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Open data
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Basic information
Entry | Database: PDB / ID: 8eze | ||||||
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Title | Brain-derived 42-residue amyloid-beta fibril type B | ||||||
![]() | Beta-amyloid protein 42![]() | ||||||
![]() | PROTEIN FIBRIL / amyloid-b 42 (Ab42) fibril / Alzheimer' / s disease (AD) / Polymorphism. | ||||||
Function / homology | ![]() regulation of epidermal growth factor-activated receptor activity / signaling receptor activator activity / cytosolic mRNA polyadenylation / collateral sprouting in absence of injury / microglia development / regulation of synapse structure or activity / Formyl peptide receptors bind formyl peptides and many other ligands / ![]() ![]() ![]() ![]() ![]() ![]() ![]() ![]() ![]() ![]() ![]() ![]() ![]() ![]() ![]() ![]() ![]() ![]() Similarity search - Function | ||||||
Biological species | ![]() ![]() | ||||||
Method | ![]() ![]() | ||||||
![]() | Tycko, R. / Lee, M. / Yau, Y.-M. / Louis, J.M. | ||||||
Funding support | ![]()
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![]() | ![]() Title: Structures of brain-derived 42-residue amyloid-β fibril polymorphs with unusual molecular conformations and intermolecular interactions. Authors: Myungwoon Lee / Wai-Ming Yau / John M Louis / Robert Tycko / ![]() Abstract: Fibrils formed by the 42-residue amyloid-β peptide (Aβ42), a main component of amyloid deposits in Alzheimer's disease (AD), are known to be polymorphic, i.e., to contain multiple possible ...Fibrils formed by the 42-residue amyloid-β peptide (Aβ42), a main component of amyloid deposits in Alzheimer's disease (AD), are known to be polymorphic, i.e., to contain multiple possible molecular structures. Previous studies of Aβ42 fibrils, including fibrils prepared entirely in vitro or extracted from brain tissue and using solid-state NMR (ssNMR) or cryogenic electron microscopy (cryo-EM) methods, have found polymorphs with differences in amino acid sidechain orientations, lengths of structurally ordered segments, and contacts between cross-β subunit pairs within a single filament. Despite these differences, Aβ42 molecules adopt a common S-shaped conformation in all previously described high-resolution Aβ42 fibril structures. Here we report two cryo-EM-based structures of Aβ42 fibrils that are qualitatively different, in samples derived from AD brain tissue by seeded growth. In type A fibrils, residues 12 to 42 adopt a ν-shaped conformation, with both intra-subunit and intersubunit hydrophobic contacts to form a compact core. In type B fibrils, residues 2 to 42 adopt an υ-shaped conformation, with only intersubunit contacts and internal pores. Type A and type B fibrils have opposite helical handedness. Cryo-EM density maps and molecular dynamics simulations indicate intersubunit K16-A42 salt bridges in type B fibrils and partially occupied K28-A42 salt bridges in type A fibrils. The coexistence of two predominant polymorphs, with differences in N-terminal dynamics, is supported by ssNMR data, as is faithful propagation of structures from first-generation to second-generation brain-seeded Aβ42 fibril samples. These results demonstrate that Aβ42 fibrils can exhibit a greater range of structural variations than seen in previous studies. | ||||||
History |
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Structure visualization
Structure viewer | Molecule: ![]() ![]() |
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Downloads & links
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Download
PDBx/mmCIF format | ![]() | 858.7 KB | Display | ![]() |
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PDB format | ![]() | 732.8 KB | Display | ![]() |
PDBx/mmJSON format | ![]() | Tree view | ![]() | |
Others | ![]() |
-Validation report
Arichive directory | ![]() ![]() | HTTPS FTP |
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-Related structure data
Related structure data | ![]() 28741MC ![]() 8ezdC C: citing same article ( M: map data used to model this data |
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Similar structure data | Similarity search - Function & homology ![]() |
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Links
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Assembly
Deposited unit | ![]()
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Number of models | 9 |
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Components
#1: Protein/peptide | ![]() Mass: 4520.087 Da / Num. of mol.: 8 / Fragment: residues 672-713 Source method: isolated from a genetically manipulated source Source: (gene. exp.) ![]() ![]() ![]() ![]() ![]() |
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-Experimental details
-Experiment
Experiment | Method: ![]() |
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EM experiment | Aggregation state: FILAMENT / 3D reconstruction method: helical reconstruction |
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Sample preparation
Component | Name: amyloid-b 42 (Ab42) fibril / Type: COMPLEX / Entity ID: all / Source: RECOMBINANT |
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Molecular weight | Value: 4514.10 kDa/nm / Experimental value: YES |
Source (natural) | Organism: ![]() ![]() |
Source (recombinant) | Organism: ![]() ![]() ![]() |
Buffer solution | pH: 7.4 / Details: 10mM Na-phosphate, 0.1% sodium azide |
Buffer component | Conc.: 10 mM / Name: Sodium Phosphate |
Specimen | Conc.: 0.34 mg/ml / Embedding applied: NO / Shadowing applied: NO / Staining applied![]() ![]() |
Specimen support | Details: The grid was glow discharged immediately before use. Grid material: COPPER / Grid mesh size: 400 divisions/in. / Grid type: Quantifoil R1.2/1.3 |
Vitrification![]() | Instrument: FEI VITROBOT MARK I / Cryogen name: ETHANE / Humidity: 99 % / Chamber temperature: 93 K Details: Preblot for 12-13 seconds and blot for 2.5-3.0 seconds before plunging |
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Electron microscopy imaging
Experimental equipment | ![]() Model: Titan Krios / Image courtesy: FEI Company |
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Microscopy | Model: FEI TITAN KRIOS |
Electron gun | Electron source![]() ![]() |
Electron lens | Mode: BRIGHT FIELD![]() |
Specimen holder | Cryogen: NITROGEN / Specimen holder model: FEI TITAN KRIOS AUTOGRID HOLDER |
Image recording | Average exposure time: 1.65 sec. / Electron dose: 50.34 e/Å2 / Detector mode: SUPER-RESOLUTION / Film or detector model: GATAN K2 SUMMIT (4k x 4k) / Num. of grids imaged: 1 / Num. of real images: 5557 |
Image scans | Width: 11520 / Height: 8184 / Movie frames/image: 22 |
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Processing
EM software |
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Image processing | Details: Gatan Imaging Filter (GIF) Quantum LS | ||||||||||||||||||||||||||||||||||||||||||||
CTF correction![]() | Details: CTFFIND-4 / Type: NONE | ||||||||||||||||||||||||||||||||||||||||||||
Helical symmerty | Angular rotation/subunit: 179.36 ° / Axial rise/subunit: 2.48 Å / Axial symmetry: C1 | ||||||||||||||||||||||||||||||||||||||||||||
Particle selection | Num. of particles selected: 285760 | ||||||||||||||||||||||||||||||||||||||||||||
3D reconstruction![]() | Resolution: 2.76 Å / Resolution method: FSC 0.143 CUT-OFF / Num. of particles: 92019 / Algorithm: FOURIER SPACE Details: 3D refinement and post-processing were performed with 21 (screw) symmetry Num. of class averages: 1 / Symmetry type: HELICAL | ||||||||||||||||||||||||||||||||||||||||||||
Atomic model building | Protocol: OTHER Details: Manually generated model was fit into the density using PHENIX and UCSF Chimera. Further refinements were performed using Xplor-NIH. |