Comprehensive characterization of protein–protein interactions perturbed by disease mutations

Feixiong Cheng, Junfei Zhao, Yang Wang, Weiqiang Lu, Zehui Liu, Yadi Zhou, William R. Martin, Ruisheng Wang, Jin Huang, Tong Hao, Hong Yue, Jing Ma, Yuan Hou, Jessica A. Castrillon, Jiansong Fang, Justin D. Lathia, Ruth A. Keri, Felice C. Lightstone, Elliott Marshall Antman, Raul RabadanDavid E. Hill, Charis Eng, Marc Vidal, Joseph Loscalzo

Research output: Contribution to journalArticlepeer-review

1 Scopus citations

Abstract

Technological and computational advances in genomics and interactomics have made it possible to identify how disease mutations perturb protein–protein interaction (PPI) networks within human cells. Here, we show that disease-associated germline variants are significantly enriched in sequences encoding PPI interfaces compared to variants identified in healthy participants from the projects 1000 Genomes and ExAC. Somatic missense mutations are also significantly enriched in PPI interfaces compared to noninterfaces in 10,861 tumor exomes. We computationally identified 470 putative oncoPPIs in a pan-cancer analysis and demonstrate that oncoPPIs are highly correlated with patient survival and drug resistance/sensitivity. We experimentally validate the network effects of 13 oncoPPIs using a systematic binary interaction assay, and also demonstrate the functional consequences of two of these on tumor cell growth. In summary, this human interactome network framework provides a powerful tool for prioritization of alleles with PPI-perturbing mutations to inform pathobiological mechanism- and genotype-based therapeutic discovery.

Original languageEnglish (US)
Pages (from-to)342-353
Number of pages12
JournalNature Genetics
Volume53
Issue number3
DOIs
StatePublished - Mar 2021
Externally publishedYes

ASJC Scopus subject areas

  • Genetics

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