title: Antiparallel β-Sheet Structure within the C-Terminal Region of 42-Residue Alzheimer's Amyloid-β Peptides When They Form 150-kDa Oligomers.
abstract: Understanding the molecular structures of amyloid-β (Aβ) oligomers and underlying assembly pathways will advance our understanding of Alzheimer's disease (AD) at the molecular level. This understanding could contribute to disease prevention, diagnosis, and treatment strategies, as oligomers play a central role in AD pathology. We have recently presented a procedure for production of 150-kDa oligomeric samples of Aβ(1-42) (the 42-residue variant of the Aβ peptide) that are compatible with solid-state nuclear magnetic resonance (NMR) analysis, and we have shown that these oligomers and amyloid fibrils differ in intermolecular arrangement of β-strands. Here we report new solid-state NMR constraints that indicate antiparallel intermolecular alignment of β-strands within the oligomers. Specifically, 150-kDa Aβ(1-42) oligomers with uniform (13)C and (15)N isotopic labels at I32, M35, G37, and V40 exhibit β-strand secondary chemical shifts in 2-dimensional (2D) finite-pulse radiofrequency-driven recoupling NMR spectra, spatial proximities between I32 and V40 as well as between M35 and G37 in 2D dipolar-assisted rotational resonance spectra, and close proximity between M35 H(α) and G37 H(α) in 2D CHHC spectra. Furthermore, 2D dipolar-assisted rotational resonance analysis of an oligomer sample prepared with 30% labeled peptide indicates that the I32-V40 and M35-G37 contacts are between residues on different molecules. We employ molecular modeling to compare the newly derived experimental constraints with previously proposed geometries for arrangement of Aβ molecules into oligomers.
authors.affiliation: Department of Chemical and Biomedical Engineering, Florida Agricultural & Mechanical University-Florida State University College of Engineering, 2525 Pottsdamer Street, Tallahassee, FL 32310-6046, USA; National High Magnetic Field Laboratory, 1800 E. Paul Dirac Drive, Tallahassee, FL 32310, USA.
authors.forename: Danting
authors.initials: D
authors.lastname: Huang
authors.affiliation: Department of Chemical and Biomedical Engineering, Florida Agricultural & Mechanical University-Florida State University College of Engineering, 2525 Pottsdamer Street, Tallahassee, FL 32310-6046, USA; National High Magnetic Field Laboratory, 1800 E. Paul Dirac Drive, Tallahassee, FL 32310, USA.
authors.forename: Maxwell I
authors.initials: MI
authors.lastname: Zimmerman
authors.affiliation: Department of Neuroscience, Mayo Clinic, 4500 San Pablo Road, Jacksonville, FL 32224, USA.
authors.forename: Patricia K
authors.initials: PK
authors.lastname: Martin
authors.affiliation: Department of Neuroscience, Mayo Clinic, 4500 San Pablo Road, Jacksonville, FL 32224, USA.
authors.forename: A Jeremy
authors.initials: AJ
authors.lastname: Nix
authors.affiliation: Department of Neuroscience, Mayo Clinic, 4500 San Pablo Road, Jacksonville, FL 32224, USA.
authors.forename: Terrone L
authors.initials: TL
authors.lastname: Rosenberry
authors.affiliation: Department of Chemical and Biomedical Engineering, Florida Agricultural & Mechanical University-Florida State University College of Engineering, 2525 Pottsdamer Street, Tallahassee, FL 32310-6046, USA; National High Magnetic Field Laboratory, 1800 E. Paul Dirac Drive, Tallahassee, FL 32310, USA. Electronic address: paravastu@eng.fsu.edu.
authors.forename: Anant K
authors.initials: AK
authors.lastname: Paravastu
mesh_terms: D000595:Amino Acid Sequence; D016229:Amyloid beta-Peptides / Q000737:chemistry* / Q000378:metabolism*; D002247:Carbon Isotopes; D006801:Humans; D008958:Models, Molecular; D008969:Molecular Sequence Data; D009587:Nitrogen Isotopes; D019906:Nuclear Magnetic Resonance, Biomolecular / Q000379:methods; D010446:Peptide Fragments / Q000737:chemistry* / Q000378:metabolism*; D011487:Protein Conformation
chemical_list: D016229:Amyloid beta-Peptides; D002247:Carbon Isotopes; D009587:Nitrogen Isotopes; D010446:Peptide Fragments; C075222:amyloid beta-protein (1-42)
keywords: Alzheimer's amyloid-β; oligomer; solid-state NMR spectroscopy