title: Exploring amyloid formation by a de novo design.
abstract: Protein deposition as amyloid fibrils underlies many debilitating human disorders. The complexity and size of disease-related polypeptides, however, often hinders a detailed rational approach to study effects that contribute to the process of amyloid formation. We report here a simplified peptide sequence successfully designed de novo to fold into a coiled-coil conformation under ambient conditions but to transform into amyloid fibrils at elevated temperatures. We have determined the crystal structure of the coiled-coil form and propose a detailed molecular model for the peptide in its fibrillar state. The relative stabilities of the two structural forms and the kinetics of their interconversion were found to be highly sensitive to small sequence changes. The results reveal the importance of specific packing interactions on the kinetics of amyloid formation and show the potential of this exceptionally favorable system for probing details of the molecular origins of amyloid disease.
authors.affiliation: Wellcome Trust Centre for Cell-Matrix Research, School of Biological Sciences, University of Manchester, 2205 Stopford Building, Oxford Road, Manchester M13 PT, United Kingdom. richard.kammerer@man.ac.uk
authors.forename: Richard A
authors.initials: RA
authors.lastname: Kammerer
authors.forename: Dirk
authors.initials: D
authors.lastname: Kostrewa
authors.forename: Jesús
authors.initials: J
authors.lastname: Zurdo
authors.forename: Andreas
authors.initials: A
authors.lastname: Detken
authors.forename: Carlos
authors.initials: C
authors.lastname: García-Echeverría
authors.forename: Janelle D
authors.initials: JD
authors.lastname: Green
authors.forename: Shirley A
authors.initials: SA
authors.lastname: Müller
authors.forename: Beat H
authors.initials: BH
authors.lastname: Meier
authors.forename: Fritz K
authors.initials: FK
authors.lastname: Winkler
authors.forename: Christopher M
authors.initials: CM
authors.lastname: Dobson
authors.forename: Michel O
authors.initials: MO
authors.lastname: Steinmetz
mesh_terms: D000595:Amino Acid Sequence; D000682:Amyloid / Q000138:chemical synthesis / Q000737:chemistry* / Q000648:ultrastructure*; D002942:Circular Dichroism; D008854:Microscopy, Electron; D008958:Models, Molecular; D008969:Molecular Sequence Data; D010446:Peptide Fragments / Q000138:chemical synthesis / Q000737:chemistry; D011487:Protein Conformation; D014961:X-Ray Diffraction
chemical_list: D000682:Amyloid; D010446:Peptide Fragments