Regulation of kinase activity by combined action of juxtamembrane and C-terminal regions of receptors
Type
PreprintAuthors
Lin, Chi-Chuan
Wieteska, Lukasz
Poncet-Montange, Guillaume
Suen, Kin Man

Arold, Stefan T.

ahmed, zamal

Ladbury, John Edward

KAUST Department
Biological and Environmental Sciences and Engineering (BESE) DivisionBioscience Program
Computational Bioscience Research Center (CBRC)
Computer, Electrical and Mathematical Sciences and Engineering (CEMSE) Division
Structural Biology and Engineering
Date
2020-10-01Permanent link to this record
http://hdl.handle.net/10754/665438
Metadata
Show full item recordAbstract
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:10.1101/2020.10.01.322123Sponsors
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 LaboratoryAdditional Links
http://biorxiv.org/lookup/doi/10.1101/2020.10.01.322123ae974a485f413a2113503eed53cd6c53
10.1101/2020.10.01.322123