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    Regulation of kinase activity by combined action of juxtamembrane and C-terminal regions of receptors

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    Name:
    2020.10.01.322123v1.full.pdf
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    Description:
    Pre-print
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    Type
    Preprint
    Authors
    Lin, Chi-Chuan cc
    Wieteska, Lukasz
    Poncet-Montange, Guillaume
    Suen, Kin Man cc
    Arold, Stefan T. cc
    ahmed, zamal cc
    Ladbury, John Edward cc
    KAUST Department
    Biological and Environmental Sciences and Engineering (BESE) Division
    Bioscience Program
    Computational Bioscience Research Center (CBRC)
    Computer, Electrical and Mathematical Sciences and Engineering (CEMSE) Division
    Structural Biology and Engineering
    Date
    2020-10-01
    Permanent link to this record
    http://hdl.handle.net/10754/665438
    
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    Abstract
    Despite the kinetically-favorable, ATP-rich intracellular environment, the mechanism by which receptor tyrosine kinases (RTKs) repress activation prior to extracellular stimulation is poorly understood. RTKs are activated through a precise sequence of phosphorylation reactions starting with a tyrosine on the activation loop (A-loop) of the intracellular kinase domain (KD). This forms an essential mono-phosphorylated active intermediate state on the path to further phosphorylation of the receptor. We show that this state is subjected to stringent control imposed by the peripheral juxtamembrane (JM) and C-terminal tail (CT) regions. This entails interplay between the intermolecular interaction between JM with KD, which stabilizes the asymmetric active KD dimer, and the opposing intramolecular binding of CT to KD. A further control step is provided by the previously unobserved direct binding between JM and CT. Mutations in JM and CT sites that perturb regulation are found in numerous pathologies, revealing novel sites for potential pharmaceutical intervention.
    Citation
    Lin, C.-C., Wieteska, L., Poncet-Montange, G., Suen, K. M., Arold, S. T., ahmed, zamal, & Ladbury, J. E. (2020). Regulation of kinase activity by combined action of juxtamembrane and C-terminal regions of receptors. doi:10.1101/2020.10.01.322123
    Sponsors
    This work was funded in part by CRUK grant C57233/A22356 awarded to J.E.L. The research by S.T.A. supported by funding from King Abdullah University of Science and Technology (KAUST). Z.A. is supported by National Institutes of Health (NIH) grant R01 CA200231 and Cancer Prevention Research Institute of Texas (CPRIT) grant RP180813.
    Publisher
    Cold Spring Harbor Laboratory
    DOI
    10.1101/2020.10.01.322123
    Additional Links
    http://biorxiv.org/lookup/doi/10.1101/2020.10.01.322123
    ae974a485f413a2113503eed53cd6c53
    10.1101/2020.10.01.322123
    Scopus Count
    Collections
    Biological and Environmental Science and Engineering (BESE) Division; Preprints; Bioscience Program; Computational Bioscience Research Center (CBRC); Computer, Electrical and Mathematical Science and Engineering (CEMSE) Division

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