Structural Dissection of the First Events Following Membrane Binding of the Islet Amyloid Polypeptide

Abstract

The islet amyloid polypeptide (IAPP) is the main constituent of the amyloid fibrils found in the pancreas of type 2 diabetes patients. The aggregation of IAPP is known to cause cell death, where the cell membrane plays a dual role: being a catalyst of IAPP aggregation and being the target of IAPP toxicity. Using ATR-FTIR spectroscopy, transmission electron microscopy, and molecular dynamics simulations we investigate the very first molecular steps following IAPP binding to a lipid membrane. In particular, we assess the combined effects of the charge state of amino-acid residue 18 and the IAPP-membrane interactions on the structures of monomeric and aggregated IAPP. Distinct IAPP-membrane interaction modes for the various IAPP variants are revealed. Membrane binding causes IAPP to fold into an amphipathic α-helix, which in the case of H18K-, and H18R-IAPP readily moves beyond the headgroup region. For all IAPP variants but H18E-IAPP, the membrane-bound helix is an intermediate on the way to amyloid aggregation, while H18E-IAPP remains in a stable helical conformation. The fibrillar aggregates of wild-type IAPP and H18K-IAPP are dominated by an antiparallel β-sheet conformation, while H18R- and H18A-IAPP exhibit both antiparallel and parallel β-sheets as well as amorphous aggregates. Our results emphasize the decisive role of residue 18 for the structure and membrane interaction of IAPP. This residue is thus a good therapeutic target for destabilizing membrane-bound IAPP fibrils to inhibit their toxic actions.

Exploring the Role of Anionic Lipid Nanodomains in the Membrane Disruption and Protein Folding of Human Islet Amyloid Polypeptide Oligomers on Lipid Membrane Surfaces Using Multiscale Molecular Dynamics Simulations

“…Here, we discovered that the hydrophobic amino acids, L16 and I26, (see Figure 4 and Figure 5 ), are the major lipid binding residues of hIAPP oligomers on Lod and PS-cluster nanodomains on both the CO-raft and PS-raft. The N -terminal region (residues 1 to 20) containing residue L16 of structured hIAPP has been implicated in various experimental and computational studies [ 24 , 26 , 34 , 35 , 36 ]. In this study, we discovered that residue I26, associated with the C terminus (residues 21 to 31), which contains the fibril core of hIAPP fiber, represents an extra binding region for disordered oligomers.…”

“…The significant roles of lipid acyl chain unsaturation, headgroup charge, and CHOL in partially disordered and fibrillar hIAPP–lipid interactions and membrane permeabilization have been investigated in various lipid mixtures. Overall, hIAPP monomers or oligomers strongly bind to anionic lipids, partially because of the net +2e charge of hIAPP, and prefer unsaturated lipids over saturated lipids [ 6 , 24 , 25 , 26 ]. Experimentally, using a raft-like model membrane containing a zwitterionic PC similar to the raft membrane in this study, the presence of CHOL enhances membrane leakage with pore formation but suppresses fiber growth on membrane surfaces.…”

A coarse-grained molecular dynamics investigation on spontaneous binding of Aβ1–40 fibrils with cholesterol-mixed DPPC bilayers

“…al . [44] showed that C-terminal hydrophobic residues of islet amyloid polypeptide (IAPP) can be inserted in the membrane, while Antonschmidt et. al.…”

A Coarse-Grained Molecular Dynamics Investigation on Spontaneous Binding of Aβ1-40Fibrils with Cholesterol-mixed DPPC Bilayers

“…al . [41] showed that C-terminal hydrophobic residues of islet amyloid polypeptide (IAPP) can be inserted in the membrane, while Antonschmidt et. al .…”