Affiliation:
1. Ann Romney Center for Neurologic Diseases Brigham and Women's Hospital and Harvard Medical School Boston MA USA
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.
Funder
National Institute of Neurological Disorders and Stroke
Subject
Cell Biology,Genetics,Molecular Biology,Biochemistry,Structural Biology,Biophysics