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  Spontaneous aggregation of the insulin-derived steric zipper peptide VEALYL results in different aggregation forms with common features.

Matthes, D., Daebel, V., Meyenberg, K., Riedel, D., Heim, G., Diederichsen, U., et al. (2014). Spontaneous aggregation of the insulin-derived steric zipper peptide VEALYL results in different aggregation forms with common features. Journal of Molecular Biology, 426(2), 362-376. doi:10.1016/j.jmb.2013.10.020.

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Item Permalink: http://hdl.handle.net/11858/00-001M-0000-0015-7E96-2 Version Permalink: http://hdl.handle.net/11858/00-001M-0000-0027-CBBC-A
Genre: Journal Article

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 Creators:
Matthes, D.1, Author              
Daebel, V.2, Author              
Meyenberg, K., Author
Riedel, D.3, Author              
Heim, G.3, Author              
Diederichsen, U., Author
Lange, A.2, Author              
De Groot, B. L.1, Author              
Affiliations:
1Research Group of Computational Biomolecular Dynamics, MPI for biophysical chemistry, Max Planck Society, ou_578573              
2Research Group of Solid-State NMR, MPI for biophysical chemistry, Max Planck Society, ou_persistent35              
3Facility for Electron Microscopy, MPI for biophysical chemistry, Max Planck Society, ou_578615              

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Free keywords: chemical shift; amyloid; polymorphism; molecular dynamics; solid-state NMR
 Abstract: Recently, several short peptides have been shown to self-assemble into amyloid fibrils with generic cross-beta 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) [C-13,N-15]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 beta-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 empty set and Psi backbone torsion angles calculated with TALOS, are indicative of beta-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. (C) 2013 The Authors. Published by Elsevier Ltd. All rights reserved.

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Language(s): eng - English
 Dates: 2014-01-23
 Publication Status: Published in print
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 Rev. Method: Peer
 Identifiers: DOI: 10.1016/j.jmb.2013.10.020
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Title: Journal of Molecular Biology
Source Genre: Journal
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Pages: - Volume / Issue: 426 (2) Sequence Number: - Start / End Page: 362 - 376 Identifier: -