Direct observation of the three regions in α-synuclein that determine its membrane-bound behaviour

Giuliana Fusco, Alfonso De Simone, Tata Gopinath, Vitaly Vostrikov, Michele Vendruscolo, Christopher M. Dobson, Gianluigi Veglia

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190 Scopus citations

Abstract

α-synuclein (αS) is a protein involved in neurotransmitter release in presynaptic terminals, and whose aberrant aggregation is associated with Parkinson's disease. In dopaminergic neurons, αS exists in a tightly regulated equilibrium between water-soluble and membrane-associated forms. Here we use a combination of solid-state and solution NMR spectroscopy to characterize the conformations of αS bound to lipid membranes mimicking the composition and physical properties of synaptic vesicles. The study shows three αS regions possessing distinct structural and dynamical properties, including an N-terminal helical segment having a role of membrane anchor, an unstructured C-terminal region that is weakly associated with the membrane and a central region acting as a sensor of the lipid properties and determining the affinity of αS membrane binding. Taken together, our data define the nature of the interactions of αS with biological membranes and provide insights into their roles in the function of this protein and in the molecular processes leading to its aggregation.

Original languageEnglish (US)
Article number3827
JournalNature communications
Volume5
DOIs
StatePublished - May 29 2014

Bibliographical note

Funding Information:
We acknowledge financial support from Parkinson’s UK (G.F.), the Wellcome Trust (C.M.D., M.V.), the Medical Research Council UK (C.M.D., M.V.), NIH (G.V.) and the Leverhulme Trust (A.D.S.). We thank Dr. Youlin Xia for technical assistance in solution NMR.

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