Alpha-synuclein (aSyn) is an intrinsically disordered protein found in neurons whose dysfunction is related to the formation of aggregates in Parkinson’s Disease. The normal physiological function of aSyn is suspected to be related to the synaptic vesicle cycle, however the specific role the protein plays remains unknown. Because both the function and dysfunction of aSyn are linked to its interaction with lipid membranes, it is especially important to understand the intricacies of these interactions in order to discern the differences between normal function and disease progression. Recent work has suggested the importance of lipid packing defects in mediating aSyn-membrane binding, along with the potential importance of membrane tension. In this work, we investigate the effects of osmotic tension, lipid packing defects, and lipid depletion on aSyn binding using a combination of tryptophan fluorescence spectroscopy and optical microscopy experiments. Our results highlight the importance of lipid depletion when considering aSyn-membrane interactions, which, when put into perspective with a new mathematical framework for protein-membrane binding, furthers our understanding of the definition of a binding site for aSyn.

Characterizing the membrane binding site for alpha-synuclein

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