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Anomalous Salt Dependence Reveals an Interplay of Attractive and Repulsive Electrostatic Interactions in α-synuclein Fibril Formation

Gaspar, Ricardo LU ; Lund, Mikael LU orcid ; Sparr, Emma LU and Linse, Sara LU (2020) In Quarterly Reviews in Biophysics Discovery 1.
Abstract
α-Synuclein (α-syn) is an intrinsically disordered protein with a highly asymmetric charge distribution, whose aggregation is linked to Parkinson’s disease. The effect of ionic strength was investigated at mildly acidic pH (5.5) in the presence of catalytic surfaces in the form of α-syn seeds or anionic lipid vesicles using thioflavin T fluorescence measurements. Similar trends were observed with both surfaces: increasing ionic strength reduced the rate of α-syn aggregation although the surfaces as well as α-syn have a net negative charge at pH 5.5. This anomalous salt dependence implies that short-range attractive electrostatic interactions are critical for secondary nucleation as well as heterogeneous primary nucleation. Such... (More)
α-Synuclein (α-syn) is an intrinsically disordered protein with a highly asymmetric charge distribution, whose aggregation is linked to Parkinson’s disease. The effect of ionic strength was investigated at mildly acidic pH (5.5) in the presence of catalytic surfaces in the form of α-syn seeds or anionic lipid vesicles using thioflavin T fluorescence measurements. Similar trends were observed with both surfaces: increasing ionic strength reduced the rate of α-syn aggregation although the surfaces as well as α-syn have a net negative charge at pH 5.5. This anomalous salt dependence implies that short-range attractive electrostatic interactions are critical for secondary nucleation as well as heterogeneous primary nucleation. Such interactions were confirmed in Monte Carlo simulations of α-syn monomers interacting with surface-grafted C-terminal tails, and found to be weakened in the presence of salt. Thus, nucleation of α-syn aggregation depends critically on an attractive electrostatic component that is screened by salt to the extent that it outweighs the screening of the long-range repulsion between negatively charged monomers and negative surfaces. Interactions between the positively charged N-termini of α-syn monomers on the one hand, and the negatively C-termini of α-syn on fibrils or vesicles surfaces on the other hand, are thus critical for nucleation. (Less)
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author
; ; and
organization
publishing date
type
Contribution to journal
publication status
published
subject
keywords
Asymmetric charge distribution, Electrostatic interactions, Secondary nucleation, Protein aggregation, Self-assembly, Salt screening
in
Quarterly Reviews in Biophysics Discovery
volume
1
article number
e2
pages
11 pages
publisher
Cambridge University Press
external identifiers
  • scopus:85098690501
ISSN
2633-2892
DOI
10.1017/qrd.2020.7
language
English
LU publication?
yes
id
8eac337e-20de-4fb6-a253-c962bb1ce397
date added to LUP
2021-02-04 21:58:48
date last changed
2023-11-10 21:33:01
@article{8eac337e-20de-4fb6-a253-c962bb1ce397,
  abstract     = {{α-Synuclein (α-syn) is an intrinsically disordered protein with a highly asymmetric charge distribution, whose aggregation is linked to Parkinson’s disease. The effect of ionic strength was investigated at mildly acidic pH (5.5) in the presence of catalytic surfaces in the form of α-syn seeds or anionic lipid vesicles using thioflavin T fluorescence measurements. Similar trends were observed with both surfaces: increasing ionic strength reduced the rate of α-syn aggregation although the surfaces as well as α-syn have a net negative charge at pH 5.5. This anomalous salt dependence implies that short-range attractive electrostatic interactions are critical for secondary nucleation as well as heterogeneous primary nucleation. Such interactions were confirmed in Monte Carlo simulations of α-syn monomers interacting with surface-grafted C-terminal tails, and found to be weakened in the presence of salt. Thus, nucleation of α-syn aggregation depends critically on an attractive electrostatic component that is screened by salt to the extent that it outweighs the screening of the long-range repulsion between negatively charged monomers and negative surfaces. Interactions between the positively charged N-termini of α-syn monomers on the one hand, and the negatively C-termini of α-syn on fibrils or vesicles surfaces on the other hand, are thus critical for nucleation.}},
  author       = {{Gaspar, Ricardo and Lund, Mikael and Sparr, Emma and Linse, Sara}},
  issn         = {{2633-2892}},
  keywords     = {{Asymmetric charge distribution; Electrostatic interactions; Secondary nucleation; Protein aggregation; Self-assembly; Salt screening}},
  language     = {{eng}},
  month        = {{08}},
  publisher    = {{Cambridge University Press}},
  series       = {{Quarterly Reviews in Biophysics Discovery}},
  title        = {{Anomalous Salt Dependence Reveals an Interplay of Attractive and Repulsive Electrostatic Interactions in α-synuclein Fibril Formation}},
  url          = {{http://dx.doi.org/10.1017/qrd.2020.7}},
  doi          = {{10.1017/qrd.2020.7}},
  volume       = {{1}},
  year         = {{2020}},
}