title: Amyloid β-Protein C-Terminal Fragments: Formation of Cylindrins and β-Barrels.
abstract: In order to evaluate potential therapeutic targets for treatment of amyloidoses such as Alzheimer's disease (AD), it is essential to determine the structures of toxic amyloid oligomers. However, for the amyloid β-protein peptide (Aβ), thought to be the seminal neuropathogenetic agent in AD, its fast aggregation kinetics and the rapid equilibrium dynamics among oligomers of different size pose significant experimental challenges. Here we use ion-mobility mass spectrometry, in combination with electron microscopy, atomic force microscopy, and computational modeling, to test the hypothesis that Aβ peptides can form oligomeric structures resembling cylindrins and β-barrels. These structures are hypothesized to cause neuronal injury and death through perturbation of plasma membrane integrity. We show that hexamers of C-terminal Aβ fragments, including Aβ(24-34), Aβ(25-35) and Aβ(26-36), have collision cross sections similar to those of cylindrins. We also show that linking two identical fragments head-to-tail using diglycine increases the proportion of cylindrin-sized oligomers. In addition, we find that larger oligomers of these fragments may adopt β-barrel structures and that β-barrels can be formed by folding an out-of-register β-sheet, a common type of structure found in amyloid proteins.
authors.affiliation: Department of Chemistry and Biochemistry and ‡Department of Physics, ¶Neuroscience Research Institute and Department of Molecular, Cellular and Developmental Biology, University of California , Santa Barbara, California 93106, United States.|Departments of Chemistry and Biochemistry and Biological Chemistry, Howard Hughes Medical Institute, UCLA-DOE Institute for Genomics and Proteomics, and ∥Department of Neurology, David Geffen School of Medicine at UCLA, ∇Mary S. Easton Center for Alzheimer's Disease Research at UCLA, and Brain Research Institute and Molecular Biology Institute, University of California , 635 Charles Young Drive South, Los Angeles, California 90095, United States.
authors.forename: Thanh D
authors.initials: TD
authors.lastname: Do
authors.affiliation: Department of Chemistry and Biochemistry and ‡Department of Physics, ¶Neuroscience Research Institute and Department of Molecular, Cellular and Developmental Biology, University of California , Santa Barbara, California 93106, United States.|Departments of Chemistry and Biochemistry and Biological Chemistry, Howard Hughes Medical Institute, UCLA-DOE Institute for Genomics and Proteomics, and ∥Department of Neurology, David Geffen School of Medicine at UCLA, ∇Mary S. Easton Center for Alzheimer's Disease Research at UCLA, and Brain Research Institute and Molecular Biology Institute, University of California , 635 Charles Young Drive South, Los Angeles, California 90095, United States.
authors.forename: Nichole E
authors.initials: NE
authors.lastname: LaPointe
authors.affiliation: Department of Chemistry and Biochemistry and ‡Department of Physics, ¶Neuroscience Research Institute and Department of Molecular, Cellular and Developmental Biology, University of California , Santa Barbara, California 93106, United States.|Departments of Chemistry and Biochemistry and Biological Chemistry, Howard Hughes Medical Institute, UCLA-DOE Institute for Genomics and Proteomics, and ∥Department of Neurology, David Geffen School of Medicine at UCLA, ∇Mary S. Easton Center for Alzheimer's Disease Research at UCLA, and Brain Research Institute and Molecular Biology Institute, University of California , 635 Charles Young Drive South, Los Angeles, California 90095, United States.
authors.forename: Rebecca
authors.initials: R
authors.lastname: Nelson
authors.affiliation: Department of Chemistry and Biochemistry and ‡Department of Physics, ¶Neuroscience Research Institute and Department of Molecular, Cellular and Developmental Biology, University of California , Santa Barbara, California 93106, United States.|Departments of Chemistry and Biochemistry and Biological Chemistry, Howard Hughes Medical Institute, UCLA-DOE Institute for Genomics and Proteomics, and ∥Department of Neurology, David Geffen School of Medicine at UCLA, ∇Mary S. Easton Center for Alzheimer's Disease Research at UCLA, and Brain Research Institute and Molecular Biology Institute, University of California , 635 Charles Young Drive South, Los Angeles, California 90095, United States.
authors.forename: Pascal
authors.initials: P
authors.lastname: Krotee
authors.affiliation: Department of Chemistry and Biochemistry and ‡Department of Physics, ¶Neuroscience Research Institute and Department of Molecular, Cellular and Developmental Biology, University of California , Santa Barbara, California 93106, United States.|Departments of Chemistry and Biochemistry and Biological Chemistry, Howard Hughes Medical Institute, UCLA-DOE Institute for Genomics and Proteomics, and ∥Department of Neurology, David Geffen School of Medicine at UCLA, ∇Mary S. Easton Center for Alzheimer's Disease Research at UCLA, and Brain Research Institute and Molecular Biology Institute, University of California , 635 Charles Young Drive South, Los Angeles, California 90095, United States.
authors.forename: Eric Y
authors.initials: EY
authors.lastname: Hayden
authors.affiliation: Department of Chemistry and Biochemistry and ‡Department of Physics, ¶Neuroscience Research Institute and Department of Molecular, Cellular and Developmental Biology, University of California , Santa Barbara, California 93106, United States.|Departments of Chemistry and Biochemistry and Biological Chemistry, Howard Hughes Medical Institute, UCLA-DOE Institute for Genomics and Proteomics, and ∥Department of Neurology, David Geffen School of Medicine at UCLA, ∇Mary S. Easton Center for Alzheimer's Disease Research at UCLA, and Brain Research Institute and Molecular Biology Institute, University of California , 635 Charles Young Drive South, Los Angeles, California 90095, United States.
authors.forename: Brittany
authors.initials: B
authors.lastname: Ulrich
authors.affiliation: Department of Chemistry and Biochemistry and ‡Department of Physics, ¶Neuroscience Research Institute and Department of Molecular, Cellular and Developmental Biology, University of California , Santa Barbara, California 93106, United States.|Departments of Chemistry and Biochemistry and Biological Chemistry, Howard Hughes Medical Institute, UCLA-DOE Institute for Genomics and Proteomics, and ∥Department of Neurology, David Geffen School of Medicine at UCLA, ∇Mary S. Easton Center for Alzheimer's Disease Research at UCLA, and Brain Research Institute and Molecular Biology Institute, University of California , 635 Charles Young Drive South, Los Angeles, California 90095, United States.
authors.forename: Sarah
authors.initials: S
authors.lastname: Quan
authors.affiliation: Department of Chemistry and Biochemistry and ‡Department of Physics, ¶Neuroscience Research Institute and Department of Molecular, Cellular and Developmental Biology, University of California , Santa Barbara, California 93106, United States.|Departments of Chemistry and Biochemistry and Biological Chemistry, Howard Hughes Medical Institute, UCLA-DOE Institute for Genomics and Proteomics, and ∥Department of Neurology, David Geffen School of Medicine at UCLA, ∇Mary S. Easton Center for Alzheimer's Disease Research at UCLA, and Brain Research Institute and Molecular Biology Institute, University of California , 635 Charles Young Drive South, Los Angeles, California 90095, United States.
authors.forename: Stuart C
authors.initials: SC
authors.lastname: Feinstein
authors.affiliation: Department of Chemistry and Biochemistry and ‡Department of Physics, ¶Neuroscience Research Institute and Department of Molecular, Cellular and Developmental Biology, University of California , Santa Barbara, California 93106, United States.|Departments of Chemistry and Biochemistry and Biological Chemistry, Howard Hughes Medical Institute, UCLA-DOE Institute for Genomics and Proteomics, and ∥Department of Neurology, David Geffen School of Medicine at UCLA, ∇Mary S. Easton Center for Alzheimer's Disease Research at UCLA, and Brain Research Institute and Molecular Biology Institute, University of California , 635 Charles Young Drive South, Los Angeles, California 90095, United States.
authors.forename: David B
authors.initials: DB
authors.lastname: Teplow
authors.affiliation: Department of Chemistry and Biochemistry and ‡Department of Physics, ¶Neuroscience Research Institute and Department of Molecular, Cellular and Developmental Biology, University of California , Santa Barbara, California 93106, United States.|Departments of Chemistry and Biochemistry and Biological Chemistry, Howard Hughes Medical Institute, UCLA-DOE Institute for Genomics and Proteomics, and ∥Department of Neurology, David Geffen School of Medicine at UCLA, ∇Mary S. Easton Center for Alzheimer's Disease Research at UCLA, and Brain Research Institute and Molecular Biology Institute, University of California , 635 Charles Young Drive South, Los Angeles, California 90095, United States.
authors.forename: David
authors.initials: D
authors.lastname: Eisenberg
authors.affiliation: Department of Chemistry and Biochemistry and ‡Department of Physics, ¶Neuroscience Research Institute and Department of Molecular, Cellular and Developmental Biology, University of California , Santa Barbara, California 93106, United States.|Departments of Chemistry and Biochemistry and Biological Chemistry, Howard Hughes Medical Institute, UCLA-DOE Institute for Genomics and Proteomics, and ∥Department of Neurology, David Geffen School of Medicine at UCLA, ∇Mary S. Easton Center for Alzheimer's Disease Research at UCLA, and Brain Research Institute and Molecular Biology Institute, University of California , 635 Charles Young Drive South, Los Angeles, California 90095, United States.
authors.forename: Joan-Emma
authors.initials: JE
authors.lastname: Shea
authors.affiliation: Department of Chemistry and Biochemistry and ‡Department of Physics, ¶Neuroscience Research Institute and Department of Molecular, Cellular and Developmental Biology, University of California , Santa Barbara, California 93106, United States.|Departments of Chemistry and Biochemistry and Biological Chemistry, Howard Hughes Medical Institute, UCLA-DOE Institute for Genomics and Proteomics, and ∥Department of Neurology, David Geffen School of Medicine at UCLA, ∇Mary S. Easton Center for Alzheimer's Disease Research at UCLA, and Brain Research Institute and Molecular Biology Institute, University of California , 635 Charles Young Drive South, Los Angeles, California 90095, United States.
authors.forename: Michael T
authors.initials: MT
authors.lastname: Bowers
mesh_terms: D000595:Amino Acid Sequence; D016229:Amyloid beta-Peptides / Q000737:chemistry*; D001798:Blood Proteins / Q000737:chemistry*; D046529:Microscopy, Electron, Transmission; D011487:Protein Conformation; D021241:Spectrometry, Mass, Electrospray Ionization
chemical_list: D016229:Amyloid beta-Peptides; D001798:Blood Proteins; C031022:cylindrin