title: Out-of-register β-sheets suggest a pathway to toxic amyloid aggregates.
abstract: Although aberrant protein aggregation has been conclusively linked to dozens of devastating amyloid diseases, scientists remain puzzled about the molecular features that render amyloid fibrils or small oligomers toxic. Here, we report a previously unobserved type of amyloid fibril that tests as cytotoxic: one in which the strands of the contributing β-sheets are out of register. In all amyloid fibrils previously characterized at the molecular level, only in-register β-sheets have been observed, in which each strand makes its full complement of hydrogen bonds with the strands above and below it in the fibril. In out-of-register sheets, strands are sheared relative to one another, leaving dangling hydrogen bonds. Based on this finding, we designed out-of-register β-sheet amyloid mimics, which form both cylindrin-like oligomers and fibrils, and these mimics are cytotoxic. Structural and energetic considerations suggest that out-of-register fibrils can readily convert to toxic cylindrins. We propose that out-of-register β-sheets and their related cylindrins are part of a toxic amyloid pathway, which is distinct from the more energetically favored in-register amyloid pathway.
authors.affiliation: UCLA-DOE Institute for Genomics and Proteomics, The Howard Hughes Medical Institute, Molecular Biology Institute and Molecular Biology Institute, University of California, Los Angeles, CA 90095, USA.
authors.forename: Cong
authors.initials: C
authors.lastname: Liu
authors.forename: Minglei
authors.initials: M
authors.lastname: Zhao
authors.forename: Lin
authors.initials: L
authors.lastname: Jiang
authors.forename: Pin-Nan
authors.initials: PN
authors.lastname: Cheng
authors.forename: Jiyong
authors.initials: J
authors.lastname: Park
authors.forename: Michael R
authors.initials: MR
authors.lastname: Sawaya
authors.forename: Anna
authors.initials: A
authors.lastname: Pensalfini
authors.forename: Dawei
authors.initials: D
authors.lastname: Gou
authors.forename: Arnold J
authors.initials: AJ
authors.lastname: Berk
authors.forename: Charles G
authors.initials: CG
authors.lastname: Glabe
authors.forename: James
authors.initials: J
authors.lastname: Nowick
authors.forename: David
authors.initials: D
authors.lastname: Eisenberg
mesh_terms: D000682:Amyloid / Q000737:chemistry*; D003224:Congo Red / Q000494:pharmacology; D018360:Crystallography, X-Ray / Q000379:methods; D005456:Fluorescent Dyes / Q000494:pharmacology; D006801:Humans; D006860:Hydrogen Bonding; D046529:Microscopy, Electron, Transmission / Q000379:methods; D008958:Models, Molecular; D008968:Molecular Conformation; D010455:Peptides / Q000737:chemistry; D011487:Protein Conformation; D017433:Protein Structure, Secondary; D011506:Proteins / Q000737:chemistry; D013816:Thermodynamics; D014961:X-Ray Diffraction; D001613:beta 2-Microglobulin / Q000737:chemistry
chemical_list: D000682:Amyloid; D005456:Fluorescent Dyes; D010455:Peptides; D011506:Proteins; D001613:beta 2-Microglobulin; D003224:Congo Red