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J. Biol. Chem., Vol. 279, Issue 46, 48420-48425, November 12, 2004

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Identifying Structural Features of Fibrillar Islet Amyloid Polypeptide Using Site-directed Spin Labeling^*

Sajith A. Jayasinghe and Ralf Langen

From the Department of Biochemistry and Molecular Biology, Zilkha Neurogenetic Institute, University of Southern California, Los Angeles, California 90033

Pancreatic amyloid deposits, composed primarily of the 37-residue islet amyloid polypeptide (IAPP), are a characteristic feature found in more than 90% of patients with type II diabetes. Although IAPP amyloid deposits are associated with areas of pancreatic islet -cell dysfunction and depletion and are thought to play a role in disease, their structure is unknown. We used electron paramagnetic resonance spectroscopy to analyze eight spin-labeled derivatives of IAPP in an effort to determine structural features of the peptide. In solution, all eight derivatives gave rise to electron paramagnetic resonance spectra with sharp lines indicative of rapid motion on the sub-nanosecond time scale. These spectra are consistent with a rapidly tumbling and highly dynamic peptide. In contrast, spectra for the fibrillar form exhibit reduced mobility and the presence of strong intermolecular spin-spin interactions. The latter implies that the peptide subunits are ordered and that the same residues from neighboring peptides are in close proximity to one another. Our data are consistent with a parallel arrangement of IAPP peptides within the amyloid fibril. Analysis of spin label mobility indicates a high degree of order throughout the peptide, although the N-terminal region is slightly less ordered. Possible similarities with respect to the domain organization and parallelism of Alzheimer's amyloid peptide fibrils are discussed.

Received for publication, June 18, 2004 , and in revised form, August 2, 2004.

^* This work was supported by the Beckman Foundation and the Pew Scholars Program in the Biomedical Sciences (to R. L.). The costs of publication of this article were defrayed in part by the payment of page charges. This article must therefore be hereby marked "advertisement" in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.

To whom correspondence should be addressed: Dept. of Biochemistry and Molecular Biology, Zilkha Neurogenetic Institute, 1501 San Pablo St., Los Angeles, CA 90033. Tel.: 323-442-1323; Fax: 323-442-4404; E-mail: langen{at}usc.edu.

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