A Complex Interplay of Anionic Phospholipid Binding Regulates 3'-Phosphoinositide-Dependent-Kinase-1 Homodimer Activation.

ABSTRACT: 3'-Phosphoinositide-dependent-Kinase-1 (PDK1) is a master regulator whereby its PI3-kinase-dependent dysregulation in human pathologies is well documented. Understanding the direct role for PtdIns(3,4,5)P₃ and other anionic phospholipids in the regulation of PDK1 conformational dynamics and its downstream activation remains incomplete. Using advanced quantitative-time-resolved imaging (Fluorescence Lifetime Imaging and Fluorescence Correlation Spectroscopy) and molecular modelling, we show an interplay of antagonistic binding effects of PtdIns(3,4,5)P₃ and other anionic phospholipids, regulating activated PDK1 homodimers. We demonstrate that phosphatidylserine maintains PDK1 in an inactive conformation. The dysregulation of the PI3K pathway affects the spatio-temporal

SUBMITTER: Heras-Martinez GL 

PROVIDER: S-EPMC6787260 | biostudies-literature | 2019 Oct

REPOSITORIES: biostudies-literature