The Parkinson's disease protein alpha-synuclein (alpha Syn) promotes membrane fusion and fission by interacting with various negatively charged phospholipids. Despite postulated roles in endocytosis and exocytosis, plasma membrane (PM) interactions of alpha Syn are poorly understood. Here, we show that phosphatidylinositol 4,5-bisphosphate (PIP2) and phosphatidylinositol 3,4,5-trisphosphate (PIP3), two highly acidic components of inner PM leaflets, mediate PM localization of endogenous pools of alpha Syn in A2780, HeLa, SK-MEL-2, and differentiated and undifferentiated neuronal SH-SY5Y cells. We demonstrate that alpha Syn binds to reconstituted PIP2 membranes in a helical conformation in vitro and that PIP2 synthesizing kinases and hydrolyzing phosphatases reversibly redistribute alpha Syn in cells. We further delineate that alpha Syn-PM targeting follows phosphoinositide-3 kinase (PI3K)-dependent changes of cellular PIP2 and PIP3 levels, which collectively suggests that phosphatidylinositol polyphosphates contribute to alpha Syn's function(s) at the plasma membrane.
alpha-Synuclein plasma membrane localization correlates with cellular phosphatidylinositol polyphosphate levels / Jacob Reeba, Susan; Eichmann, Cedric; Dema, Alessandro; Mercadante, D; Selenko, Philipp. - In: ELIFE. - ISSN 2050-084X. - 10:(2021). [10.7554/eLife.61951]
alpha-Synuclein plasma membrane localization correlates with cellular phosphatidylinositol polyphosphate levels
Mercadante D;
2021
Abstract
The Parkinson's disease protein alpha-synuclein (alpha Syn) promotes membrane fusion and fission by interacting with various negatively charged phospholipids. Despite postulated roles in endocytosis and exocytosis, plasma membrane (PM) interactions of alpha Syn are poorly understood. Here, we show that phosphatidylinositol 4,5-bisphosphate (PIP2) and phosphatidylinositol 3,4,5-trisphosphate (PIP3), two highly acidic components of inner PM leaflets, mediate PM localization of endogenous pools of alpha Syn in A2780, HeLa, SK-MEL-2, and differentiated and undifferentiated neuronal SH-SY5Y cells. We demonstrate that alpha Syn binds to reconstituted PIP2 membranes in a helical conformation in vitro and that PIP2 synthesizing kinases and hydrolyzing phosphatases reversibly redistribute alpha Syn in cells. We further delineate that alpha Syn-PM targeting follows phosphoinositide-3 kinase (PI3K)-dependent changes of cellular PIP2 and PIP3 levels, which collectively suggests that phosphatidylinositol polyphosphates contribute to alpha Syn's function(s) at the plasma membrane.I documenti in IRIS sono protetti da copyright e tutti i diritti sono riservati, salvo diversa indicazione.
