Regulation of kinase activity by combined action of juxtamembrane and C-terminal regions of receptors
Suen, Kin Man
Arold, Stefan T.
Ladbury, John Edward
KAUST DepartmentBiological and Environmental Sciences and Engineering (BESE) Division
Computational Bioscience Research Center (CBRC)
Computer, Electrical and Mathematical Sciences and Engineering (CEMSE) Division
Structural Biology and Engineering
Permanent link to this recordhttp://hdl.handle.net/10754/665438
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AbstractDespite 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.
CitationLin, 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
SponsorsThis 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.
PublisherCold Spring Harbor Laboratory