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

Martina Pannuzzo (1), Antonio Raudino (2), Danilo Milardi (3), Carmelo La Rosa (2), Mikko Karttunen(4)

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.

Read the article published in "Nature Scientific Reports" (27 September 2013)

1  Computational Biology, University of Erlangen-Nuremberg, Germany
2  Chemical Sciences, University of Catania, Italy
3  Biostrutture e Bioimmagini, CNR, Catania, Italy
4  Chemistry & Nanotechnology, University of Waterloo, Canada