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Chemphyschem. 2016 Sep 5;17(17):2744-53. doi: 10.1002/cphc.201600413. Epub 2016 Jun 27.

A Detailed Analysis of the Morphology of Fibrils of Selectively Mutated Amyloid β (1-40).

Author information

1
Institute for Medical Physics and Biophysics, Leipzig University, Härtelstrasse 16-18, 04107, Leipzig, Germany.
2
Institute of Physics, Biophysics, Martin Luther University Halle-Wittenberg, B.-Heimann-Strasse 7, 06120, Halle, Germany.
3
Department of Chemistry, Tata Institute of Fundamental Research, Homi Bhabha Road, Colaba, Mumbai, 400 005, India.
4
Department of Chemistry, Northwestern University, 2145 Sheridan Road, Evanston, IL, 60208-3113, USA.
5
Leibniz Institute of Surface Modification (IOM), Permoserstrasse 15, 04318, Leipzig, Germany.
6
Wilhelm-Ostwald Institute of Physical and Theoretical Chemistry, Leipzig University, Linnéstrasse 3, 04103, Leipzig, Germany.
7
TIFR Centre for Interdisciplinary Sciences, Tata Institute of Fundamental Research, Leipzig University, 21 Brundavan Colony, Narsingi, Hyderabad, 500075, India.
8
Institute for Medical Physics and Biophysics, Leipzig University, Härtelstrasse 16-18, 04107, Leipzig, Germany. daniel.huster@medizin.uni-leipzig.de.
9
Department of Chemistry, Tata Institute of Fundamental Research, Homi Bhabha Road, Colaba, Mumbai, 400 005, India. daniel.huster@medizin.uni-leipzig.de.

Abstract

A small library of rationally designed amyloid β [Aβ(1-40)] peptide variants is generated, and the morphology of their fibrils is studied. In these molecules, the structurally important hydrophobic contact between phenylalanine 19 (F19) and leucine 34 (L34) is systematically mutated to introduce defined physical forces to act as specific internal constraints on amyloid formation. This Aβ(1-40) peptide library is used to study the fibril morphology of these variants by employing a comprehensive set of biophysical techniques including solution and solid-state NMR spectroscopy, AFM, fluorescence correlation spectroscopy, and XRD. Overall, the findings demonstrate that the introduction of significant local physical perturbations of a crucial early folding contact of Aβ(1-40) only results in minor alterations of the fibrillar morphology. The thermodynamically stable structure of mature Aβ fibrils proves to be relatively robust against the introduction of significantly altered molecular interaction patterns due to point mutations. This underlines that amyloid fibril formation is a highly generic process in protein misfolding that results in the formation of the thermodynamically most stable cross-β structure.

KEYWORDS:

NMR spectroscopy; amyloids; fibrils; mutagenesis; peptides

PMID:
27224205
DOI:
10.1002/cphc.201600413
[Indexed for MEDLINE]

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