Molecular insights into the membrane-associated phosphatidylinositol 4-kinase IIα, Nature Communications 5,Article number: 3552,Published 28 March 2014
发布时间：2014年04月01日
Nature Communications 5, Article number: 3552 doi:10.1038/ncomms4552 Received 22 September 2013 Accepted 05 March 2014 Published 28 March 2014
Molecular insights into the membrane-associated phosphatidylinositol 4-kinase IIα
Qiangjun Zhou, Jiangmei Li, Hang Yu, Yujia Zhai, Zhen Gao, Yanxin Liu, Xiaoyun Pang, Lunfeng Zhang, Klaus Schulten, Fei Sun & Chang Chen
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 ‘integral’ membrane-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’s activity. We conclude from our results that PI4KIIα’s activity is regulated indirectly through changes in the membrane environment.
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Molecular insights into the membrane-associated phosphatidylinositol 4-kinase IIα, Nature Communications 5,Article number: 3552,Published 28 March 2014
Nature Communications 5, Article number: 3552 doi:10.1038/ncomms4552 Received 22 September 2013 Accepted 05 March 2014 Published 28 March 2014
Molecular insights into the membrane-associated phosphatidylinositol 4-kinase IIα
Qiangjun Zhou, Jiangmei Li, Hang Yu, Yujia Zhai, Zhen Gao, Yanxin Liu, Xiaoyun Pang, Lunfeng Zhang, Klaus Schulten, Fei Sun & Chang Chen
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 ‘integral’ membrane-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’s activity. We conclude from our results that PI4KIIα’s activity is regulated indirectly through changes in the membrane environment.
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文章链接：http://www.nature.com/ncomms/2014/140328/ncomms4552/full/ncomms4552.html