Effect of pressure on islet amyloid polypeptide aggregation: revealing the polymorphic nature of the fibrillation process.
Type II diabetes mellitus is a disease which is characterized by peripheral insulin resistance coupled with a progressive loss of insulin secretion that is associated with a decrease in pancreatic islet beta-cell mass and the deposition of amyloid in the extracellular matrix of beta-cells, which lead to islet cell death. The principal component of the islet amyloid is a pancreatic hormone called islet amyloid polypeptide (IAPP). High-pressure coupled with FT-IR spectroscopic and AFM studies were carried out to elucidate further information about the aggregation pathway as well as the aggregate structures of IAPP. To this end, a comparative fibrillation study of IAPP fragments was carried out as well. As high hydrostatic pressure (HHP) is acting to weaken or even prevent hydrophobic self-organization and electrostatic interactions, application of HHP has been used as a measure to reveal the importance of these interactions in the fibrillation process of IAPP and its fragments. IAPP preformed fibrils exhibit a strong polymorphism with heterogeneous structures, a large population of which are rather sensitive to high hydrostatic pressure, thus indicating a high percentage of ionic and hydrophobic interactions and loose packing of these species. Conversely, fragments 1-19 and 1-29 are resistant to pressure treatment, suggesting more densely packed aggregate structures with less void volume and strong cooperative hydrogen bonding. Furthermore, the FT-IR data indicate that fragment 1-29 has intermolecular beta-sheet conformational properties different from those of fragment 1-19, the latter exhibiting polymorphic behavior with more disordered structures and less strongly hydrogen bonded fibrillar assemblies. The data also suggest that hydrophobic interactions and/or less efficient packing of amino acids 30-37 region leads to the marked pressure sensitivity observed for full-length IAPP.
Radovan
Diana
D
Department of Chemistry, Physical Chemistry I-Biophysical Chemistry, Dortmund University of Technology, D-44227 Dortmund, Germany.
Smirnovas
Vytautas
V
Winter
Roland
R
D000682:Amyloid / Q000737:chemistry* / Q000378:metabolism* / Q000648:ultrastructure; D003922:Diabetes Mellitus, Type 1 / Q000209:etiology / Q000378:metabolism; D006801:Humans; D057927:Hydrophobic and Hydrophilic Interactions; D006874:Hydrostatic Pressure; D058228:Islet Amyloid Polypeptide; D007700:Kinetics; D018625:Microscopy, Atomic Force; D010446:Peptide Fragments / Q000737:chemistry* / Q000378:metabolism* / Q000648:ultrastructure; D017550:Spectroscopy, Fourier Transform Infrared; D055672:Static Electricity
D000682:Amyloid; D058228:Islet Amyloid Polypeptide; D010446:Peptide Fragments