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

Author

Listed:
  • Qiangjun Zhou

    (National Laboratory of Biomacromolecules, Institute of Biophysics, Chinese Academy of Sciences
    University of Chinese Academy of Sciences)

  • Jiangmei Li

    (National Laboratory of Biomacromolecules, Institute of Biophysics, Chinese Academy of Sciences)

  • Hang Yu

    (Center for Biophysics and Computational Biology, University of Illinois at Urbana-Champaign)

  • Yujia Zhai

    (National Laboratory of Biomacromolecules, Institute of Biophysics, Chinese Academy of Sciences)

  • Zhen Gao

    (National Laboratory of Biomacromolecules, Institute of Biophysics, Chinese Academy of Sciences
    University of Chinese Academy of Sciences)

  • Yanxin Liu

    (University of Illinois at Urbana-Champaign)

  • Xiaoyun Pang

    (National Laboratory of Biomacromolecules, Institute of Biophysics, Chinese Academy of Sciences
    University of Chinese Academy of Sciences)

  • Lunfeng Zhang

    (National Laboratory of Biomacromolecules, Institute of Biophysics, Chinese Academy of Sciences
    University of Chinese Academy of Sciences)

  • Klaus Schulten

    (Center for Biophysics and Computational Biology, University of Illinois at Urbana-Champaign
    University of Illinois at Urbana-Champaign)

  • Fei Sun

    (National Laboratory of Biomacromolecules, Institute of Biophysics, Chinese Academy of Sciences)

  • Chang Chen

    (National Laboratory of Biomacromolecules, Institute of Biophysics, Chinese Academy of Sciences
    Beijing Institute for Brain Disorders)

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.

Suggested Citation

  • Qiangjun Zhou & Jiangmei Li & Hang Yu & Yujia Zhai & Zhen Gao & Yanxin Liu & Xiaoyun Pang & Lunfeng Zhang & Klaus Schulten & Fei Sun & Chang Chen, 2014. "Molecular insights into the membrane-associated phosphatidylinositol 4-kinase IIα," Nature Communications, Nature, vol. 5(1), pages 1-10, May.
    • Handle: RePEc:nat:natcom:v:5:y:2014:i:1:d:10.1038_ncomms4552
    DOI: 10.1038/ncomms4552
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    1. Alessia Calcagni’ & Leopoldo Staiano & Nicolina Zampelli & Nadia Minopoli & Niculin J. Herz & Giuseppe Tullio & Tuong Huynh & Jlenia Monfregola & Alessandra Esposito & Carmine Cirillo & Aleksandar Baj, 2023. "Loss of the batten disease protein CLN3 leads to mis-trafficking of M6PR and defective autophagic-lysosomal reformation," Nature Communications, Nature, vol. 14(1), pages 1-19, December.

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