title: De novo amyloid proteins from designed combinatorial libraries.
abstract: Amyloid deposits are associated with several neurodegenerative diseases, including Alzheimer's disease and the prion diseases. The amyloid fibrils isolated from these different diseases share similar structural features. However, the protein sequences that assemble into these fibrils differ substantially from one disease to another. To probe the relationship between amino acid sequence and the propensity to form amyloid, we studied a combinatorial library of sequences designed de novo. All sequences in the library were designed to share an identical pattern of alternating polar and nonpolar residues, but the precise identities of these side chains were not constrained and were varied combinatorially. The resulting proteins self-assemble into large oligomers visible by electron microscopy as amyloid-like fibrils. Like natural amyloid, the de novo fibrils are composed of beta-sheet secondary structure and bind the diagnostic dye, Congo red. Thus, binary patterning of polar and nonpolar residues arranged in alternating periodicity can direct protein sequences to form fibrils resembling amyloid. The model amyloid fibrils assemble and disassemble reversibly, providing a tractable system for both basic studies into the mechanisms of fibril assembly and the development of molecular therapies that interfere with this assembly.
authors.affiliation: Department of Chemistry, Princeton University, Princeton, NJ 08544-1009, USA.
authors.forename: M W
authors.initials: MW
authors.lastname: West
authors.forename: W
authors.initials: W
authors.lastname: Wang
authors.forename: J
authors.initials: J
authors.lastname: Patterson
authors.forename: J D
authors.initials: JD
authors.lastname: Mancias
authors.forename: J R
authors.initials: JR
authors.lastname: Beasley
authors.forename: M H
authors.initials: MH
authors.lastname: Hecht
mesh_terms: D000595:Amino Acid Sequence; D000682:Amyloid / Q000737:chemistry*; D008969:Molecular Sequence Data; D019151:Peptide Library; D017433:Protein Structure, Secondary
chemical_list: D000682:Amyloid; D019151:Peptide Library