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Alzheimer's Aβ Peptides with Disease-Associated N-Terminal Modifications: Influence of Isomerisation, Truncation and Mutation on Cu(2+) Coordination
BACKGROUND: The amyloid-β (Aβ) peptide is the primary component of the extracellular senile plaques characteristic of Alzheimer's disease (AD). The metals hypothesis implicates redox-active copper ions in the pathogenesis of AD and the Cu(2+) coordination of various Aβ peptides has been widely...
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Formato: | Texto |
Lenguaje: | English |
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Public Library of Science
2010
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Acceso en línea: | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3012727/ https://www.ncbi.nlm.nih.gov/pubmed/21209855 http://dx.doi.org/10.1371/journal.pone.0015875 |
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author | Drew, Simon C. Masters, Colin L. Barnham, Kevin J. |
author_facet | Drew, Simon C. Masters, Colin L. Barnham, Kevin J. |
author_sort | Drew, Simon C. |
collection | PubMed |
description | BACKGROUND: The amyloid-β (Aβ) peptide is the primary component of the extracellular senile plaques characteristic of Alzheimer's disease (AD). The metals hypothesis implicates redox-active copper ions in the pathogenesis of AD and the Cu(2+) coordination of various Aβ peptides has been widely studied. A number of disease-associated modifications involving the first 3 residues are known, including isomerisation, mutation, truncation and cyclisation, but are yet to be characterised in detail. In particular, Aβ in plaques contain a significant amount of truncated pyroglutamate species, which appear to correlate with disease progression. METHODOLOGY/PRINCIPAL FINDINGS: We previously characterised three Cu(2+)/Aβ1–16 coordination modes in the physiological pH range that involve the first two residues. Based upon our finding that the carbonyl of Ala2 is a Cu(2+) ligand, here we speculate on a hypothetical Cu(2+)-mediated intramolecular cleavage mechanism as a source of truncations beginning at residue 3. Using EPR spectroscopy and site-specific isotopic labelling, we have also examined four Aβ peptides with biologically relevant N-terminal modifications, Aβ1[isoAsp]–16, Aβ1–16(A2V), Aβ3–16 and Aβ3[pE]–16. The recessive A2V mutation preserved the first coordination sphere of Cu(2+)/Aβ, but altered the outer coordination sphere. Isomerisation of Asp1 produced a single dominant species involving a stable 5-membered Cu(2+) chelate at the amino terminus. The Aβ3–16 and Aβ3[pE]–16 peptides both exhibited an equilibrium between two Cu(2+) coordination modes between pH 6–9 with nominally the same first coordination sphere, but with a dramatically different pH dependence arising from differences in H-bonding interactions at the N-terminus. CONCLUSIONS/SIGNIFICANCE: N-terminal modifications significantly influence the Cu(2+) coordination of Aβ, which may be critical for alterations in aggregation propensity, redox-activity, resistance to degradation and the generation of the Aβ3–× (× = 40/42) precursor of disease-associated Aβ3[pE]–x species. |
format | Text |
id | pubmed-3012727 |
institution | National Center for Biotechnology Information |
language | English |
publishDate | 2010 |
publisher | Public Library of Science |
record_format | MEDLINE/PubMed |
spelling | pubmed-30127272011-01-05 Alzheimer's Aβ Peptides with Disease-Associated N-Terminal Modifications: Influence of Isomerisation, Truncation and Mutation on Cu(2+) Coordination Drew, Simon C. Masters, Colin L. Barnham, Kevin J. PLoS One Research Article BACKGROUND: The amyloid-β (Aβ) peptide is the primary component of the extracellular senile plaques characteristic of Alzheimer's disease (AD). The metals hypothesis implicates redox-active copper ions in the pathogenesis of AD and the Cu(2+) coordination of various Aβ peptides has been widely studied. A number of disease-associated modifications involving the first 3 residues are known, including isomerisation, mutation, truncation and cyclisation, but are yet to be characterised in detail. In particular, Aβ in plaques contain a significant amount of truncated pyroglutamate species, which appear to correlate with disease progression. METHODOLOGY/PRINCIPAL FINDINGS: We previously characterised three Cu(2+)/Aβ1–16 coordination modes in the physiological pH range that involve the first two residues. Based upon our finding that the carbonyl of Ala2 is a Cu(2+) ligand, here we speculate on a hypothetical Cu(2+)-mediated intramolecular cleavage mechanism as a source of truncations beginning at residue 3. Using EPR spectroscopy and site-specific isotopic labelling, we have also examined four Aβ peptides with biologically relevant N-terminal modifications, Aβ1[isoAsp]–16, Aβ1–16(A2V), Aβ3–16 and Aβ3[pE]–16. The recessive A2V mutation preserved the first coordination sphere of Cu(2+)/Aβ, but altered the outer coordination sphere. Isomerisation of Asp1 produced a single dominant species involving a stable 5-membered Cu(2+) chelate at the amino terminus. The Aβ3–16 and Aβ3[pE]–16 peptides both exhibited an equilibrium between two Cu(2+) coordination modes between pH 6–9 with nominally the same first coordination sphere, but with a dramatically different pH dependence arising from differences in H-bonding interactions at the N-terminus. CONCLUSIONS/SIGNIFICANCE: N-terminal modifications significantly influence the Cu(2+) coordination of Aβ, which may be critical for alterations in aggregation propensity, redox-activity, resistance to degradation and the generation of the Aβ3–× (× = 40/42) precursor of disease-associated Aβ3[pE]–x species. Public Library of Science 2010-12-30 /pmc/articles/PMC3012727/ /pubmed/21209855 http://dx.doi.org/10.1371/journal.pone.0015875 Text en Drew et al. http://creativecommons.org/licenses/by/4.0/ This is an open-access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are properly credited. |
spellingShingle | Research Article Drew, Simon C. Masters, Colin L. Barnham, Kevin J. Alzheimer's Aβ Peptides with Disease-Associated N-Terminal Modifications: Influence of Isomerisation, Truncation and Mutation on Cu(2+) Coordination |
title | Alzheimer's Aβ Peptides with Disease-Associated N-Terminal Modifications: Influence of Isomerisation, Truncation and Mutation on Cu(2+) Coordination |
title_full | Alzheimer's Aβ Peptides with Disease-Associated N-Terminal Modifications: Influence of Isomerisation, Truncation and Mutation on Cu(2+) Coordination |
title_fullStr | Alzheimer's Aβ Peptides with Disease-Associated N-Terminal Modifications: Influence of Isomerisation, Truncation and Mutation on Cu(2+) Coordination |
title_full_unstemmed | Alzheimer's Aβ Peptides with Disease-Associated N-Terminal Modifications: Influence of Isomerisation, Truncation and Mutation on Cu(2+) Coordination |
title_short | Alzheimer's Aβ Peptides with Disease-Associated N-Terminal Modifications: Influence of Isomerisation, Truncation and Mutation on Cu(2+) Coordination |
title_sort | alzheimer's aβ peptides with disease-associated n-terminal modifications: influence of isomerisation, truncation and mutation on cu(2+) coordination |
topic | Research Article |
url | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3012727/ https://www.ncbi.nlm.nih.gov/pubmed/21209855 http://dx.doi.org/10.1371/journal.pone.0015875 |
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