α-Helical Structures Drive Early Stages of Self-Assembly of Amyloidogenic Amyloid Polypeptide Aggregate Formation in Membranes

Abstract

The human islet amyloid polypeptide (hIAPP) is the primary component in the toxic islet amyloid deposits in type-2 diabetes. hIAPP self-assembles to aggregates that permeabilize membranes and constitutes amyloid plaques. Uncovering the mechanisms of amyloid self-assembly is the key to understanding amyloid toxicity and treatment. Although structurally similar, hIAPP's rat counterpart, the rat islet amyloid polypeptide (rIAPP), is non-toxic. It has been a puzzle why these peptides behave so differently. We combined multiscale modelling and theory to explain the drastically different dynamics of hIAPP and rIAPP: The differences stem from electrostatic dipolar interactions. hIAPP forms pentameric aggregates with the hydrophobic residues facing the membrane core and stabilizing water-conducting pores. We give predictions for pore sizes, the number of hIAPP peptides, and aggregate morphology. We show the importance of curvature-induced stress at the early stages of hIAPP assembly and the α-helical structures over β-sheets. This agrees with recent fluorescence spectroscopy experiments.

Elucidation of the Aggregation Pathways of Helix–Turn–Helix Peptides: Stabilization at the Turn Region Is Critical for Fibril Formation

“…6–8 Despite the dominant role of the cross-β-sheet in mature fibrils, 9–11 compelling evidence points to an intermediate role for the α-helix in the cascade. 12–15 Many aggregating proteins exhibit α-helical character when associated with membrane. 15–17 However, the crowded environment in cells makes the study of in vivo aggregation challenging.…”

Human IAPP amyloidogenic properties and pancreatic β-cell death

“…In-between perturbations include hIAPP surface adsorption and formation of channels [78][79][80][81]. Nevertheless, the single, main mechanism that makes hIAPP cytotoxic is far from being established [78]. Brender [79] has proposed two main theories of membrane disruption by hIAPP.…”

“…The effects on membranes may range from a change in fluidity and permeability to bilayer disruption and extraction of membrane lipids. In-between perturbations include hIAPP surface adsorption and formation of channels [78][79][80][81]. Nevertheless, the single, main mechanism that makes hIAPP cytotoxic is far from being established [78].…”

Resveratrol interferes with the aggregation of membrane-bound human-IAPP: A molecular dynamics study

“…The GROMOS 53A6 force field [35,36] was used. This forcefield has been shown to perform well in simulating proteineprotein and membrane-protein systems [37,16]. The SPC (simple point charge) water model [38] was used.…”

“…In particular resveratrol (trans-3,5,4 0 -trihydroxystilben), has evidenced significant beneficial effects in patients with T2DM [20]. Moreover, several studies have demonstrated that resveratrol may inhibit IAPP amyloid aggregation in the presence of negatively charged membranes [16,21]. Molecular Dynamics simulations have also demonstrated that resveratrol inhibits the aggregation of IAPP segment 22e27 by interfering with the intersheet side-chain stacking driven by aromatic rings [22] Nevertheless, there is still need of a more detailed structural characterization of the dynamics of membrane/peptide assemblies to fully understand the mechanism by which resveratrol inhibits IAPP fibrillogenesis and toxicity.…”