Lipid Membranes Modulate the Structure of Islet Amyloid Polypeptide

• Published in: Biochemistry (Easton) Vol. 44; no. 36; pp. 12113 - 12119
• Main Authors: Jayasinghe, Sajith A, Langen, Ralf
• Format: Journal Article
• Language: English
• Published: United States American Chemical Society 13.09.2005
• Subjects: Amino Acid Sequence; Amyloid - chemistry; Amyloid - metabolism; Animals; Circular Dichroism; Enzyme Stability; Humans; Islet Amyloid Polypeptide; Islets of Langerhans - chemistry; Kinetics; Membrane Lipids - chemistry; Membrane Lipids - metabolism; Molecular Sequence Data; Protein Structure, Secondary; Rats; Sequence Homology, Amino Acid; Spectrometry, Fluorescence
• ISSN: 0006-2960; 1520-4995
• DOI: 10.1021/bi050840w

The 37-residue islet amyloid polypeptide (IAPP) is thought to play an important role in the pathogenesis of type II diabetes. Despite a growing body of evidence implicating membrane interaction in IAPP toxicity, the membrane-bound form has not yet been well characterized. Here we used circular dichroism (CD) and fluorescence spectroscopy to investigate the molecular details of the interaction of IAPP with lipid membranes of varying composition. In the presence of membranes containing negatively charged phosphatidylserine (PS), we observed significant acceleration in the formation of IAPP aggregates. This acceleration is strongly modulated by the PS concentration and ionic strength, and is also observed at physiologically relevant PS concentrations. CD spectra of IAPP obtained immediately after the addition of membranes containing PS revealed features characteristic of an α-helical conformation approximately ∼15−19 residues in length. After a longer incubation with membranes, IAPP gave rise to CD spectra characteristic of a β-sheet conformation. Taken together, our CD and fluorescence data indicate that conditions that promote weakly stable α-helical conformations may promote IAPP aggregation. The potential roles of IAPP−membrane interaction and the novel membrane-bound α-helical conformation in IAPP aggregation are discussed.