title: 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.
authors.affiliation: Istituto di Biostrutture e Bioimmagini, Consiglio Nazionale delle Ricerche, Catania, Italy.
authors.forename: Michele F M
authors.initials: MF
authors.lastname: Sciacca
authors.affiliation: Dipartimento di Scienze Chimiche, Università degli Studi di Catania, Catania, Italy; Department of Physics, Tampere University of Technology, Tampere, Finland.
authors.forename: Fabio
authors.initials: F
authors.lastname: Lolicato
authors.affiliation: Dipartimento di Scienze Chimiche, Università degli Studi di Catania, Catania, Italy.
authors.forename: Giacomo
authors.initials: G
authors.lastname: Di Mauro
authors.affiliation: Istituto di Biostrutture e Bioimmagini, Consiglio Nazionale delle Ricerche, Catania, Italy.
authors.forename: Danilo
authors.initials: D
authors.lastname: Milardi
authors.affiliation: Dipartimento di Scienze Chimiche, Università degli Studi di Catania, Catania, Italy.
authors.forename: Luisa
authors.initials: L
authors.lastname: D'Urso
authors.affiliation: Dipartimento di Scienze Chimiche, Università degli Studi di Catania, Catania, Italy.
authors.forename: Cristina
authors.initials: C
authors.lastname: Satriano
authors.affiliation: Biophysics, University of Michigan, Ann Arbor, Michigan; Department of Chemistry, University of Michigan, Ann Arbor, Michigan; Institute for Advanced Study, Technische Universität München, Lichtenbergstrasse, Garching, Germany. Electronic address: ramamoor@umich.edu.
authors.forename: Ayyalusamy
authors.initials: A
authors.lastname: Ramamoorthy
authors.affiliation: Dipartimento di Scienze Chimiche, Università degli Studi di Catania, Catania, Italy. Electronic address: clarosa@unict.it.
authors.forename: Carmelo
authors.initials: C
authors.lastname: La Rosa
mesh_terms: D015060:1,2-Dipalmitoylphosphatidylcholine / Q000378:metabolism; D002462:Cell Membrane / Q000378:metabolism*; D002784:Cholesterol / Q000378:metabolism*; D006801:Humans; D058228:Islet Amyloid Polypeptide / Q000737:chemistry / Q000378:metabolism*; D007700:Kinetics; D008051:Lipid Bilayers / Q000737:chemistry / Q000378:metabolism; D021962:Membrane Microdomains / Q000737:chemistry / Q000378:metabolism; D056004:Molecular Dynamics Simulation; D010713:Phosphatidylcholines / Q000378:metabolism; D016062:Porosity; D011485:Protein Binding; D017433:Protein Structure, Secondary; D013499:Surface Properties
chemical_list: D058228:Islet Amyloid Polypeptide; D008051:Lipid Bilayers; D010713:Phosphatidylcholines; D015060:1,2-Dipalmitoylphosphatidylcholine; D002784:Cholesterol; C017251:1,2-oleoylphosphatidylcholine