Adding hydrophobicity or positive charges to the cytosolic half of the α‐synuclein 3–11 helix increases membrane association and S129 phosphorylation

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Abstract
The neuronal protein α‐synuclein is centrally involved in the neurodegeneration occurring in Parkinson's disease and related synucleinopathies. α‐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 α‐synuclein biology in health and disease.
Funding Information
  • National Institute of Neurological Disorders and Stroke (NS099328, NS109209, NS121826, NS133979)

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