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- EMDB-44183: Filament of D-TLKIVWR, a D-peptide that disaggregates Alzheimer's... -

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Basic information

Entry
Database: EMDB / ID: EMD-44183
TitleFilament of D-TLKIVWR, a D-peptide that disaggregates Alzheimer's Paired Helical Filaments, determined by Cryo-EM
Map data
Sample
  • Complex: D-peptide TLKIVWR
    • Protein or peptide: DTH-DLE-DLY-DIL-DVA-DTR-DAR
KeywordsAlzheimer's disease / Tau / fibril / cryo-EM / helix / UNKNOWN FUNCTION
Biological speciessynthetic construct (others)
Methodhelical reconstruction / cryo EM / Resolution: 3.7 Å
AuthorsHou K / Ge P / Sawaya MR / Eisenberg DS
Funding support United States, 3 items
OrganizationGrant numberCountry
National Institutes of Health/National Institute on Aging (NIH/NIA)1R01AG070895 United States
National Institutes of Health/National Institute on Aging (NIH/NIA)RF1AG065407 United States
Department of Energy (DOE, United States)DOE-FC02-02ERG United States
CitationJournal: bioRxiv / Year: 2024
Title: How short peptides can disassemble ultra-stable tau fibrils extracted from Alzheimer's disease brain by a strain-relief mechanism.
Authors: Ke Hou / Peng Ge / Michael R Sawaya / Joshua L Dolinsky / Yuan Yang / Yi Xiao Jiang / Liisa Lutter / David R Boyer / Xinyi Cheng / Justin Pi / Jeffrey Zhang / Jiahui Lu / Shixin Yang / ...Authors: Ke Hou / Peng Ge / Michael R Sawaya / Joshua L Dolinsky / Yuan Yang / Yi Xiao Jiang / Liisa Lutter / David R Boyer / Xinyi Cheng / Justin Pi / Jeffrey Zhang / Jiahui Lu / Shixin Yang / Zhiheng Yu / Juli Feigon / David S Eisenberg
Abstract: Reducing fibrous aggregates of protein tau is a possible strategy for halting progression of Alzheimer's disease (AD). Previously we found that the D-peptide D-TLKIVWC disassembles tau fibrils from ...Reducing fibrous aggregates of protein tau is a possible strategy for halting progression of Alzheimer's disease (AD). Previously we found that the D-peptide D-TLKIVWC disassembles tau fibrils from AD brains (AD-tau) into benign segments with no energy source present beyond ambient thermal agitation. This disassembly by a short peptide was unexpected, given that AD-tau is sufficiently stable to withstand disassembly in boiling SDS detergent. To consider D peptide-mediated disassembly as a potential therapeutic for AD, it is essential to understand the mechanism and energy source of the disassembly action. We find assembly of D-peptides into amyloid-like fibrils is essential for tau fibril disassembly. Cryo-EM and atomic force microscopy reveal that these D-peptide fibrils have a right-handed twist and embrace tau fibrils which have a left-handed twist. In binding to the AD-tau fibril, the oppositely twisted D-peptide fibril produces a strain, which is relieved by disassembly of both fibrils. This strain-relief mechanism appears to operate in other examples of amyloid fibril disassembly and provides a new direction for the development of first-in-class therapeutics for amyloid diseases.
History
DepositionMar 20, 2024-
Header (metadata) releaseMar 12, 2025-
Map releaseMar 12, 2025-
UpdateMar 12, 2025-
Current statusMar 12, 2025Processing site: RCSB / Status: Released

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Structure visualization

Supplemental images

emd_44183.png

Downloads & links

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Map

FileDownload / File: emd_44183.map.gz / Format: CCP4 / Size: 125 MB / Type: IMAGE STORED AS FLOATING POINT NUMBER (4 BYTES)
Projections & slices

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AxesX (Sec.)Y (Row.)Z (Col.)
1.07 Å/pix.
x 320 pix.
= 341.44 Å		1.07 Å/pix.
x 320 pix.
= 341.44 Å		1.07 Å/pix.
x 320 pix.
= 341.44 Å

Surface

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Images are generated by Spider.

Voxel sizeX=Y=Z: 1.067 Å
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Histogram

Histogram (log scale)
Contour LevelBy AUTHOR: 7.2
Minimum - Maximum-14.952505 - 23.653642999999999
Average (Standard dev.)0.000000000006745 (±1.0)
SymmetrySpace group: 1
Details

EMDB XML:

Map geometry
Axis orderZYX
Origin000
Dimensions320320320
Spacing320320320
CellA=B=C: 341.44 Å
α=β=γ: 90.0 °

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Supplemental data

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Mask #1

Fileemd_44183_msk_1.map
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Half map: #2

Fileemd_44183_half_map_1.map
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Half map: #1

Fileemd_44183_half_map_2.map
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Sample components

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Entire : D-peptide TLKIVWR

EntireName: D-peptide TLKIVWR
Components
  • Complex: D-peptide TLKIVWR
    • Protein or peptide: DTH-DLE-DLY-DIL-DVA-DTR-DAR

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Supramolecule #1: D-peptide TLKIVWR

SupramoleculeName: D-peptide TLKIVWR / type: complex / ID: 1 / Parent: 0 / Macromolecule list: all
Source (natural)Organism: synthetic construct (others) / Synthetically produced: Yes

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Macromolecule #1: DTH-DLE-DLY-DIL-DVA-DTR-DAR

MacromoleculeName: DTH-DLE-DLY-DIL-DVA-DTR-DAR / type: protein_or_peptide / ID: 1 / Number of copies: 52 / Enantiomer: DEXTRO
Source (natural)Organism: synthetic construct (others)
Molecular weightTheoretical: 916.142 Da
SequenceString:
(DTH)(DLE)(DLY)(DIL)(DVA)(DTR)(DAR)

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Experimental details

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Structure determination

Methodcryo EM
Processinghelical reconstruction
Aggregation statefilament

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Sample preparation

Concentration10 mg/mL
BufferpH: 7 / Details: Dissolved in de-ionized water
GridModel: Quantifoil R1.2/1.3 / Material: COPPER / Mesh: 300 / Pretreatment - Type: GLOW DISCHARGE
VitrificationCryogen name: ETHANE / Chamber humidity: 100 % / Chamber temperature: 295 K / Instrument: FEI VITROBOT MARK IV

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Electron microscopy

MicroscopeFEI TITAN KRIOS
Image recordingFilm or detector model: GATAN K3 BIOQUANTUM (6k x 4k) / Average electron dose: 50.0 e/Å2
Electron beamAcceleration voltage: 300 kV / Electron source: FIELD EMISSION GUN
Electron opticsIllumination mode: FLOOD BEAM / Imaging mode: BRIGHT FIELD / Cs: 2.7 mm / Nominal defocus max: 2.5 µm / Nominal defocus min: 1.8 µm / Nominal magnification: 81000
Sample stageSpecimen holder model: FEI TITAN KRIOS AUTOGRID HOLDER / Cooling holder cryogen: NITROGEN
Experimental equipment
Model: Titan Krios / Image courtesy: FEI Company

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Image processing

Final reconstructionApplied symmetry - Helical parameters - Δz: 9.56 Å
Applied symmetry - Helical parameters - Δ&Phi: 2.55 °
Applied symmetry - Helical parameters - Axial symmetry: C1 (asymmetric)
Resolution.type: BY AUTHOR / Resolution: 3.7 Å / Resolution method: FSC 0.143 CUT-OFF / Software - Name: RELION (ver. 4) / Number images used: 30029
Segment selectionNumber selected: 389000 / Software - Name: crYOLO
Startup modelType of model: NONE
Final angle assignmentType: NOT APPLICABLE / Software - Name: RELION (ver. 4)
FSC plot (resolution estimation)

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Atomic model buiding 1

RefinementSpace: REAL / Protocol: AB INITIO MODEL
Output model

PDB-9b4k:
Filament of D-TLKIVWR, a D-peptide that disaggregates Alzheimer's Paired Helical Filaments, determined by Cryo-EM

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