Helical alpha-Synuclein Forms Highly Conductive Ion Channels

@article{citeulike:2068294, abstract = {Abstract: -Synuclein (S) is a cytosolic protein involved in the etiology of Parkinson's disease (PD). Disordered in an aqueous environment, S 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 S 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 S and decreased channel conductance when added to preformed channels. In contrast to the monomer, membrane permeabilization by oligomeric S was not characterized by formation of discrete channels, a requirement for PE lipid, or a membrane potential. Channel activity, -helical content, thermal stability of membrane-bound S determined by far-UV CD, and lateral mobility of S 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 S in an -helical conformation and that such channels may have a role in the normal function and/or pathophysiology of the protein.}, address = {Departments of Biological Sciences and Medicinal Chemistry and Molecular Pharmacology, Purdue University, West Lafayette, Indiana 47907-2054, Institute of Basic Biological Problems, Russian Academy of Sciences, Puschino, Moscow Region 140290, Russian Federation, and A. N. Belozersky Institute of Physico-Chemical Biology, Moscow State University, Moscow 119992, Russian Federation}, author = {Zakharov, S. D. and Hulleman, J. D. and Dutseva, E. A. and Antonenko, Y. N. and Rochet, J. C. and Cramer, W. A. }, citeulike-article-id = {2068294}, doi = {10.1021/bi701275p}, journal = {Biochemistry}, keywords = {2007, structure, synuclein}, month = {November}, posted-at = {2008-05-07 08:40:23}, priority = {0}, title = {Helical alpha-Synuclein Forms Highly Conductive Ion Channels}, url = {http://dx.doi.org/10.1021/bi701275p}, year = {2007} }

TY - JOUR ID - citeulike:2068294 L3 - citeulike-article-id:2068294 TI - Helical alpha-Synuclein Forms Highly Conductive Ion Channels JF - Biochemistry AD - Departments of Biological Sciences and Medicinal Chemistry and Molecular Pharmacology, Purdue University, West Lafayette, Indiana 47907-2054, Institute of Basic Biological Problems, Russian Academy of Sciences, Puschino, Moscow Region 140290, Russian Federation, and A. N. Belozersky Institute of Physico-Chemical Biology, Moscow State University, Moscow 119992, Russian Federation N2 - Abstract: -Synuclein (S) is a cytosolic protein involved in the etiology of Parkinson's disease (PD). Disordered in an aqueous environment, S 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 S 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 S and decreased channel conductance when added to preformed channels. In contrast to the monomer, membrane permeabilization by oligomeric S was not characterized by formation of discrete channels, a requirement for PE lipid, or a membrane potential. Channel activity, -helical content, thermal stability of membrane-bound S determined by far-UV CD, and lateral mobility of S 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 S in an -helical conformation and that such channels may have a role in the normal function and/or pathophysiology of the protein. KW - 2007 KW - structure KW - synuclein AU - Zakharov, SD AU - Hulleman, JD AU - Dutseva, EA AU - Antonenko, YN AU - Rochet, JC AU - Cramer, WA PY - 2007/11/22/ UR - http://dx.doi.org/10.1021/bi701275p ER -