Structural basis of synaptic vesicle assembly promoted by ?-synuclein.

ABSTRACT: ?-synuclein (?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 ?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 ?S and two mutational variants linked to familial Parkinson's disease to describe the structural basis of a molecular mechanism enabling ?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 ?S engineered to promote stronger interactions between synaptic vesicles. Our results characterize the nature of the active conformations of ?S that mediate the clustering of synaptic vesicles, and indicate their relevance in both functional and pathological contexts.

SUBMITTER: Fusco G 

PROVIDER: S-EPMC5031799 | biostudies-other | 2016 Sep

REPOSITORIES: biostudies-other