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 (PI4KII), 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 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 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 to the membrane, suggesting that
fluctuation of the palmitoylation insertion affects PI4KII’s
activity, a suggestion supported by mutagenesis studies. We conclude
from our results that PI4KII’s activity is regulated indirectly
through changes in the membrane environment.
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