Structure-Based Analysis Reveals Cancer Missense Mutations Target Protein Interaction Interfaces

Abstract

Recently it has been shown that cancer mutations selectively target protein-protein interactions. We hypothesized that mutations affecting distinct protein interactions involving established cancer genes could contribute to tumor heterogeneity, and that novel mechanistic insights might be gained into tumorigenesis by investigating protein interactions under positive selection in cancer. To identify protein interactions under positive selection in cancer, we mapped over 1.2 million nonsynonymous somatic cancer mutations onto 4,896 experimentally determined protein structures and analyzed their spatial distribution. In total, 20% of mutations on the surface of known cancer genes perturbed protein-protein interactions (PPIs), and this enrichment for PPI interfaces was observed for both tumor suppressors (Odds Ratio 1.28, P-value < 10−4) and oncogenes (Odds Ratio 1.17, P-value < 10−3). To study this further, we constructed a bipartite network representing structurally resolved PPIs from all available human complexes in the Protein Data Bank (2,864 proteins, 3,072 PPIs). Analysis of frequently mutated cancer genes within this network revealed that tumor-suppressors, but not oncogenes, are significantly enriched with functional mutations in homo-oligomerization regions (Odds Ratio 3.68, P-Value < 10−8). We present two important examples, TP53 and beta-2-microglobulin, for which the patterns of somatic mutations at interfaces provide insights into specifically perturbed biological circuits. In patients with TP53 mutations, patient survival correlated with the specific interactions that were perturbed. Moreover, we investigated mutations at the interface of protein-nucleotide interactions and observed an unexpected number of missense mutations but not silent mutations occurring within DNA and RNA binding sites. Finally, we provide a resource of 3,072 PPI interfaces ranked according to their mutation rates. Analysis of this list highlights 282 novel candidate cancer genes that encode proteins participating in interactions that are perturbed recurrently across tumors. In summary, mutation of specific protein interactions is an important contributor to tumor heterogeneity and may have important implications for clinical outcomes.

3D clusters of somatic mutations in cancer reveal numerous rare mutations as functional targets

“…Wang et al [11] generated a structurally solved interactome to study genetic diseases. Porta-Pardo et al [12] and Engin et al [13] used 3D structures to detect protein-protein interaction interfaces that are enriched with cancer mutations. Clustering of mutations in protein structures (CLUMPS) [14] used 3D clustering of mutations to detect cancer genes and also studied enrichment of mutations in protein-protein interaction interfaces.…”

A resource of variant effect predictions of single nucleotide variants in model organisms

“…For instance, noncoding variants can affect chromatin accessibility (Kumasaka et al , ), splice sites (Xiong et al , ) and epigenetic modifications (Rintisch et al , ). Coding variants can affect post‐translational modification (PTM) sites (Reimand et al , ; Wagih et al , ), protein folding and stability (Lorch et al , ), protein interaction interfaces (Engin et al , ) and subcellular localization (Björses et al , ), and introduce premature stop codons. Understanding the disrupted biological mechanisms underlying genetic variation is key to many applications in genetics such as genetically engineering organisms, assessing drug efficacy and drug discovery (Labaudinière, ; Lutz, ; Nelson et al , ).…”

Protein dynamics analysis reveals that missense mutations in cancer‐related genes appear frequently on hinge‐neighboring residues

“…One recent study revealed that missense mutations form clusters in various regions of the structure including protein interaction interfaces . The interaction interfaces of oncoproteins and tumor suppressors were also significantly enriched by cancer somatic missense mutations . Likewise, mutations can also be enriched on functional sites.…”

“…9 The interaction interfaces of oncoproteins and tumor suppressors were also significantly enriched by cancer somatic missense mutations. 10 Likewise, mutations can also be enriched on functional sites. For example, ATP-and GTP-binding sites in oncoproteins significantly harbor missense mutations.…”