Unveiling transient protein-protein interactions that modulate inhibition of alpha-synuclein aggregation by beta-synuclein, a pre-synaptic protein that co-localizes with alpha-synuclein

Pathology in Parkinson's disease is linked to self-association of alpha-Synuclein (alpha S) into pathogenic oligomeric species and highly ordered amyloid fibrils. Developing effective therapeutic strategies against this debilitating disease is critical and beta S, a pre-synaptic protein that co-localizes with alpha S, can act as an inhibitor of alpha S assembly. Despite the potential importance of beta S as an inhibitor of alpha S, the nature, location and specificity of the molecular interactions between these two proteins is unknown. Here we use NMR paramagnetic relaxation enhancement experiments, to demonstrate that beta S interacts directly with alpha S in a transient dimer complex with high specificity and weak affinity. Inhibition of alpha S by beta S arises from transient alpha S/beta S heterodimer species that exist primarily in head-to-tail configurations while alpha S aggregation arises from a more heterogeneous and weaker range of transient interactions that include both head-to-head and head-to-tail configurations. Our results highlight that intrinsically disordered proteins can interact directly with one another at low affinity and that the transient interactions that drive inhibition versus aggregation are distinct by virtue of their plasticity and specificity.