Synthetic alpha-helix mimetics as agonists and antagonists of islet amyloid polypeptide aggregation.
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ABSTRACT:
SUBMITTER: Saraogi I
PROVIDER: S-EPMC2872138 | biostudies-literature | 2010
REPOSITORIES: biostudies-literature
Publications
Synthetic alpha-helix mimetics as agonists and antagonists of islet amyloid polypeptide aggregation.
Saraogi Ishu I Hebda James A JA Becerril Jorge J Estroff Lara A LA Miranker Andrew D AD Hamilton Andrew D AD
Angewandte Chemie (International ed. in English) 20100101 4
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Project description:Amyloid aggregation of amyloid-beta (Aβ) and islet amyloid polypeptide (IAPP) is associated with Alzheimer's disease (AD) and type-2 diabetes (T2D), respectively. With T2D being the risk factor for AD and the ability of IAPP to cross the blood-brain barrier, the coaggregation of Aβ and IAPP has been explored to understand the cross-talk between the two diseases. Recent studies demonstrated that soluble IAPP could significantly accelerate the aggregation of Aβ while preformed amyloids of IAPP were poor "seeds" for Aβ aggregation. Here, we apply all-atom discrete molecular dynamics simulations to investigate possible molecular mechanisms for the accelerated coaggregation of IAPP and Aβ42 comparing to Aβ42 aggregation alone, which was confirmed by the complementary thioflavin-T fluorescence assay. Our simulation results suggest that peptides in the mixture tend to form heterodimers as the first step toward their coaggregation. Strong interpeptide interactions with IAPP in the heterodimer shift the helical conformation of Aβ42 in its amyloidogenic central hydrophobic core, residues 16-22 (Aβ16-22), to the extended conformation ready to form β-sheets. Our study suggests that the unfolding of Aβ16-22 helix contributes to the aggregation free-energy barrier and corresponds to the rate-limiting conformational change for Aβ42 aggregation. Therefore, we propose that soluble IAPP promotes the aggregation of Aβ42 by binding-induced conformational change of Aβ42 in its amyloidogenic core and thus reduced aggregation free-energy barrier.
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Project description:Amyloid aggregation of human islet amyloid polypeptide (IAPP) is a hallmark of type 2 diabetes (T2D), a metabolic disease and a global epidemic. Although IAPP is synthesized in pancreatic β-cells, its fibrils and plaques are found in the extracellular space indicating a causative transmembrane process. Numerous biophysical studies have revealed that cell membranes as well as model lipid vesicles promote the aggregation of amyloid-β (associated with Alzheimer's), α-synuclein (associated with Parkinson's) and IAPP, through electrostatic and hydrophobic interactions between the proteins/peptides and lipid membranes. Using a thioflavin T kinetic assay, transmission electron microscopy, circular dichroism spectroscopy, discrete molecular dynamics simulations as well as free energy calculations here we show that micellar lysophosphatidylcholine (LPC), the most abundant lysophospholipid in the blood, inhibited the amyloid aggregation of IAPP through nonspecific interactions while elevating the α-helical peptide secondary structure. This surprising finding suggests a native protective mechanism against IAPP aggregation in vivo.
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