Peptide dimer structure in an Aβ(1-42) fibril visualized with cryo-EM.
Alzheimer's disease (AD) is a fatal neurodegenerative disorder in humans and the main cause of dementia in aging societies. The disease is characterized by the aberrant formation of β-amyloid (Aβ) peptide oligomers and fibrils. These structures may damage the brain and give rise to cerebral amyloid angiopathy, neuronal dysfunction, and cellular toxicity. Although the connection between AD and Aβ fibrillation is extensively documented, much is still unknown about the formation of these Aβ aggregates and their structures at the molecular level. Here, we combined electron cryomicroscopy, 3D reconstruction, and integrative structural modeling methods to determine the molecular architecture of a fibril formed by Aβ(1-42), a particularly pathogenic variant of Aβ peptide. Our model reveals that the individual layers of the Aβ fibril are formed by peptide dimers with face-to-face packing. The two peptides forming the dimer possess identical tilde-shaped conformations and interact with each other by packing of their hydrophobic C-terminal β-strands. The peptide C termini are located close to the main fibril axis, where they produce a hydrophobic core and are surrounded by the structurally more flexible and charged segments of the peptide N termini. The observed molecular architecture is compatible with the general chemical properties of Aβ peptide and provides a structural basis for various biological observations that illuminate the molecular underpinnings of AD. Moreover, the structure provides direct evidence for a steric zipper within a fibril formed by full-length Aβ peptide.
Institute for Pharmaceutical Biotechnology, Ulm University, 89081 Ulm, Germany; Rosenstiel Basic Medical Sciences Research Center, Brandeis University, Waltham, MA 02454-9110;
Matthias
M
Schmidt
Rosenstiel Basic Medical Sciences Research Center, Brandeis University, Waltham, MA 02454-9110; Janelia Research Campus, Howard Hughes Medical Institute, Ashburn, VA 20147;
Alexis
A
Rohou
Department of Developmental Biology, Stanford University School of Medicine, Stanford, CA 94305;
Keren
K
Lasker
Institute for Pharmaceutical Biotechnology, Ulm University, 89081 Ulm, Germany;
Jay K
JK
Yadav
Institute for Biochemistry and Biotechnology, Martin Luther University Halle-Wittenberg, 06120 Halle (Saale), Germany.
Cordelia
C
Schiene-Fischer
Institute for Pharmaceutical Biotechnology, Ulm University, 89081 Ulm, Germany; marcus.faendrich@uni-ulm.de niko@grigorieff.org.
Marcus
M
Fändrich
Rosenstiel Basic Medical Sciences Research Center, Brandeis University, Waltham, MA 02454-9110; Janelia Research Campus, Howard Hughes Medical Institute, Ashburn, VA 20147; marcus.faendrich@uni-ulm.de niko@grigorieff.org.
Nikolaus
N
Grigorieff
D000595:Amino Acid Sequence; D000682:Amyloid / Q000737:chemistry / Q000648:ultrastructure*; D016229:Amyloid beta-Peptides / Q000737:chemistry / Q000648:ultrastructure*; D020285:Cryoelectron Microscopy; D018604:Epitope Mapping; D007091:Image Processing, Computer-Assisted; D007140:Immunoglobulin Fab Fragments / Q000737:chemistry; D008958:Models, Molecular; D008969:Molecular Sequence Data; D010446:Peptide Fragments / Q000737:chemistry / Q000648:ultrastructure*; D010455:Peptides / Q000737:chemistry*; D055503:Protein Multimerization; D017433:Protein Structure, Secondary
D000682:Amyloid; D016229:Amyloid beta-Peptides; D007140:Immunoglobulin Fab Fragments; D010446:Peptide Fragments; D010455:Peptides; C075222:amyloid beta-protein (1-42)
Frealix; cross-β; protein aggregation; protein folding