title: Mechanism of Nucleated Conformational Conversion of Aβ42.
abstract: Soluble oligomers and protofibrils of the Aβ42 peptide are neurotoxic intermediates in the conversion of monomeric Aβ42 into the amyloid fibrils associated with Alzheimer's disease. Nuclear magnetic resonance and Fourier transform infrared spectroscopy, along with single-touch atomic force microscopy, are used to establish the structural transitions involved in fibril formation. We show that under conditions favorable for the nucleated conformation conversion, the Aβ42 peptide aggregates into largely unstructured low-molecular weight (MW) oligomers that are able to stack to form high-MW oligomers and to laterally associate to form protofibrils. β-Sheet secondary structure develops during the irreversible lateral association of the oligomers. The first step in this conversion is the formation of an antiparallel β-hairpin stabilized by intramonomer hydrogen bonding. The antiparallel β-hairpins then associate into a cross β-sheet structure with parallel and in-register β-strands having intermonomer hydrogen bonding.
authors.affiliation: †Department of Biochemistry and Cell Biology, Stony Brook University, Stony Brook, New York 11794-5215, United States.
authors.forename: Ziao
authors.initials: Z
authors.lastname: Fu
authors.affiliation: †Department of Biochemistry and Cell Biology, Stony Brook University, Stony Brook, New York 11794-5215, United States.
authors.forename: Darryl
authors.initials: D
authors.lastname: Aucoin
authors.affiliation: ‡Departments of Neurosurgery and Medicine, Stony Brook University, Stony Brook, New York 11794-8122, United States.
authors.forename: Judianne
authors.initials: J
authors.lastname: Davis
authors.affiliation: ‡Departments of Neurosurgery and Medicine, Stony Brook University, Stony Brook, New York 11794-8122, United States.
authors.forename: William E
authors.initials: WE
authors.lastname: Van Nostrand
authors.affiliation: †Department of Biochemistry and Cell Biology, Stony Brook University, Stony Brook, New York 11794-5215, United States.
authors.forename: Steven O
authors.initials: SO
authors.lastname: Smith
mesh_terms: D000544:Alzheimer Disease / Q000378:metabolism; D016229:Amyloid beta-Peptides / Q000737:chemistry* / Q000378:metabolism / Q000648:ultrastructure*; D002942:Circular Dichroism; D006801:Humans; D018625:Microscopy, Atomic Force; D019906:Nuclear Magnetic Resonance, Biomolecular; D010446:Peptide Fragments / Q000737:chemistry* / Q000378:metabolism / Q000648:ultrastructure*; D066329:Protein Aggregates; D066263:Protein Aggregation, Pathological / Q000378:metabolism; D017433:Protein Structure, Secondary; D017550:Spectroscopy, Fourier Transform Infrared; D013696:Temperature
chemical_list: D016229:Amyloid beta-Peptides; D010446:Peptide Fragments; D066329:Protein Aggregates; C075222:amyloid beta-protein (1-42)