Scientific article

Autoregulation of Class II Alpha PI3K Activity by Its Lipid-Binding PX-C2 Domain Module

Published inMolecular Cell, vol. 71, no. 2, p. 343-351.e4
Publication date2018

Class II phosphoinositide 3-kinases (PI3K-C2) are large multidomain enzymes that control cellular functions ranging from membrane dynamics to cell signaling via synthesis of 3'-phosphorylated phosphoinositides. Activity of the alpha isoform (PI3K-C2α) is associated with endocytosis, angiogenesis, and glucose metabolism. How PI3K-C2α activity is controlled at sites of endocytosis remains largely enigmatic. Here we show that the lipid-binding PX-C2 module unique to class II PI3Ks autoinhibits kinase activity in solution but is essential for full enzymatic activity at PtdIns(4,5)P2-rich membranes. Using HDX-MS, we show that the PX-C2 module folds back onto the kinase domain, inhibiting its basal activity. Destabilization of this intramolecular contact increases PI3K-C2α activity in vitro and in cells, leading to accumulation of its lipid product, increased recruitment of the endocytic effector SNX9, and facilitated endocytosis. Our studies uncover a regulatory mechanism in which coincident binding of phosphoinositide substrate and cofactor selectively activate PI3K-C2α at sites of endocytosis.

Citation (ISO format)
WANG, Haibin et al. Autoregulation of Class II Alpha PI3K Activity by Its Lipid-Binding PX-C2 Domain Module. In: Molecular Cell, 2018, vol. 71, n° 2, p. 343–351.e4. doi: 10.1016/j.molcel.2018.06.042
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Article (Published version)
ISSN of the journal1097-2765

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