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On the role of sidechain size and charge in the aggregation of Aβ42 with familial mutations

Yang, Xiaoting LU ; Meisl, Georg; Frohm, Birgitta LU ; Thulin, Eva LU ; Knowles, Tuomas P.J. and Linse, Sara LU (2018) In Proceedings of the National Academy of Sciences of the United States of America 115(26). p.5849-5858
Abstract

The aggregation of the amyloid-β (Aβ) peptide is linked to the pathogenesis of Alzheimer’s disease (AD). In particular, some point mutations within Aβ are associated with early-onset familial Alzheimer’s disease. Here we set out to explore how the physical properties of the altered side chains, including their sizes and charges, affect the molecular mechanisms of aggregation. We focus on Aβ42 with familial mutations—A21G (Flemish), E22K (Italian), E22G (Arctic), E22Q (Dutch), and D23N (Iowa)—which lead to similar or identical pathology with sporadic AD or severe cerebral amyloid angiopathy. Through global kinetic analysis, we find that for the E22K, E22G, E22Q, and D23N mutations, the acceleration of the overall aggregation originates... (More)

The aggregation of the amyloid-β (Aβ) peptide is linked to the pathogenesis of Alzheimer’s disease (AD). In particular, some point mutations within Aβ are associated with early-onset familial Alzheimer’s disease. Here we set out to explore how the physical properties of the altered side chains, including their sizes and charges, affect the molecular mechanisms of aggregation. We focus on Aβ42 with familial mutations—A21G (Flemish), E22K (Italian), E22G (Arctic), E22Q (Dutch), and D23N (Iowa)—which lead to similar or identical pathology with sporadic AD or severe cerebral amyloid angiopathy. Through global kinetic analysis, we find that for the E22K, E22G, E22Q, and D23N mutations, the acceleration of the overall aggregation originates primarily from the modulation of the nucleation processes, in particular secondary nucleation on the surface of existing fibrils, whereas the elongation process is not significantly affected. Remarkably, the D23 position appears to be responsible for most of the charge effects during nucleation, while the size of the side chain at the E22 position plays a more significant role than its charge. Thus, we have developed a kinetic approach to determine the nature and the magnitude of the contribution of specific residues to the rate of individual steps of the aggregation reaction, through targeted mutations and variations in ionic strength. This strategy can help rationalize the effect of some disease-related mutations as well as yield insights into the mechanism of aggregation and the transition states of the wild-type protein.

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author
organization
publishing date
type
Contribution to journal
publication status
published
subject
keywords
Aggregation mechanism, Amyloid, Driving forces, Kinetic analysis, Self-assembly
in
Proceedings of the National Academy of Sciences of the United States of America
volume
115
issue
26
pages
5849 - 5858
publisher
National Acad Sciences
external identifiers
  • scopus:85049050338
ISSN
0027-8424
DOI
10.1073/pnas.1803539115
language
English
LU publication?
yes
id
cb6a140e-e66d-4113-82fc-59fbd5b5956f
date added to LUP
2018-07-04 13:33:14
date last changed
2018-08-12 04:44:54
@article{cb6a140e-e66d-4113-82fc-59fbd5b5956f,
  abstract     = {<p>The aggregation of the amyloid-β (Aβ) peptide is linked to the pathogenesis of Alzheimer’s disease (AD). In particular, some point mutations within Aβ are associated with early-onset familial Alzheimer’s disease. Here we set out to explore how the physical properties of the altered side chains, including their sizes and charges, affect the molecular mechanisms of aggregation. We focus on Aβ42 with familial mutations—A21G (Flemish), E22K (Italian), E22G (Arctic), E22Q (Dutch), and D23N (Iowa)—which lead to similar or identical pathology with sporadic AD or severe cerebral amyloid angiopathy. Through global kinetic analysis, we find that for the E22K, E22G, E22Q, and D23N mutations, the acceleration of the overall aggregation originates primarily from the modulation of the nucleation processes, in particular secondary nucleation on the surface of existing fibrils, whereas the elongation process is not significantly affected. Remarkably, the D23 position appears to be responsible for most of the charge effects during nucleation, while the size of the side chain at the E22 position plays a more significant role than its charge. Thus, we have developed a kinetic approach to determine the nature and the magnitude of the contribution of specific residues to the rate of individual steps of the aggregation reaction, through targeted mutations and variations in ionic strength. This strategy can help rationalize the effect of some disease-related mutations as well as yield insights into the mechanism of aggregation and the transition states of the wild-type protein.</p>},
  author       = {Yang, Xiaoting and Meisl, Georg and Frohm, Birgitta and Thulin, Eva and Knowles, Tuomas P.J. and Linse, Sara},
  issn         = {0027-8424},
  keyword      = {Aggregation mechanism,Amyloid,Driving forces,Kinetic analysis,Self-assembly},
  language     = {eng},
  month        = {06},
  number       = {26},
  pages        = {5849--5858},
  publisher    = {National Acad Sciences},
  series       = {Proceedings of the National Academy of Sciences of the United States of America},
  title        = {On the role of sidechain size and charge in the aggregation of Aβ42 with familial mutations},
  url          = {http://dx.doi.org/10.1073/pnas.1803539115},
  volume       = {115},
  year         = {2018},
}