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          Institute: MPI für biophysikalische Chemie     Collection: Molekulare Biologie (Dr. Thomas M. Jovin)     Display Documents

ID: 205007.0, MPI für biophysikalische Chemie / Molekulare Biologie (Dr. Thomas M. Jovin)
Impact of the acidic C-terminal region comprising amino acids 109-140 on α-synuclein aggregation in vitro
Authors:Hoyer, W.; Cherny, D. I.; Subramaniam, V.; Jovin, T. M.
Date of Publication (YYYY-MM-DD):2004-11-26
Title of Journal:Biochemistry
Issue / Number:51
Start Page:16233
End Page:16242
Sequence Number of Article:doi:10.1021/bi048453u
Copyright:c* American Chemical Society
Review Status:not specified
Audience:Not Specified
Abstract / Description:The aggregation of α-synuclein, involved in the pathogenesis of several neurodegenerative disorders such as Parkinson’s disease, is enhanced in vitro by biogenic polyamines binding to the highly charged C-terminal region aa109-140. In this study, we investigated the influence of this region on the aggregation kinetics, monitored by thioflavin T binding and static light scattering, and morphology, assessed by electron microscopy, fluorescence microscopy, and turbidity, by comparing the effect of various solution conditions on the wild-type protein, the disease related mutants A53T and A30P, and two truncated variants, syn(1-108) and syn(1-124), lacking the complete or the C-terminal half of the polyamine binding site. In the presence of the intact C-terminus, aggregation was strongly retarded in physiological buffer. This inhibition of aggregation was overridden by (i) addition of spermine or MgCl2 or lowering of pH, leading to strong charge shielding in the C-terminus or (ii) by truncation of aa125-140 or aa109-140. Addition of MgCl2 or spermine or acidification were not effective in promoting aggregation of syn(1-108). The impact of the disease-related mutations on the aggregation kinetics was dependent on the solution conditions, with the aggregation propensity order A53T ~ wt > A30P at low ionic strength, but A53T > wt ~ A30P at high ionic strength, with exceedingly potent promotion of aggregation by the A53T mutation in the presence of spermine. In contrast to full-length R-synuclein aggregates, those formed from syn(1-108) did not exhibit a pronounced polymorphism. The effects of the C-terminus on aggregation cannot be rationalized merely by a contribution to the protein net charge, but rather suggest a specific role of aa109-140 in the regulation of aggregation, presumably involving formation of intramolecular contacts.
Last Change of the Resource (YYYY-MM-DD):2004-12-23
External Publication Status:published
Document Type:Article
Communicated by:N. N.
Affiliations:MPI für biophysikalische Chemie/Abt. Thomas Jovin / 060
External Affiliations:Institute of Molecular Genetics, Russian Academy of Sciences, Kurchatov’s Square, 123182 Moscow, Russia; Biophysical Engineering Group, Faculty of Science and Technology, University of Twente, P.O. Box 217, 7500 AE Enschede, The Netherlands
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