Structural basis of synaptic vesicle assembly promoted by α-synuclein

Giuliana Fusco, Tillmann Pape, Amberley D. Stephens, Pierre Mahou, Ana Rita Costa, Clemens F. Kaminski, Gabriele S. Kaminski Schierle, Michele Vendruscolo, Gianluigi Veglia, Christopher M. Dobson () and Alfonso De Simone ()
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Giuliana Fusco: University of Cambridge
Tillmann Pape: Imperial College London
Amberley D. Stephens: University of Cambridge
Pierre Mahou: University of Cambridge
Ana Rita Costa: University of Cambridge
Clemens F. Kaminski: University of Cambridge
Gabriele S. Kaminski Schierle: University of Cambridge
Michele Vendruscolo: University of Cambridge
Gianluigi Veglia: Molecular Biology & Biophysics, University of Minnesota
Christopher M. Dobson: University of Cambridge
Alfonso De Simone: Imperial College London

Nature Communications, 2016, vol. 7, issue 1, 1-12

Abstract: Abstract α-synuclein (αS) is an intrinsically disordered protein whose fibrillar aggregates are the major constituents of Lewy bodies in Parkinson’s disease. Although the specific function of αS 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 αS and two mutational variants linked to familial Parkinson’s disease to describe the structural basis of a molecular mechanism enabling αS 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 αS engineered to promote stronger interactions between synaptic vesicles. Our results characterize the nature of the active conformations of αS that mediate the clustering of synaptic vesicles, and indicate their relevance in both functional and pathological contexts.

Date: 2016
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DOI: 10.1038/ncomms12563

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