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61 IDENTIFYING STRUCTURAL FEATURES OF ISLET AMYLOID POLYPEPTIDE USING SITE-DIRECTED SPIN LABELING.
  1. S. Bedrood,
  2. S. A. Jayasinghe,
  3. R. Langen
  1. Keck School of Medicine and Department of Biochemistry and Molecular Biology, Zilkha Neurogenetic Institute, University of Southern California, Los Angeles, CA

Abstract

Pancreatic amyloid deposits are found in over 90% of patients with type II diabetes mellitus. These deposits are primarily composed of a 37-residue islet amyloid polypeptide (IAPP). While evidence suggests an association between these amyloid plaques and pancreatic beta-cell dysfunction, elucidating the structure of these deposits can help further the understanding of its toxicity. We use electron paramagnetic resonance (EPR) spectroscopy to analyze spin-labeled derivatives of IAPP to determine structural features of the peptide in the fibrillar amyloid deposit form. A number of derivatives are made in which each residue of IAPP is spin-labeled one amino acid at a time and studied with EPR spectroscopy in order to obtain information about the local environment and structure in the region of the labeled site. While we are furthering our structural studies of the core amyloidgenic region, we have identified structural features of the amino and carboxy terminus. Analysis of the spin mobility and comparison to the amyloid found in Alzheimer's patients (ABeta) indicates a high degree of order throughout the fibrillar peptide, but the N-terminal and C-terminal regions are less ordered and more mobile. Evidence suggests that these regions are not part of the ordered core region that gives rise to fibril formation. Based upon side-chain mobilities, we will present the structural features of different regions of IAPP. Combining these structural features can lead us to creating a 3-D model of IAPP and perhaps give way to methods of treatment or dissolution of the pancreatic deposit.

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