4hnd

Publication Abstract from PubMed

Phosphatidylinositol 4-kinase IIalpha (PI4KIIalpha), 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 PI4KIIalpha 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 PI4KIIalpha 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 PI4KIIalpha to the membrane, suggesting that fluctuation of the palmitoylation insertion affects PI4KIIalpha's activity. We conclude from our results that PI4KIIalpha's activity is regulated indirectly through changes in the membrane environment.

Molecular insights into the membrane-associated phosphatidylinositol 4-kinase IIalpha.,Zhou Q, Li J, Yu H, Zhai Y, Gao Z, Liu Y, Pang X, Zhang L, Schulten K, Sun F, Chen C Nat Commun. 2014 Mar 28;5:3552. doi: 10.1038/ncomms4552. PMID:24675427^[1]

From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine.