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Design of a Coiled-Coil-based Model Peptide System to Explore the Fundamentals of Amyloid Fibril Formation

  • Michel O. Steinmetz
  • Carlos García-Echeverría
  • Richard A. Kammerer
Article

Abstract

Protein deposition as amyloid fibrils underlies more than twenty severely debilitating human disorders. Interestingly, recent studies suggest that all peptides and proteins possess an intrinsic ability to assemble into amyloid fibrils similar to those observed in disease states. The common properties and characteristics of amyloid aggregates thus offer the prospect that simple model systems can be used to systematically assess the factors that predispose a native protein to form amyloid fibrils and understand the origin and progression of fatal disorders associated with amyloid formation. Here, we report the de novo design of a 17-residue peptide model system, referred to as ccβ, which forms a protein-like coiled-coil structure under ambient solution conditions but can be easily converted into amyloid fibrils by raising the temperature. Oxidation of methionine residues at selected hydrophobic positions completely abolished amyloid fibril formation of the peptide while not interfering with its coiled-coil structure. This finding indicates that a small number of site-specific hydrophobic interactions can play a major role in the packing of polypeptide chain segments within amyloid fibrils. The simplicity and characteristics of the ccβ system make it highly suitable for probing molecular details of the assembly of amyloid structures.

Key words

Coiled coil de novo design amyloid 

Abbreviations

CD

circular dichroism

Fmoc

9-fluorenylmethoxycarbonyl

EDT

1,2-ethanedithiol

GRAVY

Grand average hydrophaty

HPLC

high-performance liquid chromatography

MALDI-TOF

matrix-assisted laser-desorption ionization time-of-flight mass spectroscopy

MBHA-resin

4-methylbenzhydrylamine-resin

PAL

tris(alkoxy)benzylamide linker

PBS

phosphate buffered saline

PEG

polyethylene glycol

TEM

transmission electron microscope

TPTU

O-(1,2-dihydro-2-oxo-pyridyl)-N, N, N′,N′-tetramethyluronium tetrafluoroborate

TFA

trifluoroacetic acid

UV

ultraviolet

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Copyright information

© Springer Science+Business Media, Inc. 2005

Authors and Affiliations

  • Michel O. Steinmetz
    • 1
  • Carlos García-Echeverría
    • 2
  • Richard A. Kammerer
    • 3
  1. 1.Biomolecular Research, Structural BiologyPaul Scherrer InstituteVilligen PSISwitzerland
  2. 2.Novartis Institutes for BioMedical ResearchBaselSwitzerland
  3. 3.Wellcome Trust Centre for Cell-Matrix ResearchSchool of Biological Sciences, University of ManchesterManchesterUK

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