α-helical structures drive early stages of self-assembly of amyloidogenic amyloid polypeptide aggregate formation in membranes.
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.
Department of Computational Biology, University of Erlangen-Nuremberg, Staudtstr. 5, 91058 Erlangen, Germany.
Martina
M
Pannuzzo
Antonio
A
Raudino
Danilo
D
Milardi
Carmelo
C
La Rosa
Mikko
M
Karttunen
D000465:Algorithms; D006801:Humans; D058228:Islet Amyloid Polypeptide / Q000737:chemistry* / Q000378:metabolism*; D008051:Lipid Bilayers / Q000737:chemistry / Q000378:metabolism; D008566:Membranes / Q000737:chemistry / Q000378:metabolism*; D018625:Microscopy, Atomic Force; D008958:Models, Molecular; D011485:Protein Binding; D055503:Protein Multimerization; D017433:Protein Structure, Secondary; D011994:Recombinant Proteins / Q000737:chemistry / Q000378:metabolism; D013816:Thermodynamics
D058228:Islet Amyloid Polypeptide; D008051:Lipid Bilayers; D011994:Recombinant Proteins