TY - JOUR
T1 - Structural basis of synaptic vesicle assembly promoted by α-synuclein
AU - Fusco, Giuliana
AU - Pape, Tillmann
AU - Stephens, Amberley D.
AU - Mahou, Pierre
AU - Costa, Ana Rita
AU - Kaminski, Clemens F.
AU - Kaminski Schierle, Gabriele S.
AU - Vendruscolo, Michele
AU - Veglia, Gianluigi
AU - Dobson, Christopher M.
AU - De Simone, Alfonso
PY - 2016/9/19
Y1 - 2016/9/19
N2 - 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.
AB - 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.
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UR - http://www.scopus.com/inward/citedby.url?scp=84988329832&partnerID=8YFLogxK
U2 - 10.1038/ncomms12563
DO - 10.1038/ncomms12563
M3 - Article
C2 - 27640673
AN - SCOPUS:84988329832
SN - 2041-1723
VL - 7
JO - Nature communications
JF - Nature communications
M1 - 12563
ER -