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Molecular insights into the membrane-associated phosphatidylinositol 4-kinase II?.


ABSTRACT: Phosphatidylinositol 4-kinase II? (PI4KII?), 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 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 simulations, biochemical and mutagenesis studies reveal 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. We conclude from our results that PI4KII?'s activity is regulated indirectly through changes in the membrane environment.

SUBMITTER: Zhou Q 

PROVIDER: S-EPMC3974213 | biostudies-literature | 2014 Mar

REPOSITORIES: biostudies-literature

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Molecular insights into the membrane-associated phosphatidylinositol 4-kinase IIα.

Zhou Qiangjun Q   Li Jiangmei J   Yu Hang H   Zhai Yujia Y   Gao Zhen Z   Liu Yanxin Y   Pang Xiaoyun X   Zhang Lunfeng L   Schulten Klaus K   Sun Fei F   Chen Chang C  

Nature communications 20140328


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  ...[more]

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