Helical α-synuclein forms highly conductive ion channels

Stanislav D. Zakharov, John D. Hulleman, Elena A. Dutseva, Yuri N. Antonenko, Jean Christophe Rochet, William A. Cramer

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Abstract

α-Synuclein (αS) is a cytosolic protein involved in the etiology of Parkinson's disease (PD). Disordered in an aqueous environment, αS develops a highly helical conformation when bound to membranes having a negatively charged surface and a large curvature. It exhibits a membrane-permeabilizing activity that has been attributed to oligomeric protofibrillar forms. In this study, monomeric wild-type αS and two mutants associated with familial PD, E46K and A53T, formed ion channels with well-defined conductance states in membranes containing 25-50% anionic lipid and 50% phosphatidylethanolamine (PE) in the presence of a trans-negative potential. Another familial mutant, A30P, known to have a lower membrane affinity, did not form ion channels. Ca2+ prevented channel formation when added to membranes before αS and decreased channel conductance when added to preformed channels. In contrast to the monomer, membrane permeabilization by oligomeric αS was not characterized by formation of discrete channels, a requirement for PE lipid, or a membrane potential. Channel activity, α-helical content, thermal stability of membrane-bound αS determined by far-UV CD, and lateral mobility of αS bound to planar membranes measured by fluorescence correlation spectroscopy were correlated. It was inferred that discrete ion channels with well-defined conductance states were formed in the presence of a membrane potential by one or several molecules of monomeric αS in an α-helical conformation and that such channels may have a role in the normal function and/or pathophysiology of the protein.

Original languageEnglish (US)
Pages (from-to)14369-14379
Number of pages11
JournalBiochemistry
Volume46
Issue number50
DOIs
StatePublished - Dec 18 2007

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ASJC Scopus subject areas

  • Biochemistry

Cite this

Zakharov, S. D., Hulleman, J. D., Dutseva, E. A., Antonenko, Y. N., Rochet, J. C., & Cramer, W. A. (2007). Helical α-synuclein forms highly conductive ion channels. Biochemistry, 46(50), 14369-14379. https://doi.org/10.1021/bi701275p