@article{9dbd23af0d484e50bd430fe52bd45310,
title = "Molecular insights into the membrane-associated phosphatidylinositol 4-kinase IIα",
abstract = "Phosphatidylinositol 4-kinase IIα (PI4KIIα), a membrane-associated PI kinase, plays a central role in cell signalling and trafficking. Its kinase activity critically depends on palmitoylation of its cysteine-rich motif (-CCPCC-) and is 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 PI4KIIα 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 PI4KIIα with the integralmembrane-binding feature. Molecular dynamics simulations, biochemical and mutagenesis studies reveal that the palmitoylation insertion, containing an amphipathic helix, contributes to the PI-binding pocket and anchors PI4KIIα to the membrane, suggesting that fluctuation of the palmitoylation insertion affects PI4KIIα activity. We conclude from our results that PI4KIIα activity is regulated indirectly through changes in the membrane environment.",
author = "Qiangjun Zhou and Jiangmei Li and Hang Yu and Yujia Zhai and Zhen Gao and Yanxin Liu and Xiaoyun Pang and Lunfeng Zhang and Klaus Schulten and Fei Sun and Chang Chen",
note = "Funding Information: We thank S. Huang, J. He, J. Qi (F. Gao{\textquoteright}s group) for on-site assistance at the SSRF beamline BL17U, and K. Zhang (F. Sun{\textquoteright}s group) for help with structure determination. We thank Prof. Xuejun C. Zhang for valuable suggestions and Dr Joy Fleming for English editing. This work was supported by grants from the Chinese Ministry of Science and Technology (2011CB910900, 2011CB910301 and 2012CB911000), the {\textquoteleft}863{\textquoteright} National High-Technology Development Program of China (0A200202D03), the National Natural Science Foundation of China (31021062, 31225012 and 31101021), the Beijing Natural Science Foundation (7132156) and the National Institutes of Health (9P41GM104601, R01-GM067887, and U54-GM087519). The authors acknowledge supercomputer time on the Stampede computer provided by the Texas Advanced Computing Center (TACC) at The University of Texas at Austin through Extreme Science and Engineering Discovery Environment (XSEDE) Grant MCA93S028, which is supported by National Science Foundation grant number OCI-1053575.",
year = "2014",
month = mar,
day = "28",
doi = "10.1038/ncomms4552",
language = "English (US)",
volume = "5",
journal = "Nature communications",
issn = "2041-1723",
publisher = "Nature Research",
}