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Human islet amyloid polypeptide monomers form ordered beta-hairpins: a possible direct amyloidogenic precursor.

ABSTRACT: Oligomerization of human islet amyloid polypeptide (IAPP) has been increasingly considered a pathogenic process in type II diabetes. Here structural features of the IAPP monomer have been probed using a combination of ion mobility mass spectrometry (IMS-MS) and all-atom replica exchange molecular dynamics (REMD) simulations. Three distinct conformational families of human IAPP monomer are observed in IMS experiments, and two of them are identified as dehydrated solution structures on the basis of our simulation results: one is an extended beta-hairpin structural family, and the second is a compact helix-coil structural family. The extended beta-hairpin family is topologically similar to the peptide conformation in the solid-state NMR fibril structure published by Tycko and co-workers. It is absent in both experiments and simulations performed on the non-amyloidogenic rat IAPP, suggesting it may play an important role in the fibrillation pathway of human IAPP. In addition, pH dependence studies show that the relative abundance of the beta-hairpin structural family is significantly enhanced at pH 8.0. This observation is consistent with the increased rate of fibrillation at high pH in vitro and offers a possible explanation of the pH dependent fibrillation in vivo. This paper, to the best of our knowledge, presents the first experimental evidence of a significant population of beta-hairpin conformers for the IAPP peptide. It is consistent with a previous suggestion in the literature that beta-sheet-rich oligomers are assembled from ordered beta-hairpins rather than from coiled structures.

SUBMITTER: Dupuis NF

PROVIDER: S-EPMC2810149 | biostudies-literature | 2009 Dec

REPOSITORIES: biostudies-literature

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Human islet amyloid polypeptide monomers form ordered beta-hairpins: a possible direct amyloidogenic precursor.

Dupuis Nicholas F NF Wu Chun C Shea Joan-Emma JE Bowers Michael T MT

Journal of the American Chemical Society 20091201 51

Oligomerization of human islet amyloid polypeptide (IAPP) has been increasingly considered a pathogenic process in type II diabetes. Here structural features of the IAPP monomer have been probed using a combination of ion mobility mass spectrometry (IMS-MS) and all-atom replica exchange molecular dynamics (REMD) simulations. Three distinct conformational families of human IAPP monomer are observed in IMS experiments, and two of them are identified as dehydrated solution structures on the basis o ...[more]

PMID: 19950949

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Project description:The death of insulin-producing beta-cells is a key step in the pathogenesis of type 2 diabetes. The amyloidogenic peptide Islet Amyloid Polypeptide (IAPP, also known as amylin) has been shown to disrupt beta-cell membranes leading to beta-cell death. Despite the strong evidence linking IAPP to the destruction of beta-cell membrane integrity and cell death, the mechanism of IAPP toxicity is poorly understood. In particular, the effect of IAPP on the bilayer structure has largely been uncharacterized. In this study, we have determined the effect of the amyloidogenic and toxic hIAPP(1-37) peptide and the nontoxic and nonamyloidogenic rIAPP(1-37) peptide on membranes by a combination of DSC and solid-state NMR spectroscopy. We also characterized the toxic but largely nonamyloidogenic rIAPP(1-19) and hIAPP(1-19) fragments. DSC shows that both amyloidogenic (hIAPP(1-37)) and largely nonamyloidogenic (hIAPP(1-19) and rIAPP(1-19)) toxic versions of the peptide strongly favor the formation of negative curvature in lipid bilayers, while the nontoxic full-length rat IAPP(1-37) peptide does not. This result was confirmed by solid-state NMR spectroscopy which shows that in bicelles composed of regions of high curvature and low curvature, nontoxic rIAPP(1-37) binds to the regions of low curvature while toxic rIAPP(1-19) binds to regions of high curvature. Similarly, solid-state NMR spectroscopy shows that the toxic rIAPP(1-19) peptide significantly disrupts the lipid bilayer structure, whereas the nontoxic rIAPP(1-37) does not have a significant effect. These results indicate IAPP may induce the formation of pores by the induction of excess membrane curvature and can be used to guide the design of compounds that can prevent the cell-toxicity of IAPP. This mechanism may be important to understand the toxicity of other amyloidogenic proteins. Our solid-state NMR results also demonstrate the possibility of using bicelles to measure the affinity of biomolecules for negatively or positively curved regions of the membrane, which we believe will be useful in a variety of biochemical and biophysical investigations related to the cell membrane.

Project description:IAPP, a 37 amino-acid peptide hormone belonging to the calcitonin family, is an intrinsically disordered protein that is coexpressed and cosecreted along with insulin by pancreatic islet ?-cells in response to meals. IAPP plays a physiological role in glucose regulation; however, in certain species, IAPP can aggregate and this process is linked to ?-cell death and Type II Diabetes. Using replica exchange molecular dynamics with extensive sampling (16 replicas per sequence and 600 ns per replica), we investigate the structure of the monomeric state of two species of aggregating peptides (human and cat IAPP) and two species of non-aggregating peptides (pig and rat IAPP). Our simulations reveal that the pig and rat conformations are very similar, and consist of helix-coil and helix-hairpin conformations. The aggregating sequences, on the other hand, populate the same helix-coil and helix-hairpin conformations as the non-aggregating sequence, but, in addition, populate a hairpin structure. Our exhaustive simulations, coupled with available peptide-activity data, leads us to a structure-activity relationship (SAR) in which we propose that the functional role of IAPP is carried out by the helix-coil conformation, a structure common to both aggregating and non-aggregating species. The pathological role of this peptide may have multiple origins, including the interaction of the helical elements with membranes. Nonetheless, our simulations suggest that the hairpin structure, only observed in the aggregating species, might be linked to the pathological role of this peptide, either as a direct precursor to amyloid fibrils, or as part of a cylindrin type of toxic oligomer. We further propose that the helix-hairpin fold is also a possible aggregation prone conformation that would lead normally non-aggregating variants of IAPP to form fibrils under conditions where an external perturbation is applied. The SAR relationship is used to suggest the rational design of therapeutics for treating diabetes.

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Human islet amyloid polypeptide monomers form ordered beta-hairpins: a possible direct amyloidogenic precursor.

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Human islet amyloid polypeptide monomers form ordered beta-hairpins: a possible direct amyloidogenic precursor.

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