Reconstitution of Helical Soluble α-Synuclein through Transient Interaction with Lipid Interfaces

α-synuclein (αSyn) is one of the key players in the pathogenesis of Parkinson’s disease (PD) and other synucleinopathies. Its misfolding and subsequent aggregation into intracellular inclusions are the pathological hallmark of these diseases and may also play a central role in the molecular cascade leading to neurodegeneration. In this work, we report the existence of a novel soluble α-helical conformer of αSyn, an archetypal “intrinsically disordered protein” (IDP), obtained through transient interaction with lipid interfaces. We describe how the stability of this conformer is highly dependent on the continuous, dynamic oligomerization of the folded species. The conformational space of αSyn appears to be highly context-dependent, and lipid bilayers might play crucial roles as molecular chaperones for cytosolic species in a cellular environment, as they do in the case of this previously unreported structure.Significance StatementBoth genetic and histopathologic evidence tie α-synuclein (αSyn) to the pathogenesis of Parkinson’s disease (PD), a widespread neurodegenerative disorder. Lipids play a central role in the dynamics of αSyn in physiology and disease. αSyn undergoes a coil-to-helix transition when binding to lipid vesicles and it is involved in the regulation of synaptic vesicle trafficking. Furthermore, recently discovered α-helical, aggregation-resistant “multimers” of αSyn could constitute a protective conformational pathway. We report the existence of a folded, lipid-unbound αSyn conformer that forms upon transient interaction with lipids and is stabilized by dynamic homooligomerization, suggesting that synaptic activity could modulate resistance towards aggregation. Our results are therefore important both for the molecular pathology of PD and the structural biology of intrinsically disordered proteins.