Spontaneous Aggregation of the Insulin-Derived Steric Zipper Peptide VEALYL Results in Different Aggregation Forms with Common Features |
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Authors: | Dirk Matthes Venita Daebel Karsten Meyenberg Dietmar Riedel Gudrun Heim Ulf Diederichsen Adam Lange Bert L. de Groot |
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Affiliation: | 1 Computational Biomolecular Dynamics Group, Max Planck Institute for Biophysical Chemistry, Am Fassberg 11, 37077 Göttingen, Germany;2 NMR-Based Structural Biology, Max Planck Institute for Biophysical Chemistry, Am Fassberg 11, 37077 Göttingen, Germany;3 Institute for Organic and Biomolecular Chemistry, University of Göttingen, Tammannstrasse 2, 37077 Göttingen, Germany;4 Electron Microscopy, Max Planck Institute for Biophysical Chemistry, Am Fassberg 11, 37077 Göttingen, Germany |
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Abstract: | Recently, several short peptides have been shown to self-assemble into amyloid fibrils with generic cross-β spines, so-called steric zippers, suggesting common underlying structural features and aggregation mechanisms. Understanding these mechanisms is a prerequisite for designing fibril-binding compounds and inhibitors of fibril formation. The hexapeptide VEALYL, corresponding to the residues B12-17 of full-length insulin, has been identified as one of these short segments. Here, we analyzed the structures of multiple, morphologically different (fibrillar, microcrystal-like, oligomeric) [13C,15N]VEALYL samples by solid-state nuclear magnetic resonance complemented with results from molecular dynamics simulations. By performing NHHC/CHHC experiments, we could determine that the β-strands within a given sheet of the amyloid-like fibrils formed by the insulin hexapeptide VEALYL are stacked in an antiparallel manner, whereas the sheet-to-sheet packing arrangement was found to be parallel. Experimentally observed secondary chemical shifts for all aggregate forms, as well as ∅ and ψ backbone torsion angles calculated with TALOS, are indicative of β-strand conformation, consistent with the published crystal structure (PDB ID: 2OMQ). Thus, we could demonstrate that the structural features of all the observed VEALYL aggregates are in agreement with the previously observed homosteric zipper spine packing in the crystalline state, suggesting that several distinct aggregate morphologies share the same molecular architecture. |
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Keywords: | MD, molecular dynamics ssNMR, solid-state nuclear magnetic resonance MAS, magic angle spinning PDSD, proton-driven spin diffusion EM, electron microscopy CP, cross-polarization |
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