Mechanism of IAPP Fibrillation at Lipid Interfaces Studied by Infrared Reflection Absorption Spectroscopy (IRRAS)
Dahabada Lopes 1, Annette Meister 2, Andrea Gohlke 1, Anton Hauser 2, Alfred Blume 2 and Roland Winter 1*
1 University of Dortmund
2 University of Halle-Wittenberg
* To whom correspondence should be addressed. E-mail: roland.winter{at}uni-dortmund.de.
Submitted on April 12, 2007
Revised on May 27, 2007
Accepted on 22 June 2007
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Abstract |
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Islet amyloid polypeptide (IAPP) is a pancreatic hormone and one of a number of proteins that are involved in the formation of amyloid deposits in the islets of Langerhans of type II diabetes mellitus patients. Though IAPP-membrane interactions are known to play a major role in the fibrillation process, the mechanism and the peptide's conformational changes involved are still largely unknown. To achieve new insights into the conformational dynamics of IAPP upon its aggregation at membrane interfaces and to relate these structures to its fibril formation, we studied the association of IAPP at various interfaces including neutral as well as charged phospholipids using infrared reflection absorption spectroscopy (IRRAS). The results obtained reveal that the interaction of human IAPP with the lipid interface is driven by the N-terminal part of the peptide and is largely driven by electrostatic interactions, as the protein is able to associate strongly with negatively charged lipids, only. A two-step process is observed upon peptide binding, involving a conformational transition from a largely 
-helical to a 
-sheet conformation, finally forming ordered fibrillar structures. As revealed by simulations of the IRRAS spectra and complementary atomic force microscopy studies, the fibrillar structures formed consists of parallel intermolecular -sheets lying parallel to the lipid interface, but still contain a significant amount of turn structures. We may assume that these dynamical conformational changes observed for negatively charged lipid interfaces play an important role as the first steps of IAPP-induced membrane damage in type II diabetes.
Key Words:
IAPP, IRRAS, amyloidogenesis, lipid monolayers, lipid-protein interactions
