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    Systems-level effects of allosteric perturbations to a model molecular switch

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    Authors
    Perica, Tina
    Mathy, Christopher J P
    Xu, Jiewei
    Jang, Gwendolyn Μ
    Zhang, Yang
    Kaake, Robyn
    Ollikainen, Noah
    Braberg, Hannes
    Swaney, Danielle L
    Lambright, David G
    Kelly, Mark J S
    Krogan, Nevan J
    Kortemme, Tanja
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    UMass Chan Affiliations
    Biochemistry and Molecular Biotechnology
    Program in Molecular Medicine
    Document Type
    Journal Article
    Publication Date
    2021-10-13
    Keywords
    GTP-binding protein regulators
    Molecular conformation
    Networks and systems biology
    Proteomic analysis
    Regulatory networks
    
    Metadata
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    Link to Full Text
    https://doi.org/10.1038/s41586-021-03982-6
    Abstract
    Molecular switch proteins whose cycling between states is controlled by opposing regulators1,2 are central to biological signal transduction. As switch proteins function within highly connected interaction networks3, the fundamental question arises of how functional specificity is achieved when different processes share common regulators. Here we show that functional specificity of the small GTPase switch protein Gsp1 in Saccharomyces cerevisiae (the homologue of the human protein RAN)4 is linked to differential sensitivity of biological processes to different kinetics of the Gsp1 (RAN) switch cycle. We make 55 targeted point mutations to individual protein interaction interfaces of Gsp1 (RAN) and show through quantitative genetic5 and physical interaction mapping that Gsp1 (RAN) interface perturbations have widespread cellular consequences. Contrary to expectation, the cellular effects of the interface mutations group by their biophysical effects on kinetic parameters of the GTPase switch cycle and not by the targeted interfaces. Instead, we show that interface mutations allosterically tune the GTPase cycle kinetics. These results suggest a model in which protein partner binding, or post-translational modifications at distal sites, could act as allosteric regulators of GTPase switching. Similar mechanisms may underlie regulation by other GTPases, and other biological switches. Furthermore, our integrative platform to determine the quantitative consequences of molecular perturbations may help to explain the effects of disease mutations that target central molecular switches.
    Source
    Perica T, Mathy CJP, Xu J, Jang GΜ, Zhang Y, Kaake R, Ollikainen N, Braberg H, Swaney DL, Lambright DG, Kelly MJS, Krogan NJ, Kortemme T. Systems-level effects of allosteric perturbations to a model molecular switch. Nature. 2021 Nov;599(7883):152-157. doi: 10.1038/s41586-021-03982-6. Epub 2021 Oct 13. PMID: 34646016; PMCID: PMC8571063.
    DOI
    10.1038/s41586-021-03982-6
    Permanent Link to this Item
    http://hdl.handle.net/20.500.14038/51671
    PubMed ID
    34646016
    Rights
    © 2021. The Author(s), under exclusive licence to Springer Nature Limited.
    ae974a485f413a2113503eed53cd6c53
    10.1038/s41586-021-03982-6
    Scopus Count
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