title: Direct observation of nucleation and growth in amyloid self-assembly.
abstract: Access to native protein structure depends on precise polypeptide folding and assembly pathways. Identifying folding missteps that may lead to the nearly 40 protein misfolding diseases could feature prominently in the development of intervention strategies. Accordingly, we have investigated the earliest steps of assembly by the folding nucleus of the Alzheimer's disease Abeta peptide with real-time imaging and fluorescence correlation spectroscopy. These analyses reveal the immediate formation of large micrometer size clusters maintaining properties of intermolecular molten globules. These dynamic unstructured aggregates serve as the nucleating sites for amyloid growth and, as with native protein folding, appear important for backbone desolvation. The resulting amyloid nucleus however is able to template monomer addition from solution at rates from 2K peptides/s at millimolar peptide concentrations. This direct observation of amyloid assembly unifies several divergent models that currently exist for protein misfolding.
authors.affiliation: The Center for Fundamental and Applied Molecular Evolution and the Center for Chemical Evolution, Department of Chemistry, Emory University, 1515 Dickey Drive, Atlanta, Georgia 30322, USA.
authors.forename: Yan
authors.initials: Y
authors.lastname: Liang
authors.forename: David G
authors.initials: DG
authors.lastname: Lynn
authors.forename: Keith M
authors.initials: KM
authors.lastname: Berland
mesh_terms: D000595:Amino Acid Sequence; D000682:Amyloid / Q000737:chemistry* / Q000378:metabolism*; D016229:Amyloid beta-Peptides / Q000737:chemistry / Q000378:metabolism; D005456:Fluorescent Dyes / Q000378:metabolism; D010446:Peptide Fragments / Q000737:chemistry / Q000378:metabolism; D055503:Protein Multimerization; D020836:Protein Structure, Quaternary; D012235:Rhodamines / Q000378:metabolism
chemical_list: D000682:Amyloid; D016229:Amyloid beta-Peptides; D005456:Fluorescent Dyes; D010446:Peptide Fragments; D012235:Rhodamines; C417223:amyloid beta-protein (16-22); C049025:rhodamine 110