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 ...

Membrane Permeation versus Amyloidogenicity: A Multitechnique Study of Islet Amyloid Polypeptide Interaction with Model Membranes / Martel, Anne; Antony, Lucas; Gerelli, Yuri; Porcar, Lionel; Fluitt, Aaron; Hoffmann, Kyle; Kiesel, Irena; Vivaudou, Michel; Fragneto, Giovanna; de Pablo, Juan J.. - In: JOURNAL OF THE AMERICAN CHEMICAL SOCIETY. - ISSN 0002-7863. - ELETTRONICO. - 139:1(2017), pp. 137-148. [10.1021/jacs.6b06985]

Membrane Permeation versus Amyloidogenicity: A Multitechnique Study of Islet Amyloid Polypeptide Interaction with Model Membranes

Yuri Gerelli;Giovanna Fragneto;
2017-01-01

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 ...
2017
File in questo prodotto:
Non ci sono file associati a questo prodotto.

I documenti in IRIS sono protetti da copyright e tutti i diritti sono riservati, salvo diversa indicazione.

Utilizza questo identificativo per citare o creare un link a questo documento: https://hdl.handle.net/11566/276296
 Attenzione

Attenzione! I dati visualizzati non sono stati sottoposti a validazione da parte dell'ateneo

Citazioni
  • ???jsp.display-item.citation.pmc??? ND
  • Scopus 45
  • ???jsp.display-item.citation.isi??? 43
social impact