title: Membrane Permeation versus Amyloidogenicity: A Multitechnique Study of Islet Amyloid Polypeptide Interaction with Model Membranes.
abstract: Islet amyloid polypeptide (IAPP) is responsible for cell depletion in the pancreatic islets of Langherans, and for multiple pathological consequences encountered by patients suffering from type 2 Diabetes Mellitus. We have examined the amyloidogenicity and cytotoxic mechanisms of this peptide by investigating model-membrane permeation and structural effects of fragments of the human IAPP and several rat IAPP mutants. In vitro experiments and molecular dynamics simulations reveal distinct physical segregation, membrane permeation, and amyloid aggregation processes that are mediated by two separate regions of the peptide. These observations suggest a "detergent-like" mechanism, where lipids are extracted from the bilayer by the N-terminus of IAPP, and integrated into amyloid aggregates. The amyloidogenic aggregation would kinetically compete with the process of membrane permeation and, therefore, inhibit it. This hypothesis represents a new perspective on the mechanism underlying the membrane disruption by amyloid peptides, and could influence the development of new therapeutic strategies.
authors.affiliation: The Institut Laue Langevin , 38042 Grenoble, France.
authors.forename: Anne
authors.identifier: 0000-0002-1232-8519
authors.initials: A
authors.lastname: Martel
authors.affiliation: Institute for Molecular Engineering, University of Chicago , Chicago, Illinois 60637, United States.
authors.forename: Lucas
authors.initials: L
authors.lastname: Antony
authors.affiliation: The Institut Laue Langevin , 38042 Grenoble, France.
authors.forename: Yuri
authors.identifier: 0000-0001-5655-8298
authors.initials: Y
authors.lastname: Gerelli
authors.affiliation: The Institut Laue Langevin , 38042 Grenoble, France.
authors.forename: Lionel
authors.initials: L
authors.lastname: Porcar
authors.affiliation: Institute for Molecular Engineering, University of Chicago , Chicago, Illinois 60637, United States.
authors.forename: Aaron
authors.initials: A
authors.lastname: Fluitt
authors.affiliation: Institute for Molecular Engineering, University of Chicago , Chicago, Illinois 60637, United States.
authors.forename: Kyle
authors.initials: K
authors.lastname: Hoffmann
authors.affiliation: The Institut Laue Langevin , 38042 Grenoble, France.
authors.forename: Irena
authors.initials: I
authors.lastname: Kiesel
authors.affiliation: Institut de Biologie Structurale (IBS), University Grenoble Alpes, CEA, CNRS , 38044 Grenoble, France.
authors.forename: Michel
authors.initials: M
authors.lastname: Vivaudou
authors.affiliation: The Institut Laue Langevin , 38042 Grenoble, France.
authors.forename: Giovanna
authors.initials: G
authors.lastname: Fragneto
authors.affiliation: Institute for Molecular Engineering, University of Chicago , Chicago, Illinois 60637, United States.
authors.forename: Juan J
authors.identifier: 0000-0002-3526-516X
authors.initials: JJ
authors.lastname: de Pablo
mesh_terms: D000682:Amyloid / Q000737:chemistry / Q000235:genetics / Q000378:metabolism*; D000818:Animals; D002462:Cell Membrane / Q000737:chemistry / Q000235:genetics / Q000378:metabolism*; D002463:Cell Membrane Permeability / Q000235:genetics; D006801:Humans; D058228:Islet Amyloid Polypeptide / Q000737:chemistry / Q000235:genetics / Q000378:metabolism*; D056004:Molecular Dynamics Simulation; D051381:Rats
chemical_list: D000682:Amyloid; D058228:Islet Amyloid Polypeptide