TY - JOUR T1 - Regulation of kinase activity by combined action of juxtamembrane and C-terminal regions of receptors JF - bioRxiv DO - 10.1101/2020.10.01.322123 SP - 2020.10.01.322123 AU - Chi-Chuan Lin AU - Lukasz Wieteska AU - Guillaume Poncet-Montange AU - Kin M. Suen AU - Stefan T. Arold AU - Zamal Ahmed AU - John E. Ladbury Y1 - 2020/01/01 UR - http://biorxiv.org/content/early/2020/10/01/2020.10.01.322123.abstract N2 - 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.Competing Interest StatementThe authors have declared no competing interest. ER -