Structural basis of synaptic vesicle assembly promoted by α-synuclein

alpha-synuclein (alpha S) is an intrinsically disordered protein whose fibrillar aggregates are the major constituents of Lewy bodies in Parkinson's disease. Although the specific function of alpha S is still unclear, a general consensus is forming that it has a key role in regulating the process of neurotransmitter release, which is associated with the mediation of synaptic vesicle interactions and assembly. Here we report the analysis of wild-type alpha S and two mutational variants linked to familial Parkinson's disease to describe the structural basis of a molecular mechanism enabling alpha S to induce the clustering of synaptic vesicles. We provide support for this 'double-anchor' mechanism by rationally designing and experimentally testing a further mutational variant of alpha S engineered to promote stronger interactions between synaptic vesicles. Our results characterize the nature of the active conformations of alpha S that mediate the clustering of synaptic vesicles, and indicate their relevance in both functional and pathological contexts.