PT  - JOURNAL ARTICLE
AU  - Wei Dong
AU  - Juan Lu
AU  - Xuejing Zhang
AU  - Yan Wu
AU  - Kaela Lettieri
AU  - Gerald R. Hammond
AU  - Yang Hong
TI  - A Polybasic Domain in aPKC Mediates Par-6-Dependent Control of Plasma Membrane Targeting and Kinase Activity
AID  - 10.1101/588624
DP  - 2019 Jan 01
TA  - bioRxiv
PG  - 588624
4099  - http://biorxiv.org/content/early/2019/03/28/588624.short
4100  - http://biorxiv.org/content/early/2019/03/28/588624.full
AB  - Mechanisms coupling the atypical PKC (aPKC) kinase activity to its subcellular localization are essential for regulating cell polarization but remain to be fully elucidated. Unlike other members of the PKC family, aPKC has no well-defined plasma membrane (PM) or calcium binding domains, leading to the assumption that its subcellular localization relies exclusively on protein-protein interactions. Here we show that in both Drosophila and mammalian cells the pseudosubstrate region (PSr) of aPKC acts as a polybasic domain sufficient to target aPKC to the PM via electrostatic binding to PM phosphoinositides. PM-targeting of aPKC requires the physical interaction between the N-terminal PB1 domains in both aPKC and Par-6, which not only allosterically exposes PSr to PM-binding, but also inhibits aPKC kinase activity. Such kinase inhibition requires the C-terminal domain of Par-6 and can be relieved through Par-6 interaction with apical polarity protein Crumbs. Our data suggest a mechanism in which allosteric regulation of polybasic PSr in aPKC by Par-6 couples the control of both aPKC subcellular localization and spatial activation of its kinase activity.