The Parkinson's disease protein α-synuclein (aSyn) promotes membrane fusion and fission by interacting with various negatively charged phospholipids. Despite postulated roles in endocytosis and exocytosis, plasma membrane (PM) interactions of αSyn 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 plasma membrane localization of endogenous pools of αSyn in A2780, HeLa, SK-MEL-2 and differentiated and undifferentiated neuronal SH-SY5Y cells. We demonstrate that αSyn binds to reconstituted PIP2-membranes in a helical conformation in vitro and that PIP2 synthesizing kinases and hydrolyzing phosphatases reversibly redistribute αSyn in cells. We further delineate that αSyn-PM targeting follows phosphoinositide-3 kinase (PI3K)-dependent changes of cellular PIP2 and PIP3 levels, which collectively suggests that phosphatidylinositol polyphosphates contribute to αSyn's cellular function(s) at the plasma membrane.
All data generated or analysed during this study are included in the manuscript and supporting files. Source data files have been provided for Figures 1,2,3 and all Supplementary Figures.
- Philipp Selenko
The funders had no role in study design, data collection and interpretation, or the decision to submit the work for publication.
- Axel T Brunger, Stanford University, United States
© 2021, Jacob et al.
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