Distinct phases of free α-synuclein--a Monte Carlo study

Proteins
Sigurður Ægir JónssonAnders Irbäck

Abstract

The α-synuclein protein (αS), implicated in Parkinson's disease, shows conformational versatility. It aggregates into β-sheet-rich fibrils, occurs in helical membrane-bound forms, is disordered as a free monomer, and has recently been suggested to have a folded helical tetramer as its main physiological form. Here, we use implicit solvent all-atom Monte Carlo methods to explore the conformational ensemble sampled by the free αS monomer. We analyze secondary structure propensities, size, and topological properties and compare with existing experimental data. Our study suggests that free αS has two distinct phases. One phase has the expected disordered character. The other phase also shows large conformational variability. However, in this phase, the β-strand content is substantial, and the backbone fold shows statistical similarities with that in αS fibrils. Presence of this phase is consistent with data from low-temperature experiments. Conversion of disordered αS to this fibril-like form requires the crossing of a rather large apparent free-energy barrier.

References

Dec 1, 1993·Proceedings of the National Academy of Sciences of the United States of America·K UédaT Saitoh
Dec 1, 1995·Proteins·D Frishman, P Argos
Aug 28, 1997·Nature·M G SpillantiniM Goedert
May 23, 1998·The Journal of Biological Chemistry·W S DavidsonJ M George
May 30, 1998·Proceedings of the National Academy of Sciences of the United States of America·M G SpillantiniM Goedert
Sep 18, 1989·Physical Review Letters·A M Ferrenberg, R H Swendsen
Feb 2, 2000·Biophysical Journal·J García De La TorreB Carrasco
Apr 26, 2000·Proceedings of the National Academy of Sciences of the United States of America·L C SerpellR A Crowther
Aug 1, 2000·The Journal of Biological Chemistry·E JoP E Fraser
Jan 22, 2001·The Journal of Biological Chemistry·V N UverskyA L Fink
Apr 5, 2001·Journal of Molecular Biology·D EliezerG Browne
Apr 6, 2001·Physical Review Letters·F Wang, D P Landau
Mar 15, 2002·The Journal of Biological Chemistry·Hirotomo MiakeMasato Hasegawa
Aug 28, 2002·Biochemical Society Transactions·O M A el-Agnaf, G B Irvine
May 27, 2003·Journal of Biomolecular NMR·Stephen NealDavid S Wishart
Aug 29, 2003·Biophysical Journal·Anders IrbäckStefan Wallin
Jan 13, 2005·Journal of the American Chemical Society·Matthew M DedmonChristopher M Dobson
Jan 27, 2005·Proceedings of the National Academy of Sciences of the United States of America·Carlos W BertonciniMarkus Zweckstetter
Oct 26, 2005·Proceedings of the National Academy of Sciences of the United States of America·Henrike HeiseMarc Baldus
Jul 19, 2006·Journal of Computational Chemistry·Anders Irbäck, Sandipan Mohanty
Nov 8, 2006·Protein Science : a Publication of the Protein Society·Joseph A MarshJulie D Forman-Kay
Jun 19, 2007·The Journal of Biological Chemistry·Min ChenRalf Langen
Aug 28, 2007·Chembiochem : a European Journal of Chemical Biology·Hai-Young KimMarkus Zweckstetter
Apr 15, 2008·Proceedings of the National Academy of Sciences of the United States of America·Sandipan MohantyUlrich H E Hansmann
Jun 14, 2008·Proceedings of the National Academy of Sciences of the United States of America·Marçal VilarRoland Riek
Sep 5, 2008·Nature Reviews. Neuroscience·Patrik BrundinTamas Revesz
Dec 6, 2008·PLoS Computational Biology·Da-Wei LiShuanghong Huo
Dec 11, 2008·Proceedings of the National Academy of Sciences of the United States of America·Christine C JaoRalf Langen
Mar 19, 2009·Proceedings of the National Academy of Sciences of the United States of America·Allan Chris M FerreonAshok A Deniz
Apr 7, 2009·Journal of Molecular Biology·Carla C RospigliosiDavid Eliezer
Apr 10, 2009·PMC Biophysics·Anders IrbäckSandipan Mohanty
May 29, 2009·Protein Science : a Publication of the Protein Society·Sebastian McClendonDavid Eliezer
Jun 26, 2009·Protein Science : a Publication of the Protein Society·Min-Kyu ChoMarkus Zweckstetter
Jul 7, 2009·Journal of Molecular Biology·Kuen-Phon WuJean Baum
Dec 24, 2009·Journal of the American Chemical Society·Jane R AllisonMichele Vendruscolo
Feb 9, 2011·Proceedings of the National Academy of Sciences of the United States of America·Lise GiehmBente Vestergaard
May 28, 2011·Journal of Molecular Biology·Simon MitternachtAnders Irbäck
Jun 22, 2011·Journal of Molecular Biology·Katerina LevitanGlenn L Millhauser

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Citations

Oct 5, 2013·The Journal of Chemical Physics·A DasS S Plotkin
Mar 13, 2014·Journal of Molecular Cell Biology·Rachel L RedlerNikolay V Dokholyan
Dec 24, 2015·European Biophysics Journal : EBJ·Mark A HealeyJack A Tuszynski
Aug 19, 2014·Protein Science : a Publication of the Protein Society·Jitka PetrlovaAnders Irbäck
Jun 26, 2013·Biophysical Journal·Sigurður Ægir JónssonAnders Irbäck
Dec 17, 2014·Journal of the American Society for Mass Spectrometry·Annalisa D'UrzoRita Grandori
May 10, 2016·The Journal of Chemical Physics·Anna BilleAnders Irbäck
Nov 10, 2015·The Journal of Chemical Physics·Anna BilleAnders Irbäck
Jan 9, 2016·PloS One·Pengfei TianDaniel Erik Otzen
Feb 10, 2018·The Journal of Chemical Physics·Daniel NilssonAnders Irbäck
Mar 27, 2020·Frontiers in Cellular Neuroscience·Deqiang HanZhiguo Chen
Apr 12, 2019·Chemical Reviews·Ioana M Ilie, Amedeo Caflisch
Jan 18, 2014·Chemical Reviews·Marco BrucaleBruno Samorì
Feb 13, 2019·The Journal of Physical Chemistry. B·Anna BilleAnders Irbäck
Aug 28, 2013·The Journal of Physical Chemistry. B·Parichita MazumderTobias S Ulmer
Nov 12, 2013·Journal of Chemical Theory and Computation·Xiaojing CongPaolo Carloni
Dec 23, 2020·Journal of Chemical Information and Modeling·Karnesh JainJerome Delhommelle

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