title: Molecular insights into the membrane-associated phosphatidylinositol 4-kinase IIα.
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.
authors.affiliation: 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].
authors.forename: Qiangjun
authors.initials: Q
authors.lastname: Zhou
authors.affiliation: 1] National Laboratory of Biomacromolecules, Institute of Biophysics, Chinese Academy of Sciences, Beijing 100101, China [2].
authors.forename: Jiangmei
authors.initials: J
authors.lastname: Li
authors.affiliation: Center for Biophysics and Computational Biology, University of Illinois at Urbana-Champaign, Urbana, Illinois 61801, USA.
authors.forename: Hang
authors.initials: H
authors.lastname: Yu
authors.affiliation: National Laboratory of Biomacromolecules, Institute of Biophysics, Chinese Academy of Sciences, Beijing 100101, China.
authors.forename: Yujia
authors.initials: Y
authors.lastname: Zhai
authors.affiliation: 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.
authors.forename: Zhen
authors.initials: Z
authors.lastname: Gao
authors.affiliation: Beckman Institute and Department of Physics, University of Illinois at Urbana-Champaign, Urbana, Illinois 61801, USA.
authors.forename: Yanxin
authors.initials: Y
authors.lastname: Liu
authors.affiliation: 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.
authors.forename: Xiaoyun
authors.initials: X
authors.lastname: Pang
authors.affiliation: 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.
authors.forename: Lunfeng
authors.initials: L
authors.lastname: Zhang
authors.affiliation: 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.
authors.forename: Klaus
authors.initials: K
authors.lastname: Schulten
authors.affiliation: National Laboratory of Biomacromolecules, Institute of Biophysics, Chinese Academy of Sciences, Beijing 100101, China.
authors.forename: Fei
authors.initials: F
authors.lastname: Sun
authors.affiliation: 1] National Laboratory of Biomacromolecules, Institute of Biophysics, Chinese Academy of Sciences, Beijing 100101, China [2] Beijing Institute for Brain Disorders, Beijing 100069, China.
authors.forename: Chang
authors.initials: C
authors.lastname: Chen
mesh_terms: D000244:Adenosine Diphosphate / Q000737:chemistry / Q000378:metabolism; D020816:Amino Acid Motifs; D002462:Cell Membrane / Q000737:chemistry / Q000201:enzymology* / Q000235:genetics; D006801:Humans; D054878:Lipoylation; D015778:Minor Histocompatibility Antigens; D010716:Phosphatidylinositols / Q000737:chemistry / Q000378:metabolism; D017853:Phosphotransferases (Alcohol Group Acceptor) / Q000737:chemistry* / Q000235:genetics / Q000378:metabolism*; D017434:Protein Structure, Tertiary; D021381:Protein Transport
chemical_list: D015778:Minor Histocompatibility Antigens; D010716:Phosphatidylinositols; D000244:Adenosine Diphosphate; D017853:Phosphotransferases (Alcohol Group Acceptor); C402182:phosphatidylinositol phosphate 4-kinase