Copper(II) inhibits the formation of amylin amyloid in vitro

Ward, Benjamin; Walker, K. L.; Exley, Christopher

doi:10.1016/j.jinorgbio.2007.09.010

Cited by 96 publications

(108 citation statements)

References 19 publications

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“…Indeed, copper(II) induces a conformational change on the protein that, although is in a more structured state (H/D exchange MS and CD results), is less prone to aggregation, in accordance with previous works. 23,46 Finally, in order to get a closer insight onto the mechanism by which copper(II) induces the above reported changes on both the conformation and aggregation properties of h-amylin, we have used the 17-29 h-amylin fragment (Figure 3) in order to carry out simulations as well as solid-state NMR measurements on the aggregated state. The reason and the validity of using this particular peptide portion has already been reported elsewhere.…”

Section: Resultsmentioning

confidence: 99%

The role of copper(ii) in the aggregation of human amylin

Sinopoli

Magrı̀²,

Milardi³

et al. 2014

Metallomics

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Amylin is the 37-residue peptide hormone produced by the islet β-cells in the pancreas and the formation of amylin aggregates is strongly associated with β-cells degeneration in type 2 diabetes, as demonstrated by more than 95% of patients exhibiting amylin amyloid upon autopsy.It is widely recognized that metal ions such as copper(II) have been implicated in the aggregation process of amyloidogenic peptides such as Aβ and α-synuclein and there is evidence that also amylin self-assembly is largely affected by copper(II). For this reason, in this work, the role of copper(II) in the aggregation of amylin has been investigated by several different experimental approaches. Mass spectrometric investigations show that copper(II) induces significant changes in the amylin structure which decrease the protein fibrillogenesis as observed by ThT measurements. Accordingly, solid-state NMR experiments together with computational analysis carried out on a model amylin fragment confirmed the non fibrillogenic nature of the copper(II) induced aggregated structure. Finally, the presence of copper(II) is also shown to have a major influence on amylin proneness to be degraded by proteases and cytotoxicity studies on different cell cultures are reported.4

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Section: Resultsmentioning

confidence: 99%

The role of copper(ii) in the aggregation of human amylin

Sinopoli

Magrı̀²,

Milardi³

et al. 2014

Metallomics

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“…Previous research on IAPP showed that in the presence of stoichiometric excesses of metal, Al(III) and Zn(II) increased, Cu(II) decreased and Fe(III) had no influence upon ThT fluorescence under near-physiological conditions [3]. The influence of Cu(II) in preventing IAPP from forming β sheet structures has since been confirmed [5][6][7][8].…”

Section: Metals and Iappmentioning

confidence: 91%

“…The role of metals in catalysing amyloidogenesis has been studied extensively and the propensities for both IAPP [3] and ProIAPP [4] to form amyloid β sheets are significantly influenced by metals. While the evidence is quite clear that Cu(II) prevents both IAPP and ProIAPP from forming amyloid β sheets the data pertaining to Al(III), Fe(III) and Zn(II) remains equivocal as to whether they promote or have little influence upon the formation of amyloid β sheets [3][4][5][6][7][8]. All metals do affect the morphologies of amyloid-like materials [4] and there are also suggestions that the subsequent aggregation of such materials towards precipitated solids is influenced by metals [9].…”

mentioning

confidence: 99%

Further insight into the role of metals in amyloid formation by IAPP1-37 and ProIAPP1-48

Mold¹,

Bunrat²,

Goswami³

et al. 2015

J Diab Res Clin Met

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Background: IAPP 1-37 and ProIAPP 1-48 are amyloidogenic peptides implicated in β-cell death in diabetes. Interactions with metals may be involved in both the cytotoxicity of these peptides and their deposition as amyloids associated with diabetes-related pathologies. Methods: We have used the complementary methods of thioflavin T (ThT) fluorescence and transmission electron microscopy (TEM) to investigate the role of seeds and specifically metal-peptide seeds in accelerating amyloid formation by ProIAPP. In addition we have used these complementary methods alongside dynamic light scattering (DLS) to observe the dynamics of IAPP amyloid formation during the earliest phase of peptide aggregation. Results: Seeding universally resulted in an acceleration of amyloid formation, as indicated by increased ThT fluorescence, over the shorter term (minutes) while having no influence upon total amyloid deposits (no differences in ThT fluorescence) over many days. Only copper-peptide seeds were ineffective in accelerating amyloid formation above that observed for sham seeds (no peptide). Different seeding environments resulted in amyloid deposits of different fibrillar and non-fibrillar morphologies following longer term incubations regardless of the uniform nature of the respective measurements of ThT fluorescence. The aggregation dynamics of IAPP, mimicking its secretion into extracellular milieus, were complex and suggested that while metals at equimolar, generally increased rates of aggregation, with the possible exception of Cu(II), the range of sub-micron and micron-sized particles observed were not easily explained by either measurement of ThT fluorescence or imaging by TEM. Conclusions: Seeding may be significant in accelerating the formation of amyloid and in influencing the final morphologies of deposited amyloids but not in determining the total deposits of amyloid. It was of interest that copper-peptide seeds did not accelerate amyloid formation in the shorter term and this could indicate an incompatible seeding morphology due to copper? This first attempt to monitor aggregation dynamics of IAPP over only minutes has shown direct impact of metals on peptide particle size which could have implications for the cytotoxicity of IAPP in diabetes.

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“…In agreement with this expectation a series of recent studies supports that copper(II) and some other metal ions can mediate the aggregation processes of hIAPP. The inhibition of the aggregation was shown in several studies [1][2][3] , while the impact of copper mediated ROS production was demonstrated in other works [4][5][6] . Moreover, it was also reported that copper(II) is able to modulate the proteolytic activity of IAPP degrading enzymes 7 .…”

Section: Introductionmentioning

confidence: 99%

Potentiometric and spectroscopic studies on the copper(ii) complexes of rat amylin fragments. The anchoring ability of specific non-coordinating side chains

et al. 2015

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Copper(II) complexes of peptides modelling the sequence of the 17-22 residues of rat amylin have been studied by potentiometric, UV-Vis, CD and ESR spectroscopic methods. The peptides were synthesized in N-terminally free forms, NH 2 -VRSSNN-NH 2 , NH 2 -VRSSAA-NH 2, NH 2 -VRAANN-NH 2 , NH 2 -VRSS-NH 2 , NH 2 -SSNN-NH 2 , NH 2 -SSNA-NH 2 and NH 2 -AANN-NH 2 , providing a possibility for the comparison of the metal binding abilities of the amino terminus and the -SSNN-domain. The amino terminus was the primary ligating site in all cases and the formation of only mononuclear complexes was obtained for the tetrapeptides. The thermodynamic stability of the (NH 2 ,N -,N -) coordinated complexes was, however, enhanced by the asparaginyl moiety in the case of NH 2 -SSNN-NH 2 , NH 2 -SSNA-NH 2 and NH 2 -AANN-NH 2 . Among the hexapeptides the formation of dinuclear complexes was characteristic for NH 2 -VRSSNN-NH 2 demonstrating the anchoring ability of the -SSNN-(SerSerAsnAsn) domain. The complexes of the heptapeptide NH 2 -GGHSSNN-NH 2 were also studied and the data supported the above mentioned anchoring ability of the -SSNN-site.

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Copper(II) inhibits the formation of amylin amyloid in vitro

Cited by 96 publications

References 19 publications

The role of copper(ii) in the aggregation of human amylin

The role of copper(ii) in the aggregation of human amylin

Further insight into the role of metals in amyloid formation by IAPP1-37 and ProIAPP1-48

Potentiometric and spectroscopic studies on the copper(ii) complexes of rat amylin fragments. The anchoring ability of specific non-coordinating side chains

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