Structures of Rat and Human Islet Amyloid Polypeptide IAPP1−19 in Micelles by NMR Spectroscopy Export

@article{citeulike:3494672, abstract = {Abstract: Disruption of the cellular membrane by the amyloidogenic peptide IAPP (or amylin) has been implicated in ²-cell death during type 2 diabetes. While the structure of the mostly inert fibrillar form of IAPP has been investigated, the structural details of the highly toxic prefibrillar membrane-bound states of IAPP have been elusive. A recent study showed that a fragment of IAPP (residues 119) induces membrane disruption to a similar extent as the full-length peptide. However, unlike the full-length IAPP peptide, IAPP119 is conformationally stable in an ±-helical conformation when bound to the membrane. In vivo and in vitro measurements of membrane disruption indicate the rat version of IAPP119, despite differing from hIAPP119 by the single substitution of Arg18 for His18, is significantly less toxic than hIAPP119, in agreement with the low toxicity of the full-length rat IAPP peptide. To investigate the origin of this difference at the atomic level, we have solved the structures of the human and rat IAPP119 peptides in DPC micelles. While both rat and human IAPP119 fold into similar mostly ±-helical structures in micelles, paramagnetic quenching NMR experiments indicate a significant difference in the membrane orientation of hIAPP119 and rIAPP119. At pH 7.3, the more toxic hIAPP119 peptide is buried deeper within the micelle, while the less toxic rIAPP119 peptide is located at the surface of the micelle. Deprotonating H18 in hIAPP119 reorients the peptide to the surface of the micelle. This change in orientation is in agreement with the significantly reduced ability of hIAPP119 to cause membrane disruption at pH 6.0. This difference in peptide topology in the membrane may correspond to similar topology differences for the full-length human and rat IAPP peptides, with the toxic human IAPP peptide adopting a transmembrane orientation and the nontoxic rat IAPP peptide bound to the surface of the membrane.}, address = {Departments of Biophysics and Chemistry, University of Michigan, Ann Arbor, Michigan 48109-1055, and Department of Chemistry, Biochemistry, Molecular Biology and Biophysics, University of Minnesota, Minneapolis, Minnesota 55455}, author = {Nanga, Ravi P. and Brender, Jeffrey R. and Xu, Jiadi and Veglia, Gianluigi and Ramamoorthy, Ayyalusamy}, citeulike-article-id = {3494672}, citeulike-linkout-0 = {http://dx.doi.org/10.1021/bi8014357}, citeulike-linkout-1 = {http://pubs.acs.org/doi/abs/10.1021/bi8014357}, day = {7}, doi = {10.1021/bi8014357}, journal = {Biochemistry}, keywords = {amylin, amyloid, diabetes, iapp, nmr, structure}, month = {November}, posted-at = {2009-04-14 05:50:27}, priority = {5}, title = {Structures of Rat and Human Islet Amyloid Polypeptide IAPP1\&\#x2212;19 in Micelles by NMR Spectroscopy}, url = {http://dx.doi.org/10.1021/bi8014357}, year = {2008} }

TY - JOUR ID - citeulike:3494672 L3 - citeulike-article-id:3494672 N2 - Abstract: Disruption of the cellular membrane by the amyloidogenic peptide IAPP (or amylin) has been implicated in ²-cell death during type 2 diabetes. While the structure of the mostly inert fibrillar form of IAPP has been investigated, the structural details of the highly toxic prefibrillar membrane-bound states of IAPP have been elusive. A recent study showed that a fragment of IAPP (residues 119) induces membrane disruption to a similar extent as the full-length peptide. However, unlike the full-length IAPP peptide, IAPP119 is conformationally stable in an ±-helical conformation when bound to the membrane. In vivo and in vitro measurements of membrane disruption indicate the rat version of IAPP119, despite differing from hIAPP119 by the single substitution of Arg18 for His18, is significantly less toxic than hIAPP119, in agreement with the low toxicity of the full-length rat IAPP peptide. To investigate the origin of this difference at the atomic level, we have solved the structures of the human and rat IAPP119 peptides in DPC micelles. While both rat and human IAPP119 fold into similar mostly ±-helical structures in micelles, paramagnetic quenching NMR experiments indicate a significant difference in the membrane orientation of hIAPP119 and rIAPP119. At pH 7.3, the more toxic hIAPP119 peptide is buried deeper within the micelle, while the less toxic rIAPP119 peptide is located at the surface of the micelle. Deprotonating H18 in hIAPP119 reorients the peptide to the surface of the micelle. This change in orientation is in agreement with the significantly reduced ability of hIAPP119 to cause membrane disruption at pH 6.0. This difference in peptide topology in the membrane may correspond to similar topology differences for the full-length human and rat IAPP peptides, with the toxic human IAPP peptide adopting a transmembrane orientation and the nontoxic rat IAPP peptide bound to the surface of the membrane. JF - Biochemistry AD - Departments of Biophysics and Chemistry, University of Michigan, Ann Arbor, Michigan 48109-1055, and Department of Chemistry, Biochemistry, Molecular Biology and Biophysics, University of Minnesota, Minneapolis, Minnesota 55455 TI - Structures of Rat and Human Islet Amyloid Polypeptide IAPP1−19 in Micelles by NMR Spectroscopy KW - amylin KW - amyloid KW - diabetes KW - iapp KW - nmr KW - structure AU - Nanga, Ravi AU - Brender, Jeffrey AU - Xu, Jiadi AU - Veglia, Gianluigi AU - Ramamoorthy, Ayyalusamy PY - 2008/11/07/ UR - http://dx.doi.org/10.1021/bi8014357 ER -