The Molecular Basis of Distinct Aggregation Pathways of Islet Amyloid Polypeptide

Wei, Lei; Jiang, Ping; Xu, Wei; Li, Hai; Zhang, Hua; Yan, Liang; Chan-Park, Mary B.; Liu, Xuewei; Tang, Kai; Mu, Yuguang; Pervushin, Konstantin

doi:10.1074/jbc.m110.166678

Cited by 106 publications

(99 citation statements)

References 58 publications

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“…Early stage oligomers formed from intrinsically disordered proteins and peptides such as IAPP [97], PI3-SH3 domain [98], Ab [22][23][24][25], and other peptides [99] were shown to be primarily unstructured. On the other hand, early stage oligomers derived from the folded proteins such as insulin [100,101], SOD-1 [102], and acylphosphatase [103,104] largely preserved the native fold of these proteins.…”

Section: Discussionmentioning

confidence: 99%

Structural, morphological, and functional diversity of amyloid oligomers

2015

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a b s t r a c tProtein misfolding and aggregation are known to play a crucial role in a number of important human diseases (Alzheimer's, Parkinson's, prion, diabetes, cataracts, etc.) as well as in a multitude of physiological processes. Protein aggregation is a highly complex process resulting in a variety of aggregates with different structures and morphologies. Oligomeric protein aggregates (amyloid oligomers) are formed as both intermediates and final products of the aggregation process. They are believed to play an important role in many protein aggregation-related diseases, and many of them are highly cytotoxic. Due to their instability and structural heterogeneity, information about structure, mechanism of formation, and physiological effects of amyloid oligomers is sparse. This review attempts to summarize the existing information on the major properties of amyloid oligomers.

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Section: Discussionmentioning

confidence: 99%

Structural, morphological, and functional diversity of amyloid oligomers

2015

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“…By X-ray reflectivity measurements, it was also shown that resveratrol inhibits hIAPP interaction with a lipid layer interacting preferentially with peptide monomers [251], a particularly valuable effect, considering that hIAPP fibrillization at the cell membrane and subsequent membrane destabilization are important determinants of hIAPP toxicity [252]. Fluorescence microscopy analysis further suggested that resveratrol redirects hIAPP aggregation towards the formation of amorphous non-toxic aggregates that do not interact with INS-1E cells [253], and following NMR analysis, it was proposed that resveratrol binds to hIAPP His-18, thereby inhibiting early formation of oligomeric intermediates [254]. …”

Section: The Anti-amyloid Properties Of Natural Phenols and Polyphmentioning

confidence: 99%

Protein Folding and Aggregation into Amyloid: The Interference by Natural Phenolic Compounds

Stefani

Rigacci

2013

IJMS

192

127

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Amyloid aggregation is a hallmark of several degenerative diseases affecting the brain or peripheral tissues, whose intermediates (oligomers, protofibrils) and final mature fibrils display different toxicity. Consequently, compounds counteracting amyloid aggregation have been investigated for their ability (i) to stabilize toxic amyloid precursors; (ii) to prevent the growth of toxic oligomers or speed that of fibrils; (iii) to inhibit fibril growth and deposition; (iv) to disassemble preformed fibrils; and (v) to favor amyloid clearance. Natural phenols, a wide panel of plant molecules, are one of the most actively investigated categories of potential amyloid inhibitors. They are considered responsible for the beneficial effects of several traditional diets being present in green tea, extra virgin olive oil, red wine, spices, berries and aromatic herbs. Accordingly, it has been proposed that some natural phenols could be exploited to prevent and to treat amyloid diseases, and recent studies have provided significant information on their ability to inhibit peptide/protein aggregation in various ways and to stimulate cell defenses, leading to identify shared or specific mechanisms. In the first part of this review, we will overview the significance and mechanisms of amyloid aggregation and aggregate toxicity; then, we will summarize the recent achievements on protection against amyloid diseases by many natural phenols.

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“…In the latter approach, the hIAPP post-translational modifications are difficult to be controlled, and recombinant hIAPP is non-amidated at its C-terminal end. Interestingly, the non-amidated hIAPP is still amyloidogenic and cytotoxic [19], but its kinetics and mechanism of oligomerization differ from those of the amidated peptide [20,21,22,23,24]. In particular, several studies demonstrated that the fibrillization of non-amidated hIAPP is significantly slower than the amidated one [22,23,24].…”

Section: Introductionmentioning

confidence: 99%

Effect of Post-Translational Amidation on Islet Amyloid Polypeptide Conformational Ensemble: Implications for Its Aggregation Early Steps

Tran

Ha-Duong

2016

IJMS

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The human islet amyloid polypeptide (hIAPP) is an intrinsically disordered protein that can self-assemble into fibrillar aggregates that play a key role in the pathogenesis of the type II diabetes mellitus. hIAPP can transiently adopt sans-serifα-helix and sans-serifβ-strand conformations that could be important intermediate species on the fibrillization pathway. However, experimental studies of the monomeric peptide conformations are limited due to its high aggregation propensity, and the early steps of the hIAPP association are not clearly characterized. In particular, the question of whether the aggregation-prone conformation is sans-serifα-helical or sans-serifβ-strand-rich is still debated. In this study, combining extensive all-atom molecular dynamics (MD) and replica exchange molecular dynamics (REMD) simulations in explicit water, we shed some light on the differences between the amidated and non-amidated hIAPP conformational ensembles. Our study shows that, when compared to the amidated monomer, the non-amidation of hIAPP induces a significantly lower propensity to form sans-serifβ-strands, especially aggregation-prone sans-serifβ-hairpins. Since the fibrillization of the non-amidated hIAPP is significantly slower than that of the amidated peptide, this indicates that the early steps of the peptide oligomerization involve the association of sans-serifβ-hairpins or sans-serifβ-strands structures.

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The Molecular Basis of Distinct Aggregation Pathways of Islet Amyloid Polypeptide

Cited by 106 publications

References 58 publications

Structural, morphological, and functional diversity of amyloid oligomers

Structural, morphological, and functional diversity of amyloid oligomers

Protein Folding and Aggregation into Amyloid: The Interference by Natural Phenolic Compounds

Effect of Post-Translational Amidation on Islet Amyloid Polypeptide Conformational Ensemble: Implications for Its Aggregation Early Steps

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