Structure and assembly mechanisms of toxic human islet amyloid polypeptide oligomers associated with copper

Lee, Shin Jung C.; Choi, Tae Su; Lee, Jong Wha; Lee, Hyuck Jin; Mun, Dong Gi; Akashi, Satoko; Lee, Sang Won; Lim, Mi Hee; Kim, Hugh I.

doi:10.1039/c6sc00153j

Cited by 39 publications

(61 citation statements)

References 54 publications

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“…Cu-induced hIAPP conformers would not only be less likely to form amyloid structures, but could actually promote the formation of off-pathway aggregates that may be more toxic to cells. 17 In summary, our study has revealed structural details of the Cu(II)−hIAPP complex, and it has identified the key residues involved in metal ion coordination. Beyond the anchoring His18 residue, Ser19 and Ser20 also play important roles by providing the deprotonated backbone amides that yield a 3N equatorial coordination mode.…”

Section: Articlementioning

confidence: 81%

“…Indeed, a recent mass spectrometry and molecular dynamics study has determined that Cu(II) binding to hIAPP favors the formation of conformers and oligomeric species that differ from those observed in metal-free hIAPP samples. 17 Metal-induced changes in the folding of hIAPP would impact different properties of this peptide. For instance, many studies have demonstrated that Cu(II) binding to hIAPP protects it from enzymatic degradation by the insulin-degrading enzyme (IDE), particularly in the region around His18.…”

Section: Articlementioning

confidence: 99%

“…31,34,35 Viability assays have demonstrated that copper induces the formation of oligomeric species, increasing the cytotoxicity of hIAPP; 31,33,34 while other studies reveal cell apoptosis caused by copper−peptide complexes. 33,34 Recent findings by Lee and co-workers 17 showed that Cu(II)containing oligomers of hIAPP form toxic aggregates with random coil conformations. On the other hand, experiments with catalase and electron paramagnetic resonance (EPR) spectroscopy demonstrated that copper can stimulate the formation of H 2 O 2 during amyloid formation, promoting progressive degeneration of β-cells.…”

Section: ■ Introductionmentioning

confidence: 99%

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Copper Coordination Features of Human Islet Amyloid Polypeptide: The Type 2 Diabetes Peptide

et al. 2016

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Human islet amyloid polypeptide (hIAPP) is the major component of amyloid deposits found in pancreatic β-cells of patients with type 2 diabetes (T2D). Copper ions have an inhibitory effect on the amyloid aggregation of hIAPP, and they may play a role in the etiology of T2D. However, deeper knowledge of the structural details of the copper− hIAPP interaction is required to understand the molecular mechanisms involved. Here, we performed a spectroscopic study of Cu(II) binding to hIAPP and several variants, using electron paramagnetic resonance (EPR), nuclear magnetic resonance (NMR), electronic absorption, and circular dichroism (CD) in the UV−vis region in combination with Born−Oppenheimer molecular dynamics (BOMD) and density functional theory geometry optimizations. We find that Cu(II) binds to the imidazole N1 of His18, the deprotonated amides of Ser19 and Ser20, and an oxygen-based ligand provided by Ser20, either via its hydroxyl group or its backbone carbonyl, while Asn22 might also play a role as an axial ligand. Ser20 plays a crucial role in stabilizing Cu(II) coordination toward the Cterminal, providing a potential link between the S20G mutation associated with early onset of T2D, its impact in Cu binding properties, and hIAPP amyloid aggregation. Our study defines the nature of the coordination environment in the Cu(II)−hIAPP complex, revealing that the amino acid residues involved in metal ion binding are also key residues for the formation of β-sheet structures and amyloid fibrils. Cu(II) binding to hIAPP may lead to the coexistence of more than one coordination mode, which in turn could favor different sets of Cu-induced conformational ensembles. Cu-induced hIAPP conformers would display a higher energetic barrier to form amyloid fibrils, hence explaining the inhibitory effect of Cu ions in hIAPP aggregation. Overall, this study provides further structural insights into the bioinorganic chemistry of T2D.

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Section: Articlementioning

confidence: 81%

Section: Articlementioning

confidence: 99%

Section: ■ Introductionmentioning

confidence: 99%

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Copper Coordination Features of Human Islet Amyloid Polypeptide: The Type 2 Diabetes Peptide

et al. 2016

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“…A sketch of the process leading to the formation of ProIAPP1-48 and IAPP and of their effect on islet β cells is depicted in Figure 1. It is widely believed that the cytotoxicity of IAPP and ProIAPP1-48 is related to their propensity to form toxic oligomers during the early stages of amyloid formation [4] and it has been suggested that metals and specifically Cu(II) potentiate toxicity through stabilisation of these oligomeric forms [12,16].…”

Section: Introductionmentioning

confidence: 99%

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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Structure and assembly mechanisms of toxic human islet amyloid polypeptide oligomers associated with copper

Abstract: The molecular interaction of hIAPP with Cu(ii) mediates the formation of off-pathway and toxic oligomers which have small-sized and random coil structures.

Cited by 39 publications

References 54 publications

Copper Coordination Features of Human Islet Amyloid Polypeptide: The Type 2 Diabetes Peptide

Copper Coordination Features of Human Islet Amyloid Polypeptide: The Type 2 Diabetes Peptide

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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