title: Atomic models of de novo designed cc beta-Met amyloid-like fibrils.
abstract: The common characteristics of amyloid and amyloid-like fibrils from disease- and non-disease-associated proteins offer the prospect that well-defined model systems can be used to systematically dissect the driving forces of amyloid formation. We recently reported the de novo designed cc beta peptide model system that forms a native-like coiled-coil structure at low temperatures and which can be switched to amyloid-like fibrils by increasing the temperature. Here, we report a detailed molecular description of the system in its fibrillar state by characterizing the cc beta-Met variant using several microscopic techniques, circular dichroism spectroscopy, X-ray fiber diffraction, solid-state nuclear magnetic resonance, and molecular dynamics calculations. We show that cc beta-Met forms amyloid-like fibrils of different morphologies on both the macroscopic and atomic levels, which can be controlled by variations of assembly conditions. Interestingly, heterogeneity is also observed along single fibrils. We propose atomic models of the cc beta-Met amyloid-like fibril, which are in good agreement with all experimental data. The models provide a rational explanation why oxidation of methionine residues completely abolishes cc beta-Met amyloid fibril formation, indicating 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 detailed structural information available for the cc beta model system provides a strong molecular basis for understanding the influence and relative contribution of hydrophobic interactions on native-state stability, kinetics of fibril formation, fibril packing, and polymorphism.
authors.affiliation: Biomolecular Research, Structural Biology, Paul Scherrer Institut, CH-5232 Villigen PSI, Switzerland. michel.steinmetz@psi.ch
authors.forename: Michel O
authors.initials: MO
authors.lastname: Steinmetz
authors.forename: Zrinka
authors.initials: Z
authors.lastname: Gattin
authors.forename: Rene
authors.initials: R
authors.lastname: Verel
authors.forename: Barbara
authors.initials: B
authors.lastname: Ciani
authors.forename: Thusnelda
authors.initials: T
authors.lastname: Stromer
authors.forename: Janelle M
authors.initials: JM
authors.lastname: Green
authors.forename: Peter
authors.initials: P
authors.lastname: Tittmann
authors.forename: Clemens
authors.initials: C
authors.lastname: Schulze-Briese
authors.forename: Heinz
authors.initials: H
authors.lastname: Gross
authors.forename: Wilfred F
authors.initials: WF
authors.lastname: van Gunsteren
authors.forename: Beat H
authors.initials: BH
authors.lastname: Meier
authors.forename: Louise C
authors.initials: LC
authors.lastname: Serpell
authors.forename: Shirley A
authors.initials: SA
authors.lastname: Müller
authors.forename: Richard A
authors.initials: RA
authors.lastname: Kammerer
mesh_terms: D000595:Amino Acid Sequence; D000682:Amyloid / Q000737:chemistry* / Q000648:ultrastructure; D018625:Microscopy, Atomic Force; D008958:Models, Molecular; D008969:Molecular Sequence Data; D019906:Nuclear Magnetic Resonance, Biomolecular; D010455:Peptides / Q000737:chemistry*; D017433:Protein Structure, Secondary; D014961:X-Ray Diffraction
chemical_list: D000682:Amyloid; D010455:Peptides