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

Research output: Contribution to journalArticlepeer-review


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.

Original languageEnglish (US)
Article number3552
JournalNature communications
StatePublished - Mar 28 2014

ASJC Scopus subject areas

  • Chemistry(all)
  • Biochemistry, Genetics and Molecular Biology(all)
  • Physics and Astronomy(all)

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