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J. Biol. Chem., Vol. 283, Issue 25, 17205-17210, June 20, 2008

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Structure of -Helical Membrane-bound Human Islet Amyloid Polypeptide and Its Implications for Membrane-mediated Misfolding^*

Melania Apostolidou, Sajith A. Jayasinghe, and Ralf Langen¹

From the Department of Biochemistry and Molecular Biology, Zilkha Neurogenetic Institute, Keck School of Medicine, University of Southern California, Los Angeles, California 90033 and Department of Chemistry and Biochemistry, California State University, San Marcos, California 92096

Human islet amyloid polypeptide (hIAPP) misfolding is thought to play an important role in the pathogenesis of type II diabetes mellitus. It has recently been shown that membranes can catalyze the misfolding of hIAPP via an -helical intermediate of unknown structure. To better understand the mechanism of membrane-mediated misfolding, we used site-directed spin labeling and EPR spectroscopy to generate a three-dimensional structural model of this membrane-bound form. We find that hIAPP forms a single -helix encompassing residues 9–22. The helix is flanked by N- and C-terminal regions that do not take up a clearly detectable secondary structure and are less ordered. Residues 21 and 22 are located in a transitional region between the -helical structure and C terminus and exhibit significant mobility. The -helical structure presented here has important implications for membrane-mediated aggregation. Anchoring hIAPP to the membrane not only increases the local concentration but also reduces the encounter between peptides to essentially a two-dimensional process. It is significant to note that the -helical membrane-bound form leaves much of an important amyloidogenic region of hIAPP (residues 20–29) exposed for misfolding. Misfolding of this and other regions is likely further aided by the low dielectric environment near the membrane that is known to promote secondary structure formation. Based upon these considerations, a structural model for membrane-mediated aggregation is discussed.

Received for publication, February 21, 2008 , and in revised form, April 23, 2008.

^* This work was supported, in whole or in part, by National Institutes of Health Grant AG027936 (to R. L.). This work was also supported by the Beckman Foundation (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.

¹ To whom correspondence should be addressed: Dept. of Biochemistry and Molecular Biology, Zilkha Neurogenetic Inst., Keck School of Medicine, University of Southern California, 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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