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

作者：Pannuzzo Martina; Raudino Antonio; Milardi Danilo; La Rosa Carmelo^*; Karttunen Mikko

来源：Scientific Reports, 2013, 3(1): 2781.

DOI：10.1038/srep02781

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%26apos;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 alpha-helical structures over beta-sheets. This agrees with recent fluorescence spectroscopy experiments.

• 出版日期2013-9-27