Systems-level analyses of protein-protein interaction network dysfunctions via epichaperomics identify cancer-specific mechanisms of stress adaptation
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Published:2023-06-23
Issue:1
Volume:14
Page:
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ISSN:2041-1723
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Container-title:Nature Communications
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language:en
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Short-container-title:Nat Commun
Author:
Rodina AnnaORCID, Xu Chao, Digwal Chander S.ORCID, Joshi Suhasini, Patel Yogita, Santhaseela Anand R.ORCID, Bay Sadik, Merugu Swathi, Alam Aftab, Yan Pengrong, Yang Chenghua, Roychowdhury Tanaya, Panchal Palak, Shrestha Liza, Kang Yanlong, Sharma SahilORCID, Almodovar Justina, Corben Adriana, Alpaugh Mary L.ORCID, Modi Shanu, Guzman Monica L.ORCID, Fei TengORCID, Taldone Tony, Ginsberg Stephen D., Erdjument-Bromage Hediye, Neubert Thomas A., Manova-Todorova Katia, Tsou Meng-Fu Bryan, Young Jason C.ORCID, Wang TaiORCID, Chiosis GabrielaORCID
Abstract
AbstractSystems-level assessments of protein-protein interaction (PPI) network dysfunctions are currently out-of-reach because approaches enabling proteome-wide identification, analysis, and modulation of context-specific PPI changes in native (unengineered) cells and tissues are lacking. Herein, we take advantage of chemical binders of maladaptive scaffolding structures termed epichaperomes and develop an epichaperome-based ‘omics platform, epichaperomics, to identify PPI alterations in disease. We provide multiple lines of evidence, at both biochemical and functional levels, demonstrating the importance of these probes to identify and study PPI network dysfunctions and provide mechanistically and therapeutically relevant proteome-wide insights. As proof-of-principle, we derive systems-level insight into PPI dysfunctions of cancer cells which enabled the discovery of a context-dependent mechanism by which cancer cells enhance the fitness of mitotic protein networks. Importantly, our systems levels analyses support the use of epichaperome chemical binders as therapeutic strategies aimed at normalizing PPI networks.
Funder
U.S. Department of Health & Human Services | National Institutes of Health
Publisher
Springer Science and Business Media LLC
Subject
General Physics and Astronomy,General Biochemistry, Genetics and Molecular Biology,General Chemistry,Multidisciplinary
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