Zinc Binding to Alzheimer's Aβ(1–16) Peptide Results in Stable Soluble Complex

Kozin, Sergey A.; Zirah, Séverine; Rebuffat, Sylvie; Hoa, Gaston Hui Bon; Debey, Pascale

doi:10.1006/bbrc.2001.5284

Cited by 129 publications

(120 citation statements)

References 46 publications

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“…In contrast, the unprotected Aβ16 aggregated immediately upon addition of Zn 2+ in physiological conditions. 21 Our solvation free energy results based on the MM/3D-RISM also show that the Zn 2+ -Aβ40 complex is less soluble and consequently more prone to aggregate to form toxic oligomers when Asp 1 is involved in the binding of Zn…”

Section: +mentioning

confidence: 57%

Effects of Zn²⁺ Binding on the Structural and Dynamic Properties of Amyloid Β Peptide Associated with Alzheimer’s Disease: Asp¹ or Glu¹¹?

Wang

2013

ACS Chem. Neurosci.

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Section: +mentioning

confidence: 57%

Effects of Zn²⁺ Binding on the Structural and Dynamic Properties of Amyloid Β Peptide Associated with Alzheimer’s Disease: Asp¹ or Glu¹¹?

Wang

2013

ACS Chem. Neurosci.

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“…Metal ion association with A␤ has frequently been correlated with Alzheimer's disease (11,35,51,52), and the link among metal-coordination structure, the impact on assembly kinetics, and overall aggregation remains critical to understanding disease etiology. Our attempts to identify individual metal sites within A␤ segments now reveal that Cu 2ϩ coordination can radically alter assembly kinetics and morphology.…”

Section: Coordination Environment Of Metal Ions In Ac-a␤(13-21)h14a Fmentioning

confidence: 99%

Engineering metal ion coordination to regulate amyloid fibril assembly and toxicity

Dong¹,

Canfield

Mehta³

et al. 2007

Proc. Natl. Acad. Sci. U.S.A.

130

133

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Protein and peptide assembly into amyloid has been implicated in functions that range from beneficial epigenetic controls to pathological etiologies. However, the exact structures of the assemblies that regulate biological activity remain poorly defined. We have previously used Zn 2؉ to modulate the assembly kinetics and morphology of congeners of the amyloid ␤ peptide (A␤) associated with Alzheimer's disease. We now reveal a correlation among A␤-Cu 2؉ coordination, peptide self-assembly, and neuronal viability. By using the central segment of A␤, HHQKLVFFA or A␤(13-21), which contains residues H13 and H14 implicated in A␤-metal ion binding, we show that Cu 2؉ forms complexes with A␤(13-21) and its K16A mutant and that the complexes, which do not selfassemble into fibrils, have structures similar to those found for the human prion protein, PrP. N-terminal acetylation and H14A substitution, Ac-A␤(13-21)H14A, alters metal coordination, allowing Cu 2؉ to accelerate assembly into neurotoxic fibrils. These results establish that the N-terminal region of A␤ can access different metal-ion-coordination environments and that different complexes can lead to profound changes in A␤ self-assembly kinetics, morphology, and toxicity. Related metal-ion coordination may be critical to the etiology of other neurodegenerative diseases.copper-binding ͉ neurotoxicity ͉ self-assembly P rotein intermolecular assembly, especially formation of amyloid fibrillar structures, is correlated with a variety of human neurodegenerative diseases, including Alzheimer's, Parkinson's, Huntington's, and Creutzfeldt-Jakob diseases (1). More recently, amyloid has been tied to many nonpathological functional roles. For example, formation and self-perpetuation of amyloids in Saccharomyces cerevisiae regulate diverse yeast phenotypic expression as a positive response to environmental fluctuations (2), and amyloid may be involved in long-term memory and synapse maintenance in the marine snail, Aplysia (3, 4). Many proteins, including archetypical globular proteins such as myoglobin, can also form amyloid fibrils, suggesting that amyloidogenesis may be an intrinsic property of any ␣-amino acid polymer (5). Accordingly, these highly ordered paracrystalline protein self-assemblies have now been recognized as useful for nanostructure fabrication and biotechnology (6-8). Fully capturing these technological opportunities and understanding the biological roles of amyloid will depend on further definition of the organized structure and assembly pathway.Increasing evidence now implicates transition metal ions, including Zn 2ϩ , Cu 2ϩ , and Fe 3ϩ , as contributors both to amyloid ␤ (A␤) assembly in vitro and to the neuropathology of Alzheimer's disease, AD (9). The obligatory region of metal ion (Zn 2ϩ /Cu 2ϩ ) binding of A␤ has been mapped to the N terminus, amino acids 1-28 (10-16). In its soluble nonamyloid conformation, the peptide contains multiple intramolecular binding sites for Zn 2ϩ and Cu 2ϩ (9, 17), and intermolecular Zn 2ϩ binding can promote A␤ aggrega...

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“…Studies suggested that H6, H13, and H14 at the N-terminal domain of Aβ coordinate with Zn 2þ (9)(10)(11)(12)(13)(14)(15)(16)(17)(18)(19)(20)(21)(22)(23)(24)(25)(26). Solution NMR of Zn 2þ -Aβ [1][2][3][4][5][6][7][8][9][10][11][12][13][14][15][16] showed that Zn 2þ is bound to these three histidines and E11 (18). A recent NMR study of Zn 2þ -Aβ proposed that Zn 2þ binds to H6, E11, H14, and D1 of rat Aβ 1-28 and to H6, E11, H13, H14, and D1 of human Aβ 1-28 (22).…”

mentioning

confidence: 99%

Zinc ions promote Alzheimer Aβ aggregation via population shift of polymorphic states

Miller

Ma²,

Nussinov³

2010

Proc. Natl. Acad. Sci. U.S.A.

279

283

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Although a key factor in Alzheimer's disease etiology is enrichment of Zn 2þ in aggregates, and there are data suggesting that zinc promotes aggregation, how Zn 2þ -Aβ coordination promotes aggregation is elusive. Here we probe the structures and mechanisms through which Zn 2þ can affect amyloidosis. By covalently linking fragments (that have experiment-based coordinates) we observed that, in oligomeric Zn 2þ -Aβ 42 , Zn 2þ can simultaneously coordinate intra-and intermolecularly, bridging two peptides. Zinc coordination significantly decreases the solvation energy for large Zn 2þ -Aβ 42 oligomers and thus enhances their aggregation tendency. Zn 2þ binding does not change the β-sheet association around the C-terminal hydrophobic region; however, it shifts the relative population of the preexisting amyloid polymorphic ensembles. As a result, although a parallel β-sheet arrangement is still preferred, antiparallel and other less structured assemblies are stabilized, also becoming major species. Overall, Zn 2þ coordination promotes Aβ 42 aggregation leading to less uniform structures. Our replica exchange molecular dynamics simulations further reproduced an experimental observation that the increasing Zn 2þ concentration could slow down the aggregation rate, even though the aggregation rates are still much higher than in Zn 2þ -free solution.conformational selection | energy landscape | metal ions | modeling amyloid assemblies | seed polymorphism A lzheimer's disease (AD) is a progressive neurodegenerative disease and the most common cause of dementia in millions of people worldwide (1). This disease accounts for the majority of clinical senile dementia associated with the formation of senile plaques (2, 3). The primary constituent of the plaques is the aggregated Aβ 40 ∕Aβ 42 peptides in the brain; therefore, factors that influence the aggregation are of high interest.In vivo studies reported that Zn 2þ , Cu þ2 , and Fe þ3 are markedly enriched in Aβ plaques (4, 5), suggesting that these ions may act as seeding factors. Oligomerization of the Aβ peptides can be rapidly induced in the presence of Zn 2þ ions under physiological conditions (4, 6, 7). Noy et al. (8) have followed Zn 2þ ionenhanced Aβ aggregation. Studies suggested that H6, H13, and H14 at the N-terminal domain of Aβ coordinate with Zn 2þ (9-26). Solution NMR of Zn 2þ -Aβ 1-16 showed that Zn 2þ is bound to these three histidines and E11 (18). A recent NMR study of Zn 2þ -Aβ 1-28 proposed that Zn 2þ binds to H6, E11, H14, and D1 of rat Aβ 1-28 and to H6, E11, H13, H14, and D1 of human Aβ 1-28 (22). In addition, X-ray absorption spectroscopy revealed that Zn 2þ coordinates with four histidines, H13 and H14 of two adjacent monomers (23). Experimental structural data for Aβ 40 ∕Aβ 42 oligomers complexed with Zn 2þ are unavailable.Although it is believed that reducing zinc-induced Aβ aggregation can decrease toxicity (27), it was also postulated that zinc can lower Aβ toxicity by selectively precipitating aggregation intermediates (28). Key questions on the...

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Zinc Binding to Alzheimer's Aβ(1–16) Peptide Results in Stable Soluble Complex

Cited by 129 publications

References 46 publications

Effects of Zn²⁺ Binding on the Structural and Dynamic Properties of Amyloid Β Peptide Associated with Alzheimer’s Disease: Asp¹ or Glu¹¹?

Effects of Zn²⁺ Binding on the Structural and Dynamic Properties of Amyloid Β Peptide Associated with Alzheimer’s Disease: Asp¹ or Glu¹¹?

Engineering metal ion coordination to regulate amyloid fibril assembly and toxicity

Zinc ions promote Alzheimer Aβ aggregation via population shift of polymorphic states

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Zinc Binding to Alzheimer's Aβ(1–16) Peptide Results in Stable Soluble Complex

Cited by 129 publications

References 46 publications

Effects of Zn2+ Binding on the Structural and Dynamic Properties of Amyloid Β Peptide Associated with Alzheimer’s Disease: Asp1 or Glu11?

Effects of Zn2+ Binding on the Structural and Dynamic Properties of Amyloid Β Peptide Associated with Alzheimer’s Disease: Asp1 or Glu11?

Engineering metal ion coordination to regulate amyloid fibril assembly and toxicity

Zinc ions promote Alzheimer Aβ aggregation via population shift of polymorphic states

Contact Info

Product

Resources

About

Effects of Zn²⁺ Binding on the Structural and Dynamic Properties of Amyloid Β Peptide Associated with Alzheimer’s Disease: Asp¹ or Glu¹¹?

Effects of Zn²⁺ Binding on the Structural and Dynamic Properties of Amyloid Β Peptide Associated with Alzheimer’s Disease: Asp¹ or Glu¹¹?