TCB Publications - Abstract

Qiangjun Zhou, Jiangmei Li, Hang Yu, Yujia Zhai, Zhen Gao, Yanxin Liu, Xiaoyun Pang, Lunfeng Zhang, Klaus Schulten, Fei Sun, and Chang Chen. Molecular insights into the membrane-associated phosphatidylinositol 4-kinase IIα. Nature Communications, 5:3552, 2014. (PMC: PMC3974213)

ZHOU2014 Phosphatidylinositol 4-kinase II$\alpha$ (PI4KII$\alpha$), a membrane-associated PI kinase, plays a central role in cell signaling and trafficking. Its kinase activity is critically dependent on palmitoylation of its cysteine-rich motif (-CCPCC-) and modulated by the membrane environment. Lack of atomic structure impairs our understanding of the mechanism regulating kinase activity. Here we present the crystal structure of human PI4KII$\alpha$ in ADP-bound form. The structure identifies the nucleotide-binding pocket that differs notably from that found in PI3Ks. Two structural insertions, a palmitoylation insertion and an RK-rich insertion, endow PI4KII$\alpha$ with the ``integral" membrane-binding feature. Molecular dynamics simulation reveals that the palmitoylation insertion, containing an amphipathic helix, contributes to the PI binding pocket and anchors PI4KII$\alpha$ to the membrane, suggesting that fluctuation of the palmitoylation insertion affects PI4KII$\alpha$ís activity, a suggestion supported by mutagenesis studies. We conclude from our results that PI4KII$\alpha$ís activity is regulated indirectly through changes in the membrane environment.

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