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

Research output: Contribution to journalArticle

82 Citations (Scopus)

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

Fingerprint

Synucleins
Ion Channels
Membranes
Membrane Potentials
Parkinson Disease
Conformations
Lipids
Fluorescence Spectrometry
Proteins
Hot Temperature
Thermodynamic stability

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

Helical α-synuclein forms highly conductive ion channels. / Zakharov, Stanislav D.; Hulleman, John D.; Dutseva, Elena A.; Antonenko, Yuri N.; Rochet, Jean Christophe; Cramer, William A.

In: Biochemistry, Vol. 46, No. 50, 18.12.2007, p. 14369-14379.

Research output: Contribution to journalArticle

Zakharov, SD, Hulleman, JD, Dutseva, EA, Antonenko, YN, Rochet, JC & Cramer, WA 2007, 'Helical α-synuclein forms highly conductive ion channels', Biochemistry, vol. 46, no. 50, pp. 14369-14379. https://doi.org/10.1021/bi701275p
Zakharov SD, Hulleman JD, Dutseva EA, Antonenko YN, Rochet JC, Cramer WA. Helical α-synuclein forms highly conductive ion channels. Biochemistry. 2007 Dec 18;46(50):14369-14379. https://doi.org/10.1021/bi701275p
Zakharov, Stanislav D. ; Hulleman, John D. ; Dutseva, Elena A. ; Antonenko, Yuri N. ; Rochet, Jean Christophe ; Cramer, William A. / Helical α-synuclein forms highly conductive ion channels. In: Biochemistry. 2007 ; Vol. 46, No. 50. pp. 14369-14379.
@article{e43305ff98b14e05ba9025a5dcb4eafb,
title = "Helical α-synuclein forms highly conductive ion channels",
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.",
author = "Zakharov, {Stanislav D.} and Hulleman, {John D.} and Dutseva, {Elena A.} and Antonenko, {Yuri N.} and Rochet, {Jean Christophe} and Cramer, {William A.}",
year = "2007",
month = "12",
day = "18",
doi = "10.1021/bi701275p",
language = "English (US)",
volume = "46",
pages = "14369--14379",
journal = "Biochemistry",
issn = "0006-2960",
publisher = "American Chemical Society",
number = "50",

}

TY - JOUR

T1 - Helical α-synuclein forms highly conductive ion channels

AU - Zakharov, Stanislav D.

AU - Hulleman, John D.

AU - Dutseva, Elena A.

AU - Antonenko, Yuri N.

AU - Rochet, Jean Christophe

AU - Cramer, William A.

PY - 2007/12/18

Y1 - 2007/12/18

N2 - 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.

AB - 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.

UR - http://www.scopus.com/inward/record.url?scp=37249003742&partnerID=8YFLogxK

UR - http://www.scopus.com/inward/citedby.url?scp=37249003742&partnerID=8YFLogxK

U2 - 10.1021/bi701275p

DO - 10.1021/bi701275p

M3 - Article

C2 - 18031063

AN - SCOPUS:37249003742

VL - 46

SP - 14369

EP - 14379

JO - Biochemistry

JF - Biochemistry

SN - 0006-2960

IS - 50

ER -