The Role of Cholesterol in Driving IAPP-Membrane Interactions

Abstract

Our knowledge of the molecular events underlying type 2 diabetes mellitus-a protein conformational disease characterized by the aggregation of islet amyloid polypeptide (IAPP) in pancreatic β cells-is limited. However, amyloid-mediated membrane damage is known to play a key role in IAPP cytotoxicity, and therefore the effects of lipid composition on modulating IAPP-membrane interactions have been the focus of intense research. In particular, membrane cholesterol content varies with aging and consequently with adverse environmental factors such as diet and lifestyle, but its role in the development of the disease is controversial. In this study, we employ a combination of experimental techniques and in silico molecular simulations to shed light on the role of cholesterol in IAPP aggregation and the related membrane disruption. We show that if anionic POPC/POPS vesicles are used as model membranes, cholesterol has a negligible effect on the kinetics of IAPP fibril growth on the surface of the bilayer. In addition, cholesterol inhibits membrane damage by amyloid-induced poration on membranes, but enhances leakage through fiber growth on the membrane surface. Conversely, if 1:2 DOPC/DPPC raft-like model membranes are used, cholesterol accelerates fiber growth. Next, it enhances pore formation and suppresses fiber growth on the membrane surface, leading to leakage. Our results highlight a twofold effect of cholesterol on the amyloidogenicity of IAPP and help explain its debated role in type 2 diabetes mellitus.

Islet Amyloid Polypeptide Membrane Interactions: Effects of Membrane Composition

“…But in this case a modest acceleration was observed. Comparison of the data presented here with this study and with previous work 51, 52, 59 highlights the high sensitivity of IAPP membrane interactions to lipid composition. In the absence of POPS, addition of 20 mole percent cholesterol to zwitterionic LUVs increased the value of T 50 by 1.5-fold relative to the value in the absence of cholesterol.…”

“…The β-cell membrane contains cholesterol, gangliosides, sphingomyelins, and the level of anionic phospholipids is reported to range from 2.5 to 13.2 mole percent of the total phospholipids 57 . The vast majority of model systems typically contain a much higher percentage of anionic lipids and lack cholesterol and gangliosides, although the effects of cholesterol have been examined in a subset of systems 52, 57–59 . Cholesterol is an important component of membranes; it modulates their biophysical properties and is important for the uptake of hIAPP in vivo 58, 60 .…”

Atomistic-level study of the interactions between hIAPP protofibrils and membranes: Influence of pH and lipid composition

“…It was also reported that in the presence of model membranes, the α-helical transient intermediates were observed in the early stage of membrane-hIAPP interaction [11]. Intermediate oligomers can disrupt membrane integrity and permeability, lead to ionic homeostasis and signal disturbance, and thereby cause cell death [4,6,12–14]. Earlier electron paramagnetic resonance (EPR) spectroscopy and nuclear magnetic resonance (NMR) studies showed that a membrane-bound hIAPP monomer adopts pH- and membrane composition-dependent helical structure in one (residues 9–22) or two regions (residues 7–17 and 21–28) [15,16].…”

Dynamic membrane interactions of antibacterial and antifungal biomolecules, and amyloid peptides, revealed by solid-state NMR spectroscopy

“…10). Studies have shown that the presence of anionic lipids enhance the binding affinity [86], negative curvature strain inducing PE lipids enhanced membrane fragmentation [96], and cholesterol to modulate the membrane mediated aggregation of human-IAPP [97]. The presence of calcium ions has been shown to promote human-IAPP aggregation and membrane fragmentation via a carpet-like mechanism [94].…”