Comprehensive characterization of protein–protein interactions perturbed by disease mutations

Cheng, Feixiong; Zhao, Junfei; Wang, Yang; Lü, Weiqiang; Liu, Zehui; Zhou, Yadi; Martin, William R.; Wang, Rui-Sheng; Huang, Jin; Hao, Tong; Yue, Hong; Ma, Jing; Hou, Yuan; Castrillon, Jessica A.; Fang, Jiansong; Lathia, Justin D.; Keri, Ruth A.; Lightstone, Felice C.; Antman, Elliott M.; Rabadán, Raúl; Hill, David E.; Eng, Charis; Vidal, Marc; Loscalzo, Joseph

doi:10.1038/s41588-020-00774-y

Cited by 167 publications

(142 citation statements)

References 66 publications

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“…We used the human protein-protein interactome from our previous studies [20,23]. Briefly, high-quality PPIs were assembled from 15 commonly used databases that include five types of evidence: yeast-two-hybrid system, protein 3D structures, literaturederived kinase-substrate interactions, literature-derived signaling networks, and affinitypurification mass spectrometry.…”

Section: Human Protein-protein Interactomementioning

confidence: 99%

“…We assembled PPI interface data from known protein complex structures, homology models, and machine learning-based computational computation as the crystal structure-derived data is very limited. Although we showed that somatic missense mutations were significantly enriched in computationally predicted PPI interfaces [20], further improving the quality of PPI interfaces (including cryogenic electron microscopy (cryo-EM) structure) are highly needed in the future. The computation for SMEs did not take the sequence composition and amino acid specific mutation rate into consideration.…”

Section: Limitation and Future Directionsmentioning

confidence: 99%

“…Finally, the human interactome is still incomplete and PPIs may have literature bias. We will continue updating the human interactome into the database, especially including more unbiased systematic PPIs data [20]. In addition, we will offer functions for selecting smaller window sizes for the functional sites.…”

Section: Limitation and Future Directionsmentioning

confidence: 99%

“…These protein structural genomic resources offer unexpected opportunities for accelerating interpretation of biological and functional consequences of cancer mutations for precision cancer medicine from systems biology perspectives [6,19]. In our recent study, we found that somatic missense mutations were highly enriched in PPI interfaces compared to non-interfaces via analysis of over 10,000 whole exomes across 33 cancer types [20]. We further showed that PPI interface mutation analysis provided likely causal relationships in tumorigenesis and experimentally validated functional effects of PPI interface mutation using a systematic binary interaction assay [8][9][10] and cell line-based functional assays [20].…”

mentioning

confidence: 98%

“…In our recent study, we found that somatic missense mutations were highly enriched in PPI interfaces compared to non-interfaces via analysis of over 10,000 whole exomes across 33 cancer types [20]. We further showed that PPI interface mutation analysis provided likely causal relationships in tumorigenesis and experimentally validated functional effects of PPI interface mutation using a systematic binary interaction assay [8][9][10] and cell line-based functional assays [20]. In summary, all previous observations from our groups and other studies provide functional proof-of-concept of both nodetic and edgetic effects of somatic mutations in human cancer.…”

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confidence: 99%

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My personal mutanome: a computational genomic medicine platform for searching network perturbing alleles linking genotype to phenotype

et al. 2021

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Massive genome sequencing data have inspired new challenges in personalized treatments and facilitated oncological drug discovery. We present a comprehensive database, My Personal Mutanome (MPM), for accelerating the development of precision cancer medicine protocols. MPM contains 490,245 mutations from over 10,800 tumor exomes across 33 cancer types in The Cancer Genome Atlas mapped to 94,563 structure-resolved/predicted protein-protein interaction interfaces (“edgetic”) and 311,022 functional sites (“nodetic”), including ligand-protein binding sites and 8 types of protein posttranslational modifications. In total, 8884 survival results and 1,271,132 drug responses are obtained for these mapped interactions. MPM is available at https://mutanome.lerner.ccf.org.

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Section: Human Protein-protein Interactomementioning

confidence: 99%

Section: Limitation and Future Directionsmentioning

confidence: 99%

Section: Limitation and Future Directionsmentioning

confidence: 99%

mentioning

confidence: 98%

mentioning

confidence: 99%

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My personal mutanome: a computational genomic medicine platform for searching network perturbing alleles linking genotype to phenotype

et al. 2021

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Genomic Landscape and Potential Regulation of RNA Editing in Drug Resistance

Mitra

Hou

et al. 2023

Advanced Science

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Adenosine‐to‐inosine RNA editing critically affects the response of cancer therapies. However, comprehensive identification of drug resistance‐related RNA editing events and systematic understanding of how RNA editing mediates anticancer drug resistance remain unclear. Here, 7157 differential editing sites (DESs) are identified from 98 127 informative RNA editing sites in tumor tissues, many of which are validated in cancer cell lines. Diverse editing patterns of DESs are discovered in resistant samples, which could not be fully explained by adenosine deaminase acting on RNA enzymes. Some RNA‐binding proteins are identified that potentially regulate these editing events. Notably, the DESs are significantly enriched in 3’‐untranslated regions (3’‐UTRs). The impact of DESs in 3’‐UTR on the microRNA (miRNA) regulations is explored, and some triplets (DES, miRNA, and gene) that may contribute to drug resistance are identified. In addition, it is determined that the functions of genes enriched with DESs are associated with drug resistance, such as apoptosis, drug metabolism, and DNA synthesis involved in DNA repair. An online resource (http://www.jianglab.cn/REDR/) to support convenient retrieval of DESs is also built. The findings reveal the landscape and potential regulatory mechanism of RNA editing in drug resistance, providing new therapeutic targets for reversing drug resistance.

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Genetic variants associated with age‐related episodic memory decline implicate distinct memory pathologies

Ali,

Milman,

Weiss

et al. 2024

Alzheimer's & Dementia

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BACKGROUNDApproximately 40% of people aged ≥ 65 experience memory loss, particularly in episodic memory. Identifying the genetic basis of episodic memory decline is crucial for uncovering its underlying causes.METHODSWe investigated common and rare genetic variants associated with episodic memory decline in 742 (632 for rare variants) Ashkenazi Jewish individuals (mean age 75) from the LonGenity study. All‐atom molecular dynamics simulations were performed to uncover mechanistic insights underlying rare variants associated with episodic memory decline.RESULTSIn addition to the common polygenic risk of Alzheimer's disease, we identified and replicated rare variant associations in ITSN1 and CRHR2. Structural analyses revealed distinct memory pathologies mediated by interfacial rare coding variants such as impaired receptor activation of corticotropin releasing hormone and dysregulated L‐serine synthesis.DISCUSSIONOur study uncovers novel risk loci for episodic memory decline. The identified underlying mechanisms point toward heterogenous memory pathologies mediated by rare coding variants.Highlights We demonstrated the contribution of the common polygenic risk of Alzheimer's disease to episodic memory decline. We discovered and replicated two risk genes associated with episodic memory decline implicated by rare variants, were discovered and replicated. We demonstrated molecular mechanisms and potential novel memory pathologies underlying interfacial rare coding variants. Molecular dynamics simulations were performed to understand the downstream effects of risk rare coding variants.

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Comprehensive characterization of protein–protein interactions perturbed by disease mutations

Cited by 167 publications

References 66 publications

My personal mutanome: a computational genomic medicine platform for searching network perturbing alleles linking genotype to phenotype

My personal mutanome: a computational genomic medicine platform for searching network perturbing alleles linking genotype to phenotype

Genomic Landscape and Potential Regulation of RNA Editing in Drug Resistance

Genetic variants associated with age‐related episodic memory decline implicate distinct memory pathologies

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