Comprehensive characterization of protein-protein interactions perturbed by disease mutations

被引：136

作者：

Cheng, Feixiong ^{[1
,2
,3
]}

Zhao, Junfei ^{[4
,5
]}

Wang, Yang ^{[6
,7
]}

Lu, Weiqiang ^{[8
,9
]}

Liu, Zehui ^{[10
]}

Zhou, Yadi ^{[1
]}

Martin, William R. ^{[1
]}

Wang, Ruisheng ^{[11
]}

Huang, Jin ^{[10
]}

Hao, Tong ^{[6
,7
]}

Yue, Hong ^{[6
,7
]}

Ma, Jing ^{[6
,12
]}

Hou, Yuan ^{[1
]}

Castrillon, Jessica A. ^{[1
]}

Fang, Jiansong ^{[1
,13
]}

Lathia, Justin D. ^{[2
,3
]}

Keri, Ruth A. ^{[3
,14
]}

Lightstone, Felice C. ^{[15
]}

Antman, Elliott Marshall ^{[16
]}

Rabadan, Raul ^{[4
,5
]}

Hill, David E. ^{[6
,7
]}

Eng, Charis ^{[1
,2
,3
,17
,18
]}

Vidal, Marc ^{[6
,7
]}

Loscalzo, Joseph ^{[11
]}

机构：

[1] Cleveland Clin, Genom Med Inst, Lerner Res Inst, Cleveland, OH 44106 USA

[2] Case Western Reserve Univ, Dept Mol Med, Cleveland Clin, Lerner Coll Med, Cleveland, OH 44106 USA

[3] Case Western Reserve Univ, Sch Med, Case Comprehens Canc Ctr, Cleveland, OH USA

[4] Columbia Univ, Herbert Irving Comprehens Ctr, Dept Syst Biol, New York, NY USA

[5] Columbia Univ, Dept Biomed Informat, New York, NY USA

[6] Dana Farber Canc Inst, Ctr Canc Syst Biol CCSB, Dept Canc Biol, Boston, MA 02115 USA

[7] Harvard Med Sch, Blavatnik Inst, Dept Genet, Boston, MA 02115 USA

[8] East China Normal Univ, Inst Biomed Sci, Shanghai Key Lab Regulatory Biol, Shanghai, Peoples R China

[9] East China Normal Univ, Sch Life Sci, Shanghai, Peoples R China

[10] East China Univ Sci & Technol, Sch Pharm, Shanghai Key Lab New Drug Design, Shanghai, Peoples R China

[11] Harvard Med Sch, Dept Med, Brigham & Womens Hosp, Boston, MA 02115 USA

[12] Res Ctr Healthcare Data Sci, Zhejiang Lab, Hangzhou, Zhejiang, Peoples R China

[13] Guangzhou Univ Chinese Med, Sci & Technol Innovat Ctr, Guangzhou, Guangdong, Peoples R China

[14] Case Western Reserve Univ, Sch Med, Dept Pharmacol, Cleveland, OH 44106 USA

[15] Lawrence Livermore Natl Lab, Biosci & Biotechnol Div, Phys & Life Sci Directorate, Livermore, CA 94550 USA

[16] Harvard Med Sch, Div Cardiovasc Med, Brigham & Womens Hosp, Boston, MA 02115 USA

[17] Case Western Reserve Univ, Sch Med, Dept Genet & Genome Sci, Cleveland, OH USA

[18] Cleveland Clin, Taussig Canc Inst, Cleveland, OH 44106 USA

来源：

NATURE GENETICS | 2021年 / 53卷 / 03期

基金：

美国国家卫生研究院;

关键词：

DISCOVERY; GENE; PROGRESSION; ANNOTATION; INHIBITOR; LANDSCAPE; COMPLEXES; SERVER; MAP;

D O I：

10.1038/s41588-020-00774-y

中图分类号：

Q3 [遗传学];

学科分类号：

071007 ; 090102 ;

摘要：

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.

引用

页码：342 / +

页数：17

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