On the structure of the copper–amylin complex

Riba, Isabel; Barran, Perdita E.; Cooper, Garth J. S.; Unwin, Richard D.

doi:10.1016/j.ijms.2015.09.001

Cited by 15 publications

(11 citation statements)

References 26 publications

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“…Mass spectrometry (MS) and ion mobility spectrometry‐mass spectrometry (IMS‐MS) have been recently proposed for monitoring hIAPP species formed within the oligomerization process as well as for probing mechanisms of inhibition of hIAPP fibril formation [55–60] . Using the same buffer conditions as for CE experiments (50 μ m hIAPP, 50 m m ammonium acetate, pH 3.7 at room temperature) the MS spectrum showed the classically observed dynamic set of hIAPP species, mostly monomer to hexamer species in multiple charge states, (Figure 6 a,b).…”

Section: Resultsmentioning

confidence: 99%

Helical γ‐Peptide Foldamers as Dual Inhibitors of Amyloid‐β Peptide and Islet Amyloid Polypeptide Oligomerization and Fibrillization

Kaffy

Berardet

Mathieu

et al. 2020

Chemistry A European J

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Type 2d iabetes (T2D) and Alzheimer's disease (AD) belongt ot he 10 deadliest diseases and are sorely lacking in effectivet reatments. Both pathologies are part of the degenerative disordersn amed amyloidoses, whichi nvolve the misfolding andt he aggregation of amyloid peptides, hIAPP for T2D and Ab 1-42 for AD. While hIAPP and Ab 1-42 inhibitorsh ave been essentiallyd esigned to target b-sheetrich structures composing the toxic amyloid oligomers and fibrils of these peptides, the strategy aiming at trapping the non-toxic monomers in their helical native conformation has been rarely explored.W er eport herein the first example of helicalf oldamers as dual inhibitors of hIAPPa nd Ab 1-42 aggregation and able to preserve the monomeric species of both amyloid peptides. Af oldamer composed of 4-amino-(methyl)-1,3-thiazole-5-carboxylic acid (ATC) units, adopting a9-helix structure reminiscent of 3 10 helix, was remarkable as demonstrated by biophysical assays combining thioflavin-Tf luorescence, transmission electronic microscopy,c apillary electrophoresis and mass spectrometry.

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Section: Resultsmentioning

confidence: 99%

Helical γ‐Peptide Foldamers as Dual Inhibitors of Amyloid‐β Peptide and Islet Amyloid Polypeptide Oligomerization and Fibrillization

Kaffy

Berardet

Mathieu

et al. 2020

Chemistry A European J

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“…It remains equivocal as to whether Al(III), Fe(III) and Zn(II) promote amyloid [7], zinc [7,8] and copper [7]. It remains equivocal as to whether Al(III), Fe(III) and Zn(II) promote amyloid (β sheet) formation while it is clear that Cu(II) prevents IAPP from assembling into-sheet structures [7] as recently confirmed [9][10][11][12][13]. ProIAPP1-48 forms amyloid less readily than IAPP and while there are few data on its interactions with metals it is also the case that Cu(II) prevents ProIAPP1-48 from forming -sheets structures more prone to amyloidogenesis [12,14,15].…”

Section: Introductionmentioning

confidence: 98%

X-Ray Absorption Spectroscopy Measurements of Cu-ProIAPP Complexes at Physiological Concentrations

et al. 2019

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The amyloidogenic islet amyloid polypeptide (IAPP) and the associated pro-peptide ProIAPP1–48 are involved in cell death in type 2 diabetes mellitus. It has been observed that interactions of this peptide with metal ions have an impact on the cytotoxicity of the peptides as well as on their deposition in the form of amyloid fibrils. In particular, Cu(II) seems to inhibit amyloid fibril formation, thus suggesting that Cu homeostasis imbalance may be involved in the pathogenesis of type 2 diabetes mellitus. We performed X-ray Absorption Spectroscopy (XAS) measurements of Cu(II)-ProIAPP complexes under near-physiological (10 μM), equimolar concentrations of Cu(II) and peptide. Such low concentrations were made accessible to XAS measurements owing to the use of the High Energy Resolved Fluorescence Detection XAS facility recently installed at the ESRF beamline BM16 (FAME-UHD). Our preliminary data show that XAS measurements at micromolar concentrations are feasible and confirm that ProIAPP1–48-Cu(II) binding at near-physiological conditions can be detected.

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“…[51] Other IM-MS based studies showed that Cu(II) ions bind to the histidine 18 residue of hIAPP, which leads to a stabilization of off-pathway oligomers and to an inhibition of hIAPP fibril formation. [52][53][54] A conformerspecific inhibition for hIAPP aggregation was furthermore reported for the molecules silibinin [55] and insulin [56]. Silibinin exclusively binds to the extended β-hairpin hIAPP monomer (amyloidogenic precursor), and as a result the oligomerization is arrested.…”

Section: Amyloid Inhibitionmentioning

confidence: 89%

Ion mobility-mass spectrometry and orthogonal gas-phase techniques to study amyloid formation and inhibition

Hoffmann

Helden

Pagel

2017

Current Opinion in Structural Biology

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Amyloidogenic peptide oligomers are responsible for a variety of neurodegenerative disorders such as Alzheimer's and Parkinson's disease. Due to their dynamic, polydisperse, and polymorphic nature, these oligomers are very challenging to characterize using traditional condensed-phase methods. In the last decade, ion mobility-mass spectrometry (IM-MS) and related gas-phase techniques have emerged as a powerful alternative to disentangle the structure and assembly characteristics of amyloid forming systems. This review highlights recent advances in which IM-MS was used to characterize amyloid oligomers and their underlying assembly pathway. In addition, we summarize recent studies in which IM-MS was used to size- and mass-select species for a further spectroscopic investigation and outline the potential of IM-MS as a tool for the screening of amyloid inhibitors.

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On the structure of the copper–amylin complex

Cited by 15 publications

References 26 publications

Helical γ‐Peptide Foldamers as Dual Inhibitors of Amyloid‐β Peptide and Islet Amyloid Polypeptide Oligomerization and Fibrillization

Helical γ‐Peptide Foldamers as Dual Inhibitors of Amyloid‐β Peptide and Islet Amyloid Polypeptide Oligomerization and Fibrillization

X-Ray Absorption Spectroscopy Measurements of Cu-ProIAPP Complexes at Physiological Concentrations

Ion mobility-mass spectrometry and orthogonal gas-phase techniques to study amyloid formation and inhibition

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