2. Academic Validation
  3. Molecular insights into the membrane-associated phosphatidylinositol 4-kinase IIα

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

  • Nat Commun. 2014 Mar 28;5:3552. doi: 10.1038/ncomms4552.
Qiangjun Zhou 1,  Jiangmei Li 2,  Hang Yu 3,  Yujia Zhai 4,  Zhen Gao 5,  Yanxin Liu 6,  Xiaoyun Pang 5,  Lunfeng Zhang 5,  Klaus Schulten 7,  Fei Sun 4,  Chang Chen 8
Affiliations

Affiliations

  • 1 1] National Laboratory of Biomacromolecules, Institute of Biophysics, Chinese Academy of Sciences, Beijing 100101, China [2] University of Chinese Academy of Sciences, Beijing 100049, China [3].
  • 2 1] National Laboratory of Biomacromolecules, Institute of Biophysics, Chinese Academy of Sciences, Beijing 100101, China [2].
  • 3 Center for Biophysics and Computational Biology, University of Illinois at Urbana-Champaign, Urbana, Illinois 61801, USA.
  • 4 National Laboratory of Biomacromolecules, Institute of Biophysics, Chinese Academy of Sciences, Beijing 100101, China.
  • 5 1] National Laboratory of Biomacromolecules, Institute of Biophysics, Chinese Academy of Sciences, Beijing 100101, China [2] University of Chinese Academy of Sciences, Beijing 100049, China.
  • 6 Beckman Institute and Department of Physics, University of Illinois at Urbana-Champaign, Urbana, Illinois 61801, USA.
  • 7 1] Center for Biophysics and Computational Biology, University of Illinois at Urbana-Champaign, Urbana, Illinois 61801, USA [2] Beckman Institute and Department of Physics, University of Illinois at Urbana-Champaign, Urbana, Illinois 61801, USA.
  • 8 1] National Laboratory of Biomacromolecules, Institute of Biophysics, Chinese Academy of Sciences, Beijing 100101, China [2] Beijing Institute for Brain Disorders, Beijing 100069, China.
PMID: 24675427 DOI: 10.1038/ncomms4552
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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