Journal
FEBS LETTERS
Volume -, Issue -, Pages -Publisher
WILEY
DOI: 10.1002/1873-3468.14773
Keywords
alpha-synuclein; amphipathic helix; membrane lipids; neurodegeneration; Parkinson's disease; vesicles
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This study reveals the significance of amino acid composition in alpha-synuclein for its interaction with cellular membranes and phosphorylation, providing insights into the biology of alpha-synuclein in health and disease.
The neuronal protein alpha-synuclein is centrally involved in the neurodegeneration occurring in Parkinson's disease and related synucleinopathies. alpha-Synuclein's membrane-induced 3-11 helix conformation has a hydrophobic membrane-embedded half and a hydrophilic cytosolic half. Here, we studied the significance of (a) the surprising hydrophobicity of amino-acids at cytosol-exposed helix position 8; (b) the absence of positively charged lysine/arginine from all cytosol-exposed positions (1-5-8-9). We found that (a) further increasing hydrophobicity or adding lysine, but not glutamate, at position 8 augments both membrane interaction and S129 phosphorylation; (b) adding lysines at cytosol-exposed positions 1, 5, 8, or 9 has similar effects. Variants abundantly present in membranes by biochemical fractionation markedly colocalized with transferrin-receptor (an endosomal marker) in immunofluorescence-microscopy, indicating accumulation at vesicle membranes. Thus, we observed a striking correlation between membrane attraction and S129 phosphorylation, relevant for understanding alpha-synuclein biology in health and disease.
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