Journal
MOLECULAR CELL
Volume 71, Issue 2, Pages 343-+Publisher
CELL PRESS
DOI: 10.1016/j.molcel.2018.06.042
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Funding
- SNF Ambizione fellowship [PZ00P3_148269]
- German funding agency DFG [TRR186/A08, SFB958/A07]
- Swiss National Science Foundation (SNF) [PZ00P3_148269] Funding Source: Swiss National Science Foundation (SNF)
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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-C2 alpha) is associated with endocytosis, angiogenesis, and glucose metabolism. How PI3K-C2 alpha 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)P-2-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-C2 alpha 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 mechanismin which coincident binding of phosphoinositide substrate and cofactor selectively activate PI3K-C2 alpha at sites of endocytosis.
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