while mutations that do not disrupt the interactome tend to be effectively neutral, the majority of human PPIs are under strong purifying selection and the stability of most human proteins is essential to human life.
Highlights
Protein-protein interactions (PPIs) form a central component of the cellular circuitry, which determines and controls complex cellular functions, along with other biomolecular interactions (Cafarelli et al, 2017)
We obtained two human structural interactomes with PPI binding interfaces annotated at the residue level: the Y2H structural interactome (Y2H-SI) consisting of 1,916 PPIs among 1,468 proteins (Supplementary Data Sheet S1A,S1B), and the literaturederived structural interactome (Lit-SI) consisting of 4,676 PPIs among 3,445 proteins (Supplementary Data Sheet S1C,S1D)
We found that non-pathogenic mutations tend to have higher relative solvent accessibility (RSA) compared to all protein residues (p 5.6 × 10−22, two-sided t-test; Figures 2A,B; Supplementary Data Sheet S2A), whereas pathogenic mutations tend to have lower RSA compared to all protein residues (p 3 × 10−14, two-sided t-test; Figures 2A,B; Supplementary Data Sheet S2B)
Summary
Protein-protein interactions (PPIs) form a central component of the cellular circuitry, which determines and controls complex cellular functions, along with other biomolecular interactions (Cafarelli et al, 2017). While the vast majority (∼92%) of non-pathogenic mutations do not disrupt the interactome (“quasi-wild-type” mutations), the majority (∼57%) of pathogenic mutations disrupt the interactome, either by disrupting the binding interface (“edgetic” mutations) or by disrupting overall protein stability (“quasinull” mutations) (Sahni et al, 2015) Using these experimentally determined mutation edgotypes as well as mutation edgotypes determined by structure-based predictions, we recently estimated that
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