Autoregulation of Class II Alpha PI3K Activity by Its Lipid-Binding PX-C2 Domain Module.
Mol Cell
; 71(2): 343-351.e4, 2018 07 19.
Article
em En
| MEDLINE
| ID: mdl-30029007
ABSTRACT
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.
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Base de dados:
MEDLINE
Assunto principal:
Fosfatidilinositol 3-Quinases
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Classe II de Fosfatidilinositol 3-Quinases
Idioma:
En
Ano de publicação:
2018
Tipo de documento:
Article